Studies Culminating in the Total Synthesis and Determination of the Absolute Configuration of (-)-Saudin

Abstract

A full account of studies that culminated in the total synthesis of both antipodes and the assignment of its absolute configuration of Saudin, a hypoglycemic natural product. Two approaches are described, the first proceeding though bicyclic lactone intermediates and related second monocyclic esters. The former was obtained via asymmetric Diels-Alder cycloaddition and the latter by an asymmetric annulation protocol. Both approaches employ a Lewis acid promoted Claisen rearrangement, with the successful approach taking advantage of bidentate chelation to control the facial selectivity of the key Claisen rearrangement

1 Introduction

Saudin (1) was isolated by Mossa et al. in 1985 from Clutya Richardiana, and its structure and relative stereochemistry was elucidated by X-ray crystallography.¹ However, the absolute stereochemistry remained unknown.¹ Saudin (1) was presumed to be a member of the Labdane class of diterpenes.^1,2 Based upon biogenetic considerations, the configuration shown in Figure 1 was tentatively assumed, although Labdane terpenes of both enantiomeric series have been found in nature.³ In Saudin (1), the Labdane skeleton has been highly modified by late stage biogenetic oxidation and rearrangement.^1,2 The skeleton is highly oxygenated and presents five contiguous stereogenic centers, three of which (C₁₃, C₉, and C₁₆) are contiguous quaternary centers, two of which are all carbon and 1,3 disposed on a 6-membered ring. The natural product was found to exhibit interesting biological activity. Treatment of laboratory animals that had been rendered chemically hyperglycemic resulted in lowering blood sugar levels although the mechanism of action remains unknown. Based on these studies, Saudin (1) was thought to have possible therapeutic value or serve as a lead structure in the development of treatments for diabetes.^1,2

Figure 1.

Several groups have investigated the preparation of this interesting and challenging natural product. Initial model studies followed by a concise total synthesis of the racemate were reported by Winkler in 1998-1999.^3,4 In 2002, we reported the first enantioselective total synthesis of both antipodes, firmly establishing the absolute stereochemistry of natural (-)-saudin, as the the structure depicted in Figure 1.⁵ Subsequent to that publication, several additional synthetic approaches have appeared including the studies of Labadie^6-8 and Stoltz.^9,10 Herein we wish to report the details of our studies that established a strategy and culminated in the total synthesis of natural (-)-saudin (1) and its antipode.

2 Results and Discussion

2.1 Retrosynthetic Analysis

Our retrosynthetic analysis, arbitrarily directed to what is now recognized as the antipode of natural (-)-Saudin (1), began with the sequential disconnection of the internal ketal unit and the furan revealing lactol 2. Functional group modifications of 2 revealed γ,δ-enone 3, the product of a putative Claisen rearrangement of bicyclic allyl vinyl ether 4. Enol ether 4 was expected to be available by O-alkylation of the enolate dianion derived from enantiomerically pure epoxylactone 5 and an enantiomerically pure allyl electrophile (halide, sulfonate, or triflate) as shown in Scheme 1. The Claisen rearrangement was identified as the key transformation in this sequence owing to the expected large driving force for rearrangement permitting the stereoselective creation of the required 1,3-disposed quaternary carbon centers at C₁₃ and C₁₆ of Saudin (1).

Scheme 1.

2.2 Assembly of Epoxy Ketone 5

A route to epoxy ketone 5 employing an asymmetric Diels-Alder reaction was first investigated.^11,12 A chiral auxiliary was employed to afford control over the absolute configuration of the quaternary center eventually residing at C₁₃. Three dienes of general structure 9, bearing both silicon and ester protecting groups (TBS acetate 9a, bis acetate 9b, and bis-OTIPS 9c) were prepared from common intermediate 8, itself derived from commercially available alkyne 7 by mercury catalyzed hydration (Scheme 2). Formation of bis acetate 9b was incomplete affording a small amount (10%) of 10.

Scheme 2.

Attempted cycloaddition of dienophile 11 with 9a-9c in the presence of a variety of Lewis acids and also under thermal conditions failed repeatedly, probably resulting from steric hindrance owing to the presence of the vinylic methyl group which disrupted orbital overlap (Figure 2). To overcome these problems a different camphor-derived dienophile 12 was designed. Chelated 12 should exist in the conformation depicted in Figure 3, avoiding steric interactions between the vinylic methyl substituent and the angular proton. The β face of the complex appears congested by the gem-dimethyl bridge and by interaction with the bridgehead proton. Thus attack of the diene should occur primarily from the bottom α face of the dienophile complex. This assumption was confirmed by nOe experiments in the presence of TiCl₄.

Figure 2.

Figure 3.

The reaction was carried out in the presence of TiCl₄. Bis triisopropyl ether derivative 9c gave best results and adducts 13 and 14 (Scheme 3) were isolated in 92% yield (ratio 13/14 = 88:12). The temperature proved to be critical since no reaction took place at -40°C while hydrolysis of the diene occurred at -10 to 0°C.

Scheme 3.

The stereochemistry of major isomer 13 was elucidated by X-ray analysis after cleavage of the silyl enol ether to afford crystalline ketone 15 (Scheme 4).¹¹ The observed stereochemistry is in agreement with the expected transition state wherein the diene approaches the imide in an endo orientation from the less hindered α face (Figure 3).

Scheme 4.

Both silyl groups of adduct 13 could be cleaved with HF affording directly keto lactone 16 (Scheme 4). Similar deprotection of the minor adduct 14 afforded lactone 12,spectroscopically identical to 16 but exhibiting equal and opposite optical rotation, confirming that 16 and 17 were enantiomeric and that both 16 and 17 were endo adducts derived from approach of the diene from the α and β face of the dienophile-LA complex, respectively (Figure 3).

Major isomer 13 was transformed into the desired enone 19 using a two-step sequence. Although attempted Saegusa reaction on the silyl enol ether failed, treatment with two equivalents of phenyl selenyl bromide afforded the unsaturated derivative 18 (a second molecule of PhSeBr probably reacts with the corresponding α-seleno derivative with elimination of diphenyldiselenide, making the oxidation step unnecessary). Subsequent deprotection of the primary silyl ether with TBAF, with concomitant lactonization, gave 19 in optically pure form (Scheme 5).^12b,13

Scheme 5.

Alternatively, lactone 19 could be obtained by Michael addition of chiral vinylogous carbamates 20 derived from methyl tetronic acid to ethyl vinyl ketone affording Michael adduct 21 after hydrolytic workup. The enantiomeric excesses were modest (60% ee as illustrated for α-methyl naphthyl amine) but employing S-proline in the cyclization of diketone 21 to hydroxy ketones 22 allowed us to enhance the ee to an acceptable 89% (Scheme 6).^12b Several chiral imines and Lewis acids were examined in an attempt to improve the selectivity in the Michael addition but all efforts were unsuccessful.

Scheme 6.

With enone 19 in hand we explored epoxidation of 19 to epoxy ketone 5 (Scheme 7). The lability of the γ-lactone ring under basic conditions precluded the use of the usual methods for nucleophilic epoxidation of 19. Alternatively, reduction of 19 with NaBH₄ afforded a mixture of allylic alcohols 23 in 75% yield. Epoxidation of the mixture 23 with mCPBA afforded the expected intermediate epoxy alcohols which were directly reoxidized with PDC to afford epoxy ketone 5 as a single diastereomer in 92% overall yield.^12,13 Apparently, the concave surface of 23 is sufficiently congested that approach of mCPBA is precluded in spite of the well-known directing effects of allylic hydroxyl groups on the stereochemistry of epoxidation.¹⁴

Scheme 7.

2.3 Preparation of the Enantiomerically Pure Sidechain Triflate 6 (X = OTf)

The alkenyl sidechain was prepared using the conventional sequence depicted in Scheme 8, starting from commercially available Roche ester 24.¹⁵ Protection of the primary alcohol as TBDPS ether followed by reduction of the carboxylic ester with DIBAl-H, gave alcohol 25. Oxidation of 25 to the unstable aldehyde and direct reaction with isopropyl diethylphosphonoacetate afforded unsaturated ester 26 in 69% yield from 24. Reduction of 26 with DIBAl-H afforded the allylic alcohol 27 in 90% overall yield. The corresponding triflate 6 (X=OTf) was prepared in situ by deprotonation with n-BuLi and reaction with triflic anhydride in an estimated >90% yield by NMR.^12,13 The allylic triflate proved to be too reactive to be isolated, thus it was generated and used in situ at low temperature.

Scheme 8.

To assure that the optical purity was maintained during preparation of 6 (X=OTf), the Mosher ester of 27 was prepared, but the resolution of the signals for the two isomers was insufficient for NMR analysis. Thus, ester 26 was degraded (ozonolysis followed by reduction) to alcohol 25 and esterification gave a single isomer of the corresponding Mosher ester (similar derivatization of racemic 25 gave a mixture of two isomers that showed different spectroscopic properties).¹²

An analogous, simpler alkenyl sidechain, lacking the secondary methyl group, was also prepared starting with 28 using the sequence depicted in Scheme 9. The alkynol 28, after protection of the primary alcohol, was alkylated with paraformaldehyde to afford 29 in 85% overall yield. The triple bond was then reduced with LAH and EtOH in THF to give exclusively the E allylic alcohol 30 in 96% yield that was similarly activated in situ as the triflate 31 (>90%).¹²

Scheme 9.

2.4 Reductive Coupling of Epoxy Ketone 5 and Triflate 6

Preliminary studies of the reduction and concomitant trapping of epoxy ketone 5 with electrophiles established that the usual one electron reductants such as Li/NH₃,¹⁶ Li napthalenide¹⁷ and Li di-tert-butylbiphenylide¹⁸ were too basic and/or nucleophilic, resulting in either degradation of 5 or reduction/elimination back to the enone 19.

Examination of the literature revealed a little used one electron reductant, Li or Na trimesitylborylide (${\mathrm{Li}}^{+}\text{or}{\mathrm{Na}}^{+}\mathrm{TMB}\stackrel{-}{\cdot }$), originally developed by Darling, based on early work of Brown and others, as an alternative to Li/NH₃ for reduction of enones and related unsaturated compounds.^19,20 Although Darling envisioned trimesitylborane (TMB) more as a medium supporting such reductions, we found that ${\mathrm{Na}}^{+}\mathrm{TMB}\stackrel{-}{\cdot }$ can be generated stoichiometrically by stirring of Na metal (5 equiv) with TMB (2.0 equiv) in anh THF at rt for 8h producing an intensely blue colored solution. Addition of epoxy ketone 5 (1 equiv) to this solution at -78°C and stirring at -78°C for 24 h followed by quenching with aq NH₄Cl afforded the hydroxy ketone 22. Alternatively, quenching with TBDMSCl (5 equiv) afforded hydroxy silyl enol ether 32 upon workup in 71% yield (Scheme 10).^12b

Scheme 10.

O-allylation of hydroxyenol dianion could also be effected by quenching with allyl bromide/HMPA then pH=7 phosphate buffer affording the corresponding O-allyl hydroxyenol ether in 64% yield. Analogously, in situ mono trapping of the presumed enolate alkoxide dianion with triflate 6 in the presence of HMPA proceeded to afford allyl hydroxyenol ether 33 in 52% yield (unoptimized), as depicted in Scheme 10.^12b

2.5 Introduction of the C₁₆ Quaternary Carbon Via Claisen Rearrangement

Regrettably, no reliable conditions were found to effect the desired thermal or Lewis acid promoted Claisen rearrangement of 33. The principal products resulted from degradation back to enone 19 and allylic alcohol 27. This outcome likely results from autocatalytic decomposition of 33 initiated by elimination of a catalytic amount of water from 33 and hydrolysis of the remaining 33 to 22 and alcohol 27 and subsequent elimination of water from 22 to afford 19 and regenerate the catalytic amount of water.

As a result, the sequence was modified by use of an allyl dienol ether lacking the labile C₉ hydroxyl group. The linearly conjugated enolate was smoothly generated by slow addition of NaHMDS in THF to enone 19 in THF at -78°C, as demonstrated by trapping with TBSOTf affording 34, exclusively, in good yield (Scheme 11).^12a,13

Scheme 11.

Having confirmed the exclusive formation of the linearly conjugated dienolate from 19, treatment of that linear Na enolate derived from 19 with HMPA followed by allylic triflate 6 at -78°C afforded the O-allylated dienol ether 35 in 77% yield. We were pleased to see that the desired thermal Claisen rearrangement of 35 now proceeded smoothly upon heating 35 for 2 h at 125°C providing a 3:1 mixture of diastereomeric Claisen rearrangement products products 36 and 37 in 76% yield (Scheme 12). Since the ketones 36 and 37 are substrates for a Cope rearrangement, prolonged heating or higher temperatures had to be avoided to prevent the undesired tandem Claisen-Cope rearrangement of 35.²¹ Indeed, when Claisen rearrangement was conducted at temperatures exceeding 125°C variable amounts of the product(s) of tandem Claisen-Cope rearrangement were isolated. At temperatures exceeding 150°C, the product(s) of tandem Claisen-Cope rearrangement became predominant or exclusive as the temperature was increased. After chromatographic separation of 36 and 37, the structure and relative stereochemistry of 36 was confirmed by single crystal X-ray analysis of crystalline ketol 38, obtained by desilylation of 36 with HF in acetonitrile in 77% yield (Scheme 13). Unfortunately, the Claisen rearrangement of 35 had afforded as the major diastereomer 36, the undesired diastereomer for conversion to Saudin (1). We reasoned that steric interactions involving the methyl substituent of the allylic chain could be held responsible for this preference (Figure 4).^12a,13

Scheme 12.

Scheme 13.

Figure 4.

Assuming that introduction of the methyl group by alkylation at C₄ would not be problematic at a later stage, we reasoned that this steric interaction should be minimized when 31 was utilized as electrophile. The O-alkylation of 19 was done under the same conditions specified above. Subsequent thermal rearrangement of 39, unfortunately, did not markedly improve the observed diastereoselectivity for the desired diastereomer 40 affording a 1:1 mixture of 40 and 41 (Scheme 14). Again, high temperatures had to be avoided to prevent formation of the products of the competing tandem Claisen-Cope process.²¹ Adducts 40 and 41 were deprotected as before with HF in acetonitrile andreadily separated chromatographically to provide free hydroxy ketone 42 and an uncharacterized desmethyl analog of 42 whose configurations were assigned by analogy to 36 and 37. The direction in the change in the observed facial selectivity (from 1:3 to 1:1) was in agreement with our reasoning, but the magnitude was less than anticipated, revealing the primary controller of the stereoselectivity was the C₁₃ quaternary center with a lesser contribution from the sidechain stereocenter.¹³

Scheme 14.

We then investigated Lewis acid promoted rearrangements of both substrates (35 and 39) with the hope that coordination with a Lewis acid would favorably alter the stereochemical outcome of the Claisen rearrangements of these substrates. The results of these studies are summarized in Table 1.¹³

Table 1.

Entry	Substrate	Lewis acid (eq)	Time (h)	Temp (°C)	36/41:37/40 (yield)a
1	39	none	2	105	1:1 (81%)
2	39	i-Bu3Al (2)	18	25	2:1 (33%)b
3	39	Me3Al (2)	0.9	25	3:1 (90%)
4	39	MAD* (4)	2	25	2.5:1 (88%)
5	39	Et2AlCl·Ph3P (2)	1.5	-50	4:1 (57%)c
6	39	Et2AlCl·Ph3P (2)	0.5	25	5:1 (94%)
7	35	none	2	125	3:1 (76%)
8	35	Me3Al (2)	0.2	45	24:1 (60%)d
9	35	MAD* (4)	2	25	24:1 (43%)d
10	35	Et2AlCl.Ph3P (2)	0.5	25	24:1 (39%)d

^aTotal yield of isolated chomatographically pure materials.

^bYield adjusted for conversion of 67%.

^cYield adjusted for conversion of 30%.

^dYields unoptimized for these cases.

The optimal Lewis acid for rearrangement of 35 and 39 was found to be the 1:1 complex of Et₂AlCl and Ph₃P, which provided high yields and clean products at room temperature. The stereoselectivity in the rearrangement of 39 appears to increase both with increasing steric bulk of the ligands on the Lewis acid, and with increasing electron deficiency of the Lewis acidic center. Under optimal conditions, using Et₂AlCl•PPh₃, the selectivity rises to 1:5 (40/41). In the case of 35 the synergism of the two asymmetric centers combine to overwhelm the magnitude of the effects owing to the nature of the Lewis acid affording a remarkable enhancement from 3:1 to 24:1 (36/37) in all cases. However, in all cases the effect of the Lewis acid promotion is to increase the selectivity toward the undesired diastereomers rather than reverse the diastereoselectivity as hoped. A plausible mechanistic rationale is shown in Figure 5. As illustrated, these results do not invalidate the previous mechanistic hypotheses, however they do indicate that kinetic and irreversible complexation of the Lewis acid is unlikely. These results further demonstrate that the interaction of the allylic side chain with the C₁₃ methyl group dominates the diastereoselectivity in the rearrangements of 35 and 39, regardless of the presence or absence of the secondary methyl group or the use of Lewis acid promoters.¹³

Figure 5.

2.6 Elaboration of Claisen Adduct 40 Toward Saudin (1)

Based on the idea that increasing the diastereoselectivity of the Claisen rerrangement could be deferred until evidence was accrued that the synthetic approach was likely to afford Saudin (1), further elaboration of ketone 40 was then undertaken. Ketone 42 was obtained in 43% yield by deprotection of the 40/41 mixture with HF in CH₃CN. After Jones oxidation of 42 to the corresponding acid and iodolactonization, iodo lactone 43 was rearranged in two steps to afford tricyclic intermediate 44 in 35% overall yield. Epoxidation with mCPBA unexpectedly gave the undesired β isomer 45, whose structure was corroborated by X-ray crystallographic analysis (Scheme 15).^12a

Scheme 15.

A less direct route was then devised to install the oxygen function at C₉, a fully substituted position, with the correct stereochemistry in a substrate suitable for the incorporation of the furan ring. (Scheme 16) The sequence begins with conversion of enol lactone 44 to Weinreb amide 46 in 95% yield.²² Oxidation of 46 with Dess-Martin periodinane²³ provided aldehyde 47 in 90% yield. Exposure of aldehyde 47 to N-bromoacetamide in aq THF affords a mixture of bromo hemiacetals 48 (6:1 α:β) in 61% yield via addition of the electrophilic bromine from the β face as expected based upon the observed stereochemistry of epoxidation of 44.²⁴ Exposure of 48 to AgBF₄ in the presence of Et₃N then provided the desired α-epoxy aldehyde 49 by silver induced ionization and concomitant epoxide formation with inversion at C₉. Addition of 3-lithio furan²⁵ to aldehyde 49 affords, again after oxidation of the intermediate mixture of alcohols with Dess-Martin periodinane,²³ the desired 3-furyl ketone 50 in 48% overall yield (unoptimized) from 49.

Scheme 16.

Unfortunately efforts to further elaborate furyl ketone 50 by initial reductive deoxygenation of the α-keto ether linkage were unsuccessful. Although cleavage of the desired C-O bond could be successfully accomplished, the resulting ketone enolate underwent undesired intramolecular aldol processes more rapidly than quenching of the enolate by protonation occurred leading to indane derivatives. Attempts to effect reductive scission of the C-O bond under acidic conditions were also unsuccessful.

2.7 A Revised Synthetic Approach Utilizing Precursors Lacking the γ-Lactone

In order to better control the diastereoselectivity of the key Claisen rearrangement, a modified retrosynthetic analysis was then devised that retained a Claisen rearrangement as the key step but employed substrates with more conformational freedom by removal of the fused γ-lactone ring. It was hoped that the increased conformational freedom would permit alteration of the reactive conformation of the enol ring by use of a Lewis acid capable of chelation between the enol oxygen and the carbonyl of the ester group at C₁₃.

To implement this approach, we required the monocyclic enone 51 rather than 19. To assess the viability of the new route, early intermediates were initially prepared in racemic form (Scheme 17).²⁶ Michael addition of ethyl 2-methylacetoacetate to ethyl vinyl ketone, catalyzed by NaOMe, afforded diketone 52, that was converted without purification to the desired 53 along with its regiosiomer 54 (53/54 ~4:1) by treatment with pyrrolidinium acetate. Since keto esters 53 and 54 were inseparable, basic hydrolysis and neutralization during which the undesired beta-keto acid derived from 54 underwent decarboxylation, afforded only the pure acid 55 which was then re-esterified under basic conditions to afford enone 51 in 50% overall yield from ethyl 2-methylacetoacetate (Scheme 17).^26c

Scheme 17.

Highly enantiomerically enriched (-)-51 was obtained using chiral vinylogous carbamate (+)-56 as starting material. Michael addition of (+)-56 to ethyl vinyl ketone in toluene at 0°C in the presence of ZnCl₂ afforded diketone (-)-51 in 61% yield. Diketone (-)-51 (>90% ee) was purified prior to cyclization. As a result, treatment of (-)-51 with pyrrolidinium acetate under reflux afforded principally (-)-53 (95% ee) with improved regioselectivity (53/54 ~18:1) in 87% yield.^26c Although the saponificationreesterification steps were unnecessary, the methyl ester (-)-51 was prepared for ease in NMR analysis (Scheme 18).^26c

Scheme 18.

The absolute configuration of (-)-51 was deduced from the mechanism of the Michael addition, since the sense of the chiral induction is well known. Furthermore, it was confirmed by transformation of lactone (+)-19 (Scheme 5) into ethyl ester (-)-53. Also by derivatization of carboxylic acid R-(+)-52 with R-(+)-α-methyl benzyl amine, which afforded a crystalline amide whose structure was corroborated by single crystal X-ray analysis.

By analogy to the enolization of enone 19, the thermodynamic enolate derived from (-)-51 was O-alkylated with allylic triflate 6 to afford Claisen precursor 57 (40% isolated yield) along with C-alkylated by-products. When 31 was used as electrophile the corresponding enol ether 58 was obtained in 65% yield (Scheme 19).

Scheme 19.

2.8 Claisen Rearrangement of Monocyclic Substrates

We envisioned that use of a bidentate Lewis acid to promote the Claisen rearrangement of 57 and 58 would allow coordination of both oxygens (those of the vinyl ether and the ester) forcing the six-membered ring into a boat conformation, favoring the axial approach from the bottom face as required.²⁸

Initial experiments were conducted using both substrates (57 and 58) to identify the best conditions for the [3,3]-sigmatropic rearrangement. TiCl₄ was employed as the Lewis acid. The results in terms of reactivity and diastereoselectivity were in agreement with those obtained previously (see Table 1).¹³ Methylated analog 57 afforded mixtures of isomers along with several by-products including large amounts of enone (+)-51. This decomposition pathway could not be avoided by introducing additives such as bases, Ph₃X (X=P, As, Sb), R₃Al, etc. or by use of less reactive Ti(IV) Lewis acids.

In contrast, the desmethyl analogue, allyl enol ether 58, upon treatment with 2.5 eq of TiCl₄, was cleanly converted into Claisen adducts 59 and 60 with very good facial selectivity (59/60 ~10:1 at -78°C) along with (+)-51 (Scheme 20). We then attempted optimization of this transformation. We noted that addition of Me₃Al as proton scavenger minimized decomposition to the enone without interfering with the stereochemical outcome as did increasing the reaction temperature, but, in the latter case, the diastereoselectivity exhibited in formation of 59 and 60 was adversely affected (59/60 ~5:1 at -30°C). The influence of the solvent was also examined resulting in the finding that less polar solvents (such as hexanes or toluene) retarded the Claisen reaction, promoting the formation of 51 and 22, while the use of THF inhibited both processes, leading to recovery of starting ether 58. To our delight. our studies led to optimized conditions involving the use of 2.5 eq of TiCl₄ and 2.5 eq of Me₃Al in CH₂Cl₂ at -65°C that permitted rearrangement of (-)-58 cleanly affording a 75% isolated yield of the desired isomer (-)-59, having the correct relative stereochemistry between the two quaternary centers C₁₃ and C₁₆, and a sidechain sufficiently functionalized for further elaboration.

Scheme 20.

The observed facial selectivity can be rationalized by invoking bidentate coordination of Ti (IV) to the oxygen atoms of the starting material, stabilizing a boat conformation in which the reaction leading to the major isomer takes place axially, as preferred stereoelectronically, and from the less hindered α face (TS I vs TS II, Figure 5).²⁸

2.9 Elaboration of Ketone (-)-59

Deprotection of silyl ether (-)-59 with 2.5 equiv of TBAF in the presence of 1 equiv of HOAc spontaneously led to a mixture of hemiketals (~1:1) that were directly converted to single methyl ketal (+)-61 in 99% yield upon treatment with excess CH₃OH/CH(OCH₃)₃ (1:1 v/v) in the presence of pTsOH hydrate (Scheme 21). Hydroboration of the less hindered, monosubstituted olefin with 9-BBN selectively afforded the expected primary alcohol (+)-62 in 87% yield. Alcohol (+)-62 was then oxidized in two steps to the corresponding carboxylic acid by sequential Swern and Pinnick oxidations (Scheme 21).^29,30 Direct oxidation of (+)-62 using PDC³¹ also proceeded efficiently (75% yield) but purification of the resulting product more problematic. Thus, the two-step sequence was employed since it proved to be higher yielding and does not require purification as well as avoiding the use of heavy metals. Direct epoxidation of the aforementioned carboxylic acid with mCPBA followed by acid treatment afforded lactone (+)-63 as a single diastereomer in 73% overall yield from (+)-62. Steric congestion around the ketone carbonyl in (+)-63 resulted in complete chemoselectivity during the addition of 3-lithiofuran²⁵ affording a δ-lactol 64. No products of addition to the other potentially electrophilic centers were observed. The crude lactol 64 was directly oxidized to acid (+)-65 in 70 % overall yield over 3 steps, via the corresponding primary alcohol tautomer of 64, using successive Swern²⁹ and Pinnick³⁰ oxidations thus avoiding undesired internal ketalization (Scheme 21).

Scheme 21.

Opening of the epoxide group of (+)-65 was promoted by BF₃.Et₂O. The intermediate carbenium ion underwent immediate intramolecular trapping by the free carboxylic acid, and the newly formed primary alcohol underwent concomitant lactonization affording as the final result of this reaction cascade bis lactone 66 that was isolated in an unoptimized 38% yield (Scheme 22).³² In order to introduce the methyl group at the α C₄ position of the δ-lactone (Saudin numbering), both ketone functions had to be protected. This protection operation, which required high temperatures and prolonged reaction times, was accomplished by treatment of 66 with TsOH in CH₃OH/CH₃O)₃CH affording ketal enol ether 67 in a mediocre 45% yield. The reaction is likely sluggish as a result of steric hindrance at the neopentyl carbonyl carbon of the cyclohexanone ring. Alkylation of 67 by treatment with LDA at -78°C and quenching with CH₃I under kinetic conditions afforded an isomeric mixture of alkylation products 68 (68β/68α ~6:1) in 71% yield (92% bsrm) resulting from mainly axial methylation in which the major isomer was confirmed to possess the desired stereochemistry at C₄ (Saudin numbering) by nOe measurements. Small amounts of saudin (1) were obtained from 68β via sequential deprotection with concomitant lactone hydrolysis and cyclization. We later observed that Saudin formed directly during the deprotection step as shown in Scheme 22. However, after attempts at optimization, the yield could be improved only modestly to 25%. Epimerization at the newly formed 2° methyl chiral center at C₄ during deprotection is most likely responsible since lactone 69α was obtained as a major by-product when starting with near homogenous 68β.

Scheme 22.

2.10 Final Elaboration of (-)-Saudin (1) from Lactone (+)-63

During the final conversion to Saudin, in order to avoid the evident thermodynamic preference for the wrong epimer at the eventual C₄ position (Saudin numbering) in lactones 68 and 69, the order of ring formation had to be modified. To accomplish this change, the lactol 64, in equilibrium with the ring opened primary alcohol 70, was protected as the acetate (-)-71 in >90% yield (81% overall directly from (+)-63 by in situ trapping with Ac₂O), to avoid its participation in the opening of the epoxide. Subsequent treatment of (-)-71 with BF₃-Et₂O as before afforded the internal ketal (+)-72 in 90% yield.³² The acetate group present in (+)-72 was saponified in near quantitative yield and the corresponding alcohol 73 was oxidized by successive Swern²⁸ and Pinnick²⁹ oxidations to carboxylic acid 74 in 96% yield over two steps. Direct transformation of 73 into 74 was successful in 65% yield using catalytic TEMPO-NaOCl and NaClO₂ as cooxidant,³³ although the yield was lower owing to competing oxidation of the furan ring.

Formation of the key δ-lactone ring was then effected by conversion of acid 74 into the crystalline enol lactone (-)-75 upon treatment of 74 with TFAA in the presence of NaOAc, in 67% overall yield from 73 over three steps. The structure and stereochemistry of (-)-75 was confirmed by single crystal X-ray analysis (Scheme 25). The creation of the enol lactone ring overcame the difficulties encountered during protection of the hindered carbonyl group. Attempted alkylation of (-)-75 with LDA followed by addition of excess MeI, under a variety of reaction conditions, led to mixtures of 76α and 76β and 74 along with unreacted (-)-75, even when excess of LDA was used. Reasoning that diisopropyl amine could enhance the proton exchange between the starting lactone enolate and 76α/β leading to epimerization and polyalkylation,³⁴ we decided to use the more hindered and stronger base Li-TMP, which is known to reduce the formation of aggregates.³⁵ Our hypothesis was confirmed when complete conversion of 75 was observed and a kinetically controlled mixture of 76 (76α/76β ~1:1.5) was isolated in 75% yield accompanied by only traces of 77. In contrast to 68α/β and 69α/β, the desired isomer was now thermodynamically preferred. Thus, after chromatographic separation of 76α and 76β, the undesired isomer 76β was epimerized to 76α by treatment with a substoichiometric amount of LDA in 88 % yield providing 76α in 70% total yield.³⁶

Scheme 25.

With the successful assembly of 76α, having the correct stereochemistry and oxidation state at all positions, it only remained to assemble the bis ketal structure of Saudin. Our first attempts involved mild selective hydrolysis of the enol lactone and treatment of the intermediate methyl ester with TMSOTf. Under these conditions, saudin was isolated in 50% overall yield from 76α. However, a by-product, containing two methoxy groups, was also obtained when the reaction was quenched before completion. Thus, in order to avoid the presence of methanol in the reaction mixture, harsher hydrolysis conditions were employed to afford the intermediate bis carboxylic acid 78. Direct treatment of the crude diacid 78 with TMSOTf afforded saudin (1) in 70% isolated yield.

The spectroscopic properties of the synthetic saudin were identical to those reported for the natural product, and as was the melting point (mp 204-206°C).^1,2 However, the optical rotation, had opposite sign ([α]_D+14; c 0.460, CHCl₃) to that of natural (-)-Saudin (1) confirming that the synthetic material was (+)-Saudin (1). The absolute configuration of natural (-)-saudin (1) can then be assigned as shown in Figure 1 and Scheme 25.

We then applied the above described sequence, beginning with R-(+)-α-methyl benzyl amine as chiral auxiliary, to achieve the first enantioselective synthesis of (-)-Saudin (1). The synthetic (-)-Saudin (1) had identical spectroscopic properties and melting point (204-206°C) to both natural (-)-Saudin (1), and synthetic (+) Saudin (1) except for optical rotation ([α]_D-14; c 0.460, CHCl₃) which was equal and opposite in sign.^1,2

3 Conclusion

The studies described herein resulted in the successful total synthesis of both natural (-)-Saudin (1) and its antipode (+)-Saudin (79), thus enabling the assignment of the absolute configuration of natural (-)-Saudin as that depicted in Figure 1 and Scheme 25. During the course of this work, novel asymmetric Diels-Alder methodology developed in our laboratory was employed. Basic studies of the effect of Lewis acid promoters on the stereochemistry of the Claisen rearrangement were undertaken resulting in the novel application of TiCl₄, a bidentate chelating promoter, to control the facial selectivity in the key Claisen rearrangement step that established the relative stereochemistry of the 1,3-disposed quaternary centers present in Saudin.

4 Experimental Section

4.1 General Methods

All non-aqueous reactions were conducted in flame or oven-dried glassware under an argon atmosphere and were stirred magnetically unless otherwise noted. Air-sensitive reagents and solutions were transferred via syringe (unless noted otherwise) and were introduced to the apparatus through rubber septa. Solids were introduced under a positive pressure of argon. Temperatures, other than room temperature, refer to bath temperatures unless otherwise indicated. All distillations were performed under an argon atmosphere or at reduced pressure attained by either a water aspirator (15-30 mm Hg) or an oil pump (< 1 mm Hg).

The phrase “concentrated in vacuo” refers to removal of solvents by means of a Büchi rotary-evaporator attached to a water aspirator (15-30 mm Hg) followed by pumping to constant weight (< 1 mm Hg).

Liquid chromatography was performed using forced flow (flash chromatography) of the indicated solvent system on EM Reagents silica gel 60 (230-400) mesh. Acid sensitive compounds were chromatographed on EM Reagents silica gel 60 (230-400) mesh which had been deactivated by stirring with 5% triethylamine / hexanes then equilibrated in the flash column with the indicated solvent system. The Waters Prep 500 system equipped with a refractive index detector was employed for preparative scale separations.

Analytical thin layer chromatography (TLC) was performed using EM silica gel 60 F-254 pre-coated glass plates (0.25 mm). Visualization was effected by either short-wave UV illumination, or by dipping into a solution of ceric ammonium molybdate (0.2 g Ce(SO₄)₂, 4.8 g (NH₄)₆Mo₇O₂₄, 10 mL conc. H₂SO₄, 90 mL H₂O) or p-anisaldehyde (0.5 mL p-anisaldehyde, 0.5 mL conc. H₂SO₄, 9 mL 95% EtOH, 2 drops HOAc) followed by heating on a hot plate.

Reagent grade solvents were used without purification for all extractions and work-up procedures. Deionized water was used for all aqueous reactions and for the preparation of all aqueous solutions. Reaction solvents and reagents were dried and purified according to published literature procedures by distillation under argon or vacuum from the appropriate drying agent: Distilled from sodium-benzophenone ketyl: tetrahydrofuran, diethyl ether. Distilled from calcium hydride: hexamethylphosphoramide, methylene chloride, toluene, triethylamine. Distilled from phosphorous pentoxide: trifluoromethanesulfonic anhydride. Recrystallized from ethanol: triphenylphosphine, 2,6-di-t-butyl-4-methylphenol (BHT). Other reagents and solvents were used as received.

Proton and carbon nuclear magnetic resonance (NMR) spectra were obtained on a General Electric/Nicolet QE-300 (300 MHz), Bruker Avance 400 MHz or Bruker Avance 500 Mhz spectrometers. In some cases, quaternary carbons could not be observed in the ¹³C spectra or peaks were insufficiently resolved resulting in fewer carbon resonances than expected. Chemical shifts are reported in ppm (δ) downfield from tetramethylsilane and are internally referenced to the deuterated solvent. 1H NMR data are reported as follows: chemical shift (multiplicity, coupling constant (Hz), number of hydrogens). Multiplicities are denoted accordingly: s (singlet), b (broad signal), d (doublet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), tt (triplet of triplets), dq (doublet of quartets), t (triplet), q (quartet), p (pentuplet), m (multiplet). Infrared spectra (IR) were acquired on a Shimadzu FT-IR taken neat and are reported in wavenumbers (cm-1) with polystyrene as a standard. Low resolution mass spectra (LRMS) were obtained using either a VG-7035 spectrometer, a Hewlet-Packard 5970 Mass selective detector coupled to a HP 5890 gas chromatograph, or a Shimadzu LCMS-2010 mass spectrometer. High resolution mass spectra were obtained at the Department of Chemistry at the State University of New York at Buffalo or the nation mass spectrometry facility at the Department of Chemistry University of California, Riverside. Ionization techniques consisted of electron impact (EI) and chemical ionization (CI). Optical rotation values were measured on a Perkin-Elmer-241 polarimeter. Samples were inserted into a cell with a path length of 1 dm. Melting points were determined using a Thomas-Hoover capillary melting point apparatus and are uncorrected. Elemental analyses were obtained from Galbraith Laboratories. X-ray structural determinations were performed using an Enraf-Nonius CAD4 diffractometer with calculations performed with the Molecular Structures Corporation TEXAN crystallographic software package.

4.2 Synthesis and characterization

4.2.1 4-Keto-3-methyl-2-penten-1-ol (8)³⁷

To a suspension of mercuric oxide (red) (2.5g, 12mmol) in water (250mL) was added sulfuric acid (~2mL). The mixture was heated to 60°C and then commercially available trans-3-methyl-2-pentene-4-yn-1-ol (7) (22g, 0.23mol) was added dropwise over 20 minutes. The resulting mixture was stirred at 60°C for 1h, then cooled to ambient temperature. The mixture was vacuum filtered through a pad of celite which was washed thoroughly with methylene chloride, and then the organic layer was separated from the biphasic filtrate. The aqueous layer was then extracted with methylene chloride (2 × 150mL). The organic layers were combined, washed with brine (200mL), dried over sodium sulfate and concentrated in vacuo. Chromatography (1:1 ether/hexane) gave 16.5g (63 %) of keto alcohol 8 as an amber liquid having 1H NMR (300 MHz, CDCl₃): δ 6.70 (t, 1H, J = 4.7Hz), 4.43 (d, 2H, J = 4.7Hz), 2.56 (s (br), 1H), 2.33 (s, 3H), 1.74 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 200.3, 142.8, 136.7, 59.7, 25.3, 11.2; IR (film): 3600-3100 (br), 2928, 1662, 1432 cm^-1; EIMS:114 (M⁺)

4.2.2 3-Methyl-2,5-triisopropylsiloxy-1,3-butadiene (9c)³⁸

To a solution of hydroxyketone 8 (19g, 0.17mol) in CH₂Cl₂ (1L) was added triethylamine (98mL, 0.71mol) followed by triisopropylsilyl triflate (108g, 0.35mol). The reaction mixture was stirred at 25°C for 16h, poured into saturated aqueous NaHCO₃ (500mL), and extracted with CH₂Cl₂ (2 × 500mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Chromatography (100% hexanes) on silica gel deactivated with 5% triethylamine / hexanes provided 68g (94%) of diene 16 as an oil: ¹H NMR (300 MHz, CDCl₃): δ 6.24 (t, 1H, J = 5.8Hz), 4.44 (s, 1H), 4.42 (s, 2H), 4.29 (s, 1H), 1.76 (s, 3H), 1.34-1.22 (m, 3H), 1.16-1.09 (m, 39H); ¹³C NMR (75 MHz, CDCl₃): δ 157.2, 130.5, 128.6, 90.5, 61.0, 18.1, 17.9, 13.5, 12.8, 12.0; IR (film): 2943, 2892, 2866, 1593, 1463 cm-1; EIMS: 269 (M⁺ - TIPS), 253 (M⁺ - OTIPS).

4.2.3 (1R,4S)-2-((3'R,4'S)-2'4'-dimethyl-1'-triisopropylsiloxy-3'-triisopropylsiloxy-methyl-cyclohexene-4'-carbonyl)-4,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (13)

To a solution of imide 12 (29g, 0.13mol) and diene 9c (68g, 0.16mol) in methylene chloride (800mL) cooled to -25°C was added titanium tetrachloride (1.0M in methylene chloride, 180mL, 0.13mol) dropwise (~17h) via syringe pump. Upon completion of the addition, the mixture was stirred an additional 1h at -20°C. Pyridine (25mL) was added, the mixture warmed to 25°C, and filtered through a silica gel pad (200g) with elution by ether, and then the filtrate was concentrated in vacuo. The crude mixture was first purified by flash chromatography (1% ether / hexanes) on silica gel deactivated with 5% triethylamine / hexanes and then further purified by MPLC (1% ether / hexane) to provide 67g (80%) of major cycloadduct 13 as a colorless oil and 9.3g (11%) of minor cycloadduct 14 as an oil. Major cycloadduct 13 had: [α]_D²⁵ -112 (c = 1.9, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 4.23 (s, 1H), 3.69 (dd, J = 10, 4.1 Hz, 1H), 3.46 (dd, J = 10, 5.1 Hz, 1H), 3.31 (s (br), 1H), 2.51 (m, 1H), 2.13 (m, 2H), 2.03 (m, 1H), 1.82-1.43 (m, 4H), 1.71 (s, 3H), 1.29 (s, 3H), 1.07 (m, 21H), 1.03 (s, 3H), 0.99 (m, 21H), 0.93 (s, 3H) 0.89 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ 178.0, 176.7, 143.0, 109.3, 66.5, 56.8, 47.2, 44.8, 30.8, 29.1, 27.0, 26.5, 18.8, 18.5, 18.1, 18.0, 17.8, 16.8, 13.2, 11.9, 9.9; IR (film): 2943, 2866, 1746, 1681, 1463 cm^-1; FAB MS: 648 (M⁺). Anal. Calc. for C₃₇H₆₉NO₄Si₂: C, 68.56; H, 10.73. Found: C, 68.18; H, 10.96.

Minor cycloadduct 14 had: [α]_D²⁵ +3.4 (c = 16, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 4.46 (s, 1H), 3.83 (dd, J = 10.2, 3.5 Hz, 1H), 3.62 (dd, J = 10.2, 4.2 Hz, 1H), 3.29 (s (br), 1H), 2.50 (m, 1H), 2.11 (m, 2H), 1.98 (m, 2H), 1.83-1.50 (m, 3H), 1.71 (s, 3H), 1.17 (s, 3H), 1.07 (m, 21H), 1.03 (s, 3H), 0.99 (m, 21H), 0.91 (s, 3H), 0.88 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ= 177.0, 176.8, 143.2, 108.3, 65.7, 64.6, 56.6, 46.4, 46.3, 45.7, 30.1, 29.4, 27.0, 26.9, 18.9, 18.1, 17.9, 16.3, 13.3, 11.9, 9.8; IR (film): 2943, 2892, 2866, 2724, 1746, 1678, 1463 cm^-1; EIMS: 495 (M⁺ - chiral auxiliary), 460 (M⁺ - CH₂OTIPS).

4.2.4 (1S,5R,6R) and (1S,5S,6R)-2,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]nonane (16)

To a solution of enol ether 13 (0.29g, 0.45mmol) in acetonitrile (5mL) at room temperature was added hydrofluoric acid (48%, ~0.5mL). The reaction mixture was capped and stirred for 3h. At this time, 10% sodium bicarbonate (10mL), and extracted with methylene chloride (3 × 10mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography (1:1 ether / hexanes) afforded 70 mg (85%) of keto lactones (5R)-16 and (5S)-16 in ~1:1 mixture of epimers as a colorless oil having [α]_D²⁵ +90 (c = 5.2, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 4.50 (dd, J = 10, 5.5 Hz, 1H), 4.36 (t, J = 9.3Hz, 1H), 4.15 (dd, J = 10, 1.9 Hz, 1H), 3.74 (t, J = 9.3 Hz, 1H), 2.81 (m, 2H), 2.60 - 1.80 (m, 10H), 1.49 (s, 3H), 1.33 (s, 3H), 1.11 (d, J = 6.5 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 210.2, 210.0, 180.6, 180.0, 69.4, 67.1, 50.2, 47.6, 43.9, 42.0, 41.4, 41.2, 36.3, 36.1, 31.1, 30.9, 22.7, 22.6, 12.6, 10.8; IR (film): 2971, 2934, 2875, 1770, 1716, 1486, 1455 cm^-1; EIMS: 182 (M⁺).

4.2.5 (1R,4S)-2-((2'R,3'R,4'S)-2'4'-Dimethyl-3'-triisopropylsiloxymethyl cyclohexanone-4'-carbonyl)-4,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (15)

To a solution of enol ether 13 (0.24g, 0.37mmol) in tetrahydrofuran (4mL) at room temperature was added tetrabutylammonium fluoride (1M in THF, 0.37mL, 0.37mmol).

The reaction mixture was stirred for 15min before being quenched with sat NH₄Cl solution and extracted with CH₂Cl₂ (3 × 10mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography (4:1 hexanes / ether) afforded 0.14g (80%) of ketone 15 as a crystalline solid. Ketone 15 could be further purified by recrystallization from heptane and had: mp 79-81°C; [α]_D²⁵ -45 (c = 5.8, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 4.35 (s, 1H), 3.81 (dd, J = 11, 4 Hz, 1H), 3.41 (d J = 11 Hz, 1H,), 3.21 (s (br), 1H), 2.94 (td, J = 13, 8 Hz, 1H), 2.66 (m, 1H), 2.38 (m, 2H), 2.00 (m, 1H), 1.81 m, 2H), 1.58 (m, 5H), 1.20 - 1.00 (m, 27H), 0.95 (s, 3H), 0.92 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 209.6, 176.2, 175.7, 65.8, 61.3, 56.2, 47.4, 46.3, 44.8, 39.9, 36.2, 31.5, 30.0, 26.0, 18.2, 17.7, 17.3, 17.1, 11.4, 11.2, 9.1; IR (film): 2963, 2943, 2867, 1743, 1716, 1674, 1458 cm^-1; EIMS: 448 (M+ - iPr)

4.2.6 (1R,5R,6S) and (1R,5S,6S)-2,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]nonane (17)

To a solution of enol ether 14 (97 mg, 0.15 mmol) in acetonitrile (3mL) at rt was added hydrofluoric acid (48%, ~0.3mL). The reaction mixture was capped and stirred for 24h. At this time the mixture was quenched with 10% sodium bicarbonate (15mL), and extracted with methylene chloride (3 × 8mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography (1:1 ether / hexanes) afforded 22 mg (81%) of ~1:1 mixture of keto lactone epimers (5S)-17 and (5R)-17 as a colorless oil that had: [α]_D²⁵ -96.9 (c = 1.96, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 4.50 (dd, , J = 10, 5.5 Hz 1H), 4.36 (t , J = 9.3Hz, 1H), 4.15 (dd, J = 10, 1.9 Hz, 1H), 3.74 (t, 9.3 Hz, 1H), 2.81 (m, 2H), 2.60 - 1.80 (m, 10H), 1.49 (s, 3H), 1.33 (s, 3H), 1.11 (d, J = 6.5 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 210.3, 210.0, 180.6, 179.9, 69.4, 67.2, 50.3, 47.7, 43.9, 41.2, 36.4, 36.1, 31.1, 31.0, 22.7, 22.6, 12.6, 10.9; IR (film): 2971, 2934, 2875, 1769, 1715, 1486, 1453 cm^-1; EIMS: 182 (M⁺).

4.2.7 (1R,4S)-2-((3'R,4'S)-2'4'-dimethyl-3'-triisopropylsiloxymethylcyclohex-2'-ene-1'-one-4'-carbonyl)-4,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (18)

To a solution of enol ether 13 (63 g, 0.097 mol) in methylene chloride (60 mL) and methanol (600 mL) was added NaHCO₃ (82 g, 0.97 mol), followed by phenylselenenyl bromide (48 g, 0.20 mol). The resulting mixture was stirred at 25°C for 3h. The reaction mixture was concentrated to remove methanol, diluted with methylene chloride (700 mL) and poured into H₂O (900mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2 × 500 mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. Chromatography (elution by 8:1 hexane/ether) provided 32g (68%) of enone 18 as an oil having: [α]_D²⁵ -66.0 (c = 15.7, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ= 4.16 (dd, J = 10, 8.7 Hz, 1H), 4.06 ( d, J = 1 Hz, 1H), 3.92 (dd, J = 10, 2.8 Hz, 1H), 3.16 (m, 2H), 2.42 (m, 2H), 2.04 (m, 1H), 1.96 (s, 3H), 1.91-1.52 (m, 3H), 1.36 (s, 3H), 1.07 (s, 24H), 0.96 (s, 3H), 0.93 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ= 203.7, 177.4, 176.2, 67.6, 64.8, 57.0, 56.2, 47.2, 47.0, 33.6, 31.1, 29.7, 29.1, 26.4, 21.5, 18.7, 18.1, 17.9, 17.7, 11.8, 9.7; IR (film) 2943, 2866, 1739, 1717, 1676, 1462 cm^-1; EIMS: 489 (M⁺), 446 (M⁺ - iPr). This material was used as obtained in the next transformation.

4.2.8 (1S)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-5-ene (19)

To a solution of enone 18 (32 g, 66 mmol) in tetrahydrofuran (300 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 69 mL, 69 mmol) The resulting solution was stirred at 25°C for 16 h. The reaction mixture was poured into 1M hydrochloric acid (500 mL) and extracted with methylene chloride (3 × 400 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Chromatography (elution by 2:1 hexane / ethyl acetate) provided 11 g (92%) of enone lactone 19 as a solid. Enone 19 was further purified by recrystallization from toluene affording 19 as a white solid with mp 97-98°C and having [α]_D²⁵ +186 (c = 1.61, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 5.01 (s, 2H), 2.60 (m, 2H), 2.24 (ddd, J = 13.2, 5, 2.2 Hz, 1H), 2.1 (m, 1H), 1.76 (s, 3H), 1.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 196.5, 178.3, 154.5, 128.8, 67.2, 41.3, 32.4, 29.5, 21.2,10.7; IR (film): 2975, 2936, 1780, 1712, 1672, 1450 cm^-1; EIMS: 180 (M⁺); Anal. Calc. for C₁₀H₁₂O₃: C, 66.65; H, 6.71. Found: C, 66.93; H, 6.94.

4.2.9 (R)-(-)-4-Hydroxy-2-methyl-3-[1'(1’-naphthyl)ethylamino]-butenoic acid γ-lactone (20)

A 250-mL pressure bottle, charged with R-(+)-α-naphthyl ethyl amine (27.1g, 0.158 mol), α-methyltetronic acid (18.0 g, 0.158 mol) and toluene (50 mL), was sealed and heated to 150°C. After 40 hr, the reaction mixture was cooled, unsealed and diluted with CH₂Cl₂ (2 L) and filtered through Buchner funnel to remove some undissolved solid. The filtrate was washed with saturated aqueous NaHCO₃ (2 × 200 mL), H₂O (100 mL) and brine (100 mL), dried over Na₂SO₄, and concentrated in vacuo to afford the crude yellowish solid. The crude solid was suspended in Et₂O (100 mL), filtered through a Buchner funnel, rinsed with Et₂O (3 × 50 mL), and concentrated in vacuo to afford 34.0 g (90%) of product 20 as a white crystalline solid. An analytical sample had: ${\left[\alpha \right]}_{\mathrm{D}}^{22}=-196$ (c = 1.18, 1:1 CH₃OH: CHCl₃); ¹H NMR (1:1 CD₃OD:CDCl₃): δ 7.78 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.36-7.20 (m, 4H), 5.10 (q, J = 7.8 Hz, 1H), 4.42 (d, J = 15.3 Hz, 1H), 4.29 (s, 1H), 3.96 (d, J = 15.3 Hz, 1H), 1.45 (d, J = 7.8 Hz, 6H); ¹³C NMR( 1:1 CD₃OD:CDCl₃): δ 178.2, 163.5, 139.0, 133.8, 129.6, 128.8, 127.8, 126.2, 125.5, 125.3, 121.7, 121.6, 88.6, 65.9, 49.8, 22.5, 6.0; IR (CHCl₃): 3374, 3017, 2944, 2833, 1635, 1448 cm^-1; EIMS: 267 (M+); HRMS calcd for C₁₇H₁₇NO₂: m/z 267.1259. Found: 267.1237. Crude 20 was used without further purification.

4.2.10 (4RS,8S)-Dimethyl-1,5-dioxo-(9S)-hydroxy-2-oxabicyclo[4.3.0]nonane (22)

To a solution of ZnCl₂ (4.24 g, 31.1 mmol) in THF (50 mL) was added TMSCl (20.0 mL, 156 mmol) and lactone 20 (8.30 g, 31.1 mmol). The mixture was cooled to -78°C, and a solution of ethyl vinyl ketone (5.59 g, 66.5 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78°C for 20 h, then the reaction was quenched by addition of 2 N HCl (5 mL) at -78°C. The reaction mixture was allowed to warm to rt and continue to stir for 2 h. The aqueous layer was extracted with Et₂O (3 × 10 mL), and the combined organic layer was washed with saturated aqueous NaHCO₃ (10 mL), H₂O (10 mL) and brine (10 mL), dried over Na₂SO₄, concentrated in vacuo, and purified by chromatography by silica gel column (elution by 9:1 then 4:1 hexanes:EtOAc) to afford 4.52 g (73%, 60% ee) of pure Michael adduct 21 having ¹H NMR: δ 4.69 (d, J = 16.9 Hz, 1H), 4.58 (d, J = 16.9 Hz, 1H), 2.48 (t, J = 7.2 Hz, 2H), 2.35 (q, J = 7.3 Hz, 2H), 1.95 (q, J = 7.2 Hz, 2H), 1.25 (s, 3H), 0.95 (t, J = 7.3 Hz, 3H); IR (CHCl₃): 2978, 2938, 1803, 1757, 1713, 1454 cm^-1; EIMS: 198 (M⁺). Diketo lactone 21 (3.30 g, 16.7 mmol) and (S)-proline (0.115 g, 1.00 mmol) were stirred in DMF (20 mL) at room temperature for 48 h. The brown-colored reaction mixture was filtered and the filtrate was diluted with H₂O (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layer was washed with H₂O (2 × 20 mL) and brine (10 mL), dried over Na₂SO₄, concentrated in vacuo, and chromatographed by silica gel column (4:1 then 1:1 hexanes:EtOAc) to afford 1.50 g (55%, 89% ee) of β-hydroxy keto lactone 22 and 1.50 g (45%) of unreacted starting diketo lactone 21. Lactone 22 had ¹H NMR: δ 4.10 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 10.5 Hz, 1H), 2.70 (q, J = 6.7 Hz, 1H), 2.59-2.52 (m, 1H), 2.44-2.32 (m, 1H), 2.18 (s, 1H), 2.05-2.02 (m, 1H), 1.88-1.82 (m, 1H), 1.49 (s, 3H), 1.16 (d, J = 6.7 Hz, 3H); ¹³C NMR: δ 207.8, 179.9, 82.7, 73.4, 49.4, 47.1, 35.9, 30.9, 13.8, 7.0; IR (CHCl₃): 3413, 2977, 2941, 1779, 1720 cm^-1; EIMS: 198 (M+); HRMS calcd for C₁₀H₁₄O₄: m/z 198.0892. Found: 198.0889.

4.2.11 (4S,8S)-Dimethyl-1,5-dioxo-2-oxabicyclo[4.3.0]non-4(9)-ene (19).^26b

A solution of β-hydroxy keto lactone 22 (0.430 g, 2.17 mmol) in toluene (50 mL) was refluxed for 2 h with azeotropic water removal via a Dean-Stark trap. Et₂O (100 mL) was added to the cooled solution which was washed with saturated, aqueous NaHCO₃ (2 × 20 mL), and brine (10 mL), dried over Na₂SO₄, and concentrated in vacuo to afford 0.391 g (100%, 89% ee) of enone lactone 19 as a white solid after recrystallization from toluene having mp 95-96°C and ${\left[\alpha \right]}_{\mathrm{D}}^{22}=+181$ (c = 6.1, CHCl₃) or 94% ee; 1H NMR: δ 5.00 (s, 2H), 2.70-2.53 (m, 2H), 2.27-2.05 (m, 2H), 1.75 (s, 3H), 1.52 (s, 3H); IR (CHCl₃): 2975, 2936, 1780, 1712, 1672, 1450 cm^-1; EIMS: 180 (M⁺).

4.2.12 (4R,8S)-Dimethyl-4(9)-epoxy-1,5-oxo-2-oxabicyclo[4.3.0]nonane (5)

To a cold (0°C) solution of enone lactone 19 (1.50 g, 8.33 mmol) in EtOH (100 mL) was added NaBH₄ (0.315 g, 8.33 mmol) with stirring. The resulting suspension was allowed to warm to room temperature and stirred for 20 hr when TLC showed almost complete consumption of starting material 19. The reaction was quenched by addition of 1N HCl (15 mL) dropwise at 0°C. The reaction mixture was concentrated to remove EtOH as much as possible and the residue was diluted with CH₂Cl₂ (50mL), washed with saturated aqueous NaHCO₃ (10 mL), H₂O (10 mL) and brine (10 mL), dried over Na₂SO₄, concentrated in vacuo, and purified by silica gel chromatography (elution by 4:1 then 1:1 hexanes : EtOAc) to afford 1.13 g (75%) of allylic alcohols 23 having ¹H NMR: δ 4.77 (d, J = 13.4 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 4.07 (t, J = 7.5 Hz, 1H), 2.75 (s, br, 1H), 2.17-2.10 (m, 1H), 1.85-1.80(m, 1H), 1.80-1.52 (m, 2H), 1.66 (s, 3H), 1.31 (s, 3H); ¹³C NMR: δ 180.6, 132.4, 131.5, 70.3, 68.1, 41.0, 29.0, 28.8, 21.9, 14.7; IR (CHCl₃): 3468, 2974, 1771 cm^-1; EIMS: 182 (M⁺). To a cold (0°C) suspension of allylic alcohols 23 (0.700 g, 3.85 mmol) and finely ground NaH₂PO₄ (1.60 g, 11.0 mmol) in CH₂Cl₂ (20 mL) was added solid 80% MCPBA (1.24 g, 5.77 mmol) portionwise in small portions. The mixture was stirred at 0°C for 10 hr before quenched with saturated aqueous Na₂S₂O₅ (5 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layer was washed with saturated aqueous NaHCO₃ (2 × 5 mL), H₂O (5 mL) and brine (10 mL), dried over Na₂SO₄, concentrated in vacuo to afford 0.543 g (71%) of epoxy alcohols pure enough to be used for subsequent reaction without further purification. For spectroscopic analysis, a sample of the epoxy alcohols was purified by silica gel chromatography (elution by 4:1 then 1:1 hexanes:EtOAc) to afford the epoxy alcohols having ¹H NMR: δ 4.26 (s, 2H), 3.80 (dd, J = 10.0 Hz, 5.6 Hz, 1H), 1.84-1.67 (m, 2H), 1.52-1.18 (m, 2H), 1.47 (s, 3H), 1.34 (s, 3H); ¹³C NMR: δ 179.3, 97.3, 76.2, 71.2, 64.7, 37.3, 28.7, 24.6, 18.0, 16.1; IR (CHCl₃): 2940, 1777, 1379 cm^-1; EIMS: 198 (M⁺). To a stirring suspension of freshly activated molecular sieves 3Å (2.2 g) and the epoxy alcohols (0.512 g, 2.59 mmol) in CH₂Cl₂ (20 mL), was added finely ground PDC³¹ (1.54 g, 4.09 mmol). The reaction mixture was stirred at room temperature for 2 h when TLC analysis (silica gel, 1:1 hexanes:EtOAc) showed the absence of the starting material. Celite (1.3 g) was added and the reaction mixture was stirred for another 20 min, then filtered through a column of silica gel, eluted with Et₂O and concentrated in vacuo to afford 0.468 g (92%) of pure epoxy ketone 5 as white crystals ${\left[\alpha \right]}_{\mathrm{D}}^{22}=+26.3$ (c = 6.85, CHCl₃) ¹H NMR: δ 4.33 (d, J = 10.8 Hz, 1H), 4.28 (d, J = 10.8 Hz, 1H), 2.72 (dt, J = 14.5, 5.8 Hz, 1H), 2.25 (dt, J = 14.5, 3.2 Hz, 1H), 2.05-1.99 (m, 2H), 1.52 (s, 3H), 1.42 (s, 3H); ¹³C NMR: δ 204.3, 177.7, 74.6, 64.0, 62.5, 37.5, 31.9, 31.1, 18.0, 12.1; IR (CHCl₃): 2937, 2834, 1782, 1720, 1464 cm^-1; EIMS (M⁺): 196; HRMS calcd for C₁₀H₁₂O₄ : m/z 196.0736. Found: 196.0748.

4.2.13 (R)-(+)-3-(t-Butyldiphenylsilyloxy)-2-methylpropanol (25).¹⁵

To a solution of 5.00 g (42.3 mmol) of (S)-(+)-Methyl-3-hydroxy-2-methylpropanoate (24) in dry DMF (40 mL) was added imidazole (6.34 g, 93.1 mmol), t-butyldiphenylchlorosilane (12.8 g, 46.5 mmol) and a catalytic amount of DMAP (0.129 g, 1.06 mmol). The reaction mixture was stirred for 2 hr when TLC (silica gel, 1:1 hexanes:EtOAc) showed the absence of the starting material. The reaction mixture was diluted with EtOAc (300 mL), the organic layer was washed with water (3 × 50 mL) and brine (20 mL), dried over Na₂SO₄, and concentrated in vacuo to afford 15.1 g (100%) of practically pure silyloxy ester as a colorless oil. For spectroscopic analysis, a sample of the silyloxy ester was prepared by silica gel column chromatography (9:1 hexanes:EtOAc): ${\left[\alpha \right]}_{\mathrm{D}}^{22}=+13.1$ (c = 4.58, CHCl₃); ¹H NMR: δ 7.78-7.69 (m, 4H), 7.47-7.41 (m, 6H), 3.91-3.68 (m, 2H), 3.72 (s, 3H), 2.80-2.73 (m, 1H), 1.20 (d, J = 6.9 Hz, 3H), 1.08 (s, 9H); ¹³C NMR: δ 175.4, 135.6, 133.5, 129.7, 127.7, 65.9, 51.5, 42.4, 26.7, 19.2, 13.5; IR (neat): 3071, 3049, 2931, 2857, 1960, 1891, 1742, 1428 cm^-1; EIMS: 325 (M-OCH3), 299 (M-t-Bu). To a cold (-78°C) solution of silyloxy ester (15.0 g, 42.1 mmol) in Et₂O (160 mL) was added dropwise 1M DIBAl-H in hexanes (84 mL, 84 mmol). The reaction mixture was warmed to room temperature and stirred for 10 hr when no starting material was left by TLC (silica gel, 4:1 hexanes:EtOAc). The clear solution was cooled to 0°C and quenched by dropwise addition of MeOH (25 mL) followed by addition of a saturated aqueous solution of Rochelle's salt (sodium potassium tartrate) (80 mL). The reaction mixture was allowed to warm to room temperature and stirred vigorously until two homogeneous layers resulted. The separated aqueous layer was extracted with Et₂O (2 × 50 mL), the combined organic layer was washed with brine (30 mL), dried over Na₂SO4, concentrated in vacuo and chromatographed (silica gel, 9:1 hexanes:EtOAc) to afford 13.8 g (100%) of pure alcohol 25 as a colorless oil: ${\left[\alpha \right]}_{\mathrm{D}}^{22}=+7.1$, c = 3.49, CHCl₃); ¹H NMR (400 MHz): δ 7.75-7.73 m, 4H), 7.50-7.42 (m, 6H), 3.80-3.63 (m, 4H), 2.76 (t, J = 5.0 Hz 1H), 2.07-2.01 (m, 1H), 1.12 (s, 9H), 0.89 (d, J = 6.9 Hz, 3H); ¹³C NMR: δ 135.6, 133.3, 129.8, 127.8, 68.5, 67.4, 37.4, 26.9, 19.2, 13.2; IR (neat): 3358 (br), 3071, 3049, 2998, 2930, 2858, 1958, 1888, 1824, 1772 cm^-1; EIMS: 271 (M-t-Bu), 269 (M-CH₃CHCH₂OH).

4.2.14 (R)-(E)-(+)-Ethyl-5-(t-butyldiphenylsilyloxy)-4-methyl-2-pentenoate (26)

To a cold (-78°C) solution of oxalyl chloride (7.0 mL, 10.3, 81.5 mmol) in CH₂Cl₂ (200 mL) was added dropwise a solution of DMSO (11.6 mL, 163 mmol) in CH₂Cl₂ (50 mL). The reaction mixture was stirred for another 15 min at -78°C after addition and then a solution of alcohol 26 (13.8 g, 38.7 mmol) in CH₂Cl₂ (100 mL) was added dropwise with stirring. After stirring for 1 hr at -78°C, Et₃N (27.3 mL, 195.6 mmol) was added dropwise and stirring was continued for 15 min at this temperature. The reaction mixture was allowed to warm to 0°C for ca. 30 min with stirring and diluted with saturated aqueous NH₄Cl (50 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 50 mL), the combined organic layer was washed with saturated aqueous NH₄Cl (2 × 100 mL), H₂O (50 mL) and brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo to afford 13.6 g (100%) of practically pure aldehyde (S)-3-(t-butyldiphenylsilyloxy)-2-methylpropanal¹⁵ having ¹H NMR: δ 9.80 (d, J = 1.3 Hz, 1H), 7.77-7.67 (m, 4H), 7.47-7.39 (m, 6H), 3.95-3.85 (m, 2H), 2.66-2.58 (m, 1H), 1.13 (d, J = 6.9 Hz, 3H), 1.08 (s, 9H). ¹³C NMR: δ 204.5, 135.6, 133.2, 129.8, 127.8, 64.1, 48.8, 26.8, 19.2, 10.3. IR (neat): 2958, 2931, 2858, 2712, 1961, 1890, 1824, 1737, 1427 cm^-1. EIMS: 269 (M-t-Bu), 239 (M-OCH₂CH(CH₃)CHO). The aldehyde was immediately used in the next step without further purification. To a cold (0°C) solution of ethyl diisopropylphosphonoacetate (14.7 g, 54.1 mmol) in THF (100 mL) under argon was added a filtered solution of t-BuOK (5.62 g, 50.1 mmol) in THF (300 mL). After stirring for 1 hr at room temperature, the reaction mixture was cooled to -78°C. To the stirred solution, crude (S)-3-(t-butyldiphenylsilyloxy)-2-methylpropanal (27.9 g, 134 mmol) in THF (100 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature, stirred for 7 hr at rt, and quenched with saturated aq NH₄Cl (80 mL) and H₂O (50 mL). The separated aqueous layer was extracted with Et₂O (2 x 100 mL) and the combined organic layer was washed with H₂O (100 mL) and brine (100 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 9:1 then 4:1 hexanes:EtOAc) to afford 30.6 g (82%) of trans- α,β-unsaturated ester 26 (trans:cis > 95:5) as a pale yellow oil having: ${\left[\alpha \right]}_{\mathrm{D}}^{22}=+13.5$ (c = 2.44, CHCl₃); ¹H NMR: δ 7.77-7.68 (m, 4H), 7.46-7.39 (m, 6H), 7.01 (dd, J = 15.8, 7.2 Hz, 1H), 5.88 (d, J = 15.8 Hz, 1H), 4.23 (q, J = 7.0 Hz, 2H), 3.62 (d, J = 6.4 Hz, 2H), 2.61-2.55 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H), 1.09 (s, 12 H); ¹³C NMR: δ 166.6, 151.3, 135.6, 133.6, 129.7, 127.7, 121.2, 67.6, 60.1, 39.1, 26.9, 19.3, 15.6, 14.3; IR (neat): 3071, 3049, 2959, 2930, 2857, 1960, 1888, 1825, 1721, 1651, 1427 cm^-1; EIMS: 351 (M⁺-OEt), 339 (M⁺-t-Bu). HRMS. Calcd for C₂₀H₂₃O₃Si: m/z 339.1416. Found: 339.1387.

4.2.15 (R)-(E)-(+)-5-(t-Butyldiphenylsilyloxy)-4-methyl-2-penten-1-ol (27)

A solution of trans-α,β-unsaturated ester 26 (7.6 g, 19.2 mmol) in Et₂O (400 mL) was cooled to -78°C. To the solution, 1M DIBAL in hexanes (48 mL, 48 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 5 h until no starting material remained by TLC (silica gel, 1:1 hexanes:EtOAc). The clear solution was quenched by dropwise addition of MeOH (60 mL) at -78°C followed by addition of a saturated aqueous solution of Rochelle's salt (sodium potassium tartrate) (200 mL). The reaction mixture was allowed to warm to rt and stir vigorously until two homogeneous layers resulted (ca. 2 hr). The separated aqueous layer was extracted with Et₂O (2 × 100 mL), and the combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by chromatography (silica gel, elution by 4:1 then 1:1 hexanes:EtOAc) to afford 22.0 g (93%) of allylic alcohol 27 as colorless oil exhibiting ${\left[\alpha \right]}_{\mathrm{D}}^{22}=+4.6$ (c = 1.00, CHCl₃); ¹H NMR: δ 7.77-7.75 (m, 4H), 7.51-7.43 (m, 6H), 5.71-5.69 (m, 2H), 4.12 (d, J = 4.9 Hz, 2H), 3.69-3.57 (m, 2H), 2.54-2.46 (m, 1H), 1.16 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H); ¹³C NMR: δ 135.7, 135.3, 134.0, 129.7, 128.9, 127.7, 68.6, 63.7, 39.0, 27.0, 19.4, 16.5; IR (neat): 3351 (br), 3071, 3049, 2959, 2930, 2857, 1958, 1888, 1824, 1427 cm^-1; EIMS: 355 (M⁺+1), 297 (M⁺-t-Bu). HRMS. Calcd for C₁₈H₂₁O₂Si: m/z 297.1311. Found: 297.1283.

4.2.16 (R)-(E)-5-(t-Butyldiphenylsilyloxy)-4-methyl-2-pentenyl trifluoromethane sulfonate (6)

To a solution of allylic alcohol 27 (500 mg, 1.41 mmol) in Et₂O (1.0 mL) was added 1.43 M solution of t-BuLi in hexanes (0.986 mL, 1.41 mmol) at -78°C. After stirring for 10 min, the reaction mixture was transferred by cannula to a solution of Tf₂O (0.237 mL, 1.41 mmol) in Et₂O (0.5 mL). The reaction mixture was stirred at -78°C for 30 min, and used immediately for the alkylation reaction.

4.2.17 4-t-Butyldiphenylsiloxy-1-butyne³⁹

To a solution of 8.4g (0.12 mol) of 3-butyn-1-ol (28) in 200 mL of anh THF was added 16 g (0.24 mol) of imidazole and 33 g (0.12 mol) t-butyldiphenylsilyl chloride. The reaction mixture was stirred at rt for 18 h, and then concentrated in vacuo. The crude residue was partitioned between ether and water and the phases were separated. The aqueous phase was then further extracted twice with 200 mL portions of ether. The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo to provide 38 g (> 99%) of alkynol silyl ether as an oil which was used without further purification: ¹H NMR (300 MHz, CDCl₃): δ 7.71 (m, 4H), 7.44 (m, 6H), 3.81 (t, J = 7.0 Hz, 2H), 2.48 (dt, , J₁ = 7.0, J₂ = 2.5 Hz, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.09 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 135.3, 133.5, 129.3, 127.3, 81.1, 68.9, 62.2, 26.6, 22.3, 18.9; IR (film): 3307, 3071, 3050, 2958, 2931, 2880, 2857, 2121, 1960, 1892, 1822, 1589, 1472, 1427 cm^-1; EIMS: 251 (M⁺ - tBu), 221 (M⁺ - Ph).

4.2.18 5-t-Butyldiphenylsilyloxy-2-pentyn-1-ol (29).⁴⁰

A solution of 38 g (0.12 mol) of 4-t-butyldiphenylsiloxy-1-butyne in 800 mL of anh THF was cooled to -78°C and 110 mL of a 1.48 M solution of n-butyllithium in hexane (0.16 mol) was added dropwise. The resulting solution was stirred at -78°C for 1h, warmed to ambient temperature over 2.5 h, and then recooled to -78°C. A 9.3 g (0.31 mol) sample of solid dry paraformaldehyde was added in one portion and the resulting suspension was allowed to warm to rt over 16 h. The mixture was concentrated in vacuo and then partitioned between 400 mL of ether and 400 mL of water. The phases were separated and the aq phase was further extracted twice with 300 mL portions of ether. The combined organic phases were dried over Na₂SO₄ and concentrated in vacuo. Chromatography (with elution by 4:1 hexane/ether) provided 36 g (85%) of 5-t-Butyldiphenylsiloxy-2-pentyn-1-ol (29) as an oil: ¹H NMR (300 MHz, CDCl₃): δ 7.72 (m, 4H), 7.44 (m, 6H), 4.22 (m, 2H), 3.82 (t, J = 7 Hz, 2H), 2.52 (m, 2H), 1.92 (s (br), 1H), 1.10 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 135.6, 133.6, 129.7, 127.7, 83.3, 79.6, 62.4, 51.2, 26.8, 22.9, 19.2; IR (film): 3583-3389 (br), 3072, 3048, 2931, 1590, 1963, 1894, 1830, 1471, 1428 cm^-1; EIMS: 281 (M⁺ - tBu), 251 (M⁺ - Ph). This material was used as obtained for further transformations.

4.2.19 5-t-Butyldiphenylsiloxy-2-penten-1-ol (30).⁴¹

Ethanol (2.4 g, 53 mmol) was added dropwise to a suspension of 1.1 g of 95% LAH (27mmol) in 80 mL of anh THF at 0°C under Ar. A solution of 8.46 g 5-t-butyldiphenylsiloxy-2-pentyn-1-ol (25 mmol) in 50 mL of anh THF was then added dropwise. Upon completion of the addition, the 0°C bath was removed and the reaction mixture was warmed to rt then heated to reflux for 1 h. The mixture was quenched carefully with water and NaOH, and the resulting white aluminum salts were vacuum filtered through a sinter glass funnel. The salts were washed repeatedly with hot ether, and the combined filtrates were dried over Na₂SO₄ and concentrated in vacuo. Chromatography (with elution by 3:1 hexanes / ether) provided 8.2 g (96%) of 5-t-Butyldiphenylsiloxy-2-penten-1-ol as a colorless oil having: ¹H NMR (300 MHz, CDCl₃): δ J = 8 Hz, 2H), 2.32 (m, 2H), 1.50 (s (br), 1H), 1.06 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 135.6, 133.9, 131.1, 129.7, 127.7, 63.6, 63.5, 35.6, 26.9, 19.3; IR (film): 3331, 3070, 3048, 2930, 2857, 1963, 1894, 1830, 1472, 1428 cm^-1; EIMS: 283 (M⁺ - tBu), 253 (M⁺ - Ph).

4.2.20 5-tert-butyldiphenylsiloxy-1-trifluoromethanesulfonyl-2-pentene (31)

To a solution of alcohol 30 (9.9 g, 29 mmol) in Et₂O (25 mL) cooled to -78°C was added nBuLi (1.5M in hexane, 19mL, 29 mmol) dropwise. The resulting solution was stirred for 0.5h, then slowly added dropwise via cannula to neat, freshly distilled triflic anhydride (8.2 g, 29 mmol) at -78°C. The solution was stirred at -78°C for 0.5h, then used immediately in subsequent reactions.

4.2.21 (4R,8S)-Dimethyl-1,5-dioxo-(9S)-hydroxy-2-oxabicyclo[4.3.0]nonane and (4S,8S)-Dimethyl-1,5-dioxo-(9S)-hydroxy-2-oxabicyclo[4.3.0]nonane (22)

To a solution of trimesitylborane (TMB) (130 mg, 0.353 mmol) in THF (1 mL) was added freshly cut sodium chips (35 mg, 1.52 mmol). The resulting blue colored solution was stirred at room temperature for 8 hr and cooled to -78°C. To it was added a solution of epoxy ketone 5 (33.0 mg, 0.168 mmol) in THF (0.5 mL) dropwise. Stirring was continued at -78°C for 3 hr quenched with 1 mL of sat aq NH₄Cl at -78°C. After warming to room temperature, the mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with H₂O (2 × 5 mL) and brine (5 mL), dried over _Na2SO4, concentrated in vacuo and chromatographed on silica gel (elution by 9:1 then 4:1 hexanes:EtOAc) to afford 31.4 mg (94%) of lactone 22 as a colorless oil having: ¹H NMR: δ 4.10 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 10.5 Hz, 1H), 2.70 (q, J = 6.7 Hz, 1H), 2.59-2.52 (m, 1H), 2.44-2.32 (m, 1H), 2.18 (s, 1H), 2.05-2.02 (m, 1H), 1.88-1.82 (m, 1H), 1.49 (s, 3H), 1.16 (d, J = 6.7 Hz, 3H); ¹³C NMR: δ 207.8, 179.9, 82.7, 73.4, 49.4, 47.1, 35.9, 30.9, 13.8, 7.0; IR (CHCl₃): 3413, 2977, 2941, 1779, 1720 cm^-1; EIMS: 198 (M⁺); HRMS calcd for C₁₀H₁₄O₄: m/z 198.0892. Found: 198.0889.

4.2.22 (4,8S)-Dimethyl-5-(dimethyl-t-butylsilyloxy)-(9S)-hydroxy-1-oxo-2-oxa bicyclo[4.3.0]non-4(5)-ene (32)

To a solution of trimesityl borane (TMB) (190 mg, 0.515 mmol) in THF (2 mL) was added freshly cut sodium chips (30 mg, 1.30 mmol). The resulting blue colored solution was stirred at room temperature for 8 hr and cooled to -78°C. To it was added a solution of epoxy ketone 5 (50.0 mg, 0.255 mmol) in THF (0.5 mL) dropwise. Stirring was continued at -78°C for 24 h followed by addition of a solution of TBDMSCl (192 mg, 1.28 mmol) in THF (0.5 mL). The reaction mixture was slowly warmed to -40°C, stirred at that temperature for 3 h and quenched with phosphate buffer (KH₂PO₄/Na₂HPO₄, pH = 7.5) (3 mL) at -40°C. After warming to room temperature, the aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layer was washed with H₂O (5 mL) and brine (5 mL), dried over Na₂SO₄, concentrated in vacuo and chromatographed by silica gel column (9:1 then 4:1 hexanes:EtOAc) to afford 56.2 mg (71%) of pure silyl enol ether 32 as a colorless oil having: ¹H NMR: δ 4.23 (d, J = 9.3 Hz, 1H), 4.17 (d, J = 9.3 Hz, 1H), 2.11-2.09 (m, 2H), 1.98-1.91 (m, 1H), 1.82 (s, 1H), 1.69 (s, 3H), 1.65-1.60 (m, 1H), 1.24 (s, 3H), 0.94 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); ¹³C NMR: δ 179.8, 149.2, 110.9, 78.3, 73.6, 45.5, 27.4, 26.8, 25.7, 18.1, 17.4, 10.3, -3.7, -3.9; IR (CHCl₃): 3596 (br), 2956, 2931, 2858, 1771, 1667, 1472 cm^-1; EIMS: 312 (M⁺). HRMS. Calcd for C₁₆H₂₈O₄Si: m/z 312.1757. Found: 312.1742.

4.2.23 (+)-5-[(E)-5'-t-Butyldiphenylsilyloxy-4'-methyl-2'-pentenyloxy]-(4,8S)-dimethyl-(9S)-hydroxy-1-oxo-2-oxabicyclo[4.3.0]non-4(5)-ene (33)

To a solution of TMB (130 mg, 0.353 mmol) in THF (1 mL) was added freshly cut sodium chips (35 mg, 1.52 mmol). The resulting blue colored solution was stirred at room temperature for 8 h and cooled to -78°C. To it was added a solution of epoxy ketone 5 (33.0 mg, 0.168 mmol) in THF (0.5 mL) dropwise. Stirring was continued at -78°C for 24 h followed by addition of HMPA (0.2 mL) and a solution of allylic triflate 6 (236 mg, 0.485 mmol, prepared in situ, see 31 above) in Et₂O (1 mL) via cannula. The reaction mixture was stirred at -78°C for 45 min and quenched with phosphate buffer (KH₂PO₄/Na₂HPO₄, pH = 7.5) (3 mL) at -78°C. After warming to room temperature, the aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layer was washed with H₂O (2 × 5 mL) and brine (5 mL), dried over Na₂SO₄, concentrated in vacuo and chromatographed on silica gel (elution with 9:1 then 4:1 hexanes:EtOAc) to afford 46.7 mg (52%) of O-alkylation product 33 as a colorless oil having: [α]_D²² + 66.0 (c = 0.90, CHCl₃); ¹H NMR: δ 7.66 (d, J = 7.6 Hz, 4H), 7.46-7.36 (m, 6H), 5.72-5.52 (m, 2H), 4.23-4.14 (m, 4H), 3.58-3.47 (m, 2H), 2.47-2.38 (m, 2H), 2.23-2.19 (m, 2H), 2.00-1.92 (m, 1H), 1.71 (s, 3H), 1.66-1.57 (m, 1H), 1.23 (s, 3H), 1.06 (s, 9H), 1.05 (d, J = 6.8 Hz, 3H); ¹³C NMR: δ 179.6, 151.8, 137.0, 135.6, 133.8, 129.6, 127.6, 125.2, 111.4, 78.2, 73.6, 68.4, 68.2, 45.4, 39.0, 27.4, 26.8, 21.8, 19.3, 17.3, 16.4, 9.7; IR (neat): 3453 (br), 3071, 3048, 2931, 2858, 1769, 1673, 1589, 1471 cm^-1; EIMS: 534 (M+), 477 (M-t-Bu); HRMS (CI). Calcd for C₃₂H₄₂O₅Si: m/z 534.2796. Found: 534.2798.

4.2.24 (-)-(1S)-4-((E)(4'R)-5'-t-butylydiphenylsiloxy-4'-methyl-2'-pentenyloxy)-2,5-dimethyl-9-oxo-8-oxabicyclo[4.3.0]nona-4,6-diene (35)

To a solution of enone 19 (0.10g, 0.57 mmol) in tetrahydrofuran (2 mL) cooled to -78°C was added sodium bistrimethylsilylamide (1.0 M in THF, 0.57 mL, 0.57 mmol) dropwise via syringe pump over 0.5h. Upon completion of the addition, hexamethylphosphoramide (HMPA) (0.50 mL) was added and the resulting dark yellow solution was stirred at -78°C for 0.5 h. Allylic triflate 6 (0.49 g, 1.0 mmol) was added via cannula as a solution in ether (1.5mL) and the resulting solution was stirred for 1 h at -78°C. The mixture was poured into aqueous sodium bicarbonate (15 mL) and extracted with ether (2 × 25 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography (7:1 hexane / ether) provided 0.23 g (77%) of allyl dienol ether 35 as an oil having: [α]_D²⁵ -66.5 (c = 5.6, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.67 (m, 4H), 7.42 (m, 6H), 6.50 (s, 1H), 5.74 (dd, J = 16, 6.7 Hz, 1H), 5.62 (dt, J = 16, 5.5 Hz, 1H), 4.30 (d, J = 5.5 Hz, 2H), 3.56 (m, 2 H), 2.42 (m, 3H), 2.01 (m, 2H), 1.75 (s, 3H), 1.30 (s, 3H), 1.08 (s, 9H), 1.07 (d, J = 9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 181.5, 149.8, 137.2, 135.6, 133.8, 130.1, 129.6, 129.4, 127.6, 125.5, 107.0, 69.1, 68.3, 42.6, 39.0, 28.2, 26.8, 22.6, 21.5, 19.3, 16.4, 10.5; IR (film): 3071, 3048, 2957, 2931, 2858, 1793, 1650, 1620, 1472, 1461, 1428 cm^-1. This material was used as obtained in the next transformation.

4.2.25 (+)-(1S,5R)-5-((3'R,4'R)-5'-tertbutyldiphenylsiloxy-4'-methyl-1'-penten-3'-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (36) and (+)-(1S,5S)-5-((3'S,4'R)-5'-tertbutyldiphenylsiloxy-4'-methyl-1'-penten-3'-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (37)

A solution of dienol ether 35 (0.32g, 0.62mmol) in toluene (5 mL) was placed in a dry, base washed sealed tube and heated at 125°C for 2h. The reaction mixture allowed to cool to ambient temperature and then concentrated in vacuo. Chromatography on silica gel (elution with 3:1 hexane / ether) provided 240mg (76%) of ketones 36 and 37 as a 3:1 mixture of diastereomeric Claisen products. The mixture could be further purified by HPLC (85:15 hexane/ether) which provided pure samples of each diastereomer. Major diastereomer (36): [α]_D²⁵ +39.0 (c = 2.64, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.64 (m, 4H), 7.41 (m, 6H), 6.74 (s, 1H), 5.56 (dt J = 16.8, 10.4 Hz, 1H,), 5.17 (dd, J = 10.6, 1.6 Hz, 1H), 4.93 (dd, J = 16.8, 1.6 Hz, 1H), 3.28 (dd, J = 10, 8 Hz, 1H), 3.16 (dd, 1H, J = 10, 8 Hz), 2.72 (dd, J = 9.7, 7.1 Hz, 1H), 2.56 (m, 1H), 2.27 (ddd,J = 18.6, 7.8, 2.3 Hz, 1H), 2.11 (m, 1H), 1.90 (m, 1H), 1.65 (m, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.06 (s, 9H), 0.84 (d, J = 9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 211.2, 180.5, 135.6, 135.5, 134.7, 133.5, 133.4, 130.0, 129.8, 129.7, 127.7, 120.0, 67.6, 52.4, 51.2, 43.9, 35.6, 34.7, 28.0, 26.8, 26.3, 21.8, 19.2, 14.0; IR (film): 2927, 2855, 1798, 1709, 1461, 1428 cm^-1; EIMS: 516 (M⁺), 459 (M⁺ - tBu). HRMS (CI). Calcd for C₃₂H₄₀O₄Si: m/z 516.7549. Found: 516.7555.

Minor diastereomer (37): [α]_D²⁵ +46.6 (c = 2.36, CHCl₃); ¹H NMR (300MHz, CDCl₃): δ 7.62 (m, 4H), 7.41 (m, 6H), 6.45 (s, 1H), 5.44 (dt, J = 17.2, 10.1 Hz, 1H), 5.04 (d, J = 17.2 Hz, 1H), 5.03 (d, J = 10 Hz, 1H), 3.62 (dd, J = 10, 3 Hz, 1H), 3.45 (dd, J = 10, 2.5 Hz, 1H), 2.66 (m, 2H), 2.31 (m, 1H), 2.17 (m, 1H), 1.75 (s, 3H), 1.72 (m, 2H), 1.13 (d, J = 9 Hz, 3H), 1.07 (s, 9H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl₃): δ 208.5, 181.1, 138.0, 135.7, 135.6, 134.2, 133.6, 133.5, 130.6, 129.8, 129.7, 127.8, 127.6, 118.5, 66.7, 55.7, 51.1, 44.3, 36.2, 34.3, 33.2, 26.9, 22.8, 19.2, 17.8, 14.6; IR (film):3071, 2931, 2857, 1798, 1716, 1634, 1462, 1428 cm^-1; EIMS: 516 (M⁺), 459 (M⁺ - tBu), 429 (M⁺ - Ph).

Lewis acid promoted Claisen rearrangements of were also conducted using the above procedure at various temperatures from -50°C to 125°C by addition of 35 in toluene to a solution of the Lewis acid promoter (2 – 4 equiv) at the requisite temperature or at rt followed by heating. The results are described in Table 1 above.

4.2.26 (+)-(1S,5S)-5-((3'S,4'R)-5'-hydroxy-4'-methyl-1'-penten-3'yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene hemiketal (38)

To a solution of ketone 36 (16 mg, 0.030 mmol) in 3:1 acetonitrile / tetrahydrofuran (0.30 mL) at rt was added 48% hydrofluoric acid (~100 μL). The reaction mixture was stirred for 36h before being diluted with methylene chloride (3mL) and poured into 10% sodium bicarbonate solution. The aqueous layer was extracted with methylene chloride (2 × 5mL) and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (elution with 3:2 hexanes / ether) provided 6.4 mg (77%) of hemiketal 38 as a white crystalline solid. Hemiketal 38 could be further purified by recrystallization from toluene to mp 195-196°C and having: [α]_D²⁵ +81 (c = 1.1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ 6.69 (s, 1H), 5.57 (ddd, J = 17, 10, 10 Hz, 1H), 5.23 (dd, J = 10, 2 Hz, 1H), 5.15 (dd, J = 17, 2 Hz, 1H), 3.60 (d, J = 8 Hz, 2H), 3.32 (t, J = 12 Hz, 1H), 2.23 (td, J = 14, 4 Hz, 1H), 2.13 (m, 1H), 2.04 (s, 1H), 1.85 (td, J = 13, 4 Hz, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.47 (s, 3H), 1.23 (s, 3H), 0.74 (d, J = 6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 187.4, 135.9, 135.2, 127.7, 119.7, 98.2, 66.3, 53.5, 44.6, 42.2, 32.6, 29.2, 28.7, 23.8, 23.7, 15.2; IR (film): 3426, 2953, 2873, 1786, 1639, 1463 cm^-1; EIMS: 278 (M⁺). The structure and stereochemistry of 38 was confirmed by single crystal X-ray analysis.

4.2.27 (-)-(1S)-4-((E)-5'-tertbutylydiphenylsiloxy-2'-pentenyloxy)-1,5-dimethyl-9-oxo-8-oxabicyclo[4.3.0]nona-4,6-diene (39)

To a solution of enone 19 (4.0 g, 22 mmol) in THF (50 mL) cooled to -78°C was added sodium bistrimethylsilylamide (1.0 M in THF, 22 mL, 22 mmol) dropwise via syringe pump over 0.5 h. Upon completion of the addition, HMPA (19 g, 0.11 mol) was added and the resulting dark yellow solution was stirred at -78°C for 0.5 h. Allylic triflate 31 (14 g, 29 mmol) was added quickly via cannula as a solution in ether and the resulting solution was stirred for 1 h at -78°C. The mixture was poured into aqueous sodium bicarbonate (120 mL) and extracted with ether (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (elution with 8:1 hexane / ether) provided 8.9 g (81%) of allyl dienol ether 39 as an oil having: [α]_D²⁵ -70.8 (c = 8.19, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.69 (m, 4H), 7.42 (m, 6H), 6.51 (s, 1H), 5.79 (dt, J = 15, 7 Hz, 1H), 5.64 (dt, J = 15, 6 Hz, 1H), 4.29 (d, J = 6 Hz, 2H), 3.73 (t, J = 7 Hz, 2H), 2.41 (m, 4H), 2.02 (m, 1H), 1.76 (s, 3H), 1.74 (m, 1H), 1.30 (s, 3H), 1.08 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 181.5, 149.8, 135.5, 133.8, 131.2, 130.1, 129.6, 129.4 127.8, 127.6, 106.8, 69.0, 63.3, 42.6, 35.6, 28.2, 26.8, 22.6, 21.5, 19.2, 10.5; IR (film): 3117, 3070, 3048, 2931, 2858, 1793, 1649, 1620, 1472, 1460, 1445, 1428 cm^-1; EIMS: 445 (M⁺ - t-Bu).

This material was used as obtained in the next transformation.

4.2.28 (+)-(1S,5R)-5-((3'R)-5'-tert-butyldiphenylsiloxy-1'-penten-3'-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (40) and (+)-(1S,5S)-5-((3'S)-5'-tert-butyl diphenylsiloxy-1'-penten-3'-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (41)

A solution of dienol ether 39 (8.9 g, 18 mmol) in toluene (15 mL) was placed in a dry, base washed sealed tube and heated to 105°C for 2 h. The reaction mixture was allowed to cool to ambient temperature, transferred to a round bottomed flask and concentrated in vacuo. Chromatography on silica gel (elution with 4:1 hexane/ether) provided 7.2 g (81%) of ketones 40 and 41 as approximately a 1:1 mixture. The mixture could be further purified by HPLC (85:15 hexane/ether) to provide the pure diastereomers: 1) 40 having: [α]_D²⁵ + 14.3 (c = 0.7, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.64(m, 4H), 7.40 (m, 6H), 6.62 (s, 1H), 5.43 (dt, 1H, J = 16.9, 9.8 Hz), 5.07 (d, 1H, J = 10.1Hz), 4.98 (d, 1H, J = 16.9 Hz), 3.72 (m, 1H), 3.54 (m, 1H), 2.81 (m, 2H), 2.36 (m, 1H), 2.16 (m, 1H), 1.79 (m, 2H), 1.62 (m, 1H), 1.55 (s, 3H), 1.12 (s, 3H), 1.04 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 208.7, 181.2, 137.9, 135.7, 135.6, 135.5, 133.4, 130.1, 129.8, 129.7, 129.6, 127.7, 127.6, 118.6, 61.5, 55.6, 44.6, 44.1, 34.0, 32.8, 31.1, 26.8, 22.2, 19.1, 13.5; IR (film): 3071, 2930, 2856, 1798, 1716, 1471, 1462, 1456, 1428 cm^-1; FDMS: 445 (M⁺ - t-Bu). HRMS. Calcd for C₃₁H₃₈O₄Si: m/z 502.7280. Found: 502.7280.

2) 41 having: [α]_D²⁵ + 30.8 (c = 7.26, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.65 (m, 4H), 7.40 (m, 6H), 6.68 (s, 1H), 5.48 (dt, J = 17, 10 Hz, 1H), 5.12 (dd, J = 10, 1 Hz, 1H), 4.97 (d, J = 17 Hz, 1H), 3.62 (m, 2H), 2.64 (m, 2H), 2.41 (ddd, J = 18.4, 6.7, 2.1 Hz, 1H), 2.05 (ddd, J = 13.2, 7.1, 2.1 Hz, 1H), 1.91 (m, 1H), 1.58 (m, 2H), 1.44 (s, 3H), 1.27 (s, 3H), 1.06 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 211.2, 180.8, 136.5, 135.7, 135.6, 133.8, 133.7, 129.7, 129.6, 129.4, 127.6, 119.4, 61.7, 52.2, 47.8, 44.1, 34.8, 33.0, 28.4, 26.9, 25.7, 21.7, 19.1; IR (film): 3133, 3071, 2931, 1790, 1714, 1471, 1462, 1455, 1428 cm^-1; FDMS: 445 (M+ - t-Bu). HRMS. Calcd for C₃₁H₃₈O₄Si: m/z 502.7280. Found: 502.7269.

Lewis acid promoted Claisen rearrangements of were also conducted using the above procedure at various temperatures from -50°C to 125°C by addition of 35 in toluene to a solution of the Lewis acid promoter (2 – 4 equiv) at the requisite temperature or at rt followed by heating heating. The results are described in Table 1 above.

4.2.29 (+)-(1S,5R)-5-((3'R)-5'-hydroxy-1'-penten-3'-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo [4.3.0]non-6-ene (42) and (+)-(1S,5S)-5-((3'S)-5'-hydroxy-1'-penten-3'yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene hemiketal

To a mixture of ketones 40 and 41 (6.2 g, 12 mmol) in acetonitrile (50 mL) was added hydrofluoric acid (48-52% aqueous solution, ca. 1 mL). The mixture was stirred at room temperature for 2 h at which time it was poured into aqueous sodium bicarbonate (100 mL) and extracted with methylene chloride (3 × 80 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (2:1 hexanes / ethyl acetate) provided 1.4 g (43%) of keto alcohol 42 and 1.2 g (37%) of the title hemiketal as a solids. Keto alcohol 42 could be further purified by recrystallization from methylene chloride / heptane and the hemiketal could be recrystallized from toluene. Keto alcohol 42 had mp 127-128°C, [α]_D²⁵ +77 (c = 6.7, CHCl₃) and ¹H NMR (300 MHz, CDCl₃): δ 6.63 (s, 1H), 5.54 (dt, J = 19, 10 Hz, 1H), 5.12 (d, J = 10 Hz, 1H), 5.10 (d, J = 17 Hz, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 2.85 (t (br), J = 11 Hz, 1H), 2.81 (td, J = 15, 6 Hz, 1H), 2.39 (dm, J = 11 Hz, 1H), 2.15 (dm, J = 13 Hz, 1H), 1.77 (m, 2H), 1.72 (s, 3H), 1.42 (m, 2H), 1.15 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 208.8, 181.2, 138.1, 135.9, 130.1, 118.7, 60.1, 55.5, 44.7, 44.2, 34.0, 32.7, 31.1, 22.1, 13.9; IR (film): 3750, 3123, 3074, 2944, 2879, 1793, 1717, 1636, 1458, 1421 cm^-1; EIMS: 264 (M⁺). Anal. Calcd for C₁₅H₂₀O₄: C, 68.15; H, 7.63. Found: C, 67.74; H, 7.81.

Title hemiketal had mp 154-155°C, [α]_D²⁵ +19.6 (c = 8.4, CHCl₃), and ¹H NMR (300 MHz, CDCl₃): δ= 6.72 (s, 1H), 6.15 (ddd, J = 17, 11, 5 Hz, 1H), 5.19 (d, J = 2 Hz, 1H), 5.14 (d (broad, J = 7 Hz), 1H), 4.07 (ddd, J = 12, 11, 3 Hz, 1H), 3.70 (dd, J = 11, 5 Hz, 1H), 2.78 (d(br), J = 13 Hz, 1H), 2.26 (s(br), 1H), 2.24 (td, J = 14, 4 Hz, 1H), 2.03 (qd, J = 13, 6 Hz, 1H), 1.82 (td, J = 14, 4 Hz, 1H), 1.67 (dt, J = 13, 3Hz, 1H), 1.55 (m, 2H), 1.45 (s, 3H), 1.34 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ= 182.2, 138.6, 136.4, 127.6, 115.9, 98.4, 60.2, 44.6, 43.6, 42.2, 32.5, 29.1, 25.5, 24.2, 23.8; IR (film): 3486, 3000, 2983, 2965, 2926, 2874, 1777, 1646, 1395 cm^-1; EIMS: 264 (M⁺).

4.2.30 (1S,5R)-5-((3'R)-5'-carboxy-1'-penten-3'-yl) -1,5-dimethyl-4,9- dioxo-8-oxa bicyclo[4.3.0]non-6-ene

To an aqueous solution of 1.5 M sulfuric acid (32.7 mL, 49.0 mmol) at 0°C was added chromium trioxide (2.04 g, 20.4 mmol). To the resulting orange solution was added a solution of keto alcohol 42 (1.30 g, 5.54 mmol) in acetone (10 mL). The mixture was stirred for 2 h before the excess chromic acid was quenched by the addition of solid tartaric acid (~2 g). When a deep blue solution resulted, the mixture was extracted with methylene chloride (3 × 40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to provide 1.36 g (98%) of the derived carboxylic acid as an oil: [α]_D²⁵ +79.6 (c = 12, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 11.4 (s (broad), 1H), 6.66 (s, 1H), 5.55 (m, 1H), 5.13 (s, 1H), 5.08 (d, J = 5 Hz, 1H), 3.23 (t, J = 9 Hz, 1H), 2.84 (td, J = 15, 6 Hz, 1H), 2.53 (dd, J = 14, 2 Hz, 1H), 2.41 (dt, J = 13, 1 Hz, 1H), 2.29 (dd, J = 15, 1 Hz, 1H), 2.17 (dm, J = 11 Hz, 1H), 1.79 (td, J = 14, 4 Hz, 1H), 1.71 (s, 3H), 1.11 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 208.1, 180.8, 177.6, 138.7, 134.0, 129.6, 119.0, 54.8, 44.1, 44.0, 34.2, 33.9, 32.8, 22.0, 13.6; IR (film): 3260(b), 3124, 2982, 1794, 1713, 1637, 1560, 1508, 1458, 1420 cm^-1; EIMS: 278 (M⁺).

This material was used directly in the next transformation.

4.2.31 (1S,5R)-5-((3'R,4'R)-4'-iodomethyl-g-lacton-3'-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (43)

To a solution of potassium iodide (4.7 g, 28 mmol) and sodium bicarbonate (1.2 g, 14 mmol) in water (25 mL), was added the preceding carboxylic acid (1.3 g, 4.7 mmol) as a solution in methylene chloride (5 mL). The mixture was stirred vigorously and then iodine (1.2 g, 4.9 mmol) was added. The mixture was stirred for 16h before being extracted with methylene chloride (3 × 20mL). The organic layers were combined, washed with 10% sodium thiosulfate solution until colorless, dried over sodium sulfate and concentrated in vacuo to provide 1.3 g (68%) of iodolactone 43 as an oil having [α]_D²⁵ +65 (c = 3.0, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 6.75 (s, 1H), 4.50 (m, 1H), 3.26 (m, 2H), 2.99 (m, 2H), 2.75 (dd, J = 18, 10 Hz, 1H), 2.56 (ddd, J = 16, 4, 3 Hz, 1H), 2.39 (dd, J = 18, 3 Hz, 1H), 2.20 (ddd, J = 13, 6, 3 Hz, 1H), 1.89, (td, J = 14, 5 Hz, 1H), 1.66 (s, 3H), 1.20(s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 208.0, 180.1, 174.1, 138.8, 128.4, 77.6, 52.3, 43.8, 43.2, 34.8, 31.8, 29.821.6, 13.9, 7.9; IR (film): 2935, 1786, 1712, 1636, 1458, 1419 cm^-1; EIMS: 404 (M⁺), 277 (M+- I). HRMS. Calcd for C₁₅H₁₇IO₅: m/z 404.2021. Found: 404.2001.

4.2.32 (1S,4aR,4bS,8aR)-1,2,3,4,4a,4b,5,6,7,8,8a,9-dodecahydro-1-carbomethoxy-1,4a-dimethyl-4,6-dioxo-7,9-dioxaphenanthrene (44)

To a solution of iodolactone 43 (1.3 g, 3.3 mmol) in tetrahydrofuran (15 mL) was added 0.5 M potassium hydroxide (13 mL, 6.6 mmol). The mixture was capped and stirred at ambient temperature for 2 h. At this time the mixture was acidified (pH<2) with concentrated hydrochloric acid, and stirred an additional 3 h. Sodium chloride (solid) was added, and the reaction mixture was extracted with tetrahydrofuran (4 × 10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. An ethereal solution of diazomethane was prepared by adding an excess of N-nitroso-N-methylurea to a biphasic mixture of ether (20 mL) and 20% potassium hydroxide solution (20 mL). The resulting yellow diazomethane solution was added directly to the above residue, and the mixture was stirred vigorously overnight to ensure complete evaporation of excess diazomethane. The reaction mixture was concentrated in vacuo and then chromatographed (2:1, hexanes / ethyl acetate) to provide 0.49g (53%) of vinyl ether 44 as a thick oil having [α]_D²⁵ -87 (c = 1.9, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 6.42 (s, 1H), 4.57 (dd, J = 13, 1.3 Hz, 1H), 4.37 (dd, J = 13, 1.3 Hz, 1H), 4.28 (m, 1H), 3.68 (s, 3H), 2.83 (ddd, J = 15, 12, 5.3 Hz, 1H), 2.72 (dd, J = 19, 7 Hz, 1H), 2.50 (m, 2H), 2.24 (dt, J = 17, 5 Hz, 1H), 2.00 (dd, J = 18, 12 Hz, 1H), 1.50 (td, J = 13, 4 Hz, 1H), 1.36 (s, 3H), 1.25 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 210.6, 176.3, 169.0, 141.3, 114.0, 71.0, 65.8, 52.4, 48.9, 43.2, 35.9, 35.8, 33.1, 29.0, 28.6, 25.0; IR (film): 2971, 2921, 1735, 1725, 1644, 1460, 1435, 1407 cm^-1; EIMS: 308 (M⁺). HRMS: Calcd. for C₁₆H₂₁O₆ (M⁺+H): m/z 309.1334. Found: 309.1324.

4.2.33 (-)-(1S,4aR,4bS,8aR,10S,10aR)-tetradecahydro-1-carbomethoxy-1,4a-dimethyl-4,6-dioxo-10(10a)-epoxy-7,9-dioxaphenanthrene (45)

To a solution of vinyl ether 44 (87 mg, 0.28 mmol) in methylene chloride was added monobasic sodium phosphate hydrate (0.23g, 1.7 mmol) and m-chloroperoxybenzoic acid (0.15 g, 0.85 mmol). The mixture was stirred at ambient temperature for 12 h before being diluted with aqueous sodium bicarbonate (5 mL) and extracted with methylene chloride (3 × 5 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (elution by 2:1 ethyl acetate / hexanes) provided 77 mg (84%) of epoxide 45 as a crystalline solid that could be further purified by recrystallization from methylene chloride / heptane to afford 45 as a white solid having mp 170°C (dec), [α]_D²⁵ -95.2 (c = 1.35, CHCl₃), and ¹H NMR (300 MHz, CDCl₃): δ 5.11 (s, 1H), 4.46 (d, J = 13 Hz, 1H), 4.32 (d, J = 12 Hz, 1 H), 3.98 (s,1H), 3.69 (s, 3H), 2.75 (m, 3H), 2.39 (m, 1H), 2.11 (dd, J = 12, 5 Hz, 1H), 2.01 (dd, J = 17, 12 Hz, 1H), 1.82 (m, 1H), 1.41 (s, 3H), 1.19 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 209.7, 172.4, 169.3, 79.6, 71.1, 62.0, 59.4, 52.4, 49.4, 45.5, 33.5, 33.4, 28.5, 26.5, 22.3, 19.7; IR (film): 2951, 1731, 1712, 1460, 1407 cm^-1; EIMS: 308 (M+ - 16 (O)). HRMS. Calcd for C₁₆H₂₁O₇: m/z 325.3392. Found: 325.3399.

4.2.34 (-)-(1S,2R,5S,8aR)-1,2,3,5,6,7,8,8a-octahydro-5-carbomethoxy-5,8a-dimethyl-1-methyl-ene carbo-N-methoxy-N-methylamido-3-oxa-8-oxo-2-naphthyl alcohol (46)

To a suspension of methoxymethylamine hydrochloride (61 mg, 0.63 mmol) in methylene chloride (1mL) at 0°C was added dropwise trimethylaluminum (2.0M in hexane, 0.32mL, 0.63mmol). When complete dissolution was observed, the solution was transferred via cannula to a solution of vinyl ether 44 (88mg, 0.29mmol) in methylene chloride (2mL) at 0°C. The reaction mixture was stirred at 0°C for 30min before being quenched with sat Rochelle's salts (10mL) and extracted with methylene chloride (3 × 10mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 0.10g (95%) of hydroxy amide 46 as an oil having [α]_D²⁵ -53 (c = 3.2, CHCl₃); ¹H NMR (300 MHz, CDCl3): δ 6.40 (s, 1H), 4.39 (m, 1H), 4.30 (m, 1H), 3.72 (m, 4H), 3.63 (s, 3H), 3.40 (t, 1H, J = 10 Hz), 3.22 (s, 3H), 2.95 (ddd, 1H, J = 17, 12, 5 Hz), 2.84 (d, 1H, J = 6 Hz), 2.53 (dt, 1H, J = 13, 5 Hz), 2.29 (m, 2H), 2.02 (d (br), 1H, J = 17 Hz), 1.53 (td, 1H, J = 13, 4 Hz), 1.39 (s, 3H), 1.30 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 212.0, 176.3, 174.2, 141.5, 115.3, 72.8, 60.7, 60.4, 52.0, 50.3, 43.0, 35.7, 34.5, 33.1, 32.0, 29.4, 28.1, 24.7; IR (film): 3396, 2949, 1723, 1711, 1641, 1434, 1390 cm^-1; EIMS: 308 (M⁺ - HN(OMe)Me). This material was of sufficient purity for use as obtained in the following transformation.

4.2.35 (-)-(1S,2R,5S,8aR)-1,2,3,5,6,7,8,8a-octahydro-5-carbomethoxy-5,8a-dimethyl-1-methylene carbo-N-methoxy-N-methylamido-3-oxa-8-oxo-2-naphthaldehyde (47)

To a solution of alcohol 46 (0.10 g, 0.28 mmol) in methylene chloride was added Dess-Martin periodinane (190 mg, 0.44 mmol) portionwise. The reaction mixture was capped and stirred at ambient temperature for 2 h. The mixture was then quenched with 10% sodium bicarbonate (2 mL) and 10% sodium thiosulfate (2 mL). When a clear biphasic mixture was obtained, the mixture was extracted with methylene chloride (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (elution by 2:1 ethyl acetate / hexanes) afforded 92 mg (90%) of aldehyde 47 as a pale yellow oil having [α]_D²⁵ -39 (c = 1.6, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 9.60 (s, 1H), 6.52 (s, 1H), 4.67 (s, 1H), 3.71 (s, 3H), 3.59 (s, 3H), 3.23 (m, 1H), 3.11 (s, 3H), 2.89 (ddd, J = 17, 12, 5 Hz, 1H), 2.51 (dt, J = 14, 5 Hz, 1H), 2.31 (dt, J = 17, 5 Hz, 1H), 2.23 (dd, J = 17, 8 Hz, 1H), 2.10 (dd, J = 17, 1 Hz, 1H), 1.57 (td, J = 13, 4 Hz, 1H), 1.41 (s, 3H), 1.36 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 210.0, 196.4, 175.8, 171.8, 140.9, 116.2, 78.4, 60.7, 51.7, 49.4, 43.1, 36.3, 35.8, 32.6, 32.1, 29.6, 28.3, 24.8; IR (film): 2950, 1724, 1645, 1446, 1387 cm^-1; EIMS: 367 (M⁺), 307 (M⁺ - N(OMe)Me). This material was used as obtained in the next transformation.

4.2.36 (1R,2R,3S,7S,8S,9R,10RS)-2-bromo-3-carbomethoxy-3,7-dimethyl-10-hydroxy-8-methylenecarbo-N-methoxy-N-methylamido-6-oxo-11,12-dioxatricyclo [6.2.1.0^2,7]do-decane (48)

To a solution of aldehyde 47 (110 mg, 0.30 mmol) in 3:1 tetrahydrofuran / water (3 mL) at rt was added N-bromoacetamide (43 mg, 0.30 mmol) in one portion. The reaction mixture was stirred for 4 h before being quenched with 10% sodium thiosulfate (3 mL) and extracted with methylene chloride (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (elution by 1:1 hexanes / ethyl acetate) provided 85 mg, (61%) of bromolactol 48 as ~6:1 mixture of lactol epimers: major epimer: [α]_D²⁵ -4.5 (c = 2.2, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 5.79 (s, 1H), 5.35 (d, J = 7 Hz, 1H), 4.20 (d, J = 3 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.42 (m, 1H), 3.20 (s, 3H), 3.05-2.82 (m, 3H), 2.36-2.18 (m, 3H), 1.82 (d (br), J = 7 Hz, 1H), 1.52 (s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 209.2, 175.0, 173.1, 101.1, 95.1, 81.4, 77.7, 61.0, 54.7, 51.8, 49.2, 38.7, 36.1, 32.7, 32.1, 28.1, 24.2, 21.8; IR (film): 3396, 2950, 1714, 1658, 1461, 1385 cm^-1; FAB MS: 464 (⁷⁹BrM⁺ +H), 466 (⁸¹BrM⁺ +H)). This material was pure enough for use directly in the next transformation.

4.2.37 (+)-(1S,2R,4R,4aS,5S,8aR)-decahydro-5-carbomethoxy-5,8a-dimethyl-1-methylenecarbo-N-methoxy-N-methylamido-3-oxa-8-oxo-2-naphthaldehyde (49)

To a solution of bromolactol 48 (37 mg, 0.080 mmol) in acetonitrile (1.5 mL) was added triethylamine (0.50 mL), and the mixture was heated to 65°C. Silver tetrafluoroborate (40 mg, 0.20 mmol) was added and the reaction mixture was stirred at 65°C for 30 min. The mixture was cooled to room temperature, quenched with 10% sodium bicarbonate (3 mL) and extracted with methylene chloride (3 × 5 mL). The combined organic layers were filtered through a plug of celite, dried over sodium sulfate, and concentrated in vacuo. The residue was quickly chromatographed on silica (100% ethyl acetate) to provide 23 mg (75%) of epoxy aldehyde 49 as an oil having: [α]_D²⁵ +9.4 (c = 1.7, CHCl₃); 1H NMR (300 MHz, CDCl₃): δ 9.48 (s, 1H), 5.11 (s, 1H), 4.63 (d, J = 2Hz, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.63 (s, 3H), 3.21 (dd, J = 7, 5Hz, 1H), 3.15 (s, 3H), 2.54 (m, 1H), 2.53 (m, 3H), 1.87 (dd, J = 13, 4Hz, 1H), 1.46 (s, 3H), 1.11 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 209.7, 196.4, 175.0, 172.4, 78.9, 78.0, 65.1, 60.4, 52.3, 51.2, 44.0, 38.2, 35.5, 32.0, 30.4, 22.7, 21.9; IR (film): 2952, 1728, 1655, 1433, 1389 cm^-1; EIMS: 383 (M⁺), 323 (M⁺ - N(OMe)Me).

This material was used as obtained in the following transformation.

4.2.38 (+)-(1S,2R,4R,4aS,5S,8aR)-decahydro-5-carbomethoxy-5,8a-dimethyl-4(4a)-epoxy-1-methylene carbo-N-methoxy -N-methylamido -3-oxa-8-oxo-2- naphthyl-3'furyl ketone (50)

To a solution of 3-tributylstannylfuran (35.7 mg, 0.10 mmol) in ether (0.8 mL) at -78°C under argon was added nBuLi (1.6 M in hexane, 0.16 mL, 0.10 mmol) and stirred for 1h. At this time, a solution of epoxy aldehyde 49 (19 mg, 0.05 mmol) in toluene (0.5 mL) precooled to -78°C was added dropwise by cannula. The reaction mixture was then stirred at -78°C for an additional 1 h before being quenched with saturated ammonium chloride solution and extracted with methylene chloride (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo.

The resulting crude mixture of 2° alcohols was dissolved in methylene chloride (2 mL) and Dess-Martin periodinane (34 mg, 0.080mmol) was added. The reaction mixture was stirred for 3 h before being quenched with 10% sodium bicarbonate (2 mL) and 10% sodium thiosulfate (2 mL). When a clear solution resulted the layers were separated and the aqueous phase washed with two additional portions of methylene chloride (10 mL total volume). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (elution with 1:1 hexanes / ethyl acetate) provided 10.5 mg (48%) of 50 as a colorless oil having: [α]_D²⁵ +9.4 (c = 0.64, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 8.17 (s, 1H), 7.43 (s, 1H), 6.77 (s, 1H), 5.17 (s, 1H), 4.98 (d, J = 2Hz, 1H), 3.83 (s, 3H), 3.72 (m, 1H), 3.57 (s, 3H), 3.22 (m, 1H), 3.04 (s, 3H), 2.80 (m, 1H), 2.70 (dd, J = 19, 6Hz, 1H), 2.54 (ddd, J = 19, 18, 4Hz, 1H), 2.42 (d (br), J = 18 Hz, 1H), 1.90 (dd, J = 13, 4Hz, 1H), 1.53 (s, 3H), 1.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 209.5, 198.0, 190.5, 175.2, 147.4, 144.4, 143.4, 125.4, 108.8, 79.1, 65.1, 60.6, 52.4, 51.4, 44.1, 40.5, 35.6, 32.2, 30.6, 29.5, 22.7, 22.1; IR (film): 2950, 1727, 1661, 1459, 1385 cm^-1. EIMS: 449 (M⁺), 389 (M⁺ - N(OMe)Me). HRMS. Calcd for C₂₂H₂₇NO₉: m/z 449.1680. Found: 449.1680.

4.2.39 (S)-(-)-Ethyl 4-Oxo-1,2,3-trimethyl-2-cyclohexene-1-carboxylate [(-)-53)]^26b

A mixture of 13.4 g of (S)-(-)-α-methylnaphthylamine (78 mmol), 11.3 g (78 mmol) of ethyl 2-methylacetoacetate and a catalytic amount (75 mg) of p-toluensulfonic acid in 100 mL of dry toluene was heated at reflux for 20 h with azeotropic removal of water using a Dean-Stark trap. After cooling to rt, ~200 mg of solid NaHCO₃ was added and the solution was filtered through a pad of silica gel using hexanes/EtOAc 4:1 containing 2% Et₃N as eluent. Evaporation of the solvent at reduced pressure afforded 20.7 g (89%) of vinylogous carbamate ([α]_D²⁰ +299 (c 5.5, CH₃OH).^26b To a suspension of anh ZnCl₂ (11 mg) in 4 mL of dry toluene was added 0.30 mL ethyl vinyl ketone (2.73 mmol, 1.3 eq) dropwise at 0°C and the resulting mixture was stirred for 40 min. After cooling the reaction mixture further to -30°C, a solution of 625 mg of carbamate ( 2.1 mmol) in 4 mL of dry toluene was added dropwise. The resulting reaction mixture was stirred at -30°C for 1.5 h, then hydrolyzed by addition of 5 mL of 10% aq HOAc with stirring and warming from 0°C to rt overnight. The aq phase was separated and extracted thoroughly four times with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and the solvent removed in vacuo. The residue was purified by chromatography (with elution by hexanes/ EtOAc 4:1) to afford 291 mg (61%) of diketone (-)-52,²⁵ [α]_D²⁵ -6 (c 5.113, CHCl₃), along with 49 mg of a mixture of (-)-53 (minor amount) and its regioisomer 54 (11% combined): ¹H-NMR (400 MHz, CDCl₃): δ 4.20 (dq, J= 7.2, 0.9, 2H), 2.42 (q, J=7.3, 2H), 2.46-2.36 (m, 2H), 2.16 (ddd, J= 14.2, 9.5, 6.0, 1H), 2.16 (s, 3H), 2.06 (ddd, J= 14.2, 9.9. 5.9, 1H), 1.34 (s, 3H), 1.27 (t, J= 7.2, 3H), 1.05 (t, J= 7.3, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ 209.7, 205.0, 172.5, 61.2, 58.6, 37.0, 35.7, 28.4, 25.9, 19.1, 13.8, 7.6: IR (neat): 2981, 2940, 1713, 1461 cm^-1; APCI (+): 229 ([M+H]⁺, 10), 211 (51), 183 (17), 145 (85), 139 (100).

A solution 286 mg (1.25 mmol) of (-)-52 in 15 mL dry toluene was heated to reflux and then 0.31 mL (3.7 mmol) of pyrrolidine was added followed by addition of 0.28 mL (5 mmol) of glacial HOAc. The mixture was stirred at reflux for 3 h with azeotropic removal of water using a Dean-Stark trap. After cooling to rt and concentration at reduced pressure, the residue was purified by chromatography (with elution by hexanes/ EtOAc 4:1) to afford 229 mg (87%) of (S)-(-)-ethyl 4-oxo-1,2,3-trimethyl-2-cyclohexene-1-carboxylate [(-)-53] ([α]_D²⁵ -82 (c 0.989, CHCl₃, 95% ee) as a yellow oil: ¹H-NMR (400 MHz, CDCl₃) δ 4.19 (dq, J= 7.2, 1.8, 2H), 2.55-2.36 (m, 3H), 1.91 (ddd, J= 11.8, 6.8, 3.8, 1H), 1.89 (q, J= 0.9, 3H), 1.80 (q, J= 0.9, 3H), 1.43 (s, 3H), 1.27 (t, J= 7.2, 3H); ¹³C-NMR (400 MHz, CDCl₃): δ 197.8, 180.6, 154.2, 132.7, 48.2, 33.7, 33.4, 22.2, 18.1, 11.4; IR (neat): 2940, 1729, 1666 cm^-1; APCI (+): 183 ([M+H]⁺, 7), 139 (100), 111 (17).

4.2.40 (S)-(-)-Methyl 4-Oxo-1,2,3-trimethyl-2-cyclohexene-1-carboxylate (-)-(51)^25c

A mixture of 10.2 g (48 mmol) of (-)-53 in 60 mL of CH₃OH and 32 mL (62.4 mmol, 1.3 equiv) of 2M aq KOH was heated at reflux for 3 h. After cooling to rt and acidification to pH ≤ 1 with 10% aq hydrochloric acid, the solution was saturated with solid NaCl and extracted thoroughly four times with EtOAc. The combined organic phases were washed once with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. An analytical sample of acid (-)-55 was purified by chromatography and had [α]_D²⁵ -96 (c 0.989, CHCl₃).^25c Crude acid (-)-55 above was dissolved in 200 mL of acetone and 33 g (240 mmol) of K₂CO₃ and 5.4 mL (57 mmol) of (CH₃)₂SO₄ were added sequentially at rt and the mixture was heated at reflux with stirring for 2 h. After cooling to rt, 150 mL of 1.5M aq NaOAc was added and stirring was continued at rt overnight. The biphasic mixture was separated and the aq phase was extracted thoroughly four times with EtOAc.

The combined organic phases were washed once with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The residue was purified by chromatography (with elution by a gradient of hexanes/EtOAc 7:1 to 4:1) to afford 8.95 g of (S)-(-)-methyl 4-oxo-1,2,3-trimethyl-2-cyclohexene-1-carboxylate [(-)-51]^26c (95% from (-)-53) as a yellow oil: [α]_D²⁵ -93 (c 1.523, CHCl₃): IR (neat): 2951, 1732, 1669, 1428 cm^-1; ¹H-NMR (400 MHz, CDCl₃): δ 3.69 (3H, s), 2.49-2.32 (3H, m), 1.92-1.84 (1H, m), 1.84 (3H, q, J= 0.9), 1.75 (3H, bs), 1.40 (3H, s); ¹³C-NMR (100 MHz, CDCl₃): δ 197.2, 175.4, 154.1, 132.3, 52.3, 48.4, 33.7, 33.3, 22.1, 17.9, 11.3. APCI (+): 197 ([MH]⁺, 100), 169 (30), 137 (34).

4.2.41

The R series of derivatives 51 – 53 and 55, were prepared starting with R(+)-α-methyl benzylamine as shown below using the procedures described for the S series above:

4.2.41.1 Ethyl R-(+)-2-acetyl-2-methyl-5-oxo-heptanoate (+)-52^26a

[α]_D²⁵ +6 (c 5.113, CHCl₃); ¹H-NMR (400 MHz, CDCl₃): δ 4.20 (dq, J= 7.2, 0.9, 2H), 2.42 (q, J=7.3, 2H), 2.46-2.36 (m, 2H), 2.16 (ddd, J= 14.2, 9.5, 6.0, 1H), 2.16 (s, 3H), 2.06 (ddd, J= 14.2, 9.9, 5.9, 1H), 1.34 (s, 3H), 1.27 (t, J= 7.2, 3H), 1.05 (t, J= 7.3, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ 209.7, 205.0, 172.5, 61.2, 58.6, 37.0, 35.7, 28.4, 25.9, 19.1, 13.8, 7.6; IR (neat): 2981, 2940, 1713, 1461 cm^-1; APCI (+): 229 ([M+H]⁺, 10), 211 (51), 183 (17), 145 (85), 139 (100).

4.2.41.2 Ethyl R-(+)-1,2,3-trimethyl-4-oxo-3-cyclohexenylcarboxylate (+)-53^26c

[α]_D +84 (c 2.155, CHCl₃, 95% ee); ¹H-NMR (400 MHz, CDCl₃) δ 4.19 (dq, J= 7.2, 1.8, 2H), 2.55-2.36 (m, 3H), 1.91 (ddd, J= 11.8, 6.8, 3.8, 1H), 1.89 (q, J= 0.9, 3H), 1.80 (q, J= 0.9, 3H), 1.43 (s, 3H), 1.27 (t, J= 7.2, 3H); ¹³C-NMR (400 MHz, CDCl₃): δ 197.8, 180.6, 154.2, 132.7, 48.2, 33.7, 33.4, 22.2, 18.1, 11.4; IR (neat): 2940, 1729, 1666 cm^-1; APCI (+): 183 ([M+H]⁺, 7), 139 (100), 111 (17).

4.2.41.3 1,2,3-Trimethyl-4-oxo-cyclohex-2-enecarboxylic acid (+)-55^26c

[α]_D +96 (c 0.989, CHCl₃); ¹H-NMR (400 MHz, CDCl₃): δ 11.24 (s(br), 1H), 2.61-2.38 (m, 3H), 1.98-1.91 (m, 1H), 1.94 (d(br), J= 0.7, 3H), 1.78 (d(br), J= 0.7, 3H), 1.44 (s,3H); ¹³C-NMR (400 MHz, CDCl₃): δ 197.8, 180.6, 154.2, 132.7, 48.2, 33.7, 33.4, 22.2, 18.1, 11.4; IR (neat): 2940, 1729, 1666, 1452 cm^-1; APCI (+): 183 ([M+H]⁺, 7), 139 (100), 111 (17).

4.2.41.4 Methyl R-(+)-1,2,3-Trimethyl-4-oxo-cyclohex-2-enecarboxylate (+)-51^26c

[α]_D +93 (c 1.523, CHCl₃); ¹H-NMR (400 MHz, CDCl₃): δ 3.69 (3H, s), 2.49-2.32 (3H, m), 1.92-1.84 (1H, m), 1.84 (3H, q, J= 0.9), 1.75 (3H, bs), 1.40 (3H, s); ¹³C-NMR (100 MHz, CDCl₃): δ 197.1, 175.4, 154.2, 132.4, 52.3, 48.4, 33.7, 33.3, 22.0, 17.9, 11.3; IR (neat): 2951, 1732, 1669, 1428 cm^-1; APCI (+): 197 ([M+H]⁺, 100), 169 (30), 137 (34).

4.2.42 1S-(+)-4-[(E)-5'-t-Butyldiphenylsilyloxy-4'-methyl-2'-pentenyloxy]-1,3-dimethyl-2-methylene-cyclohex-3-ene (58)

Allylic triflate 31 was prepared in situ as follows: (E) 5-t-butyldiphenylsilyloxy-2-penten-1-ol (8.2 g, 24 mmol),⁴¹ and a catalytic amount of 1,10-phenantroline were dissolved in ~ 60 mL of dry ether and cooled to -78°C; n-BuLi was added until the equivalence point then, after 5 min, Tf₂O (4.2 mL, 25 mmol) was added quickly. After stirring for 10 min at -78°C the reaction mixture was transferred via cannula to a solution of the enolate as described below. A solution of 4.25 g (21.7 mmol) of (-)-51 (≥95% ee) in 40 mL of anh THF was added dropwise under Ar to KHMDS (4.12 g, 20.6 mmol) in anh THF (50 mL) at -78°C followed by addition of anh HMPA (20 mL) and the mixture was stirred for 30 min at -78°C, then warmed to rt and stirred for 2 h. After recooling the reaction mixture to -78°C, the solution of 31, prepared above, was added via cannula and stirring was continued for 30 min at -78°C. The reaction mixture was then poured into sat aq NaHCO₃ (350 mL) containing Et₃N (10 mL) and the resulting mixture was stirred at rt for 20 min. The reaction mixture was extracted with three 200 mL portions of EtOAc, and the organic layer was washed successively with water and brine, dried over K₂CO₃, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel (hexanes/ EtOAc 30:1 to 1:1 containing 2% of Et₃N) to afford 6.90 g (65%) of (+)-58 having [α]_D²⁵ +37 (c 2.142, Et O) and ¹H NMR (400 MHz, C₆D₆): δ 7.86-7.84 (m, 4H), 7.34-7.32 (m, 6H), 5.72 (dt, J₁ = 15.4, J₂ = 6.5 Hz, 1H), 5.58 (dt, J₁ = 15.4, J₂ = 5.5 Hz, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.09 (d(br), J = 5.5 Hz, 2H), 3.73 (t, J = 6.5 Hz, 2H), 3.43 (s, 3H), 2.50-2.41 (m, 1H), 2.39 (dd, J₁ = 12.7, J₂ = 6.0 Hz, 1H), 2.29 (q(br), J = 6.5 Hz, 2H), 2.14-2.05 (m, 1H), 2.09 (s, 3H), 1.58-1.53 (m, 1H), 1.50 (s, 3H), 1.26 (s, 9H); ¹³C NMR (100 MHz, C₆D₆): δ 176.0, 151.4, 147.9, 136.0, 134.2, 130.1, 129.9, 128.6, 128.0, 113.4, 106.3, 68.0, 63.7, 51.5, 46.8, 36.0, 32.6, 27.1, 24.1, 23.2, 19.4, 11.7; IR (neat): 2931, 1732, 1643, 1428 cm^-1; APCI (+): 519 ([M+H]⁺, 7), 441 (100), 197 (8); API-ES (+): 519 ([M+H]⁺, 85), 323 (28), 197 (100), 157 (79), 129 (42), 102 (23).

Owing to its sensitivity sensitivity, this material was used as obtained for the following transformation.

4.2.43 (-)-(4S)-2-[(E)-5'-tertbutylydiphenylsiloxypenten-3'(R)-yl)]-2,4-dimethyl-3-methylene-4-carbomethoxycyclohexanone (59)

Freshly distilled TiCl₄ (1.5 mL, 14.0 mmol) was dissolved in anh CH₂Cl₂ (75 mL) containing suspended powdered activated 4Å MS, and a 2M solution of Me₃Al in toluene (7.0 mL, 14.0 mmol) was added under Ar at –65°C. After 10 min, a solution of 58 (2.72 g, 5.22 mmol) in 25 mL of anh CH₂Cl₂ containing suspended powdered activated 4Å MS was added dropwise, and the deep purple reaction mixture was stirred for 25 min before dilution with tech Et₂O. Water was added and, after warming to rt, the salts were dissolved by addition of 1N aq HCl. The aqueous phase was extracted three times with portions of EtOAc and the organic layer was washed successively with brine containing NaHCO₃ and brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The residue was chromatographed using a gradient of hexanes/ EtOAc (6:1 to 1:1) to afford 2.03 g (75%) of (-)-59 ([α]_D²⁵ -26 (c 1.895, CHCl₃):; ¹H NMR (400 MHz, CDCl₃): δ 7.66-7.63 (m, 4H), 7.45-7.35 (m, 6H), 5.44 (dt, J₁ = 17.0, J₂ = 10.0 Hz, 1H), 5.30 (s,1H), 5.17 (s, 1H), 5.05 (dd, J₁ = 10.0, J₂ = 1.9 Hz, 1H), 4.96 (dd, J₁ = 17.0, J₂ = 1.9 Hz, 1H), 3.68 (ddd, J₁ = 10.1, J₂ = 6.4, J₃ = 3.4 Hz, 1H), 3.63 (s, 3H), 3.54 (dt, J₁ = 10.1, J₂ = 4.6 Hz, 1H), 2.80 (ddd, J₁ = 11.8, J₂ = 10.0, J₃ = 2.2 Hz, 1H), 2.65 (ddd, J₁ = 18.1, J₂ = 12.2, J₃ = 7.8 Hz, 1H), 2.43 (ddd, J₁ = 18.1, J₂ = 7.3, J₃ = 1.9 Hz, 1H), 2.28 (ddd, J₁ = 14.7, J₂ = 12.2, J₃ = 7.3 Hz, 1H), 2.09 (ddd, J₁ = 14.7, J₂ = 7.8, J₃ = 1.9 Hz, 1H), 2.02-1.94 (m, 1H), 1.49 (s, 3H), 1.25-1.17 (m, 1H), 1.20 (s, 3H), 1.05 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 210.9, 176.3, 151.4, 137.6, 135.5, 133.7, 133.6, 129.6, 127.6, 118.0, 115.5, 61.4, 58.7, 52.1, 46.4, 45.2, 35.6, 30.4, 30.3, 27.2, 26.8, 19.1, 17.1. IR (neat): 2952, 1732, 1428 cm^-1; APCI (+): 519 ([M+H]+, 79), 441 (100), 395 (18), 263 (25). HRMS. Calcd for C₃₂H₄₃O₄Si (M+H)⁺: m/z 519.2931. Found: 519.2929.

4.2.44 (+)-(2S, 5S, 7R, 8R)-5-Carbomethoxy-5,7-dimethyl-8-(1-ethenyl)-2-methoxy-4-methylene-1-oxabicyclo[4.4.0^2,7]decane (61)

AcOH (0.37 mL, 6.5 mmol) and TBAF (1M sol. in THF, 16.2 mL, 16.2 mmol) were added successively at r.t. to a solution of 15 (3.37 g, 6.5 mmol) in THF (20 mL). After stirring for 3 h, the reaction mixture was diluted with Et₂O and EtOAc and washed with brine. The organic phase was dried over Na₂SO₄, filtered and the solvent removed in vacuo. Chromatography (hexanes/EtOAc 5:1 to 1:1) afforded an isomeric mixture of hemiketals (1.85 g) that was directly protected by treatment with catalytic TsOH-H₂O in CH₃OH/CH(OCH₃)₃ (25 mL, 1:1 v/v) at r.t. for 1 h. After quenching with solid NaHCO₃ and dilution with Et₂O the organic phase was washed with water and brine, dried over Na₂SO₄, filtered and the solvent removed in vacuo to afford (+)-61 (1.90 g) as a single isomer. An analytical sample was purified by recrystallization in hexanes to afford pure (+)-61 mp 76°C-78°C having [α]_D²⁵ +147 (c 1.347, THF); ¹H-NMR (CDCl₃, 400 MHz): δ 6.33 (ddd, J₁ = 17.3, J₂ = 10.8, J₃ = 4.5 Hz, 1H), 5.48 (1H, s), 5.21 (1H, s), 5.06 (td, J₁= 4.5, J₂ = 2.1 Hz, 1H), 5.02 (td, J₁ = 10.8, J₂ = 2.1 Hz, 1H), 3.71-3.67 (m, 2H), 3.61 (s, 3H), 3.16 (s, 3H), 3.02-2.95 (m, 1H), 2.18-2.07 (m, 2H), 1.99 (dt, J₁ = 13.7, J₂ = 4.4 Hz, 1H), 1.80 (ddd, J₁=13.7, J₂ = 4.4, J₃ = 2.8 Hz, 1H), 1.57-1.52 (m, 1H), 1.38 (dt, J₁ = 13.7, J₂ = 4.2 Hz, 1H), 1.28 (3H, s), 1.04 (3H, s); ¹³C-NMR (CDCl₃, 100 MHz): δ 177.2, 149.7, 140.9, 115.0, 113.0, 101.1, 60.9, 51.7, 47.7, 47.2, 46.8, 42.5, 31.5, 27.2, 26.5, 24.8, 23.3; IR (neat): 3078, 2950, 2879, 1728, 1634, 1460, 1435 cm^-1; APCI(+): 295 ([M+H]⁺, 2), 263 (100), 233 (18), 203 (29), 173 (13); APIES (+): 317 ([M+Na]⁺, 100).

The crude mixed ketal, which a single compound by NMR, was used as obtained for the following transformation.

4.2.45 (+)-(2S, 5S, 7R, 8S)-5-Carbomethoxy-5,7-dimethyl-8-(2-hydroxyethyl)-2-methoxy-4-methylene-1-oxabicyclo[4.4.0^2,7]decane (62)

A solution of 61 (1.90 g, 6.5 mmol) in anhyd. THF (35 mL) was added dropwise (argon atmosphere, r.t.) to a solution of 9-BBN (1.60 g, 13 mmol) in anhyd. THF (25 mL). The mixture was stirred while temperature was slowly raised from r.t. to reflux and the mixture heated at reflux 1 h. After cooling to 0°C water was carefully added, followed by addition of NaBO₃.4H₂O (8.0 g, 52 mmol) and the mixture was stirred at r.t. for 20 h. After dilution with water, the aqueous phase was extracted with Et₂O; the combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered and the solvent removed in vacuo. The crude was purified by flash chromatography on silica gel to yield 1.76 g (87% from (-)-59, three steps) of (+)-62.having: [α]_D²⁵ +120 (c 1.020, THF); ¹H-NMR (C₆D₆, 400 MHz): δ 5.33 (s, 1H), 5.23 (s, 1H), 3.64-3.54 (m. 2H), 3.88-3.31 (m, 2H), 3.30 (s, 3H), 3.00 (s, 3H), 2.41-2.34 (m, 1H), 2.34 (ddd, J₁ = 13.1, J₂ = 4.3, J₃ = 2.8 Hz, 1H), 2.23 (dt, J₁ = 13.8, J₁ = 4.3 Hz, 1H), 2.15-2.04 (2H, m), 2.04-1.96 (2H, m), 1.86 (ddd, J₁ = 13.8, J₂ = 4.5, J₃ = 2.8 Hz, 1H), 1.65 (ddd, J₁ = 13.84, J₂ = 13.1, J₃ = 4.5 Hz, 1H), 1.41-1.32 (m, 2H), 1.29 (s, 1H), 1.20 (s, 1H), 1.19-1.14 (m, 2H), 0.91 (s(br), 1H); ¹³C-NMR (C₆D₆, 100 MHz): δ 176.9, 150.0, 114.9, 101.8, 63.4, 61.6, 51.3, 49.3, 47.3, 47.0, 37.3, 35.7, 32.2, 28.1, 27.6, 27.3, 22.9; IR (neat): 3440, 2951, 1727, 1634, 1436 cm^-1; APCI (+): 281 ([M+H]⁺-MeOH, 100), 113 (19); APIES (+): 335 ([M+Na]⁺, 100), 281 (18), 113 (11), 102 (43). HRMS (CI). Calcd for C₁₇H₂₈O₅: m/z 312.1931. Found: 312.1943.

4.2.46 (+)-(3R,4S,8R)-Methyl 4,8-Dimethyl-7-oxo-8-[(4R)-tetrahydro-2-oxo-2H-pyran-4-yl]-1-oxaspiro[2.5]octane-4-carboxylate (63)

A solution of 2.0 mL (28 mmol) of DMSO in 60 mL of anh CH₂Cl₂ was treated with 7.0 mL (14 mmol) of a 2M solution of (COCl)₂ in CH₂Cl₂ at –70°C under Ar and the mixture was stirred for 30 min at -70°C. A solution of 1.76 g (5.6 mmol) of (+)-62 in 35 mL of anh CH₂Cl₂ was then added and stirring was continued at the same temperature for 30 min. A 6.2 mL portion of anh Et₃N (45 mmol) was then added. After stirring at 0°C for 20 min and dilution with CH₂Cl₂, the reaction mixture was quenched with cold water and the aq. phase was extracted four times with CH₂Cl₂. The organic phase was washed successively with 1N aq HCl, sat NaHCO₃ and brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The residue was dissolved in a mixture of tBuOH (50 mL) and 2-methyl-2-butene (6 mL) and a solution of 3.2 g of 80% NaClO₂ (28 mmol) and 6.4 g of NaH₂PO₄.H₂O (45 mmol) in 25 mL of water was added at rt. The resulting mixture was stirred for 15 min then diluted with brine. The aq phase was saturated with NaCl and extracted thoroughly four times with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The residual crude acid was dissolved in 60 mL of CH₂Cl₂ and 1.4 g of NaHCO₃ (17 mmol) and 2.9 g of ~85% mCPBA (14 mmol) were added at rt. The resulting reaction mixture was stirred overnight at rt before quenching with sat aq NaHSO₃ at 20°C (with water bath cooling). The aq phase was extracted thoroughly with CH₂Cl₂, and the combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The residue was then dissolved in 30 mL THF and 30 mL of 10% aq HCl solution was added at 20°C (with water bath cooling) and the rersulting mixture was stirred at rt for 1.5 h. After thorough extraction of the reaction mixture four times with CH₂Cl₂, the combined organic phases were washed with sat NaHCO₃ and brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Flash chromatography (elution with a gradient of hexanes/EtOAc from 1:1 to pure EtOAc) afforded 1.26 g of 15 (73% from 12) as a white solid having mp 174-176°C (from heptane/CH₂Cl₂) and [α]_D²⁵ +19 (c 0.975, CHCl₃): ¹H NMR (CDCl₃, 400 MHz): δ 4.44 (dt, J₁ = 11.5, J₂ = 4.4 Hz, 1H), 4.22 (ddd, J₁ = 11.5, J₂ = 10.4, J₃ = 3.7 Hz, 1H), 3.70 (s, 3H), 3.09 (d, J = 3.9 Hz, 1H), 2.95 (ddd, J₁ = 17.9, J₂ = 11.5, J₃ = 5.9 Hz, 1H), 2.75 (d, J = 3.9 Hz, 1H), 2.66 (dt, J₁ = 14.8, J₂ = 5.5 Hz, 1H), 2.56 (dt, J₁ = 18.0, J₂ = 4.9 Hz, 1H), 2.51-2.40 (m, 3H), 1.99-1.76 (m, 3H), 1.43 (s, 3H), 1.00 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz): δ 210.2, 172.8, 170.5, 67.5, 61.1, 54.6, 52.1, 47.1, 46.6, 36.2, 33.9, 32.4, 28.1, 24.5, 24.1, 11.1. IR (neat): 2955, 1731, 1466, 1406 cm^-1. APCI (+): 311 ([M+H]+, 100), 293 (10), 233 (6). HRMS. Calcd for C₁₆H₂₃O₆ (M+H)⁺: m/z 311.1495. Found: 311.1504.

4.2.47 (+)-(3R,4S,8R) Methyl 4,8-Dimethyl-8-[(1R)-3-(3-furanyl)-1-(2-methylene carboxy)-3-oxopropyl]-7-oxo-1-oxaspiro[2.5]octane-4-carboxylate (65)

A solution of 1.50 g of 3-tributylstannylfuran²⁵ (4.2 mmol) in anh 5 mL of THF was cooled to –78°C and 2.3 mL of a 1.6M solution of n-BuLi in hexanes (3.7 mmol) was added and the resulting mixture was stirred for 1.5 h at –78°C. At which time, a solution of (+)-63 (501 mg, 1.6 mmol) in 15 mL of anh THF was added and stirring was continued at the same temperature for 15 min. The reaction mixture was then quenched with sat aq NH₄Cl, then the cold bath was removed. After warming to rt, the phases were separated and the aq phase was extracted thoroughly four times with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo.

Oxalyl chloride (2M solution in CH₂Cl₂, 0.4 mL, 0.81 mmol) was added, at –70°C and under argon atmosphere, over DMSO (0.11 mL, 1.6 mmol) in anhyd. CH₂Cl₂ (2.5 mL) and the mixture was stirred for 30 min; a solution of a portion of the crude lactol/alcohol 64 (100 mg, 0.27 mmol) prepared above in anh CH₂Cl₂ (2.5 mL) was then added and stirring was continued at the same temperature for 30 min before Et₃N (0.34 mL, 2.43 mmol) was added. After stirring at 0°C for 20 min. and dilution with CH₂Cl₂ the reaction was quenched with cold water and the aq. phase was extracted with CH₂Cl₂; the organic phase was washed with 1N aq. HCl, sat. NaHCO₃ and brine, dried over Na₂SO₄, filtered and the solvent removed in vacuo. The residue was dissolved in tBuOH (7 mL) and 2-methyl-2-butene (1 mL) and an aq. solution (3.5 mL) of NaClO₂ (80%, 209 mg, 1.8 mmol) and NaH₂PO₄.H₂O (408 mg, 3.0 mmol) was added at rt; the mixture was stirred for 15 min before brine was added, the aq phase was saturated with NaCl and extracted with EtOAc; the organic phase was washed with brine (once), dried over Na₂SO₄, filtered and the solvent removed in vacuo to afford 74 mg (70%) of the crude title acid 65 which was used as obtained in the following transformation.

4.2.48 (1S, 5R, 6R, 10S)-6,10-Dimethyl-2,12-dioxa-3,7,11-trioxo-5-[2-oxoethyl-2-(3-furanyl)]tricyclo[7.4.0^1,6.0^1,10]tridecane (66)

A sample of the preceding crude carboxylic acid 65 (145 mg, 0.37 mmol) was dissolved in CH₃CN (10 mL) and BF₃-Et₂O (0.27 mL, 2.1 mmol) was added at rt After stirring for 10 min. the reaction was quenched with sat. aq. NaHCO₃ and the aq phase extracted with EtOAc; the organic phase was washed with brine, dried over Na₂SO₄, filtered and the solvent removed in vacuo. Flash chromatography (elution by hexanes/EtOAc 2:1 to 1:1) yielded 55 mg (38%) of dilactone 66 as an oil having: ¹H-NMR (400 MHz, CDCl₃): δ 8.02 (dd, J₁= 1.4, J₂ = 0.9 Hz,1H), 7.47 (dd, J₁= 1.9, J₂ = 1.4 Hz,1H), 6.72 (dd, J₁= 1.9, J₂ = 0.9 Hz, 1H), 4.34 (d, J=10.9 Hz, 1H), 4.02 (d, J=10.9 Hz, 1H), 3.50-3.43 (m, 1H), 2.94 (dd, J₁= 18.7, J₂ = 6.2 Hz, 1H), 2.93 (ddd, J₁= 15.4, J₂ = 12.6, J₃ = 5.5 Hz, 1H), 2.69 (dd, J₁= 17.9, J₂ = 4.1 Hz, 1H), 2.53 (dd, J₁= 17.9, J₂ = 7.3 Hz, 1H), 2.39-2.25 (m, 3H), 1.93 (ddd, J₁= 14.4, J₂ = 12.3, J₃ = 4.4 Hz, 1H), 1.66 (s, 3H), 1.14 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃):δ 208.7, 190.9, 177.7, 166.6, 147.5, 144.6, 126.9, 108.2, 92.7, 72.8, 50.9, 47.1, 33.3, 32.3, 30.3, 30.1, 17.6, 10.1.IR (neat): 3138, 2924, 1784, 1715, 1681, 1564, 1511 cm^-1; APCI (+): 361 ([M+H]⁺, 100).

This material was used in the following transformation as obtained.

4.2.49 (1S, 5R, 6R, 10S)-6,10-Dimethyl-2,12-dioxa-3,11-dioxo-5-[2,2-dimethoxy ethyl-2-(3-furanyl)]-7-methoxy-tricyclo[7.4.0^1,6.0^1,10]tridec-7-ene (67)

Toluensulfonic acid hydrate (70 mg, 0.37 mmol) was added to a solution of bis-lactone 66 (50 mg, 0.14 mmol) in CH₃OH (8 mL) and CH(OCH₃)₃ (1.5 mL) at rt. The mixture was stirred at reflux (Dean-Stark system containing 3Å MS in the trap) for 19 h. After cooling and addition of solid NaHCO₃ the mixture was diluted with EtOAc and water was added, the aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. Chromatography of the crude product on silica gel (elution by hexanes/EtOAc 2:1 to 1:2) afforded 26.4 mg (45%) of 67 as an oil having: ¹H-NMR (400 MHz, CDCl₃): δ 7.42 (m, 2H), 6.18 (t, J=1.4, 1H,, 4.55 (dd(br), J₁= 7.4, J₂ = 2.4 Hz, 1H), 4.23 (d, J=10.4 Hz, 1H), 4.06 (d, J=10.4 Hz, 1H), 3.52 (s, 3H), 3.16 (s, 3H),, 3.06 (s, 3H), 2.88 (dd, J₁= 18.8, J₂ = 6.0 Hz, 1H), 2.54 (dd, J₁= 17.4, J₂ = 7.4 Hz, 1H), 2.27 (dd, J₁= 18.8, J₂ = 11.9 Hz, 1H), 2.21-2.13 (m, 1H), 1.90 (dd, J₁= 17.4, J₂ = 2.4 Hz, 1H), 1.87 (dd, J₁= 14.5, J₂ = 9.6 Hz, 1H), 1.80 (dd, J₁= 14.5, J₂ = 2.2 Hz, 1H), 1.16 (s, 3H), 1.05 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ 181.2, 168.8, 156.8, 143.7, 141.6, 126.0, 108.5, 101.5, 92.7, 91.3, 75.4, 55.0, 48.8, 48.5, 47.0, 43.2, 36.8, 32.9 (x2), 30.4, 23.0, 9.6. IR (neat): 2939, 1778, 1745, 1660 cm^-1; APCI (+): 389 ([MCH₃OH]⁺, 100), 195 (33), 151 (10); APIES (positive): 443 ([M+Na]⁺, 99), 301(65), 233 (100), 123 (74), 102 (46).

This material was used in the following transformation as obtained.

4.2.50 (1S, 4S, 5R, 6R, 10S)-2,12-Dioxa-3,11-dioxo-5-[2,2-dimethoxyethyl-2-(3-furanyl)]-7-methoxy-4,6,10-trimethyl-tricyclo[7.4.0^1,6.0^1,10]tridec-7-ene (68β) and (1S, 4R, 5R, 6R, 10S)-2,12-Dioxa-3,11-dioxo-5-[2,2-dimethoxyethyl-2-furanyl]-7-methoxy-4,6,10-trimethyl-tricyclo[7.4.0^1,6.0^1,10]tridec-7-ene (68α)

An 0.1M solution of LDA in THF-hexanes (1.5 mL, 3 equiv) was added at –78°C under inert atmosphere over a stirred solution of 67 (21 mg, 0.05 mmol) in anh THF (1.5 mL) and anh HMPA (0.25 mL). After stirring for 1 hour excess of CH₃I (0.75 mL, freshly filtered over Al₂O₃) was added and the mixture was stirred for 1 hour while warming to rt, then quenched with sat aq NH₄Cl (3 mL). The layers were separated and the organic phase was extracted with ether; the combined organic layers were washed with brine, dried over Na₂SO₄ and the solvent removed in vacuo. The crude material was chromatographed (elution with hexanes/EtOAc 3:1 to 2:1) to obtain 18.2 mg (84%) of 68 (68β/68α ~3:1). Alternatively the reaction was carried out at –78°C to obtain, after chromatography, 71% of 68β/68α ~6:1 and 23% of 67 as an oil having for the major isomer 68β: ¹H-NMR (400 MHz, CDCl₃): δ 7.41 (t, J= 1.7, 1H), 7.34 (s(br), 1H), 6.25 (dd, J₁= 1.7, J₂ = 0.7 Hz, 1H), 4.48 (dd(br), J₁= 7.3, J₂ = 2.5 Hz, 1H), 4.24 (d, J= 10.3 Hz, 1H), 3.48 (s, 3H), 3.25 (s, 3H), 3.18 (s, 3H), 2.82 (dt, J₁= 7.6, J₂ = 7.6 Hz, 1H), 2.52 (dd, J₁= 17.4, J₂ = 7.3 Hz, 1H), 2.39 (dd(br), J₁= 10.2, J₂ = 7.6 Hz, 2H), 2.29 (dd, J₁= 14.3, J₂ = 10.2 Hz, 1H), 1.91 (dd, J₁= 17.4, J₂ = 2.5 Hz, 1H), 1.68 (d(br), J = 14.3 Hz, 1H), 1.45 (d, J = 7.6 Hz, 3H), 1.25 (s, 3H), 1.07 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ 181.4, 178.8, 156.9, 143.4, 140.8, 126.3, 109.3, 102.2, 92.5, 91.7, 75.5, 54.8, 49.8, 48.5, 47.1, 44.1, 36.5, 33.5, 33.0, 32.6, 23.1, 17.2, 12.3; IR (neat): 2926, 1784, 1715, 1674, 1563, 1463, 1386 cm^-1; APCI (+): 403 ([M+H]⁺-CH₃OH, 100), 279 (7), 195 (51), 165 (12); APIES (+): 457 ([M+Na]⁺, 100).

This material was used in the following transformation as obtained.

4.2.51 (1S, 4S, 5R, 6R, 10S)-6,10-Trimethyl-2,12-dioxa-5-[2-oxoethyl-2-(3-furanyl)]-3,7,11-trioxotricyclo[7.4.0^1,6.0^1,10]tridecane (69β), (1S, 4R, 5R, 6R, 10S)- 2,12-dioxa-5- [2-oxoethyl-2-furanyl]-4,6,10- Trimethyl-3,7,11-trioxotricyclo[7.4.0^1,6.0^1,10] tridecane (69α) and (+)Saudin (1)

Major diastereomer 68β was deprotected by treatment with dilute hydrochloric acid in CH₃OH, controlling the temperature to prevent epimerization at C-4 by dissolving a few mg of 68β in CH₃OH (0.5 mL) and aq 1N HCl (0.5 mL) was added at rt. The mixture was stirred at rt for 18 h, then at 45°C (oil bath temperature) for 4 days. ¹H-NMR after evaporation to dryness showed a clean mixture of 69 and (+)-saudin (69β/69α/(+)-saudin ~2.5:1:1). Spectroscopic data for the Major isomer 69β: ¹H-NMR (400 MHz, CDCl₃): δ 8.07 (s(br), 1H), 7.48 (s(br), 1H), 6.75 (d(br), J = 1.5 Hz, 1H), 4.34 (d, J = 10.9 Hz, 1H), 3.60 (ddd, J₁= 9.1, J₂ = 7.8, J₃ = 3.7 Hz, 1H), 3.16 (dt, J₁ = 7.8, J₂ = 7.8 Hz, 1H), 2.95 (dd, J₁= 18.1, J₂ = 9.1 Hz, 1H), 2.86 (ddd, J₁= 15.4, J₂ = 12.9, J₃ = 6.0 Hz, 1H), 2.44 (dd, J₁= 18.1, J₂ = 3.7 Hz, 1H), 2.39 (dt, J₁= 15.4, J₂ = 4.6 Hz, 2H), 2.23 (ddd, J₁= 14.1, J₂ = 6.0, J₃ = 4.6 Hz, 1H), 1.89 (ddd, J₁= 14.1, J₂ = 12.9, J₃ = 4.6 Hz, 1H), 1.66 (s, 3H), 1.29 (d, J = 7.8 Hz, 3H), 1.17 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ 209.1, 191.1, 177.6, 171.3, 147.4, 144.7, 126.8, 108.3, 92.2, 72.9, 51.5, 47.0, 36.6, 34.9, 33.1, 29.9, 17.2, 15.7, 12.4; IR (neat): 2925, 1784, 1716, 1677, 1463, 1385, 1262, 1156, 1089, 1018, 970, 801 cm^-1. APCI (+): 375 ([M+H]⁺, 100), 200 (13), 122 (11).

4.2.52 (-)-(3R,4S,8R) Methyl 8-[(1R)-1-[2-(acetyloxy)ethyl]-3-(3-furanyl)-3-oxopropyl]-4,8-dimethyl-7-oxo-1-oxaspiro[2.5]octane-4-carboxylate (71)

A solution of 1.50 g of 3-tributylstannylfuran²⁵ (4.2 mmol) in anh 5 mL of THF was cooled to -78°C and 2.3 mL of a 1.6M solution of n-BuLi in hexanes (3.7 mmol) was added and the resulting mixture was stirred for 1.5 h at –78°C. At which time, a solution of (+)-63 (501 mg, 1.6 mmol) in 15 mL of anh THF was added and stirring was continued at the same temperature for 15 min. The reaction mixture was then quenched with sat aq NH₄Cl, then the cold bath was removed. After warming to rt, the phases were separated and the aq phase was extracted thoroughly four times with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The resulting crude alcohols 64 (and/or 70) was dissolved in 10 mL of CH₂Cl₂ and acetylated under standard conditions by treatment with 0.4 mL of Ac₂O, a catalytic amount of DMAP, and 1 mL of pyridine at rt for 1 h. After quenching the reaction mixture with sat aq NaHCO₃, the aqueous phase was extracted thoroughly four times with CH₂Cl₂ and the combined organic phases were washed successively with 1N aq HCl, sat NaHCO₃, and brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Flash chromatography (elution with a gradient of hexanes/EtOAc from 1.5:1 to 1:2) afforded 550 mg of (-)-71 (81% overall from (+)-63) having [α]_D²⁵ - 4 (c 1.785, CHCl₃): ¹H NMR (CDCl₃, 400 MHz): δ 8.02 (s(br), 1H), 7.42 (s(br), 1H), 6.69 (s(br), 1H), 4.11-3.99 (m, 2H), 3.66 (s, 3H), 3.26-3.17 (m, 1H), 3.16 (dd, J₁ = 18.5, J₂ = 6.2 Hz, 1H), 3.09 (d, J = 3.9 Hz, 1H), 2.93-2.81 (m, 1H), 2.75 (d, J = 3.9 Hz, 1H), 2.63 (dd, J₁ = 18.5, J₂ = 3.1 Hz, 1H), 2.52-2.43 (m, 3H), 2.04-1.97 (m, 1H), 1.97 (s, 3H), 1.60 (s, 3H), 1.55-1.46 (m, 1H), 0.84 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 212.5, 193.1, 173.4, 170.7, 147.0, 144.2, 127.0, 108.4, 62.0, 60.8, 55.8, 51.9, 46.9 (x2), 40.3, 37.0, 31.0, 29.5, 27.8, 24.8, 20.7, 10.1; IR (neat): 3139, 2955, 1732, 1681, 1563, 1368, 1156, 1044, 954, 735 cm^-1; APCI (+): 421 ([M+H]⁺, 56), 316 (100), 343 (10), 123 (9); HRMS. Calcd for C₂₂H₂₉O₈ (M+H)⁺: m/z 421.1862. Found: 421.1877.

4.2.53 7-(2-Acetyloxyethyl-2-carboxymethyl-2,6-dimethyl-9-(3-furanyl)-10,12-dioxa tricyclo [7.2.1.0^2,6]dodecane (+)-(72)

A 0.2 mL portion of BF₃.Et₂O (1.6 mmol) was added at rt to a solution of 84 mg of (-)-71 (0.2 mmol) in 5 mL of CH₃CN. After stirring for 10 min at rt, the reaction mixture was quenched with sat aq NaHCO₃ and the aq phase extracted thoroughly four times with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Flash chromatography on silica gel (elution with a gradient of hexanes/EtOAc from 2:1 to 1:1) provided 76 mg of (+)-72 (90%) having [α]_D²⁵ +46 (c 1.250, CHCl₃): ¹H NMR (CD₃CN, 400 MHz): δ 7.57 (s(br), 1H), 7.44 (t, J = 1.8 Hz, 1H), 6.46 (d(br), J = 1.8 Hz, 1H), 4.25 (d, J = 9.3 Hz, 1H), 4.17 (d, J = 9.3 Hz, 1H), 4.06-3.99 (m, 2H), 3.71 (s, 3H), 2.92 (dt, J₁ = 14.1, J₂ = 6.5 Hz, 1H), 2.40 (ddd, J₁ = 13.6, J₂ = 6.5, J₃ = 2.3 Hz, 1H), 2.14-1.80 (m, 7H), 1.98 (s, 3H), 1.31 (s, 3H), 1.11 (s, 3H); ¹³C-NMR (CD3CN, 100 MHz): δ 212.3, 176.1, 171.7, 144.4, 141.5, 127.5, 109.4, 105.6, 91.3, 68.9, 64.3, 56.0, 52.9, 47.4, 39.5, 37.2, 36.5, 33.7, 30.3, 22.7, 21.1, 18.9; IR (neat): 2954, 1732, 1604 cm^-1; APCI (+): 421 ([M+H]⁺, 6), 361 (100), 123 (14); API-ES (+): 443 ([M+Na]⁺, 100). HRMS. Calcd for C₂₂H₂₉O₈: m/z 421.1862. Found: 421.1860.

4.2.54 (1S, 4R, 6S, 13S, 14S)-13-Carbomethoxy-13,14-dimethyl-4-(3-furanyl)-8-oxo-3,9,15-trioxatetracyclo[8.3.1.1^1,4.0^6,14]tetradec-10-ene (-)-75

Solid K₂CO₃ (800 mg, 5.8 mmol) was added at 0°C to a solution of 485 mg of (+)-72 (1.15 mmol) in 10 mL of CH₃OH, then 1 mL of H₂O was added and the mixture was stirred for 1 h at rt. After dilution of the reaction mixture with EtOAc, the organic phase was washed with H₂O and brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The crude primary alcohol 73 (438 mg) was directly oxidized to carboxylic acid 74 as previously described above for the transformation of 64 into 65.

The resulting crude acid 74 (~1.15 mmol) was dissolved in 10 mL of anh CH₂Cl₂ in the presence of 471 mg of anh NaOAc (5.7 mmol) and and the mixture cooled to 0°C. A 1 mL portion of (CF₃CO)₂O (7.0 mmol) was added at 0°C, and the reaction mixture was stirred for 1 h while warming slowly from 0°C to rt. After quenching the reaction mixture with sat aq NaHCO₃, the aq phase was separated and extracted thoroughly four times with CH₂Cl₂. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Flash chromatography (a gradient of hexanes/EtOAc from 2:1 to 1:1) yielded 289 mg of (-)-75 (67% for 4 steps from (+)-72) as a white solid having mp 128-130°C (from hexanes/Et₂O/CH₂Cl₂) and [α]_D²⁵ -31 (c 0.995, CHCl₃): ¹H NMR (CDCl₃, 400 MHz): δ 7.51 (s(br), 1H), 7.41 (t, J = 1.9 Hz, 1H), 6.45 (d(br), J = 1.9 Hz, 1H), 5.35 (dd, J₁ = 4.6, J₂ = 3.2 Hz, 1H), 4.32 (d, J = 9.0 Hz, 1H), 4.28 (d, J = 9.0 Hz, 1H), 3.71 (s, 3H), 3.07 (dd, J₁ = 18.2, J₂ = 4.6 Hz, 1H), 3.06 (dd, J₁ = 18.9, J₂ = 6.8 Hz, 1H), 2.48-2.40 (m, 2H), 2.20 (dd, J₁ = 18.2, J₂ = 3.2 Hz, 1H), 2.09 (dd, J₁ = 13.0, J₂ = 5.7 Hz, 1H), 1.85 (t, J = 13.0 Hz, 1H), 1.41 (s, 3H), 1.19 (s, 3H); 13C NMR (CDCl₃, 100 MHz): δ 175.2, 165.9, 149.4, 143.4, 140.1, 125.6, 108.1, 105.5, 103.4, 85.9, 67.7, 52.3, 45.2, 40.2, 37.9, 32.0, 31.5, 22.8, 22.1; IR (neat): 2919, 1732, 1691, 1602 cm^-1; APCI (+): 375 ([M+H]⁺, 100), 279 (60). HRMS. Calcd for C₂₀H₂₃O₇ (M+H)⁺: m/z 375.1444. Found: 375.1459.

From the less polar fractions, 58 mg of the primary trifluoroacetate of alcohol 73 (12%) was also recovered which was recycled by hydrolysis to 73.

4.2.55 (1S, 4R, 6S, 7R, 13S, 14S)-13-Carbomethoxy-4-(3-furanyl)-8-oxo-7,13,14-trimethyl-3,9,15-trioxatetracyclo[8.3.1.1^1,4.0^6,14]tetradec-10-ene (-)-(76α)

A 1.45M solution of n-BuLi in hexane (0.56 mL, 0.81 mmol) was added dropwise at -78°C under Ar to a solution of 0.15 mL of 2,2,6,6-tetramethylpiperidine (0.92 mmol) in 5 mL of anh THF and the resulting mixture was stirred for 1 h. At -78°C, a solution of 193 mg (0.52 mmol) of (-)-75 in 10 mL of anh THF was then added dropwise at such a rate that the temperature did not rise. After stirring the resulting mixture for 2.5 h at -78°C, 0.56 mL of HMPA (3.2 mmol) was added dropwise, followed after 5 min by rapid addition of 3 mL of CH₃I (xs) via syringe. The temperature of the reaction mixture was slowly raised to -50°C and stirring was continued for 35 min at ~ -50°C. After quenching the reaction mixture at ~ -45°C with 10 mL of sat aq NH₄Cl and warming to rt, the aq phase was separated and extracted thoroughly four times with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Flash chromatography on silica gel (elution using a gradient of hexanes/EtOAc from 2:1 to 1:1) afforded 59 mg, (29%) of 76α, and 92 mg (46%) of 76β. Treatment of the 92 mg (0.24 mmol) sample of 76β in 5 mL of anh THF at -78°C with 1.5 mL (0.85 equiv) of a 0.14M solution of LDA in anh THF and warming with stirring to 0°C over 1.5 h then continued stirring at 0°C for 2 h followed by quenching, isolation, and purification as above afforded 82 mg (88%) of (-)-76α or a combined yield of 70% of (-)-76α having [α]_D²⁵ -14 (c 1.390, CHCl₃): ¹H NMR (CDCl₃, 400 MHz): δ 7.52 (s(br), 1H), 7.40 (t, J = 1.8 Hz, 1H), 6.46 (d(br), J = 1.8 Hz, 1H), 5.29 (dd, J₁ = 4.4, J₂ = 3.5 Hz, 1H), 4.30 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 9.0 Hz, 1H), 3.71 (s, 3H), 3.17 (dq, J₁ = 7.1, J₂ = 6.1 Hz, 1H), 3.11 (dd, J₁ = 18.4, J₂ = 4.4 Hz, 1H), 2.32 (ddd, J₁ = 11.7, J₂ = 6.1, J₃ = 5.5 Hz, 1H), 2.17 (dd, J₁ = 18.4, J₂ = 3.5 Hz, 2H), 2.13 (dd, J₁ = 13.3, J₂ = 5.5 Hz, 2H), 1.56 (t(br), J = 12.7, 1H), 1.41 (s, 3H), 1.25 (d, J = 7.1 Hz, 1H), 1.24 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.3, 169.5, 149.8, 143.3, 140.0, 125.9, 108.1, 104.9, 103.5, 86.0, 67.7, 52.3, 45.1, 39.5, 37.6, 35.3, 34.6, 31.5, 23.1, 22.3, 13.0; IR (neat): 2918, 1732, 1693 cm^-1; APCI (+): 389 ([M+H]⁺, 100). HRMS. Calcd for C₂₁H₂₅O₇ (M+H)⁺: m/z 389.1600. Found: 389.1615.

Traces of gem-dimethyl product 77 arising from polyalkylation and minor byproducts arising from an additional alkylation of a position on the furan ring were observed to be present in the crude alkylation product by ¹H-NMR.

4.2.56 (+)-Saudin (1)

A suspension of 56 mg of 76a (0.14 mmol) in 10 mL of 2N aq KOH was degassed with Ar and heated at reflux for 3.5 h. After cooling to rt and acidification with 10% hydrochloric acid to pH ≤ 1, the resulting aq phase was saturated with solid NaCl and extracted thoroughly four times with EtOAc. The combined organic phases were washed once with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The resulting 58 mg of crude diacid 78 was directly dissolved in 10 mL of anh 1,2-dichloroethane under Ar, and 0.7 mL of an 0.5M solution of TMSOTf in 1,2-dichloroethane (0.35 mmol) was added at rt. After stirring for 1 h at rt, an additional 0.3 mL of the 0.5M solution of TMSOTf in 1,2-dichloroethane (0.14 mmol) was added and stirring was continued for an additional 1 h. At which point, the reaction mixture was quenched with sat aq NaHCO₃, the phases separated, and the aq phase extracted thoroughly four times with EtOAc. The combined organic phases were washed once with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Flash chromatography of the residue afforded 36 mg (70%) of (+)-Saudin (1) having mp 204-206°C from Et₂O/EtOAc and [α]_D²⁵ +14 (c 0.460, CHCl₃). All spectroscopic properties [IR, ¹H NMR, ¹³C NMR, APCI (positive)] except the sign of the optical rotation were identical to those of an authentic sample of natural (-)-Saudin kindly provided by Professor J. S. Mossa.^1,2

Figure 5.

Scheme 23.

Scheme 24.