Development of a convergent enantioselective synthetic route to (−)-myrocin G

Abstract

The myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (−)-myrocin G (4), the putative active form of the metabolite myrocin C (1), that featured a carefully-orchestrated tandem fragment coupling–annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (−)-myrocin G (4) to the corresponding 5-hydroxy-γ-lactone isomer myrocin C (3) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (−)-myrocin G (4) and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.

Graphical Abstract

Introduction.

The myrocins are a family of antiproliferative antibiotic pimarane diterpenes initially identified in culture filtrates of the soil fungus Myrothecium verucarria in 1989.¹ The first metabolites to be isolated, (+)-myrocin C (1) and (−)-myrocin B (2), exhibited moderate antibiotic activity against Gram-positive bacteria, yeast, and fungi (MICs ~10–100 μg/mL), and prolonged life in an Ehrlich ascites carcinoma mouse model (prolongation rate, test/control: 130% for 1 at 1.6 mg/kg, 169% for 2 at 2.4 mg/kg).² The structurally-related metabolites 5–7, which possess comparable levels of antibiotic activity, have since been isolated from cultures of widely distributed marine and soil fungi.³ Collectively, these natural products are characterized by high degrees of oxygenation of the isopimaric acid core and transformation of the angular pimarane C10 methyl group into a C1–C10–C20 cyclopropane.

In 1993, Chu-Moyer and Danishefsky reported a landmark synthesis of (±)-myrocin C (1, Scheme 1).⁴ In a key step of this synthesis, the addition of trimethylstannanyl lithium to the dienyl mesylate 9 resulted in 3-exo-tet cyclization to provide the cyclopropane 10. Epoxide opening, with elimination of the stannyl substituent in situ, generated the dienyl alcohol 11. After elaboration to the lactone 12 (desoxymyrocin C), the sensitive 5-hydroxy-γ-lactone of 1 was installed by exposure of 12 to potassium tert-butoxide under an oxygen atmosphere, followed by treatment with triethyl phosphite.

Scheme 1.

Synthesis of (±)-myrocin C (1) by Chu-Moyer and Danhisefsky.

Subsequently, Yamada et al. disclosed studies toward myrocin C (1, Scheme 2). Synthesis of the A/B ring system was accomplished via intramolecular Diels-Alder reaction of the ethynoic ester 13 and reductive methylation of the resulting diene.⁵ Simmons–Smith cyclopropanation⁶ of the allylic alcohol 14 provided the α-cyclopropane 15.

Scheme 2.

Studies toward (+)-myrocin C (1) by Yamada et al.

Danishefsky and Chu-Moyer hypothesized that myrocin C (1) could behave as a DNA cross-linking agent via double nucleotide addition.⁷ To test this, the researchers exposed synthetic myrocin C (1) to an excess of thiophenol and triethylamine. Under these conditions, the bis(sulfide) 16 was formed in 63% yield (Scheme 3A). By comparison, under the same conditions desoxymyrocin C (12) underwent only the allylic thiolation event, but not cyclopropane ring-opening (63%, Scheme 3B). The mechanism advanced comprises an initial allylic displacement of the C-9 tertiary hydroxyl group by one equivalent of thiophenol (presumably by 1,4-addition and E1cb elimination), to form 17, followed by isomerization of the 5-hydroxy-γ-lactone moiety to the corresponding diosphenol, and subsequent thiolation of the resulting activated cyclopropane 18 to furnish 16 (pathway A). Based on this reactivity, the authors speculated that myrocin C (1) might be capable of forming DNA cross-links by sequential addition of nucleotide bases on opposing strands of DNA, in parallel to a known DNA-crosslinking agent such as mitomycin C.⁸

Scheme 3.

A. The mechanism advanced for the formation of 16 from myrocin C (1) via initial addition of thiophenol with elimination of hydroxide (1➝17), ring-opening to the diosphenol 18, and addition to the cyclopropane (18➝16). B. Treatment of desoxymyrocin C (12) with thiophenol and triethylamine provided the sulfide (19), deriving from 1,4-addition and E1cb elimination. C. The model system 20, which contains the hydroxylactone residue of 1, undergoes ring-opening to the diosphenol under acidic or basic conditions.

However, to our knowledge this hypothesis remained untested, and the myrocins do not possess the basic amines or planar aromatic rings that are hallmarks of DNA-binding agents.⁹ Intrigued by the Chu-Moyer–Danishefsky hypothesis, we initiated synthetic studies of these natural products with a view to elucidating their DNA-damaging activity. Our synthetic design was guided by a model study of 20 by Hoffmann and co-workers (Scheme 3C).¹⁰ In this work, the researchers found that the intermediate 20, which contains the hydroxylactone residue found in myrocin C (1), was susceptible to ring-opening under both acidic and basic conditions. This suggested to us that the diosphenol form of myrocin C (1), myrocin G (4, Figure 1), may readily form under physiological conditions. While myrocin G (4) has not yet been isolated from natural sources, the ring-opened isomer of myrocin B (2), known as myrocin A (3, Figure 1), has been isolated from cultures of the fungus Apiospora montagnei.^3b Accordingly, we postulated a reordering of bond-forming steps, wherein initial isomerization of the 5-hydroxy-γ-lactone to the diosphenol precedes alkylation (Scheme 3A, pathway B). Based on this analysis, we targeted the diosphenol isomers 3 and 4 for synthesis. We recently reported the successful synthesis of (−)-myrocin G (4).¹¹ Here we present the full development of our synthetic route to myrocin G (4), evaluation of its DNA damaging properties in vitro, and the synthesis of affinity probes for target identification studies.

Figure 1.

Myrocins A–G (1–7) and isopimaric acid (8).

Results.

From the outset, we sought a short and convergent synthetic strategy toward 3 or 4 that would maximize modularity and overall yield, and facilitate biological studies. Reasoning that substrate-directed diastereoselective introduction of the two peripheral all-carbon quaternary stereocenters (C4 and C13) would be challenging, we focused on strategies involving the separate construction of these stereocenters, followed by late-stage fragment-coupling.¹² Our initial retrosynthetic analysis is shown in Scheme 4. Retrosynthetic conversion of the target to the ene-1,4-dione 22 revealed the possibility of introducing the cyclopropane ring through an anionic Winstein cyclization of the chloroethylphenol 23.¹³ We envisioned that the phenol 23 could be prepared via oxidation of a Diels–Alder adduct derived from the diene 25 and the enone 24. At this early stage in our studies, we elected to substitute an achiral coupling partner (vide infra) for 24, which allowed for utilization of racemic 25.

Scheme 4.

Retrosynthetic analysis of myrocin A (3) and myrocin G (4).

The synthesis of the diene (±)-25 was achieved in five steps from the enone 26 (Scheme 5A).¹⁴ Corey–Chaykovsky cyclopropanation¹⁵ of 26 at cryogenic temperatures (sodium hydride, trimethylsulfoxonium iodide, N,N-dimethylformamide (DMF), −45 °C) provided a cyclopropane intermediate (not shown) as an inseparable 5.3:1 mixture of diastereomers. The relative configuration of the major diastereomer was ultimately confirmed by X-ray crystallographic analysis of the downstream intermediate 36 (vide infra). The major sense of addition can be rationalized by addition of the sulfonium ylide to the conformer 30 of the electrophile. Ground-state stabilization of 30, either due to metal chelation of the β-ketoester function or donation of the axial methyl group σ_C–C bond into the carbonyl’s extended π-system, is consistent with the increased diastereoselectivities observed at lower reaction temperatures (Scheme 5B). Cyclopropane ring-opening (hydrogen chloride) then furnished the β-chloromethyl ketone 27. At this stage, the two diastereomers were readily separated by flash-column chromatography (85% yield of the desired diastereomer 27, two steps). Triflation (trifluoromethanesulfonic anhydride, 2,4,6-tri-tert-butylpyrimidine (TTBP), 85%) and vinylation (ethyl vinyl ether, palladium(II) acetate, triethylamine) afforded the 1,3-diene 29. The ethyl vinyl ether 29 was prone to hydrolysis under acidic conditions and could not be purified. To circumvent the spontaneous decomposition of this intermediate, one equivalent of TTBP was added to the product mixture immediately following aqueous workup, and the resulting mixture used directly in the following step.

Scheme 5.

A. Synthesis of the diene 29. B. Stereochemical model for the addition of the sulfonium ylide to 26.

Dimethylaluminum chloride-catalyzed Diels–Alder addition of 29 and the enone 31 provided the adduct 32 as an intractable mixture of diastereomers (Scheme 6). We found that treatment of the partially-purified mixture with excess ceric(IV) ammonium nitrate (CAN) directly furnished the aryl ether 35 (22% yield from 31). In line with prior studies,¹⁶ this double-dehydrogenation is believed to proceed via sequential hydride abstraction steps. We believe that the C11 ketone is integral to this process by facilitating deprotonation of the transiently formed α,β-unsaturated oxonium 33 to generate the reactive enol ether 34 (Scheme 6). Removal of the ethyl substituent of 35 by treatment with boron tribromide provided the phenol 36 (62%). X-ray crystallographic analysis of 36 confirmed that the chloromethyl substituent was generated with the desired relative stereochemistry (syn to the carboethyoxy substituent). A two-step sequence comprising formation of an ortho-quinone (2-iodoxybenzoic acid, 59%) and reduction (sodium dithionate, 63%) formed the catechol 37. However, attempts to achieve the base-mediated cyclopropanation of 37 were unsuccessful. For example, treatment of 37 with potassium carbonate and TTBP produced the pyran 40 as the major isolable product. The mechanism of formation of 40 may involve selective deprotonation of the C6 hydroxyl group (due to its cross-conjugation with the C11 ketone), O-alkylation of the C11 ketone, epimerization of the intermediate para-quinone oxonium ion, and isomerization to furnish the styrene 40 (31%). Similar results were obtained upon treatment with other bases or simple heating under neutral conditions. Ketalization of 37 and related structures and protection of the C6 phenol were also unsuccessful, precluding further elaboration.

Scheme 6.

Synthesis of the catechol 37 and attempted cyclopropanation.

This undesired reactivity, coupled with the low material throughput of the route, prompted us to investigate alternative cyclopropanation strategies. Drawing on the work of Rodríguez and coworkers,¹⁷ we targeted the para-quinone methide 46 as a precursor to the cyclopropane (Scheme 7). Such an intermediate would be readily accessible using the chemistry we had developed earlier. Diels–Alder addition of 31 and the simplified diene 41 (prepared in two steps from commercial materials),¹⁸ followed by double dehydrogenation (CAN), provided the aryl ether 42 (53% over two steps). Although the phenol 45 could be accessed by direct hydroxylation of the aryl ether 42 (phthaloyl peroxide (51a), hexafluoroisopropanol (HFIP), then potassium carbonate, methanol, 24%),¹⁹ we found that application of this method was limited in our case by competing benzylic oxidation and poor scalability. As an alternative, the three-step procedure utilized previously to access the catechol 37 was adopted, to provide 43 in 74% over three steps. The pK_a difference between the aryl hydroxyl residues was now leveraged to effect site-selective methylation of 43, furnishing the mono catechol ether 44 (lithium carbonate, iodomethane, 41%).²⁰

Scheme 7.

Synthesis of the cyclopropanes 48 and 49.

Exposure of 44 to silver(I) oxide cleanly produced the requisite para-quinone methide 46, which was characterized by ¹H and ¹³C NMR spectroscopy.²¹ The characteristic para-quinone C–H proton at C1 appeared as a distinct doublet of doublets (J = 6.7, 3.3 Hz) at 8.07 ppm, and the corresponding carbon (detected by HSQC) resonated at 150.3 ppm (chloroform-d). Treatment of the unpurified para-quinone methide 46 with diazomethane at cryogenic temperatures (−78 °C) then gave the cyclopropane 48 as a single diastereomer (¹H NMR analysis).¹⁷ Though the cyclopropane 48 was not stable to flash-column chromatography, the unpurified product could be characterized by ¹H and ¹³C NMR spectroscopy. Though the mechanism of this transformation is as yet unresolved, it likely proceeds through initial [3+2] cycloaddition, followed by extrusion of dinitrogen.²² Other, more common cyclopropanation methods, such as reaction with the Corey–Chaykovsky reagent, resulted exclusively in isomerization to the corresponding styrene. The stereochemical outcome of the cyclopropanation was established by synthesis of the phenol 50 from 49 and by ring-opening with hydrogen chloride (25%, three steps). This was shown (by ¹H NMR analysis) to be identical to the phenol prepared from the aryl ether 36 (whose relative stereochemistry had been established by X-ray crystallography, vide supra) by hydroxylation (4,5-dichlorophthalyoyl peroxide (51b), HFIP, then sodium bicarbonate, methanol, 23%).²³ The cyclopropanation is believed to be directed by minimization of non-bonded interactions with the C4 methyl group, which may adopt an axial orientation due to σ_C–C donation into the extended π-system, analogous to the enone 26 (vide supra). This sense of addition is in accord with the studies of Rodríguez and co-workers.¹⁷

Despite extensive efforts and precedent suggesting the feasibility of nucleophilic epoxidation on a similar system,²⁴ we were unable to achieve the epoxidation of 48 to provide 52 (Scheme 8). An alternative approach involving formation of an extended enolate (or enolate equivalent) derived from the C11 ketone and oxygenation of the resulting extended enolate system was also unsuccessful. These endeavors were further hampered by the extreme sensitivity of the cyclopropane 48, which decomposed appreciably within 1 h at −20 °C, thereby necessitating the time-consuming conversion of 44→48 immediately prior to any of these experiments.

Scheme 8.

Strategy pursued to convert the cyclopropane 48 to the epoxide 52 and the hydroxyketone 54.

At this juncture, it became apparent that strategies proceeding through the divinylcyclopropane intermediate 48 were untenable. Cognizant that the difficulties in handling and modifying 48 were likely related to facile re-aromatization of the B-ring, we aimed to mitigate this undesirable mode of reactivity by introducing the C9 alcohol prior to B-ring annulation. The retrosynthetic approach that emerged from these considerations is depicted in Scheme 9. Disconnection of the diosphenol double bond via a redox-neutral aldol cyclodehydration revealed the α-hydroxyketone intermediate 55. Fragment coupling between an organometallic species derived from the iodocyclopropane 58 and an enone electrophile 57 would then join the A and C ring subunits while simultaneously establishing the C9 alcohol and furnishing 56.

Scheme 9.

Revised retrosynthetic analysis of myrocin G (4) via fragment coupling of 57 and 58.

Stereochemical control in the fragment coupling reaction was predicted by topographical analysis of the coupling partners and inference of known stereochemical preferences in nucleophilic 1,2-additions to cycloalkanones.²⁵ In particular, we postulated that non-bonded interactions between the C4 center in the nucleophile and the C8 substituent in the electrophile would orient the two fragments as shown in 59, to deliver the desired C9 epimer (Figure 2). The alternative orientation 60 was projected to be disfavored due to superposition of the bulk of the incoming nucleophile over the plane of the electrophile.

Figure 2.

Transition state models for 1,2-nucleophilic addition of 58 to 57.

Preparation of the racemic A-ring coupling fragment 65 required only minor modifications to our prior synthesis of 31 (Scheme 10). Kinetic deprotonation of cyclohex-2-ene-1-one with excess lithium bis(trimethylsilyl) amide (LiHMDS), C-selective carboxylation with N-tert-butoxycarbonylimidazole, and tandem methylation with iodomethane furnished the enone 63 in a single operation (54%). Dehydroiodination (iodine, pyridine, 77%)²⁶ and Corey–Chaykovsky cyclopropanation then provided the corresponding iodocyclopropane as a 2.4:1 mixture of diastereomers. Recrystallization of the diastereomeric mixture enabled isolation of the desired diastereomer 65 in 47% yield. The relative stereochemistry of 65 was established by X-ray analysis.

Scheme 10.

Synthesis of iodocyclopropane fragment 65.

It was found that clean and rapid (<30 min) magnesium–iodine exchange could be effected using iso-propylmagnesium chloride–lithium chloride complex in toluene at cryogenic temperatures (−78 °C, Scheme 11).²⁷ Addition of the α-iodoenone 66,²⁸ followed by warming of the solution to 23 °C over 3 h, provided the adduct 69 as a 7:1 mixture of C9 diastereomers. Recrystallization of the partially purified mixture afforded the desired C9 epimer in 87% isolated yield and enabled structural confirmation by X-ray crystallographic analysis (Scheme 11). Similar results were obtained when the α-ethynylenone 67 was utilized as the electrophile (7:1 dr; 81% after desilylation with potassium carbonate in methanol).

Scheme 11.

Formation of the fragment coupling products 69 and 70.

With the adduct 69 in hand, we next pursued methods to directly convert the vinyl iodide function to the corresponding α-hydroxyketone (Scheme 12). Silylation of the C9 alcohol (chlorotrimethylsilane, imidazole) formed the silyl ether 72. Lithiation (n-butyllithium) and attempted trapping with various electrophiles (such as the glycolamide 75²⁹) did not provide the expected products. Instead, the vinyl silane 72 was obtained. This product presumably arises via retro-[1,4]-Brook rearrangement of the vinyllithium intermediate. Alternatively, lithiation and attempted electrophile trapping of the methoxymethyl ether 73 (sodium iodide, chloromethyl methyl ether, N,N-diisopropylethylamine, 85%) afforded the strained cyclobutanol 74, the structure of which was confirmed by X-ray crystallographic analysis. These products 72 and 74 could be isolated in 52% and 48% yield respectively when electrophiles were omitted from the reaction mixtures.

Scheme 12.

Formation of the vinyl silane 72 and the cyclobutanol 74 from the vinyl iodide 69.

Collectively, these results seemed to indicate that intermolecular reactions of organolithium species derived from the adduct 69 were kinetically disfavored due to steric congestion of the reactive site. Accordingly, we shifted toward evaluating the enyne 71 as an alternative α-hydroxyketone precursor (Scheme 13). Subjection of the enyne 71 to the conditions reported by Kita and coworkers³⁰ for the synthesis of α-hydroxyketones (bis(trifluoroacetoxy)iodo)benzene, water) did not provide the expected product. Instead, the ketofuran 76 was isolated in 38% yield, presumably by intramolecular trapping of the activated alkyne by the C9 alcohol. Oxidative functionalization of the alkyne using derivatives of 71 protected at the C9 position were also unsuccessful. However, the synthesis of 76 was nonetheless useful in that it allowed us to tentatively assess the viability of our annulation strategy. As expected, treatment of 76 with sodium hydroxide in ethanol returned the aldol product 77 (66%). The relative stereochemistry of 77 was established by nuclear Overhauser effect analysis of the product in dimethylsulfoxide-d₆, which revealed a correlation between the C5 hydroxyl proton and the C20 cyclopropane proton.

Scheme 13.

Elaboration of 71 to the pentacyclic aldol product 77.

Concurrent with these efforts, we also explored multistep installation of the α-hydroxyketone residue. Ultimately, we were able to access the α-hydroxyketone 79 in two steps from the vinyl iodide 69 (Scheme 14). Stille cross-coupling of 69 and tributyl(1-ethoxyvinyl)tin [copper(I) iodide, tetrakis(triphenylphosphine)palladium(0), cesium fluoride, 94%], followed by dihydroxylation of the resulting alkyl vinyl ether [potassium osmate(VI) dihydrate, 4-methylmorpholine N-oxide] provided the α-hydroxyketone 79 (41%). However, in contrast to our experience with the ketofuran 76, attempted aldol reactions of 79 resulted only in decomposition under a variety of conditions.

Scheme 14.

Elaboration of the addition product 69 to the aldol product 85.

While we were unable to definitively establish a mechanism for this decomposition, we reasoned that aldol reactions of 79 were not strictly analogous to those of 76 because of the presence of two free hydroxyl functions of 79. To address this, we converted 79 to the bis(protected) derivative 83. Initial bis(silylation) with excess TMSCl and imidazole, followed by selective cleavage of the primary trimethylsilyl ether (aqueous hydrochloric acid) formed the C9 trimethylsilyl protected intermediate (not shown, Scheme 14). Subsequent exposure to silver(I) oxide in the presence of iodomethane then delivered the methyl ether 83.

Unexpectedly, treatment of the methyl ether 83 with sodium tert-butoxide did not provide the C5 dehydration product 81 even under forcing conditions, but returned exclusively what appeared to be a single epimer of the intramolecular addition product 85 in 30% yield (three steps). All attempts to realize dehydration of the putative C5 alcohol were unsuccessful, and perplexingly seemed to activate the C9 alcohol instead. After careful NMR analysis, we determined that migration of the trimethylsilyl group to the transient β-C5 alkoxide 84 had occurred under the conditions of the aldol reaction. In support of this, a strong nuclear Overhauser correlation between the silyl ether residue and the C18 methyl group as well as the C6 methine proton was observed.

These mechanistic insights led us to devise an alternative strategy to achieve the desired C5 alcohol dehydration. We reasoned that we could activate the C5 alcohol toward β-elimination by modulating the electronic nature of the C5 alcohol substituent. Moreover, we anticipated that we could capitalize on the facility with which substituent migration occurred between the C9 and C5 alcohols to direct our activating group. To this end, carbomethoxylation of the C9 alcohol within 85 was accomplished by deprotonation with potassium bis(trimethylsilyl)amide followed by the addition of methyl chloroformate to provide 86 (58%, Scheme 15). Desilylation (tetrabutylammonium fluoride [TBAF]) followed by treatment with excess 1,8-diazabicyclo[5.4.0]undec-7-ene at elevated temperatures (100 °C) furnished the dehydrated product 88 in 71% yield over the two steps. We believe this reaction proceeds by 1,2-addition and formation of the cyclic carbonate 87, followed by β-elimination. However, efforts to remove the enol ether and tert-butyl ester substituents of 88 under acidic conditions resulted in decomposition, presumably because of the sensitivity of the allylic cyclopropylcarbinol toward ionization. This prompted us to search for alternative protection strategies compatible with our advanced intermediates.

Scheme 15.

Synthesis of the aldol dehydration product 88 from 85.

A short evaluation of carboxyl protecting groups was carried out. Cleavage of the tert-butyl ester moiety of the iodocyclopropane 65 could be accomplished without attendant decarboxylation simply by treatment with trifluoracetic acid (Scheme 16). Subsequent esterification (N,Nʹ-dicyclohexylcarbodiimide, 4-dimethylaminopyridine) of the liberated β-keto acid with various alcohols ultimately led to identification of the 2-(trimethylsilyl)ethyl (TMSE) group as a viable alternative to the tert-butyl group of the iodocyclopropane 65. This protecting group was not only compatible with the proposed deprotection strategy, but also conferred crystallinity to the 2-(trimethylsilyl)ethyl ester 89, a vital feature required for separation of the cyclopropane diastereomers that was not shared with other esters investigated (vide supra). Preparation of the cyclopropane 89 could also be achieved via the sequence 63→65 described previously (see Supplementary Information). Fragment coupling of 89 with the iodoenone 66 (75%, 8:1 dr) followed by Stille cross-coupling with ethyl vinyl ether, and hydrolsis of the vinyl ether function provided the methyl ketone 91 (70% from 90).

Scheme 16.

Synthesis of the methyl ketone 91 from 65.

α-Oxidation of the ketone was achieved by slight modification of the previous sequence (Scheme 17). Tandem silylation of the C9 alcohol and enoxysilane formation (trimethylsilyl trifluoromethanesulfonate, triethylamine) followed by Rubottom oxidation³¹ (3-chloroperoxybenzoic acid) furnished the silylated α-hydroxyketone 92 (70% overall).

Scheme 17.

Synthesis of disophenol 98 from 91.

At this stage, alternatives to the C6 methyl ether were evaluated. One of the earliest analogues examined was the C6 allyl carbonate 93. Surprisingly, aldol reaction of 93 (sodium tert-butoxide) returned the expected silane transfer product 95 as only a minor constituent of the product mixture (15%). Instead, the major product of this reaction was determined to be the diosphenol 98 (58%). In light of our previous experience, we rationalized formation of 98 by transfer of the allyloxycarbonyl group from the C6 primary alcohol to the C5 alkoxide 96 (path B) in preference to silyl migration from the C9 silyl ether of 94 (path A). The C5 allyl carbonate 97 is thereby activated toward β-elimination in a fashion analogous to the bridged carbonate intermediate 87 (vide supra). It is unclear whether the observed preference for allyloxy carbonyl migration is due solely to its reduced steric volume and greater electrophilicity, or if a stereochemical bias during the enolate addition step might also be implicated.

Collectively these findings prompted us to explore other ways of further exploiting the migratory propensity of substituents on the C6 and C9 alcohols. We rationally designed the alternative C-ring fragment 100, which we predicted would be capable of telescoping the fragment coupling and B-ring manipulations into a single operation (Scheme 18). The model fragment 100 was synthesized in six steps from the α-iodoenone 66. Ketalization (triethylorthoformate, ethylene glycol, para-toluenesulfonic acid), carbonylation (n-butyllithium, 75²⁹) provided the ketone 99 in 57% yield (two steps). Desilylation (TBAF), installation of the allyl carbonate (allyl chloroformate, pyridine), and subsequent ketal hydrolysis (aqueous hydrochloric acid) furnished the diketone 100 in 38% yield (three steps). Next, site-selective enoxysilane formation was accomplished via a kinetic deprotonation of 100 with LiHMDS followed by treatment with TMSCl to yield the enoxysilane 101 exclusively as the Z-isomer (65%).

Scheme 18.

Synthesis of 104 via fragment-coupling–cyclodehydration cascade reaction.

Attempted coupling of the organomagnesium derived from 89 with the fragment 101 resulted exclusively in protodeiodination of the nucleophilic component with no detectable addition product. Postulating that ketone deprotonation was competing with 1,2-addition due to the increased steric volume of the alkenyl substituent, we assayed the effects of lanthanide promoters,³² but these efforts also proved unsuccessful. Ultimately, we found that utilization of the more nucleophilic organolithium species was effective. In the event, successive treatment of the iodocyclopropane 89 with tert-butyllithium and the fragment 101 at cryogenic temperatures (−78 °C) provided the cyclodehydration compound 98 in 20% isolated yield. The mechanism we propose for this transformation involves silane transfer from the C7 enoxysilane to the C9 alkoxide 102, enolate addition to the C5 ketone, and allyloxycarbonyl transfer from the C6 to the C5 alcohol, with concomitant elimination to furnish the diosphenol 98. After further optimization, we developed a procedure involving lithium–iodide (n-butyllithium) exchange at −78 °C, followed by immediate, dropwise addition of a solution of 101 in tetrahydrofuran, aging at −78 °C for 2 h, and warming to 0 °C over 3 h. Under these conditions the annulation product 98 was obtained as a single diastereomer and in 36% yield. Conversion of 98 to the myrocin G model 104 was accomplished by treatment with excess TBAF in N,N-dimethylformamide (64%).

To translate this work into a synthesis of (−)-myrocin G itself, we first prepared enantioenriched samples of the iodocyclopropane 107 (Scheme 19). Asymmetric Robinson annulation¹⁴ of the β-ketoester 105 with diethyl acrolein furnished the enone 106 (32%, 92% ee). Dehydroiodination (iodine, pyridine) and cyclopropanation (sodium hydride, trimethylsulfoxonium iodide, 2.3:1 dr) provided the iodocyclopropane 107 in 64% overall yield after recrystallization. The C-ring coupling fragment 109 was prepared in six steps from the unsaturated ketone 108¹¹ via the sequence 66→100 (vide supra) in 19% overall yield. Tandem coupling–cyclodehydration then furnished the desired diosphenol 110 (38%). Global deprotection (TBAF) then afforded (−)-myrocin G (4) (64%).

Scheme 19.

Synthesis of (−)-myrocin G (4) and formation of bis(sulfide) 16.

As hypothesized, 4 proved a viable substrate for the double alkylation reaction previously reported for myrocin C.⁷ Treatment of 4 with excess thiophenol and triethylamine formed the bis(sulfide) 16 (74%). Thus, while we cannot rule out the pathway originally proposed by Chu-Moyer and Danishefsky (pathway A, Scheme 3A), the successful transformation of 4 to 16 is consistent with the analysis presented in the introduction.

We envisioned that isomerization of myrocin G (4) to the corresponding γ-hydroxylactone would provide access to myrocin C (3). However, attempts to achieve this using the model system 104 were unsuccessful (Scheme 20). For example, heating solutions of 104 in 1,2-dichloroethane at 100 °C resulted in decarboxylation and spontaneous oxidation of the putative ene-1,2-diol 112 to furnish the epoxide 113 (52%). These results seem to confirm a thermodynamic preference of the myrocin system for the diosphenol isomer relative to the corresponding hydroxylactone.

Scheme 20.

Synthesis of epoxide 113 via a heat induced decarboxylation of 104.

We attempted to overcome this preference by temporarily disrupting the intramolecular diosphenol hydrogen bond shown in 104 (Scheme 21). To this end, para-methoxybenzylation of the diosphenol product 98 (para-methoxybenzyl chloride, tetrabutylammonium iodide, and cesium carbonate) provided the enol ether 114 (72%). However, attempted cleavage of the 2-(trimethylsilyl)ethyl ester within 114 (TBAF) resulted only in decomposition. Reasoning that this again arose from facile decarboxylation of the liberated δ-carboxylate 117 under the basic reaction conditions, we sought to install an alternative ester protecting group that could be removed under more neutral conditions. Esterification of the acid 104 (allyl alcohol, HATU, triethylamine) and para-methoxybenzylation (vide supra) formed the allyl ester 118 (59%, two steps). Palladium-mediated deallylation was then accomplished with palladium(II) acetate, XPhos, and 1,3-dimethylbarbituric acid as the allyl scavenger. Analysis of the unpurified reaction mixture did not indicate the presence of the desired 5-alkoxy-γ-lactone, and we were only able to obtain the free acid 119 in 68% yield. All attempts to implement isomerization of 119 to 116 under a variety of conditions were unsuccessful, again due to the decarboxylation encountered earlier.

Scheme 21.

Synthesis of 119 and attempted conversion to the hemiketal 116.

Biological evaluation.

We then turned our attention to evaluating the biological activity of myrocin G (4) and several related analogues. Given that our initial synthetic studies were performed on the C13 geminal dimethyl model system, we were interested in comparing its potency to the native α-methyl–β-vinyl substituents present in 4. The utilization of 104 in place of the natural system would vastly simplify the preparation of derivatives. The racemic mixture (±)-98 was resolved by chiral stationary phase supercritical fluid chromatography, to provide the enantiomers (−)-98 and (+)-98 in greater than 99% ee (Scheme 22A). Both enantiomers were again deprotected in a straightforward manner by subjecting each compound to excess TBAF in N,N-dimethylformamide. The absolute stereochemistry of the levorotatory enantiomer of 104 is supported by the Flack and Hooft parameters obtained by X-ray analysis (see Scheme 22B and the Supporting Information). The resolved enantiomers were subsequently converted to the corresponding azide and alkyne probes (−)-120 and (−)-121 by treatment with 3-azido-1-propamine or 1-amino-3-butyne, respectively, in the presence of HATU and N,N-diisopropylethylamine. For clarity, we are showing transformations of the levorotatory enantiomer of 104, however, the same set of reactions was performed on (+)-104 to provide azide (+)-120 and alkyne (+)-121.

Scheme 22.

A. Chiral resolution of (±)-98 using Supercritical Fluid Chromatography (SFC). B. Synthesis of remote alkyne and azide containing biological probes using enantiopure myrocin analogue (−)-104.

The cytotoxicities of the compounds prepared above were evaluated against cervical (HeLa), colorectal (HCT116), leukemia (K562) and prostate (LNCaP) cancer cell lines using a CellTiter-Glo assay, which utilizes ATP production as an indicator of cell viability. Tamoxifen (60 μM) and vehicle (methyl sulfoxide) were used as positive and negative controls, respectively. As shown in Table 1, (−)-myrocin G (4) possessed low micromolar activity against the HeLa and K562 cell lines, but showed decreased potency against LNCaP and especially HCT116 cell lines. We observed no significant difference in activity between the levorotatory and dextrorotatory enantiomers of the methyl analogs 104. The azido and alkynyl esters 120 and 121, respectively, were more potent than the free carboxylic acids 104, which may reflect increased cellular uptake. Only minor differences in potency were observed between the enantiomers of the esters 120 and 121.

Table 1.

IC50 Values (in μM) of (−)-myrocin G (4), the methyl analogs 104, the azido esters 120, and the alkynyl esters 121^a

compound	cell line
	HeLa	HCT116	K562	LNCaP
(−)-myrocin G (4)	3.2 ± 4.3	1400 ± 760	3.3b	12 ± 17
methyl analog (−)-104	189 ± 89	30 ± 0.17	42 ± 3.5	54 ± 28
methyl analog (+)-104	21 ± 6.2	52 ± 2.8	59 ± 0.65	37 ± 52
azido ester (−)-120	13 ± 0.26	5.6 ± 0.92	8.1 ± 0.75	5.3 ± 1.4
azido ester (+)-120	23 ± 1.7	12 ± 1.9	14 ± 0.44	9.8 ± 1.5
alkynyl ester (−)-121	13 ± 0.04	5.3 ± 0.007	10 ± 0.33	9.0 ± 0.82
alkynyl ester (+)-121	25 ± 2.4	8.3 ± 1.0	10 ± 0.27	8.2 ± 0.43

^aCells were treated with compounds for 72 h. Tamoxifen (60 μM) was used as a positive control. Average of two replicates, unless otherwise noted.

^bSingle replicate.

To probe the DNA damaging activity of (−)-myrocin G (4), circular pBR322 plasmid DNA was incubated with varying concentration of 4 for 16 h at 37 °C (Figure 3). The DNA was then analyzed by native gel electrophoresis. We did not observe detectable levels of DNA cleavage when the plasmid DNA was treated with up to 500 μM of (−)-myrocin G (4).

Figure 3.

DNA plasmid cleavage assay employing circular pBR322 plasmid DNA and (−)-myrocin G (4). 5% DMSO was used as vehicle (negative control), and linearized pBR322 DNA was used as positive control. DNA ladder (Lane #1); 5% DMSO, pH 8.0 (Lane #2); 500 μM 4, pH 8.0 (Lane #3); 100 μM 4, pH 8.0 (Lane #4); 50 μM 4, pH 8.0 (Lane #5); 10 μM 4, pH 8.0 (Lane #6); 5 μM 4, pH 8.0 (Lane #7); 1 μM 4, pH 8.0 (Lane #8); linearized pBR322 DNA (Lane #9). Conditions (Lane #2): circular pBR322 DNA (15.2 μM in base pairs), 5% DMSO (vehicle), TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. Conditions (Lanes #3–#8): circular pBR322 DNA (15.2 μM in base pairs), 4 (500 μM–1 μM), 5% DMSO, TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. The DNA was analyzed by native gel electrophoresis (90 V, 1.5 h).

We also evaluated the cross-linking ability of the compounds. To probe for any relationship between absolute stereochemistry and cross-linking activity, we employed the enantiomeric pair (−)-104 and (+)-104, using linearized pUC19 plasmid DNA as substrate (Figure 4). The linearized pUC19 DNA was incubated with (−)-104 or (+)-104 (1–100 μM) for 16 h at 37 °C. The DNA was then analyzed by denaturing gel electrophoresis. Cisplatin (100 μM) and vehicle (methyl sulfoxide) were used as positive and negative controls, respectively, and methyl methanesulfonate (MMS, 500 μM) was used as a positive control for monoalkylation. Under these conditions we were unable to detect any DNA cross-links using either (−)-104 and (+)-104. Collectively the experiments outlined in Figures 3 and 4 suggest that DNA is unlikely to be the primary biological target of myrocins.

Figure 4.

DNA cross-linking assay employing linear pUC19 DNA and myrocin analogs(−)-104 and (+)-104. 5% DMSO was used as a negative control. Cisplatin (100 μM) and methyl methanesulfonate (MMS, 500 μM) were used as positive controls for cross-linking and monoalkylation, respectively. DNA ladder (Lane #1); 5% DMSO (Lane #2); 100 μM cisplatin (Lane #3); 500 μM MMS (Lane # 4), 100 μM (−)-104 (Lane #5); 10 μM (−)-104 (Lane #6); 1 μM (−)-104 (Lane #7); 100 μM (+)-104 (Lane #8); 10 μM (+)-104 (Lane #9); 1 μM (+)-104 (Lane #10). Conditions (Lane #2): linearized pUC19 DNA (15.4 μM in base pairs), 5% DMSO (vehicle), TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. Conditions (Lane #4): linearized pUC19 DNA (15.4 μM in base pairs), 5% DMSO (vehicle), 100 μM cisplatin, TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. Conditions (Lane #5): linearized pUC19 DNA (15.4 μM in base pairs), 5% DMSO (vehicle), 500 μM MMS, TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. Conditions (Lanes #5–#7): linearized pUC19 DNA (15.4 μM in base pairs), 5% DMSO (vehicle), (−)-104 (100 μM 1 μM), TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. Conditions (Lanes #8–#10): linearized pUC19 DNA (15.4 μM in base pairs), 5% DMSO (vehicle), (+)-104. (100 μM–1 μM), TE buffer (10 mM Tris, 1 mM EDTA, pH 8.0), 16 h, 37 °C. The DNA was analyzed by 0.4% NaOH denature agarose gel electrophoresis (90 V, 1.5 h).

Conclusion.

In summary, we have described the development of a concise and convergent synthesis of (−)-myrocin G (4), the putative active form of (+)-myrocin C (3). The total synthesis of 4 was enabled by the development of a complex stereoselective fragment coupling–cyclization cascade employing the iodocyclopropane 107 and the α-iodoenone 110. This cascade coupling was enabled by the stepwise discovery of a series of intramolecular substituent migrations. Ultimately, the successful telescoping of this migration steps allowed for efficient construction of the central ring of the myrocin system in a single step. Preliminary studies suggest that DNA is not the primary biological target of myrocins; efforts to identify their biological target are ongoing.

General Experimental Procedures.

All reactions were performed in single-neck, flame-dried, round-bottomed flasks fitted with rubber septa under a positive pressure of argon unless otherwise noted. Air- and moisture-sensitive liquids were transferred via syringe or stainless steel cannula, or were handled in a nitrogen-filled drybox (working oxygen level <10 ppm). Organic solutions were concentrated by rotary evaporation at 28–32 °C. Flash-column chromatography was performed as described by Still et al.,³³ employing silica gel (SiliaFlash® P60, 60 Å, 40–63 μm particle size) purchased from SiliCycle (Québec, Canada). Analytical thin-layered chromatography (TLC) was performed using glass plates pre-coated with silica gel (250 μm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm). Preparative thin-layered chromatography (PTLC) was performed using glass plates precoated with silica gel (250 μm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV) and/or submersion in aqueous ceric ammonium molybdate solution (CAM), para-anisaldehyde (PAA), or aqueous potassium permanganate solution (KMnO₄), followed by brief heating on a hot plate (120 °C, 10–15 s).

Materials.

Commercial solvents and reagents were used as received with the following exceptions. Dichloromethane, diethyl ether (ether), N,N-dimethylformamide, tetrahydrofuran, and toluene were purified according to the method of Pangborn et al.³⁴ Pyridine was distilled from calcium hydride under an atmosphere of nitrogen immediately prior to use. Triethylamine was distilled from calcium hydride under an atmosphere of nitrogen immediately prior to use. N,N-Di-iso-propylethylamine was distilled from calcium hydride and stored under argon. Sodium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide were stored and handled in a nitrogen-filled drybox. The molarities of n-butyllithium and iso-propylmagnesium chloride–lithium chloride complex solutions were determined using the method of Love et al.³⁵ Trimethylsilyl trifluoromethanesulfonate was purified by vacuum transfer distillation and stored under argon at −20 °C. Trimethylsulfoxonium iodide was recrystallized from water, rinsed with acetone, dried under vacuum in the presence of calcium sulfate, and stored in a desiccator with protection from light. Diazomethane was prepared according to procedure of Arndt et al.³⁶ 3-Chloroperoxybenzoic acid (mCPBA) was recrystallized from dichloromethane and stored at −20 °C. Chlorotrimethylsilane was distilled from calcium hydride and stored under argon. Compounds 4, 16, 105−109, and 110 were prepared according to previously published procedures.¹¹

Instrumentation.

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 400, 500, or 600 megahertz (MHz) at 23 °C, unless otherwise noted. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to residual proton in the NMR solvent (CHCl₃, δ 7.26; C₆HD₅, δ 7.16; CHD₂OD, δ 3.31; (CD₂H)SO(CD₃), δ 2.50). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances, b = broad, app = apparent), coupling constant in Hertz (Hz), integration, and assignment. Proton-decoupled carbon nuclear magnetic resonance spectra (¹³C NMR) were recorded at 100, 125, or 150 MHz at 23 °C, unless otherwise noted. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl₃, δ 77.0; C₆D₆, δ 128.1; CD₃OD, δ 49.0; DMSO-d₆, δ 39.5). Distortionless enhancement by polarization transfer [DEPT (135)] spectra were recorded at 125 or 150 MHz at 23 °C, unless otherwise noted. Heteronuclear single quantum coherence (HSQC), and hetereonuclear multiple bond correlation (HMBC) spectra were recorded at 125 or 150 MHz at 23 °C, unless otherwise noted. ¹³C NMR and DEPT (135)/HSQC data are combined and represented as follows: chemical shift, carbon type [obtained from DEPT (135) or HSQC experiments]. Two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) and two-dimensional rotating-frame nuclear Overhauser effect spectroscopy (2D ROESY) experiments were performed at 500 MHz at 23 °C, unless otherwise noted. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra were obtained using a Thermo Electron Corporation Nicolet 6700 FTIR spectrometer referenced to a polystyrene standard. Data are represented as follows: frequency of absorption (cm⁻¹), intensity of absorption (s = strong, m = medium, w = weak, br = broad). Analytical ultra-high-performance liquid chromatography/mass spectrometry (UPLC/MS) was performed on a Waters UPLC/MS instrument equipped with a reverse-phase C₁₈ column (1.7 μm particle size, 2.1 × 50 mm), dual atmospheric pressure chemical ionization (API)/electrospray (ESI) mass spectrometry detector, and photodiode array detector. Samples were eluted with a linear gradient of 5% acetonitrile–water containing 0.1% formic acid→100% acetonitrile containing 0.1% formic acid over 0.75 min, followed by 100% acetonitrile containing 0.1% formic acid for 0.75 min, at a flow rate of 800 μL/min. High-resolution mass spectrometry (HRMS) were obtained on a Waters UPLC/HRMS instrument equipped with a dual API/ESI high-resolution mass spectrometry detector and photodiode array detector. Unless otherwise noted, samples were eluted over a reverse-phase C₁₈ column (1.7 μm particle size, 2.1 × 50 mm) with a linear gradient of 5% acetonitrile–water containing 0.1% formic acid→95% acetonitrile–water containing 0.1% formic acid for 1 min, at a flow rate of 600 μL/min. Analytical chiral separation using supercritical fluid chromatography (SFC-UV-ESIMS) of the diosphenol 98 was performed with a Chiralpak® IC column (5 μm particle size, 2.1 × 50 mm) and a photodiode array detector. Optical rotations were measured on a Rudolph Research Analytical Autopol IV polarimeter equipped with a sodium (589 nm, D) lamp. Optical rotation data are represented as follows: specific rotation (${[\alpha ]}_D^T$, concentration (mg/mL), and solvent.

Synthetic Procedures.

Note: Synthetic intermediates not shown in the manuscript are numbered below beginning with S1.

Synthesis of the ketone 27:

A suspension of sodium hydride in mineral oil (60 wt.%, 790 mg, 19.8 mmol, 1.20 equiv) was added in one portion to a suspension of trimethylsulfoxonium iodide (4.35 g, 19.8 mmol, 1.20 equiv) in N,N-dimethylformamide (330 mL) at 23 °C. The reaction mixture was stirred for 1 h at 23 °C. The reaction mixture was then cooled over 30 min to −45 °C. A solution of the enone 26 (3.00 g, 16.5 mmol, 1 equiv) in N,N-dimethylformamide (16 mL) was then added dropwise over 1 h at −45 °C. The reaction mixture was stirred for 18 h at −45 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (300 mL) and ethyl acetate (100 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 350 mL). The organic layers were combined and the combined organic layers were washed sequentially with water (3 × 200 mL) and saturated aqueous sodium chloride solution (200 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. ¹H NMR analysis of the residue obtained indicated the formation of a 5.3:1 mixture of diastereomers. The residue was transferred to a round-bottomed flask and the vessel was outfitted with a rubber septum. The headspace in the reaction vessel was evacuated and backfilled with argon. A solution of hydrogen chloride in dioxane (4.0 M, 13.6 mL, 54.3 mmol, nominally 5.00 equiv) was added to the neat residue under argon at 23 °C. The reaction mixture was stirred for 2 d at 23 °C. The product mixture was then carefully poured into a stirred solution of saturated aqueous sodium bicarbonate solution (15 mL) and ethyl acetate (20 mL, CAUTION: gas evolution!). The mixture was stirred for 30 min at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 25 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 20% ether–hexanes) to provide the ketone 27 as a colorless oil (2.16 g, 85%).

R_f = 0.36 (20% ether–hexanes; PAA [grey]). ¹H NMR (500 MHz, chloroform-d): δ 4.26–4.15 (m, 2H, H₆), 3.47–3.45 (m, 2H, H₂), 2.57–2.53 (m, 2H, H_4a,8a), 2.42 (t, J = 13.2 Hz, 1H, H_8b), 2.16–2.06 (m, 1H, H₁), 1.90–1.84 (m, 1H, H_3a), 1.64–1.55 (m, 1H, H_3b), 1.44 (td, J = 13.7, 3.6 Hz, 1H, H_4b), 1.28 (s, 3H, H₅), 1.26 (t, J = 7.1 Hz, 3H, H₇). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 206.3 (C), 172.6 (C), 61.5 (CH₂), 56.2 (C), 49.2 (CH₂), 44.2 (CH₂), 41.5 (CH), 36.2 (CH₂), 26.6 (CH₂), 20.9 (CH₃), 14.1 (CH₃). IR (ATR-FTIR), cm⁻¹: 2937 (w), 1712 (s), 1450 (w), 1239 (m), 1159 (m). HRMS (m/z): [M+H]⁺ calcd for C₁₁H₁₈ClO₃, 233.0939; found, 233.0983.

Synthesis of the vinyl triflate 28:

A 25-mL round-bottomed flask fused to a Teflon-coated valve was charged sequentially with 2,4,6-tri-tert-butylpyrimidine (6.92 g, 28.5 mmol, 3.07 equiv), the ketone 27 (2.16 g, 9.28 mmol, 1 equiv), and dichloromethane (9.0 mL). The reaction vessel was outfitted with a rubber septum and the headspace in the vessel was evacuated. The headspace was filled with argon (1 atm). Trifluoromethanesulfonic anhydride (2.81 mL, 16.7 mmol, 1.80 equiv) was then added under argon. The reaction vessel was sealed and the sealed reaction vessel was immersed in an oil bath that had been preheated to 50 °C. The reaction mixture was stirred for 2 d at 50 °C. The product mixture was then cooled over 30 min to 23 °C. The cooled product mixture was diluted with saturated aqueous ammonium chloride solution (10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 15 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 2% ether–hexanes, grading to 33% ether–hexanes, one step) to provide the vinyl triflate 28 as a colorless oil (2.88 g, 85%).

R_f = 0.39 (20% ether–hexanes; CAM). ¹H NMR (500 MHz, chloroform-d): δ 5.85 (d, J = 2.7 Hz, 1H, H₈), 4.25–4.15 (m, 2H, H₆), 3.53–3.45 (m, 2H, H₂), 2.78–2.71 (m, 1H, H₁), 2.34 (ddd, J = 13.6, 5.2, 3.0 Hz, 1H, H_4a), 1.86 (dtd, J = 13.8, 5.4, 2.8 Hz, 1H, H_3a), 1.64 (td, J = 13.2, 2.9 Hz, 1H, H_4b), 1.54–1.44 (m, 1H, H_3b), 1.42 (s, 3H, H₅), 1.28 (t, J = 7.1 Hz, 3H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 173.1 (C), 151.0 (C), 119.7 (CH), 62.0 (CH₂), 47.6 (CH₂), 46.9 (C), 38.8 (CH), 35.1 (CH₂), 23.6 (CH₂), 22.4 (CH₃), 14.13 (CH₃). IR (ATR-FTIR), cm⁻¹: 2941 (w), 1734 (m), 1416 (m), 1211 (s), 1141 (m). HRMS (m/z): [M+H]⁺ calcd for C₁₂H₁₇ClF₃O₅S, 365.0432; found, 365.0386

Synthesis of the aryl ether 35:

Step 1: Synthesis of the diene 29:

A 50-mL round-bottomed flask fused to a Teflon-coated valve was charged sequentially with palladium(II) acetate (85.0 mg, 379 μmol, 0.05 equiv), the vinyl triflate 28 (2.77 g, 7.59 mmol, 1 equiv), methyl sulfoxide (15 mL), and triethylamine (1.59 mL, 11.4 mmol, 1.50 equiv). The reaction vessel was fitted with a rubber septum and the headspace in the vessel was evacuated. The headspace was filled with argon (1 atm). Ethyl vinyl ether (2.91 mL, 30.4 mmol, 4.01 equiv) was then added via syringe. The reaction vessel was sealed and the sealed reaction vessel was immersed in an oil bath that had been preheated to 60 °C. The reaction mixture was stirred for 1 h at 60 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted sequentially with ether (10 mL), hexanes (10 mL), and saturated aqueous sodium bicarbonate solution (10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ether–hexanes (v/v, 4 × 20 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (65 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. The filtrate was collected and 2,4,6-tri-tert-butylpyrimidine (188 mg, 759 μmol, 0.1 equiv) was added to the filtrate. The resulting mixture was concentrated. Due to the instability of the diene 29, the unpurified product was used directly in the following step.

Step 2: Synthesis of the Diels–Alder adduct 32:

A solution of dimethylaluminum chloride in hexanes (1.0 M, 6.33 mL, 6.33 mmol, 1.00 equiv) was added to a solution of 3,3-dimethylcyclohex-2-ene-1-one (31, 786 mg, 6.33 mmol, 1 equiv) in dichloromethane (3.0 mL) at −78 °C. A solution of the unpurified diene 29 obtained in the preceding step (nominally 2.18 g, 7.60 mmol, 1.20 equiv) and 2,4,6-tri-tert-butylpyrimidine (188 mg, 759 μmol, 0.12 equiv) in dichloromethane (8.0 mL) was added dropwise via syringe pump over 5 min at −78 °C. The reaction mixture was then transferred to a bath that had previously been cooled to 0 °C. The reaction mixture was stirred for 18 h at 0 °C. The product mixture was then diluted with saturated aqueous sodium bicarbonate (10 mL, CAUTION: gas evolution!). The diluted mixture was stirred for 30 min at 0 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 20 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (40 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was eluted over a plug of silica gel (6.0 cm × 3.0 cm, eluting with 20% ether–hexanes). The filtrate was collected and concentrated. The Diels–Alder adduct 32 was formed as an uncharacterized mixture of diastereomers. This mixture was used directly in the following step.

Step 3: Synthesis of the aryl ether 35:

Ceric ammonium nitrate (CAN, 16.0 g, 29.2 mmol, 4.00 equiv) was added to a solution of the unpurified Diels–Alder adduct 32 obtained in the preceding step (nominally 3.00 g, 7.30 mmol, 1 equiv) in N,N-dimethylformamide (78 mL) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The product mixture was diluted sequentially with 50% ethyl acetate–hexanes (60 mL) and saturated aqueous sodium bicarbonate (50 mL, CAUTION: gas evolution!). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 55 mL). The organic layers were combined and the combined organic layers were washed sequentially with water (3 × 100 mL) and saturated aqueous sodium chloride solution (110 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 20% ether–hexanes) to provide the aryl ether 35 as a white solid (654 mg, 22% over two steps).

R_f = 0.33 (33% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 6.54 (s, 1H, H₁₂), 4.41–4.39 (m, 1H, H₁), 4.16–3.96 (m, 4H, H_6,13), 3.72 (ddd, J = 10.6, 3.6, 1.1 Hz, 1H, H_2a), 3.47 (t, J = 10.7 Hz, 1H, H_2b), 2.85–2.78 (m, 2H, H₉), 2.51–2.44 (m, 2H, H₈), 2.33 (td, J = 3.5, 2.2 Hz, 1H, H_4a), 2.09 (td, J = 14.0, 3.3 Hz, 1H, H_3a), 1.79 (tt, J = 13.9, 3.8 Hz, 1H, H_4b), 1.68 (dtd, J = 13.4, 3.3, 0.9 Hz, 1H, H_3b), 1.48 (s, 3H, H₅), 1.39 (t, J = 7.0 Hz, 3H, H₁₄), 1.18 (t, J = 7.1 Hz, 3H, H₇), 1.07 (s, 1H, H₁₁), 1.05 (s, 1H, H₁₀). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 198.9 (C), 177.9 (C), 159.3 (C), 145.9 (C), 140.5 (C), 128.6 (C), 122.8 (C), 110.6 (CH), 63.8 (CH₂), 60.3 (CH₂), 55.0 (CH₂), 47.1 (CH₂), 45.8 (CH₂), 45.0 (C), 36.8 (CH), 33.0 (C), 29.6 (CH₂), 28.2 (CH₃), 27.9 (CH₃), 23.7 (CH₃), 19.2 (CH₂), 14.3 (CH₃), 14.2 (CH₃). IR (ATR-FTIR), cm⁻¹: 2924 (s), 1733 (m), 1585 (m), 1465 (w), 1250 (s). HRMS (m/z): [M+H]⁺ calcd for C₂₃H₃₂ClO₄, 407.1984; found, 407.1920.

Synthesis of the phenol 36:

A solution of boron tribromide in dichloromethane (1.0 M, 2.29 mL, 2.29 mmol, 3.00 equiv) was added to a solution of the aryl ether 35 (310 mg, 762 μmol, 1 equiv) in dichloromethane (4.0 mL) at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. The product mixture was then diluted sequentially with saturated aqueous sodium bicarbonate solution (3.0 mL, CAUTION: gas evolution!) and 50% ether–hexanes (v/v, 6.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 8.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (16 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered through a plug of celite (2.0 cm × 3.0 cm) and the filter cake was rinsed with ether (3 × 5.0 mL). The filtrates were combined and the combined filtrates were concentrated. The residue obtained was purified by flash-column chromatography (eluting initially with 33% ether–hexanes, grading to 50% ether–hexanes, one step) to provide the phenol 36 as a white solid (180 mg, 62%). Vapor diffusion crystallization of the phenol 36 from ether with pentanes as antisolvent provided crystals suitable for X-ray crystallographic analysis (see Supporting Information).

R_f = 0.15 (50% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.51 (s, 1H, H₁₂), 6.03 (bs, 1H, H₁₃), 4.43–4.38 (m, 1H, H₁), 4.20–4.06 (m, 2H, H₆), 3.74 (ddd, J = 10.6, 3.7, 1.1 Hz, 1H, H_2a), 3.48 (t, J = 10.7 Hz, 1H, H_2b), 2.79–2.71 (m, 2H, H₉), 2.52–2.43 (m, 2H, H₈), 2.36–2.31 (m, 1H, H_4a), 2.16 (td, J = 14.0, 3.3 Hz, 1H, H_3a), 1.80 (tt, J = 14.4, 3.7 Hz, 1H, H_4b), 1.70 (dt, J = 13.4, 3.5 Hz, 1H, H_3b), 1.53 (s, 3H, H₅), 1.20 (t, J = 7.1 Hz, 3H, H₇), 1.06 (s, 1H, H₁₁), 1.03 (s, 1H, H₁₀). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 198.9 (C), 178.9 (C), 156.9 (C), 145.8 (C), 141.6 (C), 126.9 (C), 123.3 (C), 115.2 (CH), 60.9 (CH₂), 55.0 (CH₂), 47.0 (CH₂), 45.2 (CH₂), 45.1 (C), 36.8 (CH), 32.9 (C), 29.5 (CH₂), 28.1 (CH₃), 27.9 (CH₃), 23.4 (CH₃), 19.3 (CH₂), 14.1 (CH₃). IR (ATR-FTIR), cm⁻¹: 3299 (w), 2924 (s), 2854 (m), 1722 (m), 1463 (w). HRMS (m/z): [M+H]⁺ calcd for C₂₁H₂₈ClO₄, 379.1671; found, 379.1685.

Synthesis of the catechol 37:

Step 1: Synthesis of the quinone S1:

2-Iodoxybenzoic acid (360 mg, 1.29 mmol, 3.01 equiv) was added to a solution of the phenol 36 (162 mg, 428 μmol, 1 equiv) in chloroform (2.0 mL) at 23 °C. The reaction mixture was stirred for 3 d at 23 °C. The product mixture was diluted with hexanes (5.0 mL). The diluted product mixture was stirred for 4 h at 23 °C. The resulting suspension was then filtered through a plug of celite (2.0 cm × 3.0 cm) and the filter cake was rinsed with ether (3 × 5.0 mL). The filtrates were combined and the combined filtrates were concentrated. The residue obtained was purified by flash-column chromatography (eluting with 17% ethyl acetate–hexanes) to provide the quinone S1 as a white solid (99.0 mg, 59%).

R_f = 0.35 (20% ethyl acetate–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 4.16–4.01 (m, 3H, H_1,6), 3.56–3.43 (m, 2H, H₂), 2.66–2.54 (m, 3H, H_9,8a), 2.45 (app d, J = 14.1 Hz, 1H, H_8b), 2.12–1.84 (m, 4H, H_2,3), 1.48 (s, 3H, H₅), 1.21–1.14 (m, 6H, H_7,11), 1.06 (s, 3H, H₁₀). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 200.9 (C), 182.6 (C), 178.2 (C), 175.6 (C), 147.6 (C), 143.6 (C), 140.1 (C), 138.4 (C), 61.2 (CH₂), 53.9 (CH₂), 46.4 (CH₂), 44.9 (C), 37.2 (CH₂), 36.2 (CH), 33.5 (C), 30.2 (CH₂), 29.1 (CH₃), 27.7 (CH₃), 24.0 (CH₃), 20.9 (CH₂), 14.0 (CH₃). IR (ATR-FTIR), cm⁻¹: 2957 (m), 1733 (s), 1689 (s), 1666 (s), 1466 (w), 1259 (m), 1221 (m). HRMS (m/z): [M+H]⁺ calcd for C₂₁H₂₆ClO₅, 393.1463; found, 393.1458.

Step 2: Synthesis of the catechol 37:

Sodium dithionite (80 mg, 0.457 mmol, 2.99 equiv) was added to a solution of the quinone S1 (60.0 mg, 153 μmol, 1 equiv) in 20% water–tetrahydrofuran (v/v, 6.0 mL) at 23 °C. The reaction mixture was stirred for 20 min at 23 °C. The product mixture was diluted with 50% ethyl acetate–hexanes (v/v, 10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 6.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting initially with 33% ethyl acetate–hexanes initially, grading to 50% ethyl acetate–hexanes) to provide the catechol 37 as a yellow solid (38 mg, 63%).

R_f = 0.44 (50% ethyl acetate–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 5.30 (bs, 1H, H_12/13), 4.34–4.13 (m, 3H, H_1,6), 3.74 (dd, J = 10.5, 3.6 Hz, 1H, H_2a), 3.46 (t, J = 10.5 Hz, 1H, H_2b), 2.73 (app s, 2H, H₈), 2.48 (app q, J = 15.0 Hz, 2H, H₉), 2.33–2.25 (m, 2H, H_3a,4a), 1.81–1.66 (m, 2H, H_3b,4b), 1.57 (s, 3H, H₅)*, 1.28 (t, J = 6.8 Hz, 3H, H₇), 1.10 (s, 3H, H₁₁), 1.08 (s, 3H, H₁₀). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 199.1 (C), 179.1 (C), 146.5 (C), 140.1 (C), 133.6 (C), 129.9 (C), 125.6 (C), 123.1 (C), 61.7 (CH₂), 54.6 (CH₂), 47.4 (CH₂), 45.6 (C), 37.9 (CH₂), 36.5 (CH), 32.4 (C), 29.5 (CH₂), 28.9 (CH₃), 27.8 (CH₃), 23.9 (CH₃), 19.8 (CH₂), 14.0 (CH₃). IR (ATR-FTIR), cm⁻¹: 3329 (w), 2953 (m), 2926 (m), 1719 (m), 1591 (w), 1446 (w), 1280 (s), 1259 (s), 1197 (m). HRMS (m/z): [M+H]⁺ calcd for C₂₁H₂₈ClO₅, 395.1620; found, 395.1634. *Resonance obscured by the water peak signal.

Synthesis of the pyran 40:

Potassium carbonate (3.0 mg, 21.7 μmol, 1.09 equiv) was added to a solution of the catechol 37 (8.0 mg, 20.0 μmol, 1 equiv) and 2,4,6-tri-tert-butylpyrimidine (500 μg, 2.0 μmol, 0.10 equiv) in acetone (300 μL) at 23 °C. The reaction mixture stirred for 18 h at 23 °C. The product mixture was diluted with saturated aqueous ammonium chloride solution (1.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 1.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (3.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 33% acetone–hexanes) to provide the pyran 40 as a yellow solid (2.2 mg, 31%, 1:1 mixture of C1 diastereomers).

R_f = 0.23 (33% acetone–hexanes; UV, PAA). *Denotes second diastereomer. ¹H NMR (500 MHz, chloroform-d): δ 6.32–6.28 (m, 2H, H_13,13*), 5.18–5.12 (m, 2H, H_8,8*), 4.36–4.30 (m, 2H, H_2a,2a*), 4.21–4.11 (m, 4H, H_6,6*), 3.94 (q, J = 10.4 Hz, 1H, H_2b,2b*), 3.47 (d, J = 18.1 Hz, 1H, H_9a), 3.26 (d, J = 18.3 Hz, 1H, H_9a*), 3.03–2.94 (m, 1H, H_1,1*), 2.84 (app dd, J = 18.3, 11.0 Hz, 2H, H_9b,9b*), 2.31–2.24 (m, 2H, H_4,4*), 1.79–1.67 (m, 4H, H_{3b,4a,3b*,4a*}), 1.61 (s, 6H, H_5,5*), 1.50–1.41 (m, 2H, H_4b,4b*), 1.20 (t, J = 7.2 Hz, 6H, H_7,7*), 1.16 (s, 3H, H_10a), 1.06 (s, 6H, H_10b,10a*), 0.94 (s, 3H, H_10b*). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 176.3 (C), 176.3 (C)*, 165.0 (C), 164.7 (C)*, 147.4 (C), 147.3 (C)*, 137.9 (C)*, 137.0 (C), 135.5 (C), 135.3 (C)*, 124.8 (C), 124.7 (C)*, 122.3 (C), 122.2 (C)*, 114.4 (C), 114.1 (C)*, 99.0 (CH)*, 98.3 (CH), 70.8 (CH₂), 70.7 (CH₂)*, 60.9 (CH₂, CH₂)*, 43.5 (C), 43.5 (C)*, 36.3 (CH₂), 36.3 (CH₂)*, 34.7 (CH), 34.7 (CH)*, 34.7 (CH₂), 33.4 (CH₂)*, 32.6 (C)*, 32.4 (C), 25.1 (CH₃)*, 25.1 (CH₃), 25.0 (CH₃)*, 24.8 (CH₃), 24.3 (CH₃)*, 22.1 (CH₃), 21.7 (CH₃)*, 21.7 (CH₃), 14.2 (CH₂)*, 14.2 (CH₂). IR (ATR-FTIR), cm⁻¹: 3435 (w), 2925 (s), 1711 (s), 1453 (m), 1308 (w), 1266 (w), 1165 (m). HRMS (m/z): [M+H]⁺ calcd for C₂₁H₂₆O₅, 359.1853; found, 359.1823.

Synthesis of the aryl ether 42:

Step 1: Synthesis of the diene 41:

A 50-mL round-bottomed flask fused to a Teflon-coated valve was charged sequentially with palladium(II) acetate (102 mg, 450 μmol, 0.05 equiv), ethyl 1-methyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-2-ene-1-carboxylate (S2)³⁷ (2.87 g, 9.07 mmol, 1 equiv), methyl sulfoxide (18 mL), and triethylamine (1.90 mL, 13.6 mmol, 1.50 equiv). The reaction vessel was outfitted with a rubber septum and the headspace in the vessel was evacuated. The headspace was filled with argon. Ethyl vinyl ether (3.47 mL, 36.3 mmol, 4.00 equiv) was then added via syringe. The reaction vessel was sealed and the sealed reaction vessel was immersed in an oil bath that had been preheated to 50 °C. The reaction mixture was stirred for 45 min at 50 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted sequentially with ether (20 mL), hexanes (20 mL), and saturated aqueous sodium bicarbonate solution (10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. Due to the instability of the diene 41, the unpurified product was used immediately in the following step.

R_f = 0.30 (20% ether–hexanes; CAM). ¹H NMR (500 MHz, benzene-d₆): δ 6.32 (s, 1H, H₇), 4.39 (d, J = 2.0 Hz, 1H, H_8a), 4.28–4.05 (m, 2H, H₅), 3.98 (d, J = 2.0 Hz, 2H, H_8b), 3.63–3.46 (m, 2H, H₉), 2.13–2.03 (m, 2H, H_1a,2a), 1.92 (dtd, J = 18.1, 5.9, 4.1 Hz, 1H, H_2b), 1.83–1.76 (m, 1H, H_3a), 1.65 (s, 3H, H₄), 1.64–1.58 (m, 1H, H_1b), 1.54–1.47 (m, 1H, H_3b), 1.17 (t, J = 7.0 Hz, 3H, H₆), 1.13 (t, J = 7.1 Hz, 3H, H₇). ¹³C{¹H} NMR (125 MHz, benzene-d₆): δ 176.5 (C), 162.6 (C), 138.3 (C), 127.5 (CH), 82.4 (CH₂), 63.1 (CH₂), 60.2 (CH₂), 44.2 (C), 36.5 (CH₂), 25.4 (CH₂), 24.3 (CH₃), 18.8 (CH₂), 14.4 (CH₃), 14.3 (CH₃). IR (ATR-FTIR), cm⁻¹: 2980 (m), 2941 (m), 17.28 (m), 1668 (m), 1636 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₁₄H₂₃O₃, 239.1647; found, 239.1696.

Step 2: Synthesis of the Diels–Alder adduct S3:

A solution of dimethylaluminum chloride in hexanes (1.0 M, 7.56 mL, 7.56 mmol, 1.00 equiv) was added to a solution of 3,3-dimethylcyclohex-2-ene-1-one (32, 937 mg, 7.56 mmol, 1 equiv) in dichloromethane (3.5 mL) at −78 °C. A solution of the unpurified diene 41 obtained in the preceding step (nominally 9.07 mmol, 1.20 equiv) in dichloromethane (9.0 mL) was added dropwise via syringe pump over 5 min at −78 °C. The reaction mixture was then cooled to 0 °C. The reaction mixture was stirred for 8.5 h at 0 °C. The product mixture was then diluted sequentially with saturated aqueous sodium bicarbonate solution (3.0 mL, CAUTION: gas evolution!), water (5.0 mL), and ether (35 mL). The diluted mixture was stirred for 30 min at 0 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ether–hexanes (v/v, 20 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was partially purified by elution over a short plug of silica gel (6.0 cm × 3.0 cm, eluting with 25% ether–hexanes). The filtrate was collected and concentrated. The Diels–Alder adduct S3 was formed as a mixture of diastereomers. This mixture was used directly in the following step.

Steps 3: Synthesis of the aryl ether 42:

Ceric ammonium nitrate (10.4 g, 19.0 mmol, 2.51 equiv) was added in four portions to a solution of the Diels–Alder adduct S3 (nominally 7.56 mmol, 1 equiv) in N,N-dimethylformamide (50 mL) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The product mixture was poured into a stirred solution of 50% ethyl acetate–hexanes (250 mL) and saturated aqueous sodium bicarbonate (500 mL, CAUTION: gas evolution!). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 50 mL). The organic layers were combined and the combined organic layers were washed sequentially with water (3 × 50 mL) and saturated aqueous sodium chloride solution (50 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 25% ether–hexanes) to provide the aryl ether 42 as a white solid (1.34 g, 53% over two steps).

R_f = 0.20 (20% ether–hexanes; PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.57 (s, 1H, H₇), 4.14–4.05 (m, 3H, H_5,11a), 4.00–3.96 (m, 1H, H_11b), 3.38–3.32 (m, 1H, H_1a), 3.09–3.03 (m, 1H, H_1b), 2.85–2.75 (m, 2H, H₉), 2.49–2.40 (m, 2H, H₈), 1.95–1.85 (m, 2H, H_2a,3a), 1.80–1.77 (m, 1H, H_3b), 1.75–1.66 (m, 1H, H_2b), 1.51 (s, 3H, H₄), 1.38 (t, J = 7.0 Hz, 3H, H₁₂), 1.16 (t, J = 7.1 Hz, 3H, H₆), 1.06 (s, 3H, H_10a), 1.05 (s, 3H, H_10a). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 199.2 (C), 178.2 (C), 159.3 (C), 144.9 (C), 142.0 (C), 128.2 (C), 123.8 (C), 108.9 (CH), 63.6 (CH₂), 60.1 (CH₂), 54.9 (CH₂), 45.6 (CH₂), 44.3 (C), 35.6 (CH₂), 33.2 (C), 29.5 (CH₂), 28.2 (CH₃), 28.1 (CH₃), 23.5 (CH₃), 18.9 (CH₂), 14.4 (CH₃), 14.2 (CH₃). (ATR-FTIR), cm⁻¹: 2945 (m), 2903 (m), 17.28 (m), 1868 (m), 1545 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₂H₃₁O₄, 359.2222; found, 359.2220.

Synthesis of the phenol S4:

A solution of boron tribromide in dichloromethane (1.0 M, 300 μL, 300 μmol, 3.00 equiv) was added to a solution of the aryl ether 42 (36.0 mg, 100 μmol, 1 equiv) in dichloromethane (500 μL) at 23 °C. The reaction mixture was stirred for 8 h at 23 °C. The product mixture was diluted sequentially with dichloromethane (5.0 mL) and water (3.0 mL). The diluted product mixture was stirred for 30 min at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (5.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (3.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered through a short plug of celite (2.0 cm × 2.0 cm) and the filter cake was rinsed with dichloromethane (3 × 5.0 mL). The filtrates were combined and the combined filtrates were concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting 50% ether–hexanes) to provide the phenol S4 as a white solid (32 mg, 97%).

R_f = 0.18 (50% ether–hexanes; UV, PAA).¹H NMR (600 MHz, chloroform-d): δ 7.67 (bs, 1H, H₁₁), 6.53 (s, 1H, H₇), 4.17–4.08 (m, 2H, H₅), 3.39–3.32 (m, 1H, H_1a), 3.12–3.04 (m, 1H, H_1b), 2.71 (s, 2H, H₉), 2.47–2.37 (m, 2H, H₈), 2.04–1.97 (m, 1H, H_3a), 1.92–1.85 (m, 1H, H_2a), 1.83–1.69 (m, 2H, H_2b,3b), 1.56 (s, 3H, H₄), 1.19 (t, J = 7.1 Hz, 3H, H₆), 1.02 (s, 6H, H₁₀). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 199.7 (C), 179.7 (C), 158.0 (C), 145.1 (C), 143.0 (C), 126.4 (C), 123.5 (C), 113.6 (CH), 60.8 (CH₂), 54.7 (CH₂), 45.0 (C), 44.6 (CH₂), 35.4 (CH₂), 33.1 (C), 29.7 (C), 28.1 (CH₃), 23.3 (CH₃), 19.0 (CH₂), 14.1 (CH₃). IR (ATR-FTIR), cm⁻¹: 2920 (m), 2830 (m), 1834 (m), 1669 (m), 1601 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₀H₂₆NaO₄, 353.1729; found, 353.1738.

Synthesis of the catechol 43:

Step 1: Synthesis of the quinone S5:

2-Iodoxybenzoic acid (180.0 mg, 645 μmol, 3.00 equiv) was added to a solution of the phenol S2 (71.0 mg, 215 μmol, 1 equiv) in chloroform (1.1 mL) at 23 °C. The reaction mixture was stirred for 2 d at 23 °C. The product mixture was diluted with pentane (5.0 mL). The diluted product was filtered through a short plug of celite (2.0 cm × 3.0 cm). The filter cake was rinsed with pentane (3 × 5.0 mL). The filtrates were combined and the combined filtrates were concentrated. The unpurified product was used directly in the following step.

Step 2: Synthesis of the catechol 43:

Sodium dithionite (118 mg, 680 μmol, 4.00 equiv) was added to a solution of the unpurified quinone S5 obtained in the preceding step (nominally 59.0 mg, 170 μmol, 1 equiv) in 20% water–tetrahydrofuran (v/v, 1.7 mL) at 23 °C. The reaction mixture was stirred for 20 min at 23 °C. The product mixture was diluted with 50% ethyl acetate–hexanes (10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (5.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to provide the catechol 43 as a yellow solid (59.0 mg, 80% over two steps).

R_f = 0.35 (50% ethyl acetate–hexanes; UV, PAA).¹H NMR (500 MHz, chloroform-d): δ 8.68 (bs, 1H, H₁₁), 5.56 (bs, 1H, H₁₀), 4.26–4.18 (m, 2H, H₅), 3.16–3.09 (m, 2H, H₁), 2.75 (s, 2H, H₇), 2.43 (s, 2H, H₈), 2.34–2.27 (m, 1H, H_3a), 1.82–1.57 (m, 6H, H_2,3b,4), 1.27 (t, J = 7.1 Hz, 3H, H₆), 1.07 (s, 6H, H₉). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 199.6 (C), 180.2 (C), 146.7 (C), 140.1 (C), 134.8 (C), 129.3 (C), 124.4 (C), 123.7(C), 62.0 (CH₂), 54.6 (CH₂), 45.6 (C), 37.6 (CH₂), 35.4 (CH₂), 32.5 (C), 29.7 (CH₂), 28.5 (CH₃), 28.0 (CH₃), 24.9 (CH₃), 19.9 (CH₂), 13.9 (CH₃). IR (ATR-FTIR), cm⁻¹: 2935 (m), 1728 (m), 1640 (m), 1546 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₀H₂₇O₅ 347.1858; found 347.1857.

Synthesis of the phenol 44:

Iodomethane (40.0 μL, 600 μmol, 1.20 equiv) was added to a suspension of lithium carbonate (40.0 mg, 550 μmol, 1.10 equiv) and the catechol 43 (173 mg, 500 μmol, 1 equiv) in N,N-dimethylformamide (2.0 mL) at 23 °C. The reaction mixture was stirred for 1 d at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (500 μL), water (1.0 mL), and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (2.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting initially with 20% ether–hexanes initially, grading to 50% ether–hexanes, then 50% ethyl acetate–hexanes, 2 steps) to provide the phenol 44 as a white solid (71 mg, 41%). A separate experiment employing catechol 43 (10.0 mg, 28.8 μmol, 1 equiv) provided the phenol 44 (4.1 mg, 40%).

R_f = 0.20 (25% ethyl acetate–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 5.04 (bs, 1H, H₁₁), 4.29–4.23 (m, 1H, H_5a), 4.11–4.04 (m, 1H, H_5b), 3.81 (s, 3H, H₁₀), 3.26–3.20 (m, 1H, H_1a), 3.04–2.98 (m, 1H, H_1b), 2.77 (s, 2H, H₇), 2.50–2.40 (m, 2H, H₈), 1.99–1.94 (m, 1H, H_3a), 1.89–1.82 (m, 1H, H_2a), 1.81–1.74 (m, 1H, H_2b), 1.72–1.64 (m, 1H, H_3b), 1.51 (s, 3H, H₄), 1.22 (t, J = 7.1 Hz, 3H, H₆), 1.08 (s, 6H, H₉). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 200.2 (C), 178.0 (C), 149.1 (C), 143.6 (C), 133.1 (C), 132.6 (C), 131.1 (C), 126.9 (C), 60.5 (CH₂), 60.2 (CH₃), 54.6 (CH₂), 44.8 (C), 37.6 (CH₂), 36.1 (CH₂), 32.7 (C), 28.7 (CH₂), 28.6 (CH₃), 28.3 (CH₃), 24.9 (CH₃), 18.9 (CH₂), 14.2 (CH₃). IR (ATR-FTIR), cm⁻¹: 3401 (m), 2931 (m), 1703 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₁H₂₅O₅ 361.2015; found 361.2015.

Synthesis of the phenol 45:

Phthaloyl peroxide 51a (33.0 mg, 201 μmol, 2.06 equiv) was added to a solution of the aryl ether 42 (35.0 mg, 97.8 μmol, 1 equiv) in hexafluoroisopropanol (1.0 mL) at 23 °C. The reaction mixture was stirred for 28 h at 23 °C. A second portion of phthaloyl peroxide (16.0 mg, 97.6 μmol, 1.00 equiv) was added at 23 °C. The reaction mixture was stirred for 14 h at 23 °C. The reaction mixture was then concentrated. The residue obtained was dissolved in methanol (1.0 mL) at 23 °C. Saturated aqueous sodium bicarbonate solution (200 μL) was then added. The reaction mixture was stirred for 1.5 h at 23 °C. The product mixture was diluted sequentially with 1 N hydrochloric acid solution (1.0 mL) and ethyl acetate (7.0 mL). The diluted product mixture was stirred for 20 min at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (5.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (3.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting initially with 20% ether–hexanes, grading to 50% ether–hexanes, then 66% ether–hexanes, two steps) to provide the phenol 45 as a white solid (9.0 mg, 24%).

R_f = 0.20 (25% ethyl acetate–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 4.87 (s, 1H, H₁₂), 4.22–4.16 (m, 1H, H_5a), 4.13–4.08 (m, 1H, H_5b), 4.02–3.98 (m, 2H, H₁₀), 3.28–3.28 (m, 1H, H_1a), 3.06–2.98 (m, 1H, H_1b), 2.77 (s, 2H, H₇), 2.49–2.41 (m, 2H, H₈), 1.98–1.92 (m, 1H, H_3a), 1.89–1.82 (m, 1H, H_2a), 1.80–1.68 (m, 2H, H_2b,3b), 1.53 (s, 3H, H₄), 1.40 (t, J = 7.1 Hz, 3H, H₁₁), 1.22 (t, J = 7.1 Hz, 3H, H₆), 1.08 (s, 6H, H₉). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 200.4 (C), 178.0 (C), 148.0 (C), 143.9 (C), 133.2 (C), 132.6 (C), 130.8 (C), 126.9 (C), 68.2 (CH₂), 60.5 (CH₂), 54.6 (CH₂), 44.8 (C), 37.6 (CH₂), 36.3 (CH₂), 32.7 (C), 28.7 (CH₂), 28.5 (CH₃), 28.3 (CH₃), 24.9 (CH₃), 18.8 (CH₂), 15.4 (CH₃), 14.2 (CH₃). IR (ATR-FTIR), cm⁻¹: 3205 (m), 2926 (m), 2868 (m), 1655 (m), 1566 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₂H₃₁O₅, 375.2171; found 375.2172.

Synthesis of the para-quinone methide 46:

A 50-mL round-bottomed flask fused to a Teflon-coated valve was charged sequentially silver(I) oxide (301 mg, 1.30 mmol, 10.0 equiv), the phenol 43 (47.0 mg, 130 μmol, 1 equiv), and chloroform (2.6 mL). The reaction vessel was sealed and the sealed vessel was immersed in an oil bath that had been preheated to 60 °C. The reaction mixture was stirred for 2.5 h at 60 °C. The product mixture was cooled over 20 min to 23 °C. The cooled solution was diluted with pentane (5.0 mL). The diluted mixture was eluted over a short plug of celite (0.5 cm × 2.0 cm). The filter cake was rinsed with pentane (3 × 3.0 mL). The filtrates were combined and the combined filtrates were concentrated. The para-quinone methide 46 was unstable toward purification. The unpurified product was used directly in the in the cyclopropanation below.

R_f = 0.50 (25% ether –hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 8.07 (dd, J = 6.7, 3.3 Hz, 1H, H₁), 4.27 (dtd, J = 10.8, 8.1, 7.6, 6.6 Hz, 1H, H_5a), 4.17 – 4.04 (m, 1H, H_5b), 3.83 (s, 1H, H₁₀), 2.77 – 2.62 (m, 3H, H_{7, 2a}), 2.59 – 2.51 (m, 1H, H_2b), 2.53 – 2.39 (m, 2H, H₈), 2.14 (td, J = 12.6, 5.3 Hz, 1H, H_3a), 1.79 – 1.73 (m, 1H, H_3b), 1.40 (s, 3H, H₄), 1.30–1.21 (m, 3H, H₆), 1.09 (s, 3H, H₉), 1.06 (s, 3H, H₉). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 201.7 (C), 182.5 (C), 176.0 (CH), 150.3 (C), 148.0 (C), 143.5 (C), 135.0 (C), 133.0 (C), 126.6(C), 60.8 (CH₂), 59.1 (CH₃), 54.0 (CH₂), 44.4 (C), 37.3 (CH₂), 33.0 (C), 32.0 (CH₂), 28.7 (CH₃), 27.8 (CH₃), 24.2 (CH₂), 20.3 (CH₃), 14.1 (CH₃).

Synthesis of the cyclopropane 48:

A solution of diazomethane in dichloromethane (ca. 0.66 M, 300 μL, 198 μmol, 1.52 equiv) was added dropwise via syringe to a solution of the unpurified para-quinone methide 46 obtained in the preceding step (nominally 130 μmol, 1 equiv) in dichloromethane (500 μL) at −78 °C. The reaction mixture was stirred for 1.5 h at −78 °C. The cold product mixture was then concentrated under a stream of nitrogen. The residue obtained was dissolved in pentane (2.0 mL) and the resulting solution was concentrated to furnish the cyclopropane 48 as a white solid (39 mg, 83% over two steps).

R_f = 0.25 (25% ether–hexanes; UV, PAA).¹H NMR (600 MHz, chloroform-d): δ 4.30–4.22 (m, 1H, H_5a), 4.12–4.03 (m, 1H, H_5b), 3.79 (s, 3H, H₁₀), 3.59–3.54 (m, 1H, H₁), 2.73 (dd, J = 18.8, 1.4 Hz, 1H, H_7a), 2.52 (d, J = 18.7 Hz, 1H, H_7b), 2.41 (d, J = 14.7 Hz, 1H, H_8a), 2.28 (dd, J = 14.7, 1.4 Hz, 1H, H_8b), 2.22 (dd, J = 7.2, 3.7 Hz, 1H, H_11a), 2.13 (dd, J = 8.5, 3.7 Hz, 1H, H_11b), 2.06–1.91 (m, 3H, H_2,3a), 1.54–1.50 (m, 1H, H_3b), 1.38 (s, 3H, H₄), 1.25 (t, J = 7.1 Hz, 3H, H₆), 1.07 (s, 3H, H_9a), 1.01 (s, 3H, H_9b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 200.8 (C), 181.8 (C), 176.0 (C), 151.3 (C), 149.3 (C), 146.6 (C), 142.7 (C), 60.9 (CH₂), 58.4 (CH₃), 54.1 (CH₂), 45.7 (C), 37.5 (CH₂), 32.5 (C), 29.3 (CH₂), 29.1 (CH), 29.0 (CH₃), 27.3 (CH₃), 24.5 (CH₂), 23.6 (CH₃), 18.3 (CH₂), 14.2 (CH₃). IR (ATR-FTIR), cm⁻¹: 2935 (m), 2888 (m), 1845 (m), 1650 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₂H₂₈NaO₅, 395.1834 found, 395.1835.

Synthesis of the para-quinone methide 47:

Silver(I) oxide (43.0 mg, 190 μmol, 10.0 equiv) was added to a solution of the phenol 45 (7.0 mg, 19.0 μmol, 1 equiv) in chloroform (400 μL) at 23 °C. The reaction vessel was placed in a heating block that had been preheated to 60 °C. The reaction mixture was stirred for 3 h at 60 °C. The product mixture was cooled over 20 min to 23 °C. The cooled solution was diluted with pentane (5.0 mL). The diluted mixture was eluted over a short plug of celite (0.5 cm × 2.0 cm). The filter cake was rinsed with pentane (2 × 2.5 mL). The filtrates were combined and the combined filtrates were concentrated. The para-quinone methide 47 was unstable toward purification. The unpurified product was used directly in the in the cyclopropanation below.

R_f = 0.50 (25% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 8.05 (dd, J = 6.6, 3.3 Hz, 1H, H₁), 4.32–3.98 (m, 4H, H_5,7), 2.71–2.61 (m, 3H, H_3a,9), 2.58 – 2.50 (m, 1H, H_3b), 2.50–2.40 (m, 2H, H₈), 2.12 (td, J = 12.5, 5.2 Hz, 1H, H_2a), 1.75 (ddd, J = 12.8, 5.3, 2.2 Hz, 1H, H_2b), 1.40 (s, 3H, H₄), 1.31 (t, J = 7.1 Hz, 3H, H₆), 1.25–1.19 (m, 3H, H₁₂), 1.08 (s, 3H, H₁₀), 1.05 (s, 3H, H₁₀). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 201.7 (C), 182.5 (C), 175.9 (C), 149.9 (CH), 147.6 (C), 143.4 (C), 134.7 (C), 133.0 (C), 126.7 (C), 67.2 (CH₂), 60.7 (CH₂), 54.0 (CH₂), 44.3 (C), 37.3 (CH₂), 33.0 (C), 32.1 (CH₂), 28.6 (CH₃), 27.9 (CH₃), 24.2 (CH₂), 20.5 (CH₃), 15.2 (CH₃), 14.1 (CH₃).

Synthesis of the cyclopropane 49:

A solution of diazomethane in ether (ca. 0.66 M, 400 μL) was added to a solution of the unpurified para-quinone methide 47 obtained in the preceding step (nominally 19.0 μmol, 1 equiv) at −78 °C. The reaction mixture was stirred for 45 min at −78 °C. The reaction mixture was then warmed over 10 min to −40 °C. The reaction mixture was stirred for 20 min at −40 °C. The cooled product mixture was then concentrated under a stream of nitrogen. The unpurified product was used directly in the following step.

Synthesis of the phenol 50 from 49:

A solution of hydrogen chloride in dioxane (4 M, 100 μL, 400 μmol, 21.1 equiv) was added to the unpurified cyclopropane 49 obtained in the preceding step (nominally 19.0 μmol, 1 equiv) at 23 °C. The reaction mixture was stirred for 1 h at 23 °C. The cooled product mixture was then concentrated under a stream of nitrogen. The residue obtained was purified by preparatory thin-layered chromatography (eluting with 33% ether–hexanes) to furnish the phenol 50 (2.0 mg, 25% over three steps).

R_f = 0.20 (33% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 4.88 (s, 1H, H₁₁), 4.28–4.20 (m, 2H, H_1,6a), 4.12–4.06 (m, 1H, H_6b) 4.04–3.95 (m, 2H, H₁₂), 3.71 (dd, J = 10.6, 3.6 Hz, 1H, H_2a), 3.46 (t, J = 10.7 Hz, 1H, H_2b), 2.78–2.74 (m, 2H, H₉), 2.49 (q, J = 14.7 Hz, 2H, H 8), 2.34–2.27 (m, 1H, H_3a), 2.18–2.10 (m, 1H, H_4a), 1.81–1.65 (m, 2H, H_3b,4b), 1.50 (s, 3H, H₅), 1.43–1.38 (m, 3H, H₇), 1.25–1.19 (m, 3H, H₁₃), 1.11 (s, 3H, H_10a), 1.08 (s, 3H, H_10b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 199.9 (C, C₂₂), 177.7 (C, C₁₄), 148.0 (C, C_16–21), 145.2 (C, C_16–21), 133.1 (C, C_16–21), 131.8 (C, C_16–21), 131.7 (C, C_16–21), 126.4 (C, C_16–21), 68.3 (CH₂, C₁₂), 60.6 (CH₂, C₆), 54.7 (CH₂, C₈), 47.4 (CH₂, C₂), 45.5 (C, C₁₅), 38.3 (C, C₂₃), 37.8 (CH₂, C₉), 36.3 (CH, C 1), 30.4 (CH₂, C₄), 28.9 (CH₃, C_10a), 27.8 (CH₃, C_10b), 25.1 (CH₃, C₅), 19.3 (CH₂, C₃), 15.4 (CH₂, C 7), 14.1 (CH₂, C₁₃). IR (ATR-FTIR), cm^–1: 2999 (m), 2888 (m), 1820 (m), 1750 (m), 1729 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₂H₃₂ClO₅, 423.1938 found, 423.1938.

Synthesis of the phenol 50 from 36:

4,5-Dichlorophthaloyl peroxide 51b (81 wt%, 37.0 mg, 130 μmol, 2.50 equiv) was added to a solution of the aryl ether 36 (21.0 mg, 50.0 μmol, 1 equiv) in hexafluoroisopropanol (500 μL) at 23 °C. The reaction was stirred for 30 min at 23 °C. The reaction vessel was then placed in a heating block that had been preheated to 45 °C. The reaction mixture was stirred and heated for 3 h at 40 °C. The reaction mixture was then cooled over 20 min to 23 °C. The cooled mixture was concentrated. The residue obtained was dissolved in tetrahydrofuran (450 μL). Aqueous sodium phosphate buffer solution (pH 7.0, 100 μL) was added at 23 °C. The resulting mixture was briefly (~3 s) subjected to vacuum. The headspace was then backfilled with argon (1 atm). The reaction mixture was stirred under argon for 1 h at 23 °C. The product mixture was diluted sequentially with water (1.0 mL) and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 2.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting initially with 33% ether–hexanes, grading to 50% ether–hexanes) to provide the phenol 50 as a yellow oil (5.0 mg, 23%).

¹H NMR and ¹³C NMR spectroscopic data for 50 obtained in this way were inagreement with those obtained by an independent route (46→50).

Synthesis of the β-ketoester 63:

Cyclohex-2-ene-1-one (4.84 mL, 50.0 mmol, 1 equiv) was added to a solution of lithium bis(trimethylsilyl)amide (19.2 g, 115 mmol, 2.30 equiv) in tetrahydrofuran (50 mL) at −78 °C. The reaction mixture was stirred for 1 h at −78 °C. A solution of the 1-(tert-butoxycarbonyl)imidazole (12.6 g, 75.0 mmol, 1.50 equiv) in tetrahydrofuran (35 mL) was then added dropwise via syringe pump over 20 min at −78 °C. The reaction vessel was immediately removed from the cooling bath and the reaction mixture was allowed to warm over 1.5 h to 23 °C. Upon warming, a turbid, dark-red mixture formed. Iodomethane (9.34 mL, 150 mmol, 3.00 equiv) was then added at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (50 mL) and water (50 mL). The resulting mixture was poured into a solution of 75% ether–pentane (v/v, 300 mL). The biphasic mixture was stirred for 10 min at 23 °C. The stirred mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ether (100 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 14% ether–hexanes) to provide the enone 63 as a pale yellow oil (5.66 g, 54%).

R_f = 0.26 (20% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 6.90–6.86 (m, 1H, H₁), 6.03 (ddd, J = 10.1, 2.6, 1.5 Hz, 1H, H₆), 2.51–2.40 (m, 2H, H_2a,3a), 2.35–2.27 (m, 1H, H_2b), 1.90–1.81 (m, 1H, H_3b), 1.42 (s, 9H, H₅), 1.34 (s, 3H, H₄). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 197.3 (C), 171.8 (C), 148.8 (CH), 129.1 (CH), 81,7 (C), 53.9 (C), 33.6 (CH₂), 27.8 (3 × CH₃), 23.8 (CH₂), 20.3 (CH₃). IR (ATR-FTIR), cm⁻¹: 3005 (m), 2998 (m), 1655 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₁₂H₁₉O₃, 211.1334 found, 211.1334.

Synthesis of the α-iodoenone 64:

Iodine (6.27 g, 24.8 mmol, 1.80 equiv) was added to a solution of the enone 63 (2.61 g, 12.4 mmol, 1 equiv) in 50% pyridine–dichloromethane (v/v, 30 mL) at 23 °C. The reaction mixture was stirred for 24 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous sodium thiosulfate solution (30 mL), water (10 mL), ether (100 mL) and ethyl acetate (100 mL). The resulting biphasic mixture was stirred for 20 min at 23 °C. The stirred mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed sequentially with aqueous hydrochloric acid solution (1 N, 5 × 20 mL) and saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by elution over a short plug of silica gel (3.0’ 5.0 cm, eluting with 20% ether–hexanes). The filtrate was collected and concentrated. The residue obtained was triturated with pentane (5 × 10 mL) to furnish the α-iodoenone 64 as a colorless solid (3.20 g, 77%).

R_f = 0.35 (20% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 7.59–7.56 (m, 1H, H₁), 2.59–2.51 (m, 1H, H_2a), 2.49–2.43 (m, 1H, H_3a), 2.37–2.30 (m, 1H, H_2b), 1.96–1.89 (m, 1H, H_3b), 1.41 (s, 9H, H₅), 1.38 (s, 3H, H₄). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 190.8 (C), 171.0 (C), 156.8 (CH), 102.2 (C), 82.4 (C), 54.0 (C), 33.4 (CH₂), 27.9 (CH₂), 27.8 (3 × CH₃), 21.0 (CH₃). IR (ATR-FTIR), cm⁻¹: 2973 (m), 2933 (m), 1720 (m), 1685 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₁₂H₁₈IO₃, 337.0301; found 337.0301.

Synthesis of the iodocyclopropane 65:

Trimethylsulfoxonium iodide (2.74 g, 12.5 mmol, 1.40 equiv) was added in one portion to a suspension of sodium hydride (90%, 316 mg, 11.87 mmol, 1.33 equiv) in N,N-dimethylformamide (190 mL) at 23 °C. The resulting suspension was stirred for 40 min at 23 °C. The reaction mixture was cooled to −45 °C and stirred for 2 h at −45 °C. A solution of the α-iodoenone 64 (3.0 g, 8.92 mmol, 1 equiv) in N,N-dimethylformamide (17 mL) was then added dropwise via syringe pump over 1 h at −45 °C. The reaction mixture was placed in an ice bath and stirred for 18 h at 0 °C. The cold product mixture was then diluted sequentially with saturated aqueous ammonium chloride solution (20 mL), water (20 mL), and 50% ethyl acetate–hexanes (v/v, 150 mL). The resulting biphasic mixture was transferred to a separatory funnel the layers that formed were separated. The aqueous layer was extracted with 50% ethyl acetate–hexanes (v/v, 3 × 20.0 mL). The organic layers were combined and the combined organic layers were washed sequentially with water (3 × 10 mL) and saturated aqueous sodium chloride solution (30 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. ¹H NMR analysis of the unpurified product mixture indicated the presence of a 2.4:1 mixture of diastereomers. The residue obtained was recrystallized from 5% ether–hexanes to furnish the α-iodocyclopropane 65 as an off-white solid (1.46 g, 47%). Vapor diffusion crystallization of the cyclopropane 65 from ether with pentane as antisolvent provided crystals suitable for X-ray crystallographic analysis (see Supporting Information).

[major diastereomer] R_f = 0.36 (20% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 2.25–2.17 (m, 2H, H₁,_2a), 2.09 (td, J = 13.7, 4.6 Hz, 1H, H_3a), 1.97 (app t, J = 6.6 Hz, 1H, H_6a), 1.93–1.87 (m, 1H, H_3b), 1.67–1.61 (m, 1H, H_2b), 1.54 (dd, J = 8.7, 6.8 Hz, 1H, H_6b), 1.42 (s, 9H, H₅),1.29 (s, 3H, H₄). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 200.4 (C), 171.7 (C), 81.8 (C), 53.7 (C), 30.7 (CH), 28.7 (CH₂), 27.8 (3 × CH₃), 21.9 (CH₂), 21.3 (CH₂), 18.1 (CH₂), 7.8 (C). IR (ATR-FTIR), cm⁻¹: 2976 (m), 2867 (m), 1730 (m), 1701 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₁₃H₁₉INaO₃, 373.0277; found 373.0277.

Synthesis of the fragment coupling product 69:

A solution of iso-propylmagnesium chloride–lithium chloride complex in tetrahydrofuran (1.21 M, 530 μL, 641 μmol, 1.11 equiv) was added dropwise to a solution of the iodocyclopropane 65 (225 mg, 642 μmol, 1.11 equiv) in toluene (2.6 mL) at −78 °C. The reaction mixture was stirred for 30 min at −78 °C. A solution of the iodoenone 66 (145 mg, 580 μmol, 1 equiv) in toluene (500 μL) was then added to the reaction mixture at −78 C. The reaction vessel was removed from its cooling bath and the reaction mixture was then warmed over 3 h to 23 °C. The product mixture was diluted with saturated aqueous ammonium chloride solution (500 μL), water (3.0 mL), and 25% hexanes–ether (v/v, 20.0 mL) at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with water (3.0 mL) and saturated aqueous sodium chloride solution (3.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 14% ether–hexanes). The fractions containing product (TLC) were combined and the combined fractions were concentrated. The residue obtained was recrystallized from 5% ether–pentane to provide the adduct 69 as a white solid (240 mg, 87%). X-ray crystallographic analysis of 69 obtained in this way indicated that the diastereomer depicted was the major diastereomer formed (see Supporting Information).

[major diastereomer] R_f= 0.43 (20% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.32 (s, 1H, H₈), 2.73 (bs, 1H, H₇), 2.21 (t, J = 13.7 Hz, 1H, H_11a), 2.13–1.99 (m, 3H, H_4a,10), 1.74–1.58 (m, 4H, H_3,4b,9b), 1.54–1.49 (m, 1H, H_8b), 1.42 (s, 9H, H₆), 1.36 (s, 3H, H₅), 1.21 (s, 3H, H_9a), 1.03 (s, 3H, H_9b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 205.7 (C), 172.8 (C), 152.0 (CH), 106.2 (C), 81.1 (C), 72.4 (C), 54.9 (C), 41.7 (C), 38.0 (C), 32.9 (CH₂), 31.3 (C), 30.4 (CH₃), 29.9 (CH₂), 27.8 (3 × CH₃), 25.4 (CH₃), 23.7 (CH), 22.8 (CH₃), 17.5 (CH₂), 11.5 (CH₂). IR (ATR-FTIR), cm⁻¹: 2973 (m), 2931 (m), 2863 (m), 1737 (m), 1680 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₁H₃₂IO₄, 475.1345; found 475.1345.

Synthesis of the α-ethynylenone 67:

A round-bottom flask was charged with bis(triphenylphosphine)palladium(II) dichloride (206 mg, 293 μmol, 0.05 equiv), copper(I) iodide (33.6 mg, 176 μmol, 0.03 equiv), and the iodoenone 66 (1.47 g, 5.88 mmol, 1 equiv). The reaction vessel was sealed with a rubber septum. Tetrahydrofuran (30 mL) and triethylamine (2.90 mL, 20.8 mmol, 3.54 equiv) were then added in succession to the reaction vessel. The resulting suspension was deoxygenated by brief exposure to vacuum (~30 s) and subsequent backfilling with argon (1 atm). This process was repeated three times. Trimethylsilylacetylene (1.50 mL, 10.9 mmol, 1.87 equiv) was then added to the reaction mixture under argon at 23 °C. The reaction mixture was stirred for 7 h at 23 °C. The product mixture was diluted with 25% pentane–ether (v/v, 60 mL), saturated aqueous ammonium chloride solution (5.0 mL), and water (15 mL). The resulting biphasic mixture was stirred for 5 min at 23 °C. The mixture was then transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 10% ether–hexanes) to provide the ethynylenone 67 as a yellow solid (799 mg, 62%).

R_f = 0.35 (20% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 7.01 (s, 1H, H₄), 2.50 (dd, J = 7.4, 6.2 Hz, 2H, H₂), 1.88–1.83 (m, 2H, H₁), 1.18 (s, 6H, H₅), 0.21 (s, 9H, H₃). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 195.1 (C), 163.9 (CH), 122.5 (C), 99.1 (C), 97.2 (C), 35.5 (CH₂), 34.3 (CH₂), 33.6 (C), 27.5 (2 × CH₃), −0.11 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2965 (m), 2865 (m), 1730 (m), 1737 (m), 1692 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₁₃H₂₀NaOSi, 243.1181; found 243.1180.

Synthesis of the adduct 71:

Step 1: Synthesis of the adduct 70

A solution of iso-propylmagnesium chloride–lithium chloride complex in tetrahydrofuran (1.21 M, 50.0 μL, 60.0 μmol, 1.20 equiv) was added dropwise to a solution of the iodocyclopropane 65 (21.0 mg, 60.0 μmol, 1.20 equiv) in toluene (500 μL) at −78 °C. The reaction mixture was stirred for 30 min at −78 °C. A solution of the ethynylenone 67 (11.0 mg, 50.0 μmol, 1 equiv) in toluene (100 μL) was then added to the reaction mixture at −78 °C. The reaction vessel was removed from its cooling bath and the reaction mixture was then warmed over 3 h to 23 °C. The product mixture was then diluted with saturated aqueous ammonium chloride solution (200 μL), water (1.0 mL), and 25% hexanes–ether (v/v, 5.0 mL) at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with water (1.0 mL) and saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was used directly in the next step.

Step 2: Synthesis of the adduct 71:

Potassium carbonate (8.3 mg, 60.0 μmol, 1.20 equiv) was added to a solution of the unpurified fragment coupling product 70 obtained in the preceding step (nominally 50.0 μmol, 1 equiv) in methanol (250 μL) at 23 °C. The reaction mixture was stirred for 3 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (200 μL), water (1.0 mL), and 25% hexanes–ether (v/v, 5.0 mL) at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with water (1.0 mL) and saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 20% ether–hexanes) to provide the alkyne 71 as a white solid (15.0 mg, 81% over two steps).

R_f= 0.20 (25% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.07 (s, 1H, H₈), 2.89 (s, 1H, H₇), 2.36 (bs, 1H, H₁₂), 2.11 (td, J = 13.0, 5.9 Hz, 1H, H_11a), 2.05–1.88 (m, 4H, H_3a,4a,10), 1.68–1.45 (m, 7H, H_{1,3b,4b,8a,11}), 1.44–1.40 (m, 10H, H_8b,6), 1.12 (s, 3H, H_9a), 1.03 (s, 3H, H_9b). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 208.1 (C), 172.5 (C), 150.9 (CH), 121.1 (C), 83.0 (C), 81.2 (CH), 71.7 (C), 55.0 (C), 37.9 (C), 33.2 (CH₂), 33.1 (CH₂), 32.0 (C), 29.3 (CH₃), 29.0 (CH₃), 27.8 (3 × CH₃), 27.5 (CH₂), 22.3 (CH), 21.4 (CH₃), 17.4 (CH₂), 10.2 (CH₂). * IR (ATR-FTIR), cm⁻¹: 2935 (m), 2830 (m), 1739 (m), 1683 (m), 1446 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₃H₃₃O₄, 373.2379; found 373.2379. *The quaternary tert-butyl carbon was not observed due to coincidence with the residual solvent peak.

Synthesis of the vinyl silane 72:

Step 1: Synthesis of the silyl ether S6:

Imidazole (20.0 mg, 294 μmol, 2.96 equiv) was added in one portion to a solution of the adduct 69 (47 mg, 99.1 μmol, 1 equiv) and chlorotrimethylsilane (20.0 μL, 158 μmol, 1.59 equiv) in dichloromethane (500 μL) at 23 °C. The reaction mixture was stirred for 2 d at 23 °C. The product mixture was diluted with water (1.0 mL) and 50% ether–pentane (v/v, 5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered through a plug of silica gel (0.5 cm × 1.0 cm) and the filter cake was rinsed with ether (3 × 3.0 mL). The filtrates were combined and the combined filtrates were concentrated to provide the silyl ether as a colorless oil. The unpurified silyl ether was used directly in the following step.

Step 2: Synthesis of the vinyl silane 72:

A solution of n-butyllithium in hexanes (2.4 M, 60.0 μL, 0.143 mmol, 1.44 equiv) was added to a solution of the unpurified silyl ether S6 obtained in the preceding step (nominally, 99.1 μmol, 1 equiv) in tetrahydrofuran (500 μL) at −78 °C. The reaction mixture was stirred for 20 min at −78 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (500 μL), water (1.0 mL) and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 5% ether–hexanes) to provide the vinyl silane 72 as a colorless oil (21.6 mg, 52%, two steps).

R_f = 0.41 (10% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 5.72 (s, 1H, H₈), 5.23 (s, 1H, H₁₂), 2.15–2.06 (m, 1H, H_4a), 2.02–1.91 (m, 3H, H_3,11a), 1.76–1.68 (m, 1H, H_11b), 2.01–1.94 (m, 1H, H_3b), 1.58–1.46 (m, 4H, H_2,4b,10), 1.42 (s, 9H, H₆), 1.34–1.23 (s, 4H, H_1a,5), 1.11 (, J = 8.3, 5.7 Hz, 1H, H_1b) 1.01 (s, 3H, H_9a), 0.95 (s, 3H, H_9b), 0.14 (s, 9H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 212.1 (C), 172.3 (C), 151.3 (CH), 139.2 (C), 81.4 (C), 77.5 (C), 55.4 (C), 36.2 (C), 34.9 (CH₂), 33.7 (CH₂), 33.3 (C), 29.7 (CH₃), 29.3 (CH₃), 28.3 (CH₂), 27.8 (3 × CH₃), 21.1 (CH₂), 20.3 (CH), 16.7 (CH₂), 9.9 (CH₂), 1.6 (3 × CH₃). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₄H₄₀NaO₄Si, 443.2594; found 443.2588.

Synthesis of the methoxymethyl ether 73:

Chloromethyl methyl ether (40.0 μL, 527 μmol, 5.27 equiv) was added to a solution of sodium iodide (57.0 mg, 381 μmol, 3.81 equiv) in tetrahydrofuran (400 μL) at 23 °C. The reaction mixture was stirred for 5 min at 23 °C. A solution of the adduct 69 (47 mg, 99.1 μmol, 1 equiv) and di-iso-propylethylamine (10.0 μL, 574 μmol, 5.74 equiv) in tetrahydrofuran (200 μL) was added at 23 °C. The reaction vessel was sealed and the sealed vessel was placed in a heating block that had been preheated to 75 °C. The reaction mixture was stirred for 21 h at 75 °C. The product mixture was then cooled over 30 min to 23 °C. The cooled product mixture was diluted with saturated aqueous sodium bicarbonate solution (1.0 mL), water (1.0 mL), and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 5% ether–hexanes) to provide the methoxymethyl ether 73 as a colorless oil (44.0 mg, 85%).

R_f = 0.46 (10% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.57 (s, 1H, H₈), 4.81 (d, J = 6.8 Hz, 1H, H_7a), 4.51 (d, J = 6.8 Hz, 1H, H_7b), 3.36 (s, 1H, H₁₂), 2.80 (td, J = 13.9, 4.5 Hz, 1H, H_11a), 2.31–2.20 (m, 2H, H_2,4a), 2.08 (td, J = 13.7, 4.5 Hz, 1H, H_3a), 2.01–1.96 (m, 1H, H_4b), 1.80–1.70 (m, 3H, H_1a,10a,11b), 1.60–1.58 (m, 1H, H_3b), 1.51–1.46 (m, 1H, H_10b), 1.42 (s, 9H, H₆), 1.36 (s, 3H, H₅), 1.32–1.25 (m, 4H, H_1b,9a), 1.03 (s, 3H, H_9b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 204.9 (C), 173.1 (C), 155.5 (CH), 101.7 (C), 91.5 (CH₂), 81.0 (C), 76.8 (C)*, 55.9 (CH₃), 55.1 (C), 43.0 (C), 37.5 (C), 32.7 (CH₂), 31.3 (CH₂), 30.9 (CH₃), 30.0 (CH₃), 27.8 (3 × CH₃), 25.5 (CH₃), 24.0 (CH), 23.1 (CH₃), 17.8 (CH₂), 11.9 (CH₂). IR (ATR-FTIR), cm⁻¹: 2975 (m), 2933 (m), 2868 (m), 1732 (m), 1682 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C 23H₃₅INaO₅, 541.1427; found 541.1448. *Resonance obscured by solvent signal.

Synthesis of the cyclobutanol 74:

A solution n-butyllithium in hexanes (2.4 M, 40.0 μL, 94.9 μmol, 1.20 equiv) was added to a solution of the methoxymethyl ether 73 (41.0 mg, 79.1 μmol, 1 equiv) in tetrahydrofuran (400 μL) at −78 °C. The reaction mixture was stirred for 30 min at −78 °C. The reaction mixture was then warmed over 1 h to 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (500 μL), water (1.0 mL) and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 25% ether–hexanes) to provide the cyclobutanol 74 as a white solid (15.0 mg, 48%). Vapor diffusion crystallization of the cyclobutanol 74 from ether with hexanes as antisolvent provided crystals suitable for X-ray crystallographic analysis (see Supporting Information).

R_f = 0.20 (25% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 5.74 (s, 1H, H₈), 4.61 (d, J = 6.7 Hz, 1H, H_7a), 4.51 (d, J = 6.7 Hz, 1H, H_7b), 3.38 (s, 1H, H₁₂), 1.99–1.92 (m, 1H, H_3a), 1.90–1.82 (m, 2H, H_10a,11a), 1.78–1.72 (m, 1H, H_3b), 1.47 (s, 3H, H₆), 1.46–1.40 (m, 3H, H_4,11b), 1.35 (s, 3H, H₅), 1.31–1.27 (m, 1H, H₂), 1.13 (m, 3H, H_9a), 1.00 (s, 3H, H_9b), 0.74 (d, J = 9.5, 5.1 Hz, 1H, H_1a), 0.55 (d, J = 6.4, 5.2 Hz, 1H, H_1b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 176.5 (C), 146.0 (C), 135.1 (CH), 93.2 (CH₂), 82.1 (C), 82.0 (C), 80.0 (C), 55.8 (CH₃), 46.4 (C), 40.1 (C), 33.8 (C), 32.9 (CH₂), 30.4 (CH₃), 29.3 (CH₂), 29.3 (CH₃), 28.1 (3 × CH₃), 22.1 (CH₂), 19.2 (CH₂), 19.1 (CH₃), 13.8 (CH), 9.0 (CH₂). HRMS-CI (m/z): [M + Na]⁺ calcd for C 23H₃₆NaO₅, 415.2460; found 415.2459.

Synthesis of the ketofuran 76:

A 10-mL round bottom flask fused to a Teflon-coated valve was charged with [bis(trifluoroacetoxy)iodo]benzene (94.6 mg, 220 μmol, 2.20 equiv), the adduct 71 (37.2 mg, 100 μmol, 1 equiv), and 1% water–acetonitrile (v/v, 2.0 mL). The reaction chamber was sealed and the reaction vessel was immersed in an oil bath that had been preheated to 80 °C. The reaction mixture was stirred for 1.5 h at 80 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted sequentially with saturated aqueous sodium bicarbonate solution (2.0 mL) and 50% ether–ethyl acetate (v/v, 10.0 mL) at 23 °C. The resulting biphasic mixture was then transferred to a separatory funnel and the layers that formed were separated. The organic layers were combined and the combined layers were washed sequentially with water (3 × 2.0 mL) and saturated aqueous sodium chloride solution (3.0 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was used purified by preparative thin-layered chromatography (eluting with 50% ether–hexanes) to provide the ketofuran 76 as an amorphous solid (14.7 mg, 38%).

R_f = 0.26 (50% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.51 (s, 1H, H₁), 4.29 (dd, J = 17.4, 1.0 Hz, 1H, H_7a), 4.06 (dd, J = 17.4, 1.0 Hz, 1H, H_7b), 2.38 (dt, J = 13.2, 3.4 Hz, 1H, H_10a), 2.13–2.08 (m, 1H, H_4a), 1.99–1.95 (m, 2H, H₃), 1.71–1.65 (m, 1H, H_10b), 1.63–1.51 (m, 3H, H_4b,11), 1.46–1.41 (m, 10H, H_1a,6), 1.27–1.23 (m, 4H, H_2,5), 1.17 (s, 3H, H_9a), 1.08 (s, 3H, H_9b), 0.75 (dd, J = 8.3, 6.6 Hz, 1H, H_1b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 204.2 (C), 203.7 (C), 172.4 (C), 146.3 (CH), 134.2 (C), 83.3 (C), 81.4 (C), 70.7 (CH₂), 55.3 (C), 34.2 (C), 33.9 (C), 33.6 (CH₂), 31.4 (CH₂), 28.7 (CH₂), 28.4 (2 × CH₃), 27.8 (3 × CH₃), 21.0 (CH), 20.7 (CH₃), 16.7 (CH₂), 8.9 (CH₂). IR (ATR-FTIR), cm⁻¹: 2961 (m), 2955 (m), 2870 (m), 1732 (s), 1691 (m), 1654 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₃H₃₄O₅, 390.2406; found, 390.2433.

Synthesis of the aldol product 77:

Powdered sodium hydroxide (1.0 mg, 25.0 μmol, 2.03 equiv) was added to a solution of the ketofuran 76 (5.0 mg, 12.3 μmol, 1 equiv) in ethanol (240 μL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (200 μL), water (1.0 mL), and ethyl acetate (5.0 mL) at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layers were combined and the combined organic layers were washed with water (2.0 mL) and saturated aqueous sodium chloride solution (2.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 50% ether–hexanes) to provide the aldol product 77 as a white solid (3.2 mg, 66%). The stereochemistry of the newly generated alcohol was determined by 2D NOESY analysis, which indicated an NOE between positions 12 and 1 (see Supporting Information).

R_f = 0.58 (33% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, dimethylsulfoxide-d₆): δ 6.20 (s, 1H, H₈), 4.89 (s, 1H, H₁₂), 4.74 (s, 1H, H₉), 1.80–1.64 (m, 4H, H_3,13), 1.52–1.41 (m, 3H, H_2,4a,14a), 1.41 (s, 9H, H₆), 1.22–1.18 (m, 1H, H_4b), 1.16–1.10 (m, 1H, H_14b), 1.10 (s, 3H, H_9a), 1.03 (s, 3H, H_9b), 0.99 (s, 3H, H₅), 0.69 (t, J = 6.2 Hz, 1H, H_1a), 0.35 (dd, J = 9.4, 6.0 Hz, 1H, H_1b). ¹³C{¹H} NMR (150 MHz, dimethylsulfoxide-d₆): δ 198.2 (C), 174.2 (C), 137.2 (C), 1364 (CH), 84.4 (CH), 83.0 (C), 79.7 (C), 78.3 (C), 47.1 (C), 36.3 (C), 33.3 (CH₂), 32.7 (C), 29.2 (CH₃), 27.7 (3 × CH₃), 27.3 (CH₃), 22.6 (CH₂), 21.2 (CH₂), 18.3 (CH₂), 17.6 (CH₃), 12.7 (CH), 8.9 (CH₂). IR (ATR-FTIR), cm⁻¹: 2930 (m), 1752 (m), 1726 (m), 1555 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₃H₃₂NaO₅, 411.2147; found, 411.2154.

Synthesis of the vinyl ether 78:

A screw-capped pressure vessel was charged with copper(I) iodide (24.0 mg, 124 μmol, 0.10 equiv), cesium fluoride (414 mg, 2.73 mmol, 2.20 equiv), tetrakis(triphenylphosphine)-palladium(0) (72.0 mg, 62.0 μmol, 0.05 equiv), the adduct 69 (590 mg, 1.24 mmol, 1 equiv), and acetonitrile (6.2 mL). The reaction vessel was fitted with a rubber septum and the headspace in the vessel was evacuated. The headspace was back-filled with argon. Tributyl(1-ethoxyvinyl) tin (460 μL, 1.36 mmol, 1.10 equiv) was added to the suspension under argon at 23 °C. The reaction chamber was then sealed and the reaction vessel was immediately placed into a bath that had been preheated to 60 °C. The reaction mixture was stirred for 6 h at 65 °C. The product mixture was then cooled over 30 min to 23 °C. The cooled product mixture was diluted with ether (30 mL). The diluted mixture was filtered through a pad of celite (2.5 × 4.0 cm) and the filter cake was rinsed with ether (3 × 10 mL). The filtrates were combined and the combined filtrates were transferred to a separatory funnel that had been charged with pentane (20 mL). The diluted filtrates were washed sequentially with saturated aqueous sodium bicarbonate solution (15 mL), saturated aqueous ammonium chloride solution (15 mL), and saturated aqueous sodium chloride solution (25 mL). The washed organic layer was dried over sodium sulfate. The solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 16% ether–hexanes) to provide the vinyl ether 78 as a yellow oil (490 mg, 94%).

R_f = 0.58 (33% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, benzene-d₆): δ 5.92 (s, 1H, H₁₀), 4.04 (s, 1H, H_11a), 3.67 (s, 1H, H_11b), 3.17 (q, J = 7.0 Hz, 2H, H₁₂), 2.96 (s, 1H, H₁₄), 2.84 (t, J = 15.4 Hz, 1H, H_7a), 2.14 – 2.05 (m, 1H, H_8a), 2.04–1.93 (m, 2H, H_1,2a), 1.69 (d, J = 10.2 Hz, 1H, H_7b), 1.66 – 1.60 (m, 2H, H_6a,3a), 1.56–1.47 (m, 1H, H_3b), 1.41–1.37 (m, 2H, H_6b,8b), 1.36 (s, 3H, H₄), 1.32 (s, 3H, H₉), 1.28 (s, 9H, H₅), 0.98 (s, 3H, H₉), 0.79 (t, J = 7.0 Hz, 3H, H₁₃). ¹³C{¹H} NMR (150 MHz, benzene-d₆): δ 205.4 (C), 172.9 (C), 164. 7 (C), 142.7 (CH), 136.1 (C), 84.7. (CH₂), 80.4 (C), 70.1 (C), 63.1 (CH₂), 55.2 (C), 39.9 (CH2), 33.8 (C), 32.9 (CH₂), 31.8 (CH₂), 31.3 (CH₃), 30.5 (CH₂), 27.8 (3 × CH₃), 25.7 (CH₃), 23.5 (CH₃), 22.5 (CH), 18.9 (CH₂), 14.3 (CH₃), 10.9 (CH₂). IR (ATR-FTIR), cm⁻¹: 2990 (m), 1851 (m), 1776 (m), 1501 (m). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₅H₃₉O₅, 419.2797; found, 419.2777.

Synthesis of the diol 79:

Potassium osmate(VI) dihydrate (15.7 mg, 42.5 μmol, 5.0 mol%) was added to a mixture of the vinyl ether 78 (355 mg, 850 μmol, 1 equiv) and N-methyl-morpholine N-oxide (498 mg, 4.25 mmol, 5.00 equiv) in 66% acetone–water (v/v, 3.0 mL) at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. The product mixture was poured into a stirring mixture of ethyl acetate (15 mL) and saturated aqueous sodium thiosulfate solution (10 mL). The diluted product mixture was stirred for 10 min at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 20% ethyl acetate–hexanes) to provide the diol 79 as a white solid (143 mg, 41%).

R_f = 0.10 (33% ethyl acetate–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.39 (s, 1H, H₁₀), 4.67 (dd, J = 18.6, 4.4 Hz, 1H, H_11a), 4.14 (dd, J = 18.6, 4.5 Hz, 1H, H_11b), 3.15 (t, J = 4.7 Hz, 1H, H₁₂), 2.76 (s, 1H, H₁₃), 2.36 (tt, J = 14.1, 2.8 Hz, 1H, H_7a), 2.23–2.10 (m, 1H, H₁), 2.07 (td, J = 13.7, 4.7 Hz, 1H, H_3a), 2.01–1.89 (m, 2H, H₂), 1.71 (td, J = 13.8, 3.4 Hz, 1H, H_8a), 1.61–1.52 (m, 2H, H_6a,7b), 1.51–1.44 (m, 2H, H_3a,8b),1.40 (s, 9H, H₅), 1.27 (s, 3H, H_9a), 1.23 (dd, J = 8.5, 5.1 Hz, 1H, H_6b), 1.11 (s, 3H, H_9b), 1.04 (s, 3H, H₄). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 207.3 (C), 203.5 (C), 172.7 (C), 151.4 (CH), 137.7 (C), 81.1 (C), 69.7 (C), 64.5 (CH₂), 55.0 (C), 39.8 (C), 33.4 (C), 32.5 (CH₂), 31.8 (CH₂), 30.3 (CH₃), 29.1 (CH₃), 27.8 (3 × CH₃), 25.2 (CH₃), 23.8 (CH), 21.5 (CH₃), 17.7 (CH₂), 11.7 (CH₂). IR (ATR-FTIR), cm⁻¹: 2905 (m), 1745 (m), 1733 (m), 1616 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₃H₃₄NaO₆, 429.2253; found, 429.2205.

Synthesis of the silyl migration product 85:

Step 1: Synthesis of the silyl ether S7:

Chlorotrimethylsilane (102 μL, 812 μmol, 2.21 equiv) was added to a solution of the hydroxyketone 79 (150 mg, 369 μmol, 1 equiv), 4-dimethylaminopyridine (9.0 mg, 73.9 μmol, 20.0 mol%), and imidazole (121 mg, 1.77 mmol, 4.80 equiv) in dichloromethane (3.7 mL) at 23 °C. The reaction mixture was stirred for 22 h at 23 °C. The product mixture was diluted sequentially with 1 N aqueous hydrochloric acid solution (1.0 mL) and ethyl acetate (5.0 mL). The diluted product mixture was stirred for 30 min at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel that had been charged with ethyl acetate (10 mL) and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The silyl ether S7 obtained in this way was used directly in the following step.

Step 2: Synthesis of the methyl ether 83:

Silver(I) oxide (427 mg, 1.85 mmol, 5.01 equiv) was added in one portion to a solution of the unpurified silyl ether S7 obtained in the preceding step (nominally, 369 μmol, 1 equiv) in 50% iodomethane–acetonitrile (v/v, 7.5 mL) at 23 °C. The reaction mixture was stirred vigorously for 18 h at 23 °C. The product mixture was filtered through a plug of celite (2.0 cm × 3.0 cm). The filter cake was rinsed with dichloromethane (3 × 5.0 mL). The filtrates were combined and the combined filtrates were concentrated. The methyl ether 83 obtained in this way was used in the next step without further purification.

Step 3: Synthesis of the silyl migration product 85:

A dispersion of sodium hydride in mineral oil (60% wt., 16.0 mg, 443 μmol, 1.20 equiv) was added in one portion to a solution of the unpurified methyl ether 83 obtained in the preceding step (nominally, 369 μmol, 1 equiv) in 5% tert-butanol–tetrahydrofuran (v/v, 4.9 mL) at 0 °C. The reaction mixture was stirred for 2 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (2.0 mL), water (2.0 mL), and ethyl acetate (15 mL). The resulting biphasic mixture was transferred to a separatory funnel that had been charged with ethyl acetate (10 mL) and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (5.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 25% ether–hexanes) to provide the silyl migration product 85 as a colorless oil (54.5 mg, 30%). 2D NOESY analysis indicated a correspondence between positions 4 and 7 and 7 and 13 (see Supporting Information).

R_f = 0.25 (25% ether–hexanes; PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.83 (s, 1H, H₁₁), 4.92 (s, 1H, H₆), 3.52 (s, 3H, H₁₃), 1.97–1.89 (m, 1H, H_2a), 1.81–1.75 (m, 2H, H_2b,9a), 1.59–1.53 (m, 3H, H_3,10a), 1.45 (s, 9H, H₅), 1.43–1.40 (m, 1H, H_10b), 1.39–1.30 (m, 1H, H₁), 1.25 (s, 3H, H₄), 1.15–1.08 (m, 6H, H_8a,3b,12a), 1.01 (s, 3H, H_12b), 0.67 (dd, J = 9.8, 6.3 Hz, 1H, H_8b), 0.13 (s, 9H, H₇). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 197.3 (C), 176.5 (C), 145.6 (CH), 134.1 (C), 85.3 (CH), 80.1 (C), 76.2 (C), 74.6 (C), 59.2 (CH₃), 35.4 (C), 33.8 (CH₃), 32.1 (C), 28.3 (CH₃), 29.7 (3 × CH₃), 27.5 (CH₃), 27.3 (CH₂), 26.2 (CH₂), 18.9 (CH₂), 18.9 (CH₃), 15.4 (CH), 12.1 (CH₂), 2.6 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2999 (m), 2750 (m), 1645 (m), 1605 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₇H₄₄NaO₆Si, 515.2805; found, 515.2801.

Synthesis of the methyl carbonate 86:

A solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 250 μL, 250 μmol, 1.50 equiv) was added dropwise via syringe pump over 5 min to a solution of the silyl migration product 85 (82.0 mg, 167 μmol, 1 equiv) in tetrahydrofuran (1.7 mL) at −78 °C. The reaction mixture was stirred for 5 min at −78 °C. Methyl chloroformate (128 μL, 1.67 mmol, 10.0 equiv) was then added at −78 °C. The reaction mixture was stirred for 5 h at −78 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (500 μL), water (1.0 mL), and ethyl acetate (10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (2.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 16% ether–hexanes) to provide the methyl carbonate 86 as a colorless oil (149 mg, 58%).

R_f = 0.40 (20% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 6.75 (s, 1H, H₁₁), 4.41 (s, 1H, H₆), 3.61 (s, 3H, H₁₄), 3.56 (s, 3H, H₁₃), 2.06 (td, J = 13.9, 5.8 Hz, 1H, H_3a), 1.95–1.86 (m 1H, H_2a), 1.84–1.80 (m, 1H, H_2b), 1.63–1.53 (m, 3H, H_9,10a), 1.41 (s, 9H, H₅), 1.37 (s, 3H, H₄), 1.22–1.14 (m, 2H, H_1,3b,10b), 1.12 (s, 3H, H_12a), 1.01 (s, 3H, H_12b) 0.84–0.80 (m, 1H, H_8a), 0.67 (t, J = 7.0 Hz, 1H, H_8b), 0.12 (s, 9H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 194.9 (C), 173.9 (C), 153.3 (C), 143.6 (CH), 135.0 (C), 85.7 (C), 80.4 (CH), 79.7 (C), 74.6 (C), 60.58 (CH₃), 54.2 (CH₃), 48.1 (C), 33.9 (C), 33.8 (CH₂), 31.8 (C), 28.1 (CH₃), 27.8 (3 × CH₃), 27.7 (CH₃), 27.5 (CH₂), 25.2 (CH₂), 19.1 (CH₃), 18.6 (CH₂), 14.8 (CH₃), 13.8 (CH₂), 2.7 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 3010 (m), 2650 (m), 1855 (m), 1805 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₉H₄₆NaO₈Si, 573.2860; found, 573.2891.

Synthesis of the methyl vinyl ether 88:

Step 1: Synthesis of methyl carbonate S8:

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 130 μL, 130 μmol, 1.24 equiv) was added to a solution of the methyl carbonate 86 (53.5 mg, 97.2 μmol, 1 equiv) in tetrahydrofuran (1.0 mL) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (500 μL), water (500 μL), and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The methyl carbonate S8 obtained in this way was used in the next step without further purification.

Steps 2: Synthesis of the methyl vinyl ether 88:

1,8-Diazabicyclo[4.5.0]undec-7-ene (259 μL, 1.67 mmol, 17.2 equiv) was added to a solution of the unpurified methyl carbonate S8 obtained in the preceding step (nominally, 97.2 μmol, 1 equiv) dissolved in N,N-dimethylformamide (1.7 mL) at 23 °C. The reaction vessel was placed in a heating block that had been preheated to 100 °C. The reaction mixture was stirred and heated for 2 h at 100 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (500 μL), water (3.0 mL), and ethyl acetate (10.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 33% ether–hexanes) to furnish the methyl vinyl ether 88 as colorless oil (23.0 mg, 71% over two steps).

R_f = 0.20 (33% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.87 (s, 1H, H₁₁), 3.67 (s, 3H, H₂₂), 2.01–1.86 (m, 3H, H₃), 1.77 (td, J = 13.9, 4.8 Hz, 1H, H_9a), 1.71–1.63 (m, 2H, H_1,3a), 1.51–1.43 (m, 2H, H_3b,10), 1.40–1.37 (m, 10H, H_5,9b), 1.29 (s, 3H, H₄), 1.12 (m, 3H, H_12a), 1.00 (s, 3H, H_12b), 0.96 (dd, J = 8.9, 5.9 Hz, 1H, H_8a), 0.86 (t, J = 6.2 Hz, 1H, H_8b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 181.4 (C), 174.7 (C), 148.8 (CH), 148.2 (C), 146.0 (C), 134.8 (C), 80.1 (CH), 70.7 (C), 58.7 (CH₃), 44.7 (C), 32.8 (C), 31.4 (CH₂), 29.6 (CH₃), 29.7 (CH₃), 28.8 (CH₂), 27.8 (3 × CH₃), 26.2 (CH₃), 26.1 (CH₂), 21.4 (CH₃), 17.4 (CH₂), 14.9 (CH), 12.7 (CH₂). IR (ATR-FTIR), cm⁻¹: 2980 (m), 2900 (m), 2350 (w), 1735 (s),1680 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₄H₃₄NaO₅, 425.2304; found, 425.2302.

Synthesis of the iodocyclopropane 89:

Step 1: Synthesis of the carboxylic aid S9:

Trifluoroacetic acid (110 μL, 1.43 mmol, 10.0 equiv) was added to a solution of the cyclopropane 65 (50.0 mg, 143 μmol, 1 equiv) in dichloromethane (800 μL) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The product mixture was concentrated. The residue obtained was re-concentrated twice from 50% ether–pentane (v/v, 4.0 mL). The carboxylic acid S9 was obtained as an off-white solid and was used in the next step without purification.

Step 2: Synthesis of the iodocyclopropane 89:

N,N’-Cyclohexylcarbodiimide (30.0 mg, 145 μmol, 1.01 equiv), 4-dimethylamino pyridine (2.0 mg, 16.3 μmol, 0.10 equiv), and 2-trimethylsilylethanol (68.5 μL, 429 μmol, 3.00 equiv) were added in sequence to a solution of the unpurified carboxylic acid S9 obtained in the preceding step (nominally, 143 μmol, 1 equiv) in dichloromethane (800 μL) at 23 °C. The reaction mixture was stirred for 3 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (200 μL), water (1.0 mL), and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with water (1.0 mL) and saturated aqueous sodium chloride solution (2.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was partitioned into two portions and each portion was purified by flash-column chromatography (eluting with 25% ether–hexanes) to furnish the cyclopropane 89 as a white solid (55.7 mg, 99% over two steps). Vapor diffusion crystallization of 89 from ether with pentanes as antisolvent provided crystals suitable for X-ray crystallographic analysis (see Supporting Information).

R_f = 0.36 (20% ether–hexanes; faintly UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 4.17 (ddt, J = 10.3, 7.1, 3.7 Hz, 2H, H₅), 2.27–2.19 (m, 2H, H1, H_2a), 2.13 (td, J = 13.6, 4.4 Hz, 1H, H_3a), 2.01 (t, J = 6.8 Hz, 1H, H_8a), 1.92 (dq, J = 12.0, 2.9, 2.5 Hz, 1H, H_2b), 1.65 (dt, J = 14.3, 3.9 Hz, 1H, H_3b), 1.56 (dd, J = 8.8, 7.0 Hz, 1H, H_8b), 1.35 (s, 3H, H₄) 1.04–0.93 (m, 2H, H₆), 0.03 (s, 9H, H₇). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 200.2 (C), 172.8 (C), 64.0 (CH₂), 53.1 (C), 30.7 (CH), 28.6 (CH₂), 22.1 (CH₃), 21.5 (CH₂), 18.1 (CH₂), 17.3 (CH₂), 7.5 (C), −1.6 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2953 (w), 1737 (s), 1692 (s). HRMS-CI (m/z): [M + Na]⁺ calcd for C 14H₂₃INaO₃Si, 417.0353; found, 417.0396.

Synthesis of the adduct 90:

A solution of iso-propylmagnesium chloride–lithium chloride complex in tetrahydrofuran (1.25 M, 8.40 mL, 10.5 mmol, 1.05 equiv) was added dropwise to a solution of the iodocyclopropane 89 (4.14 g, 10.5 mmol, 1.1 equiv) in toluene (50 mL) at −78 °C. The reaction mixture was stirred for 30 min at −78 °C. A solution of the iodoenone 66 (2.5 g, 10.0 mmol, 1 equiv) in toluene (5.0 mL) was then added to the reaction mixture over 30 min at −78 °C. The reaction mixture was then removed from the cooling bath and warmed over 1 h to 23 °C. The warmed mixture was stirred for 19 h at 23 °C. The product mixture was diluted with saturated aqueous ammonium chloride solution (15 mL), water (50 mL), and 66% ether–pentane (v/v, 150 mL) at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with water (25 mL) and saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 14% ether–hexanes) to provide the adduct 90 as a pale yellow oil (8:1 mixture of diastereomers, 4.35 g, 80%).

[major diastereomer] R_f = 0.25 (20% ether–hexanes; PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.33 (s, 1H, H₁₁), 4.21–4.11 (m, 2H, H₅), 2.78 (bs, 1H, H₁₃), 2.28–1.98 (m, 4H, H_3a,9a,10), 1.72–1.49 (m, 7H, H_1,2,3b,8,9b), 1.43 (s, 3H, H₄), 1.21 (s, 3H, H_9a), 1.04 (s, 3H, H_9b), 1.01–0.93 (m, 2H, H₆), 0.04 (s, 9H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 205.3 (C), 173.9 (C), 152.2 (CH), 149.9 (C), 106.7 (C), 72.4 (CH₂), 63.5(C), 54.4 (C), 38.0 (C), 32.9 (CH₂), 31.5 (C), 30.4 (CH₃), 29.9 (CH₂), 25.4 (CH₃), 23.5 (CH), 23.1 (CH₃), 17.4 (CH₂), 17.1 (CH₂), 11.5 (CH₂), −1.5 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 3515 (m), 2953 (m), 2930 (m), 1738 (m), 1681 (m), 1446 (w). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₂H₃₅INaO₄Si₁, 541.1247; found, 541.1266.

Synthesis of the methyl ketone 91:

A screw-capped pressure vessel was charged with copper(I) iodide (22.0 mg, 120 μmol, 0.20 equiv), cesium fluoride (973 mg, 6.41 mmol, 1.10 equiv), tetrakis(triphenylphosphine)-palladium(0) (336 mg, 290 μmol, 0.05 equiv), the adduct 90 (3.02 g, 5.82 mmol, 1 equiv), and acetonitrile (30 mL). The reaction vessel was fitted with a rubber septum and the headspace in the vessel was evacuated. The headspace was back-filled with argon. Tributyl(1-ethoxyvinyl) tin (2.20 mL, 6.48 mmol, 1.11 equiv) was added to the suspension under argon at 23 °C. The reaction chamber was then sealed and the reaction vessel was immediately placed into an oil bath that had been preheated to 65 °C. The reaction mixture was stirred and heated for 9 h at 65 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted with ethyl acetate (30 mL). The diluted mixture was filtered through a pad of celite (2.5 × 4.0 cm) and rinsed with ethyl acetate (3 × 15 mL). The filtrates were combined and the combined filtrates were transferred to a separatory funnel. The filtrates were washed sequentially with 30% aqueous ammonium hydroxide solution (w/v, 3 × 10 mL), saturated aqueous sodium bicarbonate solution (25 mL), and saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and concentrated. The residue obtained was dissolved in tetrahydrofuran (30 mL). 1 N aqueous hydrochloric acid solution (7.00 mL, 7.00 mmol, 1.20 equiv) was added at 23 °C. The reaction mixture was stirred for 1.5 h at 23 °C. The product mixture was then diluted sequentially with saturated aqueous sodium bicarbonate (30 mL, CAUTION: gas evolution!), water (15 mL), and ethyl acetate (60 mL) at 23 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 15 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and concentrated. The residue obtained was purified by flash-column chromatography (eluting with 33% ether–hexanes) to provide the methyl ketone 91 as a white solid (1.77 g, 70%).

R_f = 0.20 (33% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 6.49 (d, J = 1.3 Hz, 1H, H₁₁), 4.24–4.03 (m, 2H, H₅), 3.16 (s, 1H, H₁₄), 2.41 (t, J = 14.2 Hz, 1H, H_9a), 2.22 (s, 3H, H₁₃), 2.21–2.17 (m, 1H, H₁), 2.09 (dt, J = 13.5, 9.1 Hz, 1H, H_3a), 2.02–1.96 (m, 2H, H₂), 1.66 (td, J = 13.8, 3.3 Hz, 1H, H_10a), 1.54–1.39 (m, 4H, H_3b,8a,9b,10b), 1.29 (s, 3H, H_12a), 1.21 (dd, J = 8.5, 5.0 Hz, 1H, H_8b), 1.12 (s, 3H, H₁₄), 1.10 (s, 3H, H_12b), 0.95 (ddd, J = 8.8, 7.4, 4.3 Hz, 1H, H₆), 0.02 (s, 9H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 206.5 (C), 204.4 (C), 173.9 (C), 151.8 (CH), 140.3 (C), 69.9 (C), 63.5 (CH₂), 54.7 (C), 39.6 (C), 33.3 (C), 32.8 (CH₂), 32.1 (CH₂), 30.6 (CH₃), 28.7 (CH₂), 26.6 (CH₃), 25.2 (CH₃), 22.8 (CH), 21.4 (CH₃), 17.4 (CH₂), 17.1 (CH₂), 11.3 (CH₂), −1.5 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2953 (w), 1737 (s), 1692 (s). HRMS-CI (m/z): 9530 (w), 1730 (s), 1671 (s), 1370 (s); [M + Na]+ calcd for C₂₄H₃₈NaO₅Si, 457.2386; found, 457.2394.

Synthesis of the hydroxyketone 92:

Step 1: Synthesis of the enoxysilane S10:

Trimethylsilyl trifluoromethanesulfonate (1.86 mL, 10.3 mmol, 8.00 equiv) was added to a solution of triethylamine (2.17 ml, 15.4 mmol, 12.0 equiv) and the methyl ketone 91 (650.0 mg, 1.28 mmol, 1 equiv) in dichloromethane (6.5 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The cold product mixture was then diluted sequentially with saturated aqueous sodium bicarbonate solution (5.0 mL), water (5.0 mL) and dichloromethane (15 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed with saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The enoxysilane residue S10 was found to readily hydrolyze to the corresponding methyl ketone and was consequently used directly in the next step without purification.

Steps 2: Synthesis of the hydroxyketone 92:

3-Chloroperoxybenzoic acid (332.1 mg, 1.92 mmol, 1.5 equiv) was added in one portion to a solution of the unpurified enoxysilane S10 obtained in the preceding step (nominally, 1.28 mmol, 1 equiv) in dichloromethane (6.5 mL) at 0 °C. The reaction mixture was immediately removed from the cooling bath and allowed to warm over 30 min to 23 °C. The reaction mixture was stirred for 2 h at 23 °C. The product mixture was diluted sequentially with 10% aqueous sodium thiosulfate solution (w/v, 6 mL), water (5.0 mL), and ethyl acetate (15 mL) at 23 °C. The resulting biphasic mixture was stirred for 1 h at 23 °C. The mixture was then transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with 10% aqueous potassium carbonate solution (w/v, 2 × 6 mL) and saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 33% ethyl acetate–hexanes) to provide the hydroxyketone 92 as a white solid (468 mg, 70% over two steps).

R_f = 0.20 (33% ethyl acetate–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.45 (s, 1H, H₁₁), 4.49 (dd, J = 17.6, 4.4 Hz, 1H, H_13a), 4.25 (dd, J = 17.6, 4.3 Hz, 1H, H_13b), 4.15 – 4.08 (m, 2H, H₅), 3.41 (t, J = 4.5 Hz, 1H, H₁₅), 2.49 (td, J = 14.3, 3.3 Hz, 1H, H_9a), 2.30 (ddt, J = 8.9, 6.3, 3.3 Hz, 1H, H₁), 2.24–2.03 (m, 2H, H_2a, H_3a), 1.96 (dq, J = 13.4, 3.4 Hz, 1H, H_2b), 1.66 (td, J = 14.0, 3.1 Hz, 1H, H₁₀), 1.60–1.57 (m, 1H, H_8a), 1.53–1.45 (m, 2H, H_3b, H_9b, H_10b), 1.25 (s, 3H, H_12a), 1.16 (dd, J = 8.5, 5.0 Hz, 1H, H_8b), 1.14 (s, 3H, H_12b), 1.08 (s, 3H, H₄), 0.94 (ddd, J = 10.6, 6.8, 2.3 Hz, 2H, H₆), 0.02 (s, 9H, H₁₄), 0.00 (s, 9H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 207.1 (C), 199.0 (C), 174.2 (C), 153.1 (CH), 136.6 (C), 72.0 (C), 64.5 (CH₂), 63.4 (CH₂), 54.5 (C), 40.8 (C), 34.1 (CH₂), 33.5 (C), 32.2 (CH₂), 29.7 (CH₃), 29.5 (CH₂), 25.5 (CH₃), 24.3 (CH), 21.9 (CH₃), 17.8 (CH₂), 17.1 (CH₂), 12.2 (CH₂), 2.2 (3 × CH₃), −1.5 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2954 (m), 2930 (m), 2361 (m), 2339 (m), 1398 (w). HRMS-CI (m/z): [M + Na]⁺ calcd for C₂₇H₄₆NaO₆Si₂, 545.2731; found, 545.2794.

Synthesis of the allyl carbonate 93:

Allyl chloroformate (407 μL, 3.82 mmol, 5.00 equiv) was added dropwise via syringe to a solution of the hydroxyketone 92 (400 mg, 0.765 mmol, 1 equiv) in 5% pyridine–dichloromethane (v/v, 4.0 mL) at 0 °C. The reaction mixture was allowed to warm with its bath over ~1 h to 23 °C. The reaction mixture was stirred for an additional 1 h at 23 °C. The product mixture was diluted sequentially with ethyl acetate (10 mL) and water (10 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with 1 N aqueous hydrogen chloride solution (3 × 4 mL), saturated aqueous sodium bicarbonate solution (10 mL), and saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 33% ether–hexanes) to provide the allyl carbonate 93 as a colorless oil (0.446 g, 96%).

R_f = 0.33 (20% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 6.41 (s, 1H, H₁₁), 6.02–5.87 (m, 1H, H₁₆), 5.46–5.34 (m, 1H, H_17a), 5.33–5.23 (m, 1H, H_17b), 5.14 (d, J = 16.1 Hz, 1H, H_13a), 4.68 (d, J = 16.3 Hz, 1H, H_13b), 4.66–4.64 (m, 2H, H₁₅), 4.18–4.06 (m, 2H, H₅), 2.47 (td, J = 15.4, 14.6, 4.0 Hz, 1H, H_9a), 2.29 (td, J = 7.0, 6.4, 3.2 Hz, 1H, H₁), 2.15 (tt, J = 13.5, 3.6 Hz, 1H, H_2a), 2.06 (td, J = 13.5, 4.1 Hz, 1H, H_3a), 1.90 (dq, J = 13.2, 3.4 Hz, 1H, H_2b), 1.71–1.63 (m, 1H, H_10a), 1.56 (app t, J = 6.0 Hz, 1H, H_8a), 1.54–1.44 (m, 3H, H_3b,9b,10b), 1.25 (s, 3H, H_12a), 1.16–1.12 (m, 7H, H_4,8b,12b), 0.93 (ddd, J = 9.8, 6.6, 1.3 Hz, 2H, H₆), 0.02 (s, 9H, H₁₄), 0.01 (s, 9H, H₇). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 207.2 (C), 192.1 (C), 174.3 (C). 154.6 (C), 151.9 (CH), 137.1 (C), 131.4 (CH), 118.7 (CH₂), 72.0 (C), 68.7 (CH₂), 68.2 (CH₂), 63.4 (CH₂), 54.6 (C), 40.8 (C), 34.0 (CH₂), 33.5 (C), 32.2 (CH₂), 29.8 (CH₃), 29.7 (CH₂), 25.7 (CH₃), 24.5 (CH), 22.1 (CH₃), 17.8 (CH₂), 17.1 (CH₂), 12.4 (CH₂), 2.2 (3 × CH₃), −1.5 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2953 (m), 2901 (w), 1754 (s), 1695 (s), 1624 (w). HRMS-CI (m/z): [M + Na]⁺ calcd for C₃₁H₅₀NaO₈Si₂, 629.2942; found, 629.2994.

Synthesis of the diosphenol 98 and the silyl transfer product 95:

A solution of the carbonate 93 (509 mg, 840 μmol, 1 equiv) in tetrahydrofuran (1.6 mL) was added via syringe pump over 20 min to a solution of sodium tert-butoxide (173 mg, 1.80 mmol, 2.14 equiv) in tetrahydrofuran (4.4 mL) at −78 °C. The reaction mixture was stirred for 2 h at −78 °C. The reaction mixture was then transferred to an ice bath at 0 °C. The reaction mixture was stirred for additional 20 min at 0 °C. The product mixture was diluted with saturated aqueous ammonium chloride solution (4.0 mL), water (3.0 mL) and ethyl acetate (20 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting initially with 14% ether–hexanes, grading to 33% ether–hexanes, one step) to provide separately the diosphenol 98 as a yellow oil (246 mg, 58%) and the silane transfer product 95 (79 mg, 15%).

Separation of the enantiomers of 98 was achieved by preparative chiral stationary phase supercritical fluid chromatography (eluting with 15% methanol–supercritical carbon dioxide) to furnish separately (+)-98 (${[\alpha ]}_D^{20}=+23.4$ (c= 0.4, chloroform)) and (−)-98 (${[\alpha ]}_D^{20}=-28.1$ (c= 0.4, chloroform)).

Diosphenol 98: R_f = 0.37 (50% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.78 (d, J = 1.3 Hz 1H, H₁₁), 6.21 (s, 1H, H₁₃), 4.19 (td, J = 10.8, 6.1 Hz, 1H, H_5a), 4.11 (td, J = 10.8, 6.4 Hz, 1H, H_5b), 3.57 (d, J = 5.6 Hz, 1H, H₁₃), 1.97 (ddd, J = 17.7, 10.7, 3.9 Hz, 1H, H_9a), 1.91–1.85 (m, 1H, H_9b), 1.78 (td, J = 12.6, 5.0 Hz, 1H, H_3b), 1.65 (td, J = 12.6, 5.0 Hz, 2H, H_1,10a), 1.53–1.47 (m, 2H, H₂), 1.43 (td, J = 12.4, 10.0, 3.1 Hz, 2H, H_3a,10b), 1.38 (s, 3H, H₄), 1.14 (s, 3H, H₁₂), 1.00 (s, 3H, H₁₂), 0.98–0.86 (m, 4H, H_6,8), 0.00 (s, 9H, H₇), −0.02 (s, 9H, H₁₄). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 183.2 (C), 177.0 (C), 149.0 (CH), 143.3 (C), 134.4 (C), 133.8 (C), 75.1 (C), 63.2 (CH₂), 44.0 (C), 32.8 (C), 31.6 (CH₂), 29.7 (C), 29.2 (CH₂), 29.1 (CH₃), 27.4 (CH₂), 26.8 (CH₃), 19.8 (CH₃), 17.7 (CH₂), 17.3 (CH₂), 15.7 (CH₂), 13.2 (CH₂), 2.85 (3 × CH₃), −1.35 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2954 (m), 2901 (m), 1734 (s), 1718 (m), 1636 (w). HRMS-CI (m/z): [M + H]⁺ calcd for C₂₈H₄₉O₆Si₂, 505.2806; found, 505.2877.

Silyl transfer product 95: R_f = 0.29 (50% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.89 (s, 1H, H₁₁), 5.59 (s, 1H, H₁₆), 5.29 (d, J = 5.6 Hz, 1H, H₁₅), 4.32–4.06 (m, 2H, H₅), 3.57 (d, J = 5.6 Hz, 1H, H₁₃), 1.98–1.91 (m, 1H, H_2a), 1.83–1.77 (m, 2H, H_2b,3a), 1.63–1.54 (m, 3H, H_9,10a), 1.45–1.41 (m, 1H, H_10b), 1.40–1.36 (m, 4H, H_1,4), 1.18–1.13 (m, 2H, H_3b,8a), 1.11 (s, 3H, H_12a), 1.07–0.97 (m, 5H, H_6,12b), 0.69 (dd, J = 9.4, 6.6 Hz, 1H, H_8b), 0.11 (s, 9H, H₁₄), 0.04 (s, 9H, H₇). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 198.5 (C), 179.6 (C), 147.2 (CH), 133.1 (C), 76.2 (C), 75.9 (CH), 74.4 (C), 63.7 (CH₂), 44.8 (C), 35.0 (C), 33.7 (CH₂), 32.3 (C), 28.3 (CH₃), 27.5 (CH₃), 27.2 (CH₂), 26.2 (CH₂), 18.7 (CH₂), 18.3 (CH₃), 17.0 (CH₂), 15.2 (CH₂), 12.5 (CH₂), 2.6 (3 × CH₃), −1.5 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2903 (m), 2901 (m), 1705 (s), 1632 (m). [M + Na]⁺ calcd for C₂₇H₄₆NaO₆Si₂, 545.2731; found, 545.2744.

Synthesis of the ketal S11:

Triethyl orthoformate (3.00 mL, 27.4 mmol, 5.04 equiv) was added to a solution of ethylene glycol (1.20 mL, 21.5 mmol, 3.95 equiv), para-toluenesulfonic acid monohydrate (52.0 mg, 273 μmol, 0.05 equiv) and the iodoenone 66 (1.36 g, 5.44 mmol, 1 equiv) in ether (7.0 mL) under argon in a screw-capped pressure vessel at 23 °C. The reaction vessel was sealed under argon and the sealed vial was placed in an oil bath that had been preheated to 40 °C. The reaction mixture was stirred and heated for 2 d at 40 °C. The product mixture was cooled over 30 min to ~23 °C. The cooled product mixture was diluted with ethyl acetate (20 mL). The diluted mixture was transferred to a separatory funnel and washed sequentially with saturated aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 10% ether–hexanes) to provide the ketal S11 as a yellow oil (1.39 g, 87%).

¹H NMR spectroscopic data for S11 obtained in this way were in agreement with those reported by Takahashi et al.³⁸

Synthesis of the ketone 99:

A solution of n-butyllithium in hexanes (2.33 M, 3.00 mL, 6.99 mmol, 1.07 equiv) was added dropwise via syringe to a solution of the ketal S11 (2.00 g, 6.53 mmol, 1 equiv) in tetrahydrofuran (30 mL) at −78 °C. The reaction mixture was stirred at −78 °C for 2 min. A solution of the amide 75 (1.82 g, 7.79 mmol, 1.19 equiv) in tetrahydrofuran (8.0 mL) was then added to the reaction mixture slowly at −78 °C. The reaction mixture was stirred for 2 h at −78 °C and warmed gradually with its cooling bath over 21 h to 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (5.0 mL), water (10 mL), and ethyl acetate (75 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted ethyl acetate (2 × 15 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting initially with 10% ether–hexanes initially, grading to 14% ether–hexanes, 1 step) to provide the ketone 99 as a colorless oil (1.45 g, 65%).

R_f = 0.39 (20% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 6.47 (s, 1H, H₅), 4.48 (s, 1H, H₆), 4.17–4.08 (m, 2H, H_4a), 4.03–3.96 (m, 2H, H_4b), 1.81–1.73 (m, 2H, H₃), 1.63–1.57 (m, 2H, H₂), 1.06 (s, 6H, H₁), 0.90 (s, 9H, H₆), 0.07 (s, 6H, H₈). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 198.8 (C), 151.6 (CH), 134.2 (C), 106.2 (C), 68.5 (CH₂), 64.6 (2 × CH₂), 33.6 (CH₂), 32.7 (C), 30.6 (CH₂), 28.0 (2 × CH₃), 25.8 (3 × CH₃), 18.5 (C), −5.4 (2 × CH₃). IR (ATR-FTIR), cm⁻¹: 2956 (m), 2857 (m), 1705 (m), 1627 (w). HRMS-CI (m/z): [M + H]⁺ calcd for C 18H₃₃O₄Si, 341.2143; found, 341.2144.

Synthesis of the diketone 100:

Step 1: Synthesis of the ketone S12:

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 5.30 ml, 5.30 mmol, 1.11 equiv) was added to a solution of the ketone 99 (1.69 g, 4.79 mmol, 1 equiv) in tetrahydrofuran (24 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (15 mL), water (15 mL), and ethyl acetate (50 mL) at 0 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The ketone product S12 obtained in this way was used directly in the following step.

Step 2: Synthesis of the carbonate S13:

Allyl chloroformate (2.60 mL, 24.5 mmol, 5.11 equiv) was added dropwise via syringe to a solution of the unpurified ketone S12 obtained in the preceding step (nominally 4.79 mmol, 1 equiv) in 5% pyridine–dichloromethane (w/v, 15 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and warmed gradually with its cooling bath over 14 h to 23 °C. Additional allyl chloroformate (1.00 mL, 9.41 mmol, 1.96 equiv) was added carefully to the reaction mixture at 23 °C. The reaction mixture was stirred for 3 h at 23 °C. The product mixture was diluted sequentially with ethyl acetate (75 mL) and 1 N aqueous hydrogen chloride solution (30 mL), with stirring. The resulting biphasic mixture was stirred for 30 min at 23 °C and then transferred to a separatory funnel. The layers that formed were separated. The organic layer was washed sequentially with 1 N aqueous hydrogen chloride solution (3 × 20 mL), saturated aqueous sodium bicarbonate solution (20 mL), and saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The carbonate S13 obtained in this way was used without further purification.

Step 3: Synthesis of the diketone 100:

Aqueous hydrogen chloride solution (1 N, 24.0 mL, 24.0 mmol, 5.01 equiv) was added to a solution of the unpurified carbonate S13 obtained in the preceding step (nominally 4.79 mmol, 1 equiv) in tetrahydrofuran (50 mL) at 23 °C. The reaction mixture was stirred for 5 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous sodium bicarbonate solution (50 mL), water (30 mL), and ethyl acetate (150 mL), with stirring. The resulting biphasic mixture was stirred for 30 min at 23 °C. The mixture was then transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was used purified by flash-column chromatography (eluting with 50% ether–hexanes) to furnish the diketone 100 as a colorless oil (422 mg, 64% over three steps).

R_f = 0.47 (50% ether–hexanes; UV, PAA). ¹H NMR (500 MHz, chloroform-d): δ 7.64 (s, 1H, H₄), 6.00–5.89 (m, 1H, H₇), 5.44–5.34 (m, 1H, H_8a), 5.31–5.24 (m, 1H, H_8b), 5.16 (s, 2H, H₅), 4.66 (d, J = 5.3 Hz, 2H, H₆), 2.54 (t, J = 7.0 Hz, 2H, H₃), 1.89 (t, J = 6.8 Hz, 2H, H₂), 1.23 (s, 6H, H₁). ¹³C{¹H} NMR (125 MHz, chloroform-d): δ 196.9 (C), 191.7 (C), 168.5 (CH), 154.7 (C), 133.2 (C), 131.4 (CH), 118.8 (CH₂), 71.9 (CH₂), 68.8 (CH₂), 35.2 (CH₂), 35.1 (CH₂), 34.60 (C), 27.2 (2 × CH₃). IR (ATR-FTIR), cm⁻¹: 2962 (w), 1750 (s), 1704 (s), 1679 (s), 1598 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₁₄H₁₈NaO₅, 289.1046; found, 289.1049.

Synthesis of the enoxysilane 101:

A solution of lithium bis(trimethylsilyl)amide (95%, 74.0 mg, 420 μmol, 1.40 equiv) in tetrahydrofuran (800 μL) at 23 °C was transferred via cannula to a solution of chlorotrimethylsilane (50.0 μL, 394 μmol, 1.31 equiv) and the diketone 100 (80.0 mg, 300 μmol, 1 equiv) in tetrahydrofuran (1.2 mL) at −78 °C. The reaction mixture was stirred for 1 h at −78 °C. The product mixture was diluted sequentially with triethylamine (600 μL) and ethyl acetate (10 mL) at −78 °C. The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution (3.0 mL) and saturated aqueous sodium chloride solution (3.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 20% ether–hexanes) to provide the enoxysilane 101 as a colorless oil (66.0 mg, 65%). While the enoxysilane 101 could be purified by silica-based flash-column chromatography, two-dimensional thin-layer chromatographic analysis indicated partial hydrolysis to the parent diketone 100. Nonetheless, the enoxysilane 101 could be stored for extended periods (>2 weeks) neat at −20 °C without observable decomposition (¹H NMR analysis).

R_f = 0.31 (25% ether–hexanes; UV, PAA). ¹H NMR (600 MHz, benzene-d₆): δ 8.46 (s, 1H, H₅), 6.79 (s, 1H, H₄), 5.59–5.55 (m, 1H, H₇), 5.05 (d, J = 17.8 Hz, 1H, H_8a), 4.89 (d, J = 10.5 Hz, 1H, H_8b), 4.31 (d, J = 5.3 Hz, 2H, H₆), 2.18 (t, J = 5.5 Hz, 2H, H₃), 1.26 (t, J = 6.8 Hz, 2H, H₂), 0.75 (s, 6H, H₁), 0.35 (s, 9H, H₉). ¹³C{¹H} NMR (150 MHz, benzene-d₆): δ 195.4 (C), 154.8 (CH), 152.6 (C), 134.9 (C), 131.6 (CH), 131.1 (C), 126.9 (CH), 118.4 (CH₂), 68.8 (CH₂), 36.0 (CH₂), 35.5 (CH₂), 32.9 (C), 27.7 (2 × CH₃), 0.5 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2962 (m), 1752 (s), 1705 (s), 1681 (s), 1603 (m). HRMS-CI (m/z): [M + Na]⁺ calcd for C₁₇H₂₆NaO₅Si, 361.1447; found, 361.1446.

Synthesis of the diosphenol 98 by the fragment coupling–cyclization cascade:

A solution of n-butyllithium in hexanes (2.20 M, 50.0 μL, 110 μmol, 2.20 equiv) was added to a solution of the iodocyclopropane 89 (43.0 mg, 110 μmol, 2.20 equiv) in tetrahydrofuran (500 μL) at −78 °C. A solution of the enoxysilane 101 (17.0 mg, 50.0 μmol, 1 equiv) in tetrahydrofuran (150 μL) was added then immediately added dropwise down the inside wall of the flask. The reaction mixture was stirred for 2 h at −78 °C. The reaction mixture was then immersed in a cooling bath at 0 °C. The reaction mixture was stirred for 3 h at 0 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (150 μL), water (500 μL), and ethyl acetate (8.0 mL). The resulting biphasic solution was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (2.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by preparatory thin-layered chromatography (eluting with 16% ether–hexanes) to furnish the diosphenol 98 as light-yellow oil (9.0 mg, 36%).

¹H NMR and ¹³C NMR spectroscopic data for 98 obtained in this way agreed with those obtained by the cyclodehydration sequence 93 → 98.

Synthesis of the myrocin G methyl analog 104:

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.168 ml, 0.168 mmol, 2.10 equiv) was added to a solution of the diosphenol 98 (38.0 mg, 0.0753 mmol, 1 equiv) in N,N-dimethylformamide (350 μL) at 23 °C. The reaction mixture was stirred for 6 h at 23 °C. The reaction vessel was placed in an oil bath that had been preheated to 35 °C. The reaction mixture was stirred and heated for 2 h at 35 °C. The reaction vessel was removed from the oil bath and allowed to cool over 5 min to ~23 °C. The cooled product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (3.0 mL), water (3.0 mL), and ethyl acetate (15 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 4.0 mL). The organic layers were combined and the combined organic layers were washed sequentially with water (3 × 3.0 mL) and saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 1% acetic acid–50% acetone–hexanes). The fractions containing product (TLC analysis) were combined and the combined fractions were diluted with 60 mL of toluene and then concentrated to provide the methyl analog product 104 as an off-white solid (15.9 mg, 64%).

Deprotection of the enantiomers of (+)-98 and (−)-98 under the above described conditions furnished (+)-104 (${[\alpha ]}_D^{20}=68.8$ (c= 0.12, methanol)) and (−)-104 (${[\alpha ]}_D^{20}=-82.8$ (c= 0.10, methanol)). Vapor diffusion crystallization of (−)-104 from ethyl acetate with methanol as antisolvent provided crystals suitable for X-ray crystallographic analysis (see Supporting Information).

R_f = 0.20 (1% acetic acid–50% acetone–hexanes; UV, PAA). ¹H NMR (600 MHz, methanol-d₄): δ 6.81 (d, J = 5.6 Hz, 1H, H₁₁), 2.06 (ddd, J = 18.5, 9.5 Hz, 1H, H_2a), 1.91–1.83 (m, 2H, H_2b,3a), 1.79–1.71 (m, 1H, H_10a), 1.68 (dd, J = 10.4, 5.0 Hz, 1H, H₁), 1.57 (td, J = 13.9, 12.8 Hz, 1H, H_9a), 1.51–1.39 (m, 2H, H_10b,9b), 1.37 (s, 3H, H₄), 1.31–1.27 (m, 1H, H_3b), 1.12 (s, 3H, H₁₂), 1.06 (dd, J = 8.9, 5.7 Hz, 1H, H_8a), 1.04 (s, 3H, H₁₂), 0.93 (t, J = 6.2 Hz, 1H, H_8b). ¹³C{¹H} NMR (150 MHz, methanol-d₄): δ 183.7 (C), 180.9 (C), 150.2 (CH), 145.5 (C), 135.3 (C), 135.2 (C), 72.3 (C), 45.1 (C), 45.1 (C), 33.8 (C), 32.3 (CH₂), 30.6 (CH₂), 29.9 (CH₃), 29.4 (C), 27.7 (CH₂), 26.5 (CH₃), 20.1 (CH₃), 18.5 (CH₂), 16.6 (CH), 13.4 (CH₂). IR (ATR-FTIR), cm⁻¹: 2945 (m), 2933 (m), 1712 (s), 1658 (s), 1604 (s). HRMS- CI (m/z): [M + H]⁺ calcd for C₁₉H₂₅O₅, 333.1702; found, 333.1728.

Synthesis of the epoxide 113:

A solution of the methyl analog 104 (5.0 mg, 0.0150 mmol, 1 equiv) in 1,2-dichloroethane (250 μL) was stirred and heated for 3 h at 100 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (1.0 mL), water (2.0 mL), and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 3.0 mL). The organic layers were combined and the combined organic layers were washed sequentially with water (3 × 2.0 mL) and saturated aqueous sodium chloride solution (3.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 33% ethyl acetate–hexanes) to furnish the epoxide 113 as light yellow oil (2.4 mg, 52%).

R_f = 0.24 (33% ethyl acetate–hexanes, PAA). ¹H NMR (600 MHz, chloroform-d): δ 6.91 (s, 1H, H₆), 2.02 – 1.94 (m, 2H, H_9a,3a), 1.83 – 1.70 (m, 3H, H_9b,3b,8a), 1.70 – 1.59 (m, 1H, H₁), 1.53–1.45 (m, 2H, H_{8b, 2a}), 1.40 (s, 3H, H₃), 1.29 (dd, J = 14.1, 3.4 Hz, 1H, H_2b), 1.15 (s, 3H, H₇), 1.01 (s, 3H, H₇), 0.95 (t, J = 5.7 Hz, 1H, H_10a), 0.44 (dd, J = 8.9, 5.6 Hz, 1H, H_10b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 196.5 (C), 188.2 (C), 150.1 (CH), 134.9 (C), 70.4 (C), 67.8 (C), 66.9 (C), 33.1 (C), 31.0 (CH2), 29.5 (CH3), 28.3 (C), 27.3 (CH2), 26.8 (CH2), 25.7 (CH3), 17.9 (CH2), 17.9 (CH3), 16.7 (CH), 12.2 (CH2). IR (ATR-FTIR), cm⁻¹: 2903 (m), 2833 (m), 1802 (s), 1604 (s). HRMS- CI (m/z): [M + Na]⁺ calcd for C₁₈H₂₂NaO₄, 325.1416; found, 325.1414.

Synthesis of the benzyl ether 114:

Para-methoxybenzoyl chloride (3.8 mg, 24.0 μmol, 1.20 equiv) was added to a suspension of the diosphenol 98 (10.0 mg, 20.0 μmol, 1 equiv), tetrabutylammonium iodide (1.8 mg, 4.8 μmol, 0.20 equiv), and cesium carbonate (7.8 mg, 24.0 μmol, 1.20 equiv) in acetonitrile (200 μL) at 23 °C. The reaction mixture was stirred for 15 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (100 μL), water (500 μL) and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (2.0 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 16% ether–hexanes) to provide the benzyl ether 114 as a white solid (9.0 mg, 72%).

R_f = 0.25 (33% ethyl acetate–hexanes; PAA). ¹H NMR (600 MHz, chloroform-d): δ 7.44 (d, J = 8.6 Hz, 2H, H₁₁), 6.87 (d, J = 8.6 Hz, 2H, H₁₂), 6.71 (s, 1H, H₁₆), 5.00 (d, J = 9.9 Hz, 1H, H_10a), (d, J = 9.9 Hz, 1H, H_10a), 4.58 (d, J = 9.9 Hz, 1H, H_10b), 3.86–3.79 (m, 5H, H_13,14), 2.01–1.95 (m, 1H, H_6a), 1.89–1.84 (m, 1H, H_6b), 1.77 (td, J = 13.9, 4.7 Hz, 1H, H_3a), 1.67–1.61 (m, 2H, H_2a), 1.53–1.45 (m, 3H, H_1,3b,7a), 1.40–1.36 (m, 4H, H_3b,4,7b), 1.14 (s, 3H, H_9a), 0.99 (s, 3H, H_9b), 0.89–0.85 (s, 1H, H_5a), 0.80 (t, J = 6.3 Hz, 1H, H_5b), 0.75–0.70 (m, 2H, H₁₅), 0.07 (s, 9H, H₁₇), −0.11 (s, 9H, H₁₆). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 183.3 (C), 176.1 (C), 159.2 (C), 147.2 (C), 146.4 (C), 146.3 (C), 136.2 (C), 130.2 (CH), 129.9 (C), 113.4 (CH), 74.9 (C), 72.2 (CH₂), 62.8 (CH₂), 55.2 (CH₃), 44.1 (C), 32.4 (C), 31.8 (CH₂), 29.6 (CH₂), 29.3 (CH₃), 28.7 (CH₂), 26.5 (CH₃), 26.5 (CH₂), 21.8 (CH₃), 17.4 (CH₂), 16.9 (CH), 15.0, 12.2 (CH₂), 2.7 (3 × CH₃), −1.6 (3 × CH₃). IR (ATR-FTIR), cm⁻¹: 2913 (m), 2763 (m), 1770 (s), 1699 (s). HRMS- CI (m/z): [M + Na]⁺ calcd for C₃₅H₅₂NaO₆Si₂, 647.3200; found, 647.3245.

Synthesis of the allyl ester 118:

Step 1: Synthesis of the diosphenol allyl ester S14:

Allyl alcohol (30.0 μL, 441 μmol, 16.3 equiv) was added to a solution of the analogue 104 (9.0 mg, 27.1 μmol, 1 equiv) and 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (22.0 mg, 136 μmol, 5.00 equiv) in tetrahydrofuran (300 μL) at 23 °C. The reaction mixture was stirred for 5 d at 23 °C. The product mixture was diluted with saturated aqueous ammonium chloride solution (2.0 mL), water (1.0 mL), and ethyl acetate (5.0 mL). The diluted product mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 2.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (1.0 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was eluted over a short plug of silica gel (1.0 cm × 3.0 cm, eluting with 50% ether–hexanes). The filtrate was collected and concentrated. The diosphenol allyl ester S14 obtained in this way was used in the following step without further purification.

Step 2: Synthesis of the allyl ester 118:

Tetrabutylammonium iodide (1.2 mg, 3.40 μmol, 0.20 equiv), cesium carbonate (6.6 mg, 20.0 μmol, 1.20 equiv) and para-methoxybenzoyl chloride (2.70 μL, 20.0 μmol, 1.20 equiv) were added in sequence to a solution of the unpurified allyl ester diosphenol S14 obtained in the preceding step (nominally, 17.0 μmol, 1 equiv) in 33% tetrahydrofuran–acetonitrile (v/v, 300 μL) at 23 °C. The reaction mixture was stirred for 16 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (1.0 mL), water (1.0 mL) and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (2.0 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting iwith 25% ethyl acetate–hexanes initially, grading to 50% ethyl acetate–hexanes, 1 step) to provide the allyl ester 118 as a colorless oil (7.5 mg, 59% over two steps).

R_f = 0.40 (50% ethyl acetate–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 7.33 (d, J = 8.6 Hz, 2H, H₁₁), 6.92 (s, 1H, H₈), 6.86 (d, J = 8.6 Hz, 2H, H₁₂), 5.81–5.74 (m, 1H, H₁₅), 5.16 (d, J = 17.2 Hz, 1H, H_16a), 5.09 (d, J = 10.5 Hz, 1H, H_16b), 4.92 (d, J = 10.6 Hz, 1H, H_10a), 4.82 (d, J = 10.6 Hz, 1H, H_10b), 4.43–4.38 (m, 1H, H_14a), 4.35–4.31 (m, 1H, H_14b), 3.79 (s, 3H, H₁₃), 1.98–1.84 (m, 2H, H₆), 1.80 (td, J = 13.9, 4.7 Hz, 1H, H_3a), 1.72–1.62 (m, 2H, H_2a,6b), 1.51–1.36 (m, 5H, H_1,2b,3b,7), 1.22 (s, 3H, H₄), 1.15 (s, 3H, H_9a), 1.01 (s, 3H, H_9b), 0.95 (dd, J = 8.9, 5.9 Hz, 1H, H_5a), 0.84 (t, J = 6.2 Hz, 1H, H_5b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 181.6 (C), 175.3 (C), 159.5 (C), 149.1 (CH), 146.6 (C), 145.2 (C), 134.9 (C), 132.7 (C), 130.7 (CH), 129.2 (C), 117.3 (CH), 113.6 (CH₂), 71.9 (C), 70.6 (CH₂), 65.4 (CH₂), 55.2 (CH₃), 43.8 (C), 32.9 (C), 31.3 (CH₂), 28.4 (CH₃), 28.0 (CH₂), 26.1 (CH₃), 26.0 (CH₂), 21.0 (CH₃), 17.2 (CH₂), 14.5 (CH₂), 12.7 (CH₂). HRMS-CI (m/z): [M + Na]⁺ calcd for C₃₀H₃₆NaO₆, 515.2410; found 515.2404.

Synthesis of the carboxylic acid 119:

A one-dram vial was sequentially charged with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.9 mg, 4.0 μmol, 0.40 equiv), the allyl ester 118 (4.0 mg, 10.0 μmol, 1 equiv), palladium(II) acetate (1.0 mg, 4.0 μmol, 0.40 equiv), 1,3-dimethylbarbituric acid (7.8 mg, 50.0 μmol, 5.00 equiv), and tetrahydrofuran (200 μL). The reaction vessel was sealed and the sealed vessel was placed on a heating block that had been preheated to 40 °C. The reaction mixture was stirred and heated for 1 h at 40 °C. The reaction mixture was then warmed to 50 °C. The reaction mixture was stirred and heated for 2.5 h at 50 °C. The reaction mixture was then warmed to 70 °C. The reaction mixture was stirred and heated for 2.5 h at 70 °C. The product mixture was cooled over 30 min to 23 °C. The cooled product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (1.0 mL), water (1.0 mL) and ethyl acetate (5.0 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 3.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (2.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 50% ethyl acetate–hexanes) to provide the free acid 119 as a white solid (2.5 mg, 68%).

R_f = 0.10 (50% ethyl acetate–hexanes; UV, PAA). ¹H NMR (600 MHz, chloroform-d): δ 7.33 (d, J = 8.6 Hz, 2H, H₁₁), 6.92 (s, 1H, H₈), 6.85 (d, J = 8.6 Hz, 2H, H₁₂), 4.94–4.90 (m, 2H, H₁₀), 3.78 (s, 3H, H₁₃), 1.99–1.87 (m, 2H, H₆), 1.80 (td, J = 13.9, 4.8 Hz, 1H, H_3a), 1.72–1.64 (m, 2H, H_2a,6b), 1.51–1.37 (m, 5H, H_1,2b,3b,7), 1.21 (s, 3H, H₄), 1.15 (s, 3H, H_9a), 1.01 (s, 3H, H_9b), 0.97 (dd, J = 8.8, 6.0 Hz, 1H, H_5a), 0.86 (t, J = 5.9 Hz, 1H, H_5b). ¹³C{¹H} NMR (150 MHz, chloroform-d): δ 181.7 (C), 178.7 (C), 159.5 (C), 149.2 (CH), 146.7 (C), 144.7 (C), 134.9 (C), 130.7 (C), 129.1 (CH), 113.6 (CH), 72.1 (C), 70.7 (CH₂), 55.2 (CH₃), 43.4 (C), 32.9 (C), 31.9 (CH₂), 31.3 (CH₃), 28.4 (CH₃), 28.0 (CH₂), 26.1 (CH₃), 26.0 (CH₂), 14.5 (CH₂), 20.7 (CH₃), 17.2 (CH₂), 14.5 (CH₂), 12.7 (CH₂). HRMS- CI (m/z): [M + Na]⁺ calcd for C₂₇H₃₂NaO₆, 475.2097; found, 475.2093.

Synthesis of the azido ester (−)-120:

3-Azido-1-propanamine (3.1 μL, 0.0301 mmol, 2.0 equiv) was added to a solution of the analogue (−)-104 (5.0 mg, 15.0 μmol, 1 equiv), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (1.5 mg, 23.0 μmol, 1.50 equiv), and N,N-diisopropylethylamine (13.0 μL, 75.0 μmol, 5.00 equiv) in N,N-dimethylformamide (300 μL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and then was warmed to to 23 °C. The reactiom mixture was stirred for 30 min at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (2.0 mL), water (1.0 mL), and ethyl acetate (5.0 mL). The diluted product mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 2.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (2.0 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 50% ethyl acetate–hexanes) to provide the azido ester (−)-120 as a colorless oil (5.9 mg, 95%).

Azido ester (+)-120 was prepared in an analogous fashion. ¹H NMR and ¹³C{¹H} NMR data for (+)-120 obtained matched that of the (−)-120.

R_f = 0.30 (50% ethyl acetate–hexanes, UV, PAA).¹H NMR (500 MHz, methanol-d₄): δ 7.30 (t, J = 5.5 Hz, 1H, H₁₁), 6.81 (s, 1H, H₈), 3.37 – 3.31 (m, 2H, H₁₂), 3.22 (q, J = 6.4 Hz, 2H, H₁₄), 2.04 (tt, J = 14.2, 4.2 Hz, 1H, H_7a), 1.85 (ddt, J = 13.7, 4.8, 2.5 Hz, 1H, H_7b), 1.79–1.69 (m, 3H, H_13,3a), 1.75–1.68 (m, 1H, H₁), 1.67 (tt, J = 6.0, 3.1 Hz, 1H, H_3b), 1.58 (td, J = 13.6, 12.6, 3.4 Hz, 1H, H_2a), 1.51–1.36 (m, 2H, H_2b,15), 1.39–1.37 (m, 5H, H_4,6), 1.29 (s, 3H, H₉), 1.12–1.07 (m, 1H, H_5a), 1.03–0.983 (m, 4H, H_9,5b). ¹³C{¹H} NMR (150 MHz, methanol-d₄): δ 182.5 (C), 178.9 (C), 178.8 (C), 148.9 (CH), 133.8 (C), 133.0 (C), 70.8 (C), 49.06 (CH₂), 44.7(C), 44.7 (C), 36.9 (CH₂), 32.3(C), 30.9 (CH₂), 30.3 (CH₂), 28.4 (CH₃), 28.1(CH₂), 26.3(CH₂), 25.0 (CH₃), 18.2 (CH₃), 17.2 (CH₂), 15.14 (CH₃), 12.1 (CH₂). IR (ATR-FTIR), cm⁻¹: 3404 (m), 2957 (m), 2926 (m), 1652 (s), 1605 (s). HRMS- CI (m/z): [M + Na]⁺ calcd for C₂₂H₃₀N₄NaO₄, 437.2165; found, 437.2179.

Synthesis of the alkynyl ester (−)-121:

1-Amino-3-butyne (2.50 μL, 30.1 μmol, 2.00 equiv) was added to a solution of the analogue (−)-122 (5.0 mg, 15.0 μmol, 1 equiv), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (1.5 mg, 26.0 μmol, 1.50 equiv), and N,N-diisopropylethylamine (13.0 μL, 75.0 μmol, 5.00 equiv) in N,N-dimethylformamide (300 μL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and was then warmed to 23 °C. The reaction mixture was stirred for 30 min at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (2.0 mL), water (1.0 mL), and ethyl acetate (5.0 mL). The diluted product mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 2.0 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (1.0 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by preparative thin-layered chromatography (eluting with 30% hexanes–ethyl acetate) to provide the alkynyl ester (−)-121 as a yellow oil (5.8 mg, 94%).

Alkynyl ester (+)-121 was prepared in an analogous fashion. ¹H NMR and ¹³C{¹H} NMR data for (+)-121 obtained matched that of the (−)-121.

R_f = 0.35 (50% ethyl acetate–hexanes, UV, PAA).¹H NMR (500 MHz, methanol-d₄): δ 7.32 (t, J = 5.9 Hz, 1H, H₁₁), 6.81 (d, J = 1.5 Hz, 1H, H₈), 3.25–3.23 (m, 2H, H₁₂), 2.81 (s, 1H, H₁₅), 2.37 (ddt, J = 9.0, 6.7, 2.4 Hz, 2H, H₁₃), 2.23 (t, J = 2.7 Hz, 1H, H₁₄), 2.05 (tt, J = 13.9, 4.1 Hz, 1H, H_6a), 1.87–1.82 (m, 1H, H_6b), 1.79–1.70 (m, 2H, H_7a,2a), 1.67 (tt, J = 6.1, 3.1 Hz, 1H, H₁), 1.59 (td, J = 13.6, 12.6, 3.5 Hz, 1H, H_3a), 1.49–1.4 (m, 3H, H_7b,2a,3b), 1.39 (s, 3H, H₄), 1.13–1.08 (m, 4H, H_9,5a), 1.03–0.983 (m, 4H, H_9,5a). ¹³C{¹H} NMR (150 MHz, methanol-d₄): δ 183.9 (C), 180.2 (C), 150.4 (CH), 145.6 (C), 135.2 (C), 134.3 (C), 82.6 (C), 72.3 (C), 70.4 (CH), 46.0 (C), 39.9 (CH₂), 33.7 (C), 32.3 (CH₂), 31.6 (CH₂), 29.8 (CH₃), 29.5 (C), 27.7 (CH₂), 26.4 (CH₃), 19.6 (CH₃), 19.4 (CH₂), 18.6 (CH₂), 16.5 (CH), 13.6 (CH₂). IR (ATR-FTIR), cm⁻¹: 2924 (m), 22805 (m), 1738 (m), 1655 (s), 1605 (s). HRMS- CI (m/z): [M + H]⁺ calcd for C₂₃H₃₀NO₄, 384.2175; found, 384.2176.