Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jan 18;145(4):2584–2595. doi: 10.1021/jacs.2c12529

Total Syntheses of Nominal and Actual Prorocentin

Raphael J Zachmann 1, Kenzo Yahata 1, Mira Holzheimer 1, Maxime Jarret 1, Cornelia Wirtz 1, Alois Fürstner 1,*
PMCID: PMC9896551  PMID: 36652728

Abstract

graphic file with name ja2c12529_0012.jpg

The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas a structural relationship cannot be missed and a biosynthetic link was proposed, it is currently unknown whether there is any parallel in the bioactivity profile of these natural products. However, it was insinuated in the past that the structure assigned to prorocentin might need to be revised. Indeed, re-examination of the published spectra cast doubts as to the constitution of the fused/spirotricyclic BCD-ring system in the core. To clarify this issue, a flexible synthesis blueprint was devised that allowed us to obtain the originally proposed structure as well as the most plausible amended structure. The key to success was late-stage gold-catalyzed spirocyclization reactions that furnished the isomeric central segments with excellent selectivity. The lexicon of catalytic transformations used to make the required cyclization precursors comprised a titanium-mediated ester methylenation/metathesis cascade, a rare example of a gold-catalyzed allylic substitution, and chain extensions via organocatalytic asymmetric aldehyde propargylation. A wing sector to be attached to the isomeric cores was obtained by Krische allylation, followed by a superbly selective cobalt-catalyzed oxidative cyclization of the resulting di-unsaturated alcohol with the formation of a 2,5-trans-disubstituted tetrahydrofuran; the remaining terminal alkene was elaborated into an appropriate handle for fragment coupling by platinum-catalyzed asymmetric diboration/oxidation. The assembly of the different building blocks to the envisaged isomeric target compounds proved that the structure of prorocentin needs to be revised as disclosed herein.

Introduction

Despite their rather simple morphology, many dinoflagellates comprise disproportionally large genomes that encode for secondary metabolites of stunning molecular intricacy.1 The members of the Prorocentrum genus are representative: as some of them cause severe ailment such as diarrhetic shellfish poisoning if they reach the human foodchain, their metabolomes were subject to intense scrutiny in the past. Belizentrin,2,3 belizeanolide,4 formosalides,5,6 prorocentroic acid,7 limaol,8,9 and okadaic acid10,11 are no more than a small selection that illustrates the diversity and complexity of natural products derived from these monocellular organisms (Scheme 1). Arguably, the most prominent among them is okadaic acid, which is an archetypical serine/threonine phosphatase inhibitor.12,13 As such, it became an indispensable tool for investigations into the role that these ubiquitous enzymes play in cellular signaling, cell cycle control, apoptosis, or tumor promotion. Moreover, okadaic acid exhibits cytotoxic, neurotoxic, genotoxic, immunotoxic, and potentially carcinogenic properties.12,13

Scheme 1. Selected Natural Products Derived from P. lima.

Scheme 1

Open in a new tab

The strain P. lima PL021117001 collected off the northern coast of Taiwan produces, in addition to okadaic acid, yet another secondary metabolite named prorocentin.14 Although the structural features and apparent constitutional “irregularities” found in both compounds suggest that they might share parts of the biosynthesis pathway, little more is known about the biological properties of prorocentin than its fairly modest cytotoxicity against two human cancer cell lines and the apparent lack of antimicrobial activity against Staphylococcus aureus.14

The proposed molecular structure of prorocentin (1) comprises a polyketide chain adorned with four pendant methyl substituents and 13 chiral centers (Scheme 2). An all-trans triene entity, two additional site-isolated olefins, four −OH groups, a trans-epoxide, a 6/6/6 trans-fused/spirocyclic triether core, and a 2,5-trans-configured tetrahydrofuran decorate the C39 (!) carbon framework. It is important to note that the isolation team has only elucidated the relative configuration of the tricyclic core and the tetrahydrofuran entity but could not determine the stereochemical relationship between these sectors.

Scheme 2. Structures of Prorocentin to be Considered. Comparison with Limaol.

Scheme 2

Open in a new tab

Equally unknown is the absolute configuration of prorocentin. We surmised, however, that it would be antipodal to the configuration (arbitrarily) drawn by the isolation team.14 This expectation was based on the close resemblance to the C40 polyketide limaol derived from a different P. lima strain harvested in Korea,8 the absolute configuration of which was recently confirmed by total synthesis.9 What makes this extrapolation somewhat uncertain, however, is a subtle yet distinct stereochemical divergence between these apparent siblings: specifically, the fused B-ring of prorocentin features a 2,6-cis arrangement, whereas the analogous ring in limaol is 2,6-trans-configured.

For a compound of such prominent biosynthetic pedigree, structural intricacy, and exceedingly short supply,15 prorocentin received surprisingly little attention from the synthetic community in the past. Only a model study directed toward the C22–C37 segment was published, from which no firm conclusion as to the unknown stereochemical interrelation between the core and the side chain could be drawn.16 This very preliminary report, which appeared in the press in 2011, stands in striking contrast to a short symposium proceeding published by the same group already a year earlier, which insinuates that a total synthesis had been completed at that time.17 Moreover, a structure revision for prorocentin was proposed: as shown in 2, the constitution of the B-ring was amended, although the reasons that led to this particular revision had not been outlined at all.17

Although certainly alerted by this preliminary report, the lack of any experimental data left us with no other choice than taking a fresh and unbiased approach. To this end, we started with a critical reassessment of the published nuclear magnetic resonance (NMR) data of the isolated natural product. Despite this exercise, we ultimately faced the need to make two different tricyclic core segments and join them to the appropriate side chains (potentially in both enantiomeric forms) in order to establish the correct constitution as well as the relative and absolute configuration of this challenging target compound. The successful completion of this ambitious project is reported below.

Results and Discussion

Reassessment of the Spectroscopic Data

A meticulous reevaluation of the published NMR spectra of prorocentin did indeed raise doubts concerning the proposed structure. Two data points were particularly alarming. First, the COSY spectrum contained in the Supporting Information of the isolation paper14 seems to lack the expected cross peak between H15 (δH = 3.55 ppm) and presumed H16 that supposedly resonates at δH = 3.80 ppm (Scheme 3). Rather, H15 seems to show a cross peak with a proton signal at δH = 1.41 ppm (for edited spectra, see the Supporting Information). This spectral fingerprint suggests that the branching site on the core (C15) is flanked by a −CH2– rather than a −CHOH group.

Scheme 3. Key Spectroscopic Features Fitting Better to the Revised Core Structure Comprised in 2.

Scheme 3

Open in a new tab

Certain NOESY data were also deemed suspicious. Specifically, the published spectrum shows a cross peak between the signal assigned to the presumably equatorially disposed H16 (δH = 3.80 ppm) and the axial H19 (δH = 3.00 ppm) at the bridgehead of the diether ring system; although such a cross peak cannot be excluded in the first place, the intensity of the signal is rather counterintuitive.14

Both observations speak for a structure in which the −OH group is shifted by one position from C16 to C17 and is—most likely—equatorially rather than axially disposed on the trans-decaline type diether scaffold. In this case, however, the signal of the axially oriented H18 is expected to be a dd (or t) as a consequence of two large J-couplings to the vicinal protons, whereas the isolation paper reports a multiplet at δH = 3.81 ppm. However, this spectral region is fairly crowded: most notably, putative H16 resonates at δH = 3.80 ppm (m),14 and signal overlap may have obscured the assignments. Anyway, these issues together with the too low resolution of the published spectra of the natural product did not allow us to reach a firm and unambiguous conclusion. Therefore, we felt the need to make both isomers 1 and 2, which only differ in their core region, in order to clarify the issue.

Strategic Considerations

In view of the size and complexity of the target and the outlook that more than one isomeric product might be needed to answer the open questions, a convergent assembly route was of key strategic relevance. Based on the lessons learned in our previous approach to limaol,9 a gold-catalyzed spirocyclization reaction of an appropriate alkyne precursor was deemed the ideal gateway to the isomeric tricyclic BCD ring systems in 1 and 2 (Scheme 4).18−22 An alkyne is a ketone surrogate that allows potential sensitivity issues associated with the use of highly functionalized carbonyl compounds to be avoided altogether; on treatment with a carbophilic Lewis acid, however, the triple bond is amenable to highly chemoselective activation in the presence of other π-bonds and heteroatoms alike.23

Scheme 4. Retrosynthetic Analysis.

Scheme 4

Open in a new tab

Moreover, an alkyne should pay additional dividends during the assembly process. In the present case, it invites coupling of the respective “central” segment III (or V) and the “eastern” building block IV via a Sonogashira reaction.24 Although we were prepared to make the latter in both enantiomeric forms in view of the uncertain interrelation between the core and side chain, a model exercise in computational spectroscopy had suggested that the depicted antipode of IV is the much more likely candidate.25 In any case, the allylic alcohol terminus present in the core would then serve for the installation of the yet missing trans-epoxide, followed by attachment of the lateral polyunsaturated side chain I. As already mentioned above, we chose to make the synthons with the absolute configuration shown in Scheme 4 based on the expectation that prorocentin and limaol might belong to the same enantiomeric series. If correct, these premises reduce the synthetic burden in that only the two isomeric central fragments III and V and the two wing sections I and IV need to be prepared; these building blocks can then be elaborated into the conceived product structures 2 and 1, respectively, by a chemically highly conserved assembly process and endgame.

Western Fragment

Commercial propynylmagnesium bromide was quenched with iodine, and the resulting crude alkynyl iodide coupled with 3-butyn-1-ol to furnish diyne 3 (Scheme 5). Upon treatment with LiAlH4, this compound underwent a hydroxy-directed trans-reduction to give enyne 4.26

Scheme 5. Western Fragment.

Scheme 5

Open in a new tab

Reagents and conditions: (a) (1) I2, THF, −78 °C; (2) but-3-yn-1-ol, CuI (15 mol %), pyrrolidine, −78 °C to RT, 68%; (b) LiAlH4, THF, 53%; (c) Bu3SnSnBu3, BuLi, CuCN, H2O, THF, −78 to −40 °C, then 4, −10 °C, 78%; (d) TBSCl, imidazole, DMAP (20 mol %), 95%; (e) 6, Pd(PPh3)4 (10 mol %), CuTC, Ph2PO2NBu4, DMF, E/Z ≈ 10:1; and (f) Na2WO4 (25 mol %), aq H2O2, MeOH/benzene, 0 °C to RT, 63% (over both steps).

The subsequent stannylcupration with excess Bu3SnLi/CuCN in protic medium at low temperature gave stannane 5 with appreciable selectivity.27 After protection of the primary alcohol, the compound was subjected to Stille–Migita coupling with the known alkenyl iodide 6(28) under conditions previously developed in this laboratory for particularly sensitive substrates.29,30 Even then, partial isomerization could not be fully suppressed; this issue, however, was readily solved since the all-E configured product could be separated from isomeric compounds after oxidation of thioether 7 to the corresponding phenyl sulfone 8 in readiness for late-stage fragment coupling.

Eastern Fragment

Because of excellent previous experiences with the cobalt-catalyzed oxidative Mukaiyama cyclization of unsaturated alcohols,31−33 we resorted to this transformation for the formation of the 2,5-trans-disubstitued tetrahydrofuran ring contained in the eastern sector of prorocentin, using compound 10 as the substrate (Scheme 6).34 Although the secondary alcohol is flanked by two different alkenes, we have previously shown that the desired oxidative 5-exo-trig cyclization outcompetes other conceivable reaction modes.34a This substrate was best prepared from commercial 9 and allyl acetate by means of an asymmetric Krische allylation using [Ir(cod)Cl]2 as a precatalyst in combination with the BIPHEP ligand 20.35 Since alcohol 10 is rather volatile, the yields were consistently better when the reaction was performed on a larger scale; it is distinguished by an excellent level of induction (96% ee).36

Scheme 6. Eastern Fragment.

Scheme 6

Open in a new tab

Reagents and conditions: (a) allyl acetate, [Ir(cod)Cl)]2 (2.5 mol %), 20 (5 mol %), Cs2CO3, 4-chloro-3-nitrobenzoic acid, THF, 81% [2 g scale], 96% ee; (b) 21 (10 mol %), tBuOOH, iPrOH, O2, 55 °C, dr > 20:1, 72% [4 g scale]; (c) PIDA, TEMPO (30 mol %), MeCN, H2O, 86% [3.3 g scale]; (d) N,O-dimethyl hydroxylamine hydrochloride, CDI, CH2Cl2, 89% [2.8 g scale]; (e) (1) 2-methyl-1-propenylmagnesium bromide, THF, 0 °C; (2) DBU cat., CH2Cl2, 98% [2.1 g scale]; (f) NaBH4, CeCl3·7H2O, MeOH, −78 °C, dr > 20:1, 94% [2.0 g scale]; (g) 2-(bromomethyl)naphthalene, NaH, TBAI, THF/DMF (2:1), 90% [0.6 g scale]; (h) (1) Pt(dba)3 (3 mol %), 22 (4 mol %), B2pin2, THF, 60 °C; (2) NaBO3·4H2O, THF/H2O, dr > 20:1, 76% [2.1 g scale]; (i) NaH, THF, then 24, 0 °C to RT; (j) 23, CuCN (10 mol %), THF, 0 °C, 74% (over both steps) [850 mg scale]; (k) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to RT, 99% [200 mg scale]; (l) NIS, 2,6-lutidine, HFIP, THF, 0 °C, 80% [260 mg scale]; (m) TBAF, HOAc, THF, 83% [220 mg scale]; (n) DDQ, CH2Cl2, pH 7 buffer, 98% [110 mg scale]; the scales of substrates shown in this and the other schemes refer to the single largest batches.

As expected, this di-unsaturated compound underwent a highly selective cobalt-catalyzed oxidative etherificaton to furnish the desired trans-configured THF derivative 11 in 72% yield as the only isomer; to this end, cobalt complex 21 proved optimal.37,38 Subsequent oxidation of the newly formed primary alcohol to the corresponding acid was followed by elaboration into enone 13 by the addition of 2-methyl-1-propenylmagnesium bromide to Weinreb amide 12. Somewhat unexpectedly, the crude material contained variable amounts of ketone with the double bond out of conjugation; exposure to catalytic DBU rectified the outcome and gave the desired product in almost quantitative yield. Equally rewarding was the excellent diastereoselectivity with which the carbonyl group of 13 could be reduced to the required allylic alcohol under Luche conditions.39 To secure stability as well as ready deprotection at a later stage, the −OH group was converted into the corresponding 2-naphthylmethyl (rather than a simple benzyl) ether 14 prior to transformation of the alkene terminus into the functionality needed for the envisaged late-stage fragment union.40,41

After some experimentation, it was found that a platinum-catalyzed asymmetric diborylation/oxidation sequence under the auspices of 22 as the ligand served this purpose very well.42,43 The reaction furnished diol 15 in 76% yield (dr > 20:1) and proved nicely scalable.36 Upon treatment with excess NaH and the bulky sulfonyl imidazole derivative 24, the diol was converted into the corresponding epoxide, which was immediately subjected to ring opening with the silylated Grignard reagent 23 in the presence of catalytic CuCN to give product 16 in good overall yield.44

This compound is stable for extended periods of time and therefore served as the “stock form” of the eastern fragment. Prior to use, however, the alkenylsilane must be converted into an alkenyl halide. All attempts at affecting this transformation in the presence of the unprotected C26–OH group (prorocentin numbering) failed;45 the ether derivative 19 was the only detectable product in the crude mixture. The problem was remedied by transiently capping the −OH group as TBS-ether, which underwent clean iodo-desilylation on treatment with NIS in CH2Cl2/HFIP to furnish alkenyl iodide 17;46 the medium was supplemented with 2,6-lutidine to ensure a basic pH in order to keep the silyl ether intact at all time. Only after the iodo-desilylation had been completed, the silyl and naphthylmethyl protecting groups were successively removed with the aid of TBAF/HOAc and DDQ, respectively, to give product 18 in readiness for fragment coupling.41

It is also worth mentioning that access to the enantiomeric form of this building block could follow the exact same route since all critical stereodetermining transformations are under ligand control. As will be shown below, however, it actually proved unnecessary to make ent-18 in order to complete the project.

“Original” Central Fragment

Based on our hypothesis concerning the absolute configuration of prorocentin, 2-deoxy-d-ribose was chosen as the entry point for the synthesis of the central fragment composed in the originally proposed structure 1 (Scheme 7). A literature-known sequence of Wittig reaction, thermodynamic acetalization, and TBS protection afforded multigram quantities of product 25.47 Next, ozonolysis followed by Carreira alkynylation48 with TBS-protected propargyl alcohol as the reagent and global desilylation led to triol 26, again on scale. After Lindlar hydrogenation of the triple bond, which proceeded without significant amounts of overreduction only when performed in a non-protic medium at 0 °C,49 the resulting product 27 served the formation of the distinguishing 2,6-cis configured future B-ring very well. Specifically, this rather challenging stereochemical pattern was set by gold-catalyzed allylic substitution under buffered conditions.50 The reaction is convenient as the alcohol to be activated does not need to be converted into a better leaving group; rather, the triol 27 can be used as is. We found that the reaction was best carried out with the cationic gold complex 36; under these conditions, a high yield was secured on a gram scale. Most importantly, however, the observed stereoselectivity was excellent, and the outcome matched the prediction, as confirmed by X-ray diffraction analysis of the resulting product 28 (see the Supporting Information). Esterification on treatment with methacryloyl chloride led to diene 29, which is polymerization-prone and therefore needed to be processed without delay. As expected, treatment with the second-generation Hoveyda–Grubbs-type catalyst 37(51) transformed this substrate into the corresponding unsaturated lactone by RCM.52 For the curvature of this rigid tricyclic olefin, simple hydrogenation over Pd/C sufficed to give 30 as the only product, in which the methyl branch is properly set, as confirmed by NOESY data. Semi-reduction of the lactone with Dibal-H in CH2Cl2 was followed by chain extension of the resulting hemiketal via Wittig olefination to form enoate 31 in good yield.

Scheme 7. Core of Nominal Prorocentin.

Scheme 7

Open in a new tab

Reagents and conditions: (a) Ph3P=CHCOOEt, THF, reflux; (b) pMeOC6H4CH(OMe)2, CSA (20 mol %), CH2Cl2; (c) TBSCl, imidazole, DMF, 49% (over three steps) [10 g scale]; (d) O3, CH2Cl2, −78 °C, then PPh3, 92% [2.4 g scale]; (e) TBSOCH2C≡CH, Zn(OTf)2, (−)-N-methylephedrine, Et3N, toluene; (f) TBAF, THF, dr > 20:1, 65% (over both steps) [5 g scale]; (g) H2, Lindlar catalyst, quinoline, EtOAc, 0 °C, 91% [2.6 g scale]; (h) 36 (5 mol %), 2,6-di-tert-butylpyridine (15 mol %), THF/CH2Cl2, MS 4 Å, dr > 20:1, 86% [950 mg scale]; (i) methacryloyl chloride, Et3N, DMAP (15 mol %), CH2Cl2, 86% [765 mg scale]; (j) 37 (15 mol %), toluene, reflux, 67–77% [1.3 g scale]; (k) Pd/C, H2 (1 atm), EtOAc, dr > 20:1, 95% [1.05 g scale]; (l) Dibal-H, CH2Cl2, −78 °C, 96% [1.01 g scale]; (m) Ph3P=CHCOOEt, THF/toluene, 80 °C, 58–74% [970 mg scale]; (n) Dibal-H, THF, −78 °C, quant. [670 mg scale]; (o) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 90% [330 mg scale]; (p) Dibal-H, CH2Cl2, −78 °C, 93% [600 mg scale]; (q) oxalyl chloride, DMSO, Et3N, CH2Cl2, −78 °C; (r) 38, 39 (30 mol %), toluene, 68% (over both steps) + 16% of isomer [500 mg scale]; (s) Ac2O, pyridine, DMAP (10 mol %), CH2Cl2, quant. [460 mg scale]; and (t) DDQ, CH2Cl2, pH 7 buffer, 66% [500 mg scale].

Subtle differences in reactivity deserve mentioning at this point. While the lactone carbonyl of 30 was readily reduced with Dibal-H in CH2Cl2, the conversion of the ester group in 31 to the corresponding allylic alcohol mandated the use of excess Dibal-H in THF. This reagent left the p-methoxybenzylidene acetal intact even on prolonged stirring; in CH2Cl2, in contrast, Dibal-H eventually allowed the acetal ring of 32 to be cleaved and the primary alcohol 33 to be secured in high yield on gram scale.

Oxidation to the corresponding aldehyde was best performed under Swern conditions.53 The subsequent asymmetric propargylation proceeded nicely under an organocatalytic setting originally developed by Schaus and Barnett for ketones,54 which we had already adapted to elaborate aldehyde substrates in our total synthesis of limaol.9,55 A Mosher ester analysis confirmed that the newly formed alcohol of the major product had been properly set.36 Simple adjustment of the protecting groups converted compound 34 into the central fragment 35 to be incorporated into nominal prorocentin as outlined below.56

“Revised” Central Fragment

Because of the different oxygenation pattern of the revised central BCD ring system, a more involved route had to be devised. It starts with the conversion of d-glucose into β-hydroxy aldehyde 44 on a multigram scale (Scheme 8).57,58 Although α-branched and hence expected to be more amenable to asymmetric Carreira alkynylation than the corresponding aldehyde passed through en route to product 26,48 the reaction with propyne as the nucleophile essentially met with failure; this result came as a surprise since our group (and others) had already performed successful asymmetric propynylations under these conditions in the past.59−61 This setback forced us to pursue a three-step workaround, commencing with the high-yielding addition of propynylmagnesium bromide to 44, oxidation of the mixture of diastereomeric alcohols 45 thus formed with MnO2, followed by stereoselective-modified Noyori-type transfer hydrogenation of the resulting ynone using the tethered ruthenium catalyst 57.62,63

Scheme 8. Revised Core.

Scheme 8

Open in a new tab

Reagents and conditions: (a) 43 (0.03 mol %), H2 (15 bar), MeOH, 98% ee, quant. [8.5 g scale]; (b) BH3 SMe2, THF, −30 °C; (c) TBSCl, imidazole, CH2Cl2, 92% (over both steps) [8.5 g scale]; (d) LiOH, THF, MeOH, H2O, 0 °C to RT, quant. [13.1 g scale]; (e) pMeOC6H4CH(OMe)2, pTsOH·H2O, DMF; (f) NaIO4, NaOAc, HOAc, aq MeOH, 56% (over two steps) [11 g scale]; (g) propynylmagnesium bromide, THF, dr = 2:1, 81% [4.2 g scale]; (h) MnO2, CH2Cl2, 61% [8 g scale]; (i) 57 (5 mol %), HCOOH/Et3N, CH2Cl2, dr > 20:1, 91% [4.8 g scale]; (j) TBSCl, imidazole, CH2Cl2, 87% [4.4 g scale]; (k) 42, EDC, DMAP, CH2Cl2, 97% [1.4 g scale]; (l) H2 (1 atm), Lindlar catalyst, quinoline (30 mol %), EtOAc, 0 °C, 98% [7.1 g scale]; (m) 58, THF/toluene, 47% [7 g scale]; (n) H2 (1 bar), Pt/C cat., EtOH, 0 °C, dr > 20:1, 74–83% [3.2 g scale]; (o) TBAF, THF, 81% [2.4 g scale]; (p) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C; (q) Ph3P=CHCOOMe, CH2Cl2, 86% (over both steps) [1.1 g scale]; (r) Dibal-H, THF, −78 °C, 83% [1.1 g scale]; (s) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 95% [940 mg scale]; (t) Dibal-H, CH2Cl2, −78 °C, 87–93% [1.45 g scale]; (u) oxalyl chloride, DMSO, Et3N, CH2Cl2, −78 to 0 °C; (v) 38, 39 (30 mol %), toluene, dr > 20:1, 44–59% yield (over two steps) [1.16 g scale]; (w) Ac2O, pyridine, DMAP, CH2Cl2, 90% [610 mg scale]; and (x) DDQ, CH2Cl2, pH 7 buffer, 77% [580 mg scale].

The selective protection of the propargylic site proceeded uneventfully on scale, thus setting the stage for the esterification of the remaining −OH group in 46 with acid 42. This compound, in turn, derives from itaconic acid monoester 40 by asymmetric hydrogenation using the particularly effective rhodium catalyst 43,64,65 chemoselective reduction of acid 41 with borane, and subsequent adjustment of the protecting groups.

With compound 47 in hand, the stage was set for one of the most demanding transformations of the entire total synthesis endeavor reported herein. In careful consideration of the pertinent literature,66−68 the triple bond in 47 was first reduced to the corresponding Z-alkene 48.69 When treated with a large excess of Tebbe’s reagent (58), best generated in situ from Cp2TiCl2 and Me3Al,70 in a mixture of THF and toluene, the ester group first succumbed to olefination with the formation of enol ether 49. On prolonged stirring, diene 49 reacted further to give the desired cyclic enol ether 50. Although the yield of product was only 47%, this olefination/metathesis cascade could be performed on a >7 g scale, such that a good material throughput was secured. In contrast to what the literature precedent had suggested, however, the use of the Petasis reagent in lieu of the original Tebbe complex failed to afford product 50;66 rather, the reaction invariably stopped at the stage of 49. The same is true for the Takai–Utimoto reagent, which did not induce ring closure either.71 All attempts at converting 49 in a separate step into the cyclic enol ether 50 with the aid of classical Schrock or Grubbs-type catalysts for olefin metathesis were to no avail either.69,72

The hydrogenation of 50 proceeded stereoselectively to set the distinctive 2,6-cis-substitution pattern of the B-ring of prorocentin;73 this outcome is clearly manifested in the J-coupling pattern of the protons on the rim. Of all catalysts tested, only platinum on charcoal in EtOH gave well reproducible results without jeopardizing the aromatic ring of the p-methoxybenzylidene acetal. Although the selective deprotection of the primary TBS-ether in 51 is possible with HF·pyridine in pyridine, it was not overly high yielding (66%). Rather, it proved advantageous to cleave both silyl groups at the same time and subject the resulting diol 52 to a pleasingly effective mono-oxidation. As it turned out, Dess–Martin periodinane74 in CH2Cl2 at 0 °C transformed the primary alcohol into the corresponding aldehyde without touching the secondary −OH group to any noticeable extent. The crude product was then subjected to chain extension by Wittig olefination, and the resulting ester 53 was reduced with Dibal-H in THF.

From this point onward, the route follows the steps described above for the original core segment 35. Thus, reduction of the ester terminus of 53 was followed by protection of both −OH groups in the resulting product, which furnished silyl ether derivative 54. This compound was subjected to regioselective cleavage of the acetal on treatment with Dibal-H in CH2Cl2. The resulting primary alcohol was oxidized, and the aldehyde thus formed was instantly subjected to ligand-controlled asymmetric propargylation,54 which afforded 55 as the only detectable product.36 Acetylation, followed by oxidative cleavage of the PMB-ether, furnished the fully functional core segment 56 as needed for the projected end game.

Actual Prorocentin

With good amounts of all the required building blocks in hand, the completion of the total syntheses of the two conceived targets 1 and 2 could be performed in parallel. Although the individual products of the two series are isomeric to each other, only minor differences were observed from the chemical point of view. Therefore, the discussion can be focused on the conquest of actual prorocentin.

The first critical fragment union consisted of the palladium-catalyzed Sonogashira coupling of the terminal alkyne 56 with the eastern fragment 18 (Scheme 9).24 The reaction proceeded slowly but cleanly, provided iPr2NH was chosen as the reaction medium. Gratifyingly, the resulting polyfunctionalized enyne 59 was well behaved in the subsequent gold/Brønsted acid co-catalyzed spirocyclization, which afforded product 62 as the only isomer in 69% yield. It is the gold catalyst 36 that triggers the decisive first 6-endo-dig cyclization by the attack of the C26–OH group onto the distal end of the triple bond; as a result, the required 6/6-spirocyclic array ultimately prevails over all other conceivable regioisomeric spiroacetals.75 The resulting enol ether 60 is then likely activated by the admixed PPTS co-catalyst to generate a reactive oxocarbenium cation 61 in situ, which gets trapped by the sterically more hindered secondary C18–OH group residing on the pre-existing tetrahydropyran ring.76 As this second step is reversible, the exclusive formation of the doubly anomeric array of 62 is readily understood. Moreover, we suppose that the observed selective migration of the exo-methylene group to the endocyclic position also occurs upon protonation of enol ether 60.77,78 This order of events can be inferred from model studies in a closely related series (see the Supporting Information).

Scheme 9. Completion of the Total Synthesis of Actual Prorocentin.

Scheme 9

Open in a new tab

Reagents and conditions: (a) Pd2(dba)3 (5 mol %), CuI (20 mol %), PPh3 (20 mol %), iPr2NH, 91% [200 mg scale]; (b) 36 (10 mol %), PPTS (10 mol %), CH2Cl2, 69% [71 mg scale]; (c) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 92% [145 mg scale]; (d) HF pyridine, pyridine, 92% [152 mg scale]; (e) Ti(OiPr)4 (15 mol %), l-(+)-DIPT, cumene hydroperoxide, CH2Cl2, −25 °C, dr > 20:1, 84% [40 mg scale]; (f) I2, PPh3, imidazole, CH2Cl2, 0 °C, 88% [34 mg scale]; (g) 8, nBuLi, THF, DMPU, then 63, −78 to −60 °C, dr ≈ 3:2, 86% [34 mg scale]; (h) (1) LiBHEt3, THF, −78 to −20 °C; (2) [(dppp)PdCl2] (10 mol %), LiBHEt3, −10 °C, 49% [34 mg scale]; and (i) HF pyridine, THF, pyridine, 50% (40% HPLC).

The completion of the total synthesis commenced by unveiling the primary allylic alcohol, which underwent a Sharpless epoxidation to introduce the yet missing trans-configured oxirane.79 Subsequent conversion of the −OH group into the corresponding primary iodide 63 was followed by C-alkylation of the deprotonated sulfone 8 to complete the carbon framework of prorocentin; neither the oxirane nor the acetate group of 63 interfered with this step, and the sensitive triene subunit also remained untouched as long as the reaction was carried out at low temperature in THF/DMPU.80 Product 64 thus formed was then treated with LiBHEt3 in THF to first cleave the axially disposed acetate decorating the C-ring.81 The mixture was then supplemented with catalytic [(dppp)PdCl2], followed by a second portion of LiBHEt3; this reagent combination entailed desulfonation by the formation of a transient allylpalladium species upon insertion into the allylic sulfone, followed by trapping of this intermediate by the admixed hydride donor.82,83 This delicate one-pot maneuver left the epoxide ring and the triene entity intact, although the desired product was isolated in modest 49% yield as the only defined compound present in the crude reaction mixture. Global deprotection with buffered HF pyridine in THF/pyridine then afforded product 2.

As foreshadowed by the reassessment of the published NMR data of the natural product and in line with the preliminary conference proceeding,17 it is this structurally revised compound 2 which represents prorocentin; the perfect match of the recorded and the reported 1H and 13C NMR data leaves no doubt whatsoever (for details, see the Supporting Information). Moreover, the rotatory power of our synthetic samples of 2 [[α]D25 = −12.0 (c 0.1, MeOH)] corresponds very well to the literature [[α]D = −12.7 (c 0.2, MeOH)].14 This comparison also confirms our original assumption that prorocentin and limaol belong to the same enantiomeric series.

Nominal Prorocentin

Although the spectral and analytical data of synthetic 2 left no room for surprise, we nevertheless completed the total synthesis of nominal prorocentin (1) as the target structure originally proposed by the isolation team (Scheme 10).14 Starting from the isomeric central fragment 35, the route leading to this target compound followed the exact same steps and therefore does not need detailed comments. An exception is the gold-catalyzed spiroketalization; although again high yielding, the reaction was slightly less selective in regioisomeric terms. In addition to the desired 6/6/6 fused/spirotricyclic product 67, small but non-negligible amounts of the 6/7/5 configured product 66 were detected. This side reaction suggests that the secondary C18–OH group flanked by a methylene unit in the cyclization precursor 65 is less hindered than that in compound 59, which resides adjacent to a bulky TBS-ether; for this gentle relief of steric pressure, this hydroxy group starts to interfere in the actual gold-catalyzed hydroalkoxylation of the triple bond, although the attack by the C26–OH is still dominant. Gratifyingly, the isomeric spiroacetal 66 could be removed by flash chromatography, and the synthesis of 1 could hence be completed with pure 67 in analogy to what has been described above (for the full Scheme, see the Supporting Information).

Scheme 10. Completion of the Total Synthesis of Nominal Prorocentin.

Scheme 10

Open in a new tab

Reagents and conditions: (a) Pd2(dba)3 (5 mol %), CuI (20 mol %), PPh3 (20 mol %), iPr2NEt, THF, 99%; and (b) 36 (10 mol %), PPTS (10 mol %), CH2Cl2, 67:66 ≈ 10:1 (NMR), 84%.

The spectral properties of 1 clearly deviate from those of the natural product. Indeed, it is the regions exo as well as endo about the branching point C15 that are unmistakably at variance with the reported data. The originally proposed structure of prorocentin (1) is hence definitely incorrect and needs to be replaced with the isomeric structure 2, which depicts the correct constitution and stereostructure of this intriguing marine natural product.

Conclusions

In the past, our group—like many others—had to revise the structure (and/or the proposed bioactivity) of numerous presumed natural products;84,85 the prorocentin case is another important entry in this list. We are stunned, however, by the fact that the correct solution had obviously been found more than a decade ago by another team but had not been prominently published.17

In any case, the conquest of prorocentin (2) and its non-natural isomer 1 by the entirely new approach disclosed herein denotes yet another triumph of π-acid catalysis in natural product synthesis. This success, however, has only been possible in concert with numerous other metal-catalyzed and organocatalytic reactions that paved the way to the required substrates. While multiple recourse to palladium catalysis, an RCM with a Grubbs-type catalyst, the Sharpless epoxidation, and catalytic (asymmetric) reductions do not come as a surprise, the demanding RCM of an enol ether by the Tebbe reagent, although long known in the literature, is noteworthy; the same is true for the exquisitely regio- and diastereoselective Mukaiyama-type oxidative etherification of a di-unsaturated alcohol derivative. Moreover, the platinum-catalyzed asymmetric diboration/oxidation of a terminal alkene and the doubly diastereomeric propargylations of chiral aldehydes that proceeded under stringent catalyst control were found equally enabling; these examples bear witness to the tremendous progress in asymmetric catalysis during the last decade and augur well for future applications.

We hope that our samples will allow us, in cooperation with expert partners, to shed light on the so far largely unknown activity of 2. This investigation is driven by the firm belief that the evolution of natural products as intricate as prorocentin comes along with innate biological implications.

Acknowledgments

Generous financial support by the Max-Planck-Society is gratefully acknowledged. We thank Dr. S. J. Hess for numerous discussions as well as for the model study concerning the spirocyclization reaction, Dr. L. E. Löffler for a computational investigation into isomeric model compounds, S. Klimmek for excellent HPLC service, and Prof. C.W. Lehmann and J. Rust for solving the X-ray structure; all of these data are contained in the Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c12529.

  • Experimental section including characterization data and NMR spectra of new compounds; crystallographic summary (compound 28); reassessed spectra of the natural product; supporting computational data; and details concerning the total synthesis of nominal prorocentin (PDF)

Open access funded by Max Planck Society.

The authors declare no competing financial interest.

Supplementary Material

ja2c12529_si_001.pdf (20.7MB, pdf)

References

  1. The Biology of Dinoflagellates, Botanical Monographs; Taylor F. J. R., Ed.; Blackwell: Oxford, 1987; Vol. 21. [Google Scholar]
  2. Domínguez H. J.; Napolitano J. G.; Fernández-Sánchez M. T.; Cabrera-García D.; Novelli A.; Norte M.; Fernández J. J.; Daranas A. Belizentrin, a Highly Bioactive Macrocycle from the Dinoflagellate Prorocentrum belizeanum. Org. Lett. 2014, 16, 4546–4549. 10.1021/ol502102f. [DOI] [PubMed] [Google Scholar]
  3. Anderl F.; Größl S.; Wirtz C.; Fürstner A. Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest. Angew. Chem., Int. Ed. 2018, 57, 10712–10717. 10.1002/anie.201805125. [DOI] [PubMed] [Google Scholar]
  4. Napolitano J. G.; Norte M.; Padrón J. M.; Fernández J. J.; Hernández Daranas A. H. Belizeanolide, a Cytotoxic Macrolide from the Dinoflagellate Prorocentrum belizeanum. Angew. Chem., Int. Ed. 2009, 48, 796–799. 10.1002/anie.200804023. [DOI] [PubMed] [Google Scholar]
  5. Lu C.-K.; Chen Y.-M.; Wang S.-H.; Wu Y.-Y.; Cheng Y.-M. Formosalides A and B, cytotoxic 17-membered ring macrolides from a marine dinoflagellate Prorocentrum sp. Tetrahedron Lett. 2009, 50, 1825–1827. 10.1016/j.tetlet.2009.02.013. [DOI] [Google Scholar]
  6. Schulthoff S.; Hamilton J. Y.; Heinrich M.; Kwon Y.; Wirtz C.; Fürstner A. The Formosalides: Structure Determination by Total Synthesis. Angew. Chem., Int. Ed. 2021, 60, 446–454. 10.1002/anie.202011472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Domínguez H. J.; Cabrera-García D.; Cuadrado C.; Novelli A.; Fernández-Sánchez T.; Fernández J. J.; Daranas A. Prorocentroic Acid, A Neuroactive Super-Carbon-Chain Compound from the Dinoflagellate Prorocentrum hoffmannianum. Org. Lett. 2021, 23, 13–18. 10.1021/acs.orglett.0c03437. [DOI] [PubMed] [Google Scholar]
  8. Yang A. R.; Lee S.; Yoo Y. D.; Kim H. S.; Jeong E. J.; Rho J. R. Limaol: A Polyketide from the Benthic Marine Dinoflagellate Prorocentrum lima. J. Nat. Prod. 2017, 80, 1688–1692. 10.1021/acs.jnatprod.7b00127. [DOI] [PubMed] [Google Scholar]
  9. Hess S. N.; Mo X.; Wirtz C.; Fürstner A. Total Synthesis of Limaol. J. Am. Chem. Soc. 2021, 143, 2464–2469. 10.1021/jacs.0c12948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Tachibana K.; Scheuer P. J.; Tsukitani Y.; Kikuchi H.; Van Engen D.; Clardy J.; Gopichand Y.; Schmitz F. J. Okadaic acid, a cytotoxic polyether from two marine sponges of the genus Halichondria. J. Am. Chem. Soc. 1981, 103, 2469–2471. 10.1021/ja00399a082. [DOI] [Google Scholar]
  11. a Isobe M.; Ichikawa Y.; Bai D.-L.; Masaki H.; Goto T. Synthesis of a marine polyether toxin, okadaic acid - total synthesis. Tetrahedron 1987, 43, 4767–4776. 10.1016/s0040-4020(01)86918-0. [DOI] [Google Scholar]; b Forsyth C. J.; Sabes S. F.; Urbanek R. A. An Efficient Total Synthesis of Okadaic Acid. J. Am. Chem. Soc. 1997, 119, 8381–8382. 10.1021/ja9715206. [DOI] [Google Scholar]; c Ley S. V.; Humphries A. C.; Eick H.; Downham R.; Ross A. R.; Boyce R. J.; Pavey J. B. J.; Pietruszka J. Total synthesis of the protein phosphatase inhibitor okadaic acid. J. Chem. Soc., Perkin Trans. 1 1998, 3907–3912. 10.1039/a807957i. [DOI] [Google Scholar]
  12. Valdiglesias V.; Prego-Faraldo M. V.; Pásaro E.; Méndez J.; Laffon B. Okadaic Acid: More than a Diarrheic Toxin. Mar. Drugs 2013, 11, 4328–4349. 10.3390/md11114328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hu W.; Xu J.; Sinkkonen J.; Wu J. Polyketides from Marine Dinoflagellates of the Genus Prorocentrum, Biosynthetic Origin and Bioactivity of Their Okadaic Acid Analogues. Mini-Rev. Med. Chem. 2010, 10, 51–61. 10.2174/138955710791112541. [DOI] [PubMed] [Google Scholar]
  14. Lu C.-K.; Chou H.-N.; Lee C.-K.; Lee T.-H. Prorocentin, a New Polyketide from the Marine Dinoflagellate Prorocentrum lima. Org. Lett. 2005, 7, 3893–3896. 10.1021/ol051300u. [DOI] [PubMed] [Google Scholar]
  15. 3 mg of prorocentin were isolated from 450 L of the culture broth after cultivation of the producing strain for four weeks in seawater medium enriched with K-nutrient at 25 °C with 8/16 h dark/light photocycles.
  16. Takemura A.; Katagiri Y.; Fujiwara K.; Kawai H.; Suzuki T. Synthesis of the C22–C37 segment of prorocentin. Tetrahedron Lett. 2011, 52, 1222–1224. 10.1016/j.tetlet.2011.01.042. [DOI] [Google Scholar]
  17. Katagiri Y.; Fujiwara K.; Takemura A.; Kawai H.; Suzuki T.. Total Synthesis and the Absolute Stereochemistry of Prorocentin. Symposium on the Chemistry of Natural Products, 2010; Vol. 52, pp 187–192. Session ID 32, Symposium Papers.
  18. Fürstner A. From Understanding to Prediction: Gold- and Platinum-Based π-Acid Catalysis for Target Oriented Synthesis. Acc. Chem. Res. 2014, 47, 925–938. 10.1021/ar4001789. [DOI] [PubMed] [Google Scholar]
  19. Toullec P. Y.; Michelet V. Gold-Catalyzed Polycyclization Toward Natural Products Synthesis. Isr. J. Chem. 2018, 58, 578–585. 10.1002/ijch.201800002. [DOI] [Google Scholar]
  20. Quach R.; Furkert D. P.; Brimble M. A. Gold Catalysis: Synthesis of Spiro, Bridged, and Fused Ketal Natural Products. Org. Biomol. Chem. 2017, 15, 3098. 10.1039/c7ob00496f. [DOI] [PubMed] [Google Scholar]
  21. Pflästerer D.; Rudolph M.; Hashmi A. S. K. Gold-Catalyzed Hydrofunctionalizations and Spiroketalizations of Alkynes as Key Steps in Total Synthesis. Isr. J. Chem. 2018, 58, 622. 10.1002/ijch.201700056. [DOI] [Google Scholar]
  22. Ganguly S.; Bhakta S.; Ghosh T. Gold-Catalyzed Synthesis of Spirocycles: Recent Advances. ChemistrySelect 2022, 7, e202201407 10.1002/slct.202201407. [DOI] [Google Scholar]
  23. Fürstner A.; Davies P. W. Catalytic Carbophilic Activation: Catalysis by Platinum and Gold π-Acids. Angew. Chem., Int. Ed. 2007, 46, 3410–3449. 10.1002/anie.200604335. [DOI] [PubMed] [Google Scholar]
  24. Chinchilla R.; Nájera C. Recent Advances in Sonogashira Reactions. Chem. Soc. Rev. 2011, 40, 5084–5121. 10.1039/c1cs15071e. [DOI] [PubMed] [Google Scholar]
  25. For a brief summary, see the Supporting Information.
  26. Karier P.; Ungeheuer F.; Ahlers A.; Anderl F.; Wille C.; Fürstner A. Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D. Angew. Chem., Int. Ed. 2019, 58, 248–253. 10.1002/anie.201812096. [DOI] [PubMed] [Google Scholar]
  27. Betzer J.-F.; Pancrazi A. Regio- and Stereoselectivity in Stannyl- and Silylcupration of Alkynes and Enynes Using Proton Sources. Synlett 1998, 1998, 1129–1131. 10.1055/s-1998-1864. [DOI] [Google Scholar]
  28. Brasseur D.; Marek I.; Normant J.-F. Diastereoselective synthesis of heterosubstituted organogembismetallic reagents. Application to a new propargylmetalation reaction of vinyl metals. Tetrahedron 1996, 52, 7235–7250. 10.1016/0040-4020(96)00248-7. [DOI] [Google Scholar]
  29. Fürstner A.; Funel J.-A.; Tremblay M.; Bouchez L. C.; Nevado C.; Waser M.; Ackerstaff J.; Stimson C. C. A versatile protocol for Stille–Migita cross coupling reactions. Chem. Commun. 2008, 2873–2875. 10.1039/B805299A. [DOI] [PubMed] [Google Scholar]
  30. For selected applications, see the following and literature cited therein:; a Fürstner A.; Bouchez L. C.; Funel J.-A.; Liepins V.; Porée F.-H.; Gilmour R.; Beaufils F.; Laurich D.; Tamiya M. Total Synthesis of Amphidinolide H and G. Angew. Chem., Int. Ed. 2007, 46, 9265–9270. 10.1002/anie.200704024. [DOI] [PubMed] [Google Scholar]; b Gagnepain J.; Moulin E.; Fürstner A. Gram-Scale Synthesis of Iejimalide B. Chem.—Eur. J. 2011, 17, 6964–6972. 10.1002/chem.201100178. [DOI] [PubMed] [Google Scholar]; c Valot G.; Regens C. S.; O’Malley D. P.; Godineau E.; Takikawa H.; Fürstner A. Total Synthesis of Amphidinolide F. Angew. Chem., Int. Ed. Engl. 2013, 52, 9534–9538. 10.1002/anie.201301700. [DOI] [PubMed] [Google Scholar]; d Zhuo C.-X.; Fürstner A. Catalysis-Based Total Syntheses of Pateamine A and DMDA-Pat A. J. Am. Chem. Soc. 2018, 140, 10514–10523. 10.1021/jacs.8b05094. [DOI] [PubMed] [Google Scholar]
  31. Inoki S.; Mukaiyama T. A Convenient Method for the Stereoselective Preparation of trans-2-Hydroxymethyltetra-hydrofurans by the Oxidative Cyclization of 5-Hydroxy-1-alkenes with Molecular Oxygen Catalyzed by Cobalt(II) Complex. Chem. Lett. 1990, 19, 67–70. 10.1246/cl.1990.67. [DOI] [Google Scholar]
  32. Mukaiyama T.; Yamada T. Recent Advances in Aerobic Oxygenation. Bull. Chem. Soc. Jpn. 1995, 68, 17–35. 10.1246/bcsj.68.17. [DOI] [Google Scholar]
  33. Menéndez Pérez B.; Schuch D.; Hartung J. Activation of molecular oxygen and its use in stereoselective tetrahydrofuran-syntheses from δ,ε-unsaturated alcohols. Org. Biomol. Chem. 2008, 6, 3532–3541. 10.1039/b804588g. [DOI] [PubMed] [Google Scholar]
  34. For applications by our laboratory, see ref (6) and the following:; a Heinrich M.; Murphy J. J.; Ilg M. K.; Letort A.; Flasz J. T.; Philipps P.; Fürstner A. Chagosensine: A Riddle Wrapped in a Mystery Inside an Enigma. J. Am. Chem. Soc. 2020, 142, 6409–6422. 10.1021/jacs.0c01700. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Heinrich M.; Murphy J. J.; Ilg M. K.; Letort A.; Flasz J.; Philipps P.; Fürstner A. Total Synthesis of Putative Chagosensine. Angew. Chem., Int. Ed. 2018, 57, 13575–13581. 10.1002/anie.201808937. [DOI] [PubMed] [Google Scholar]; c Valot G.; Mailhol D.; Regens C. S.; O’Malley D. P.; Godineau E.; Takikawa H.; Philipps P.; Fürstner A. Concise Total Syntheses of Amphidinolides C and F. Chem.—Eur. J. 2015, 21, 2398–2408. 10.1002/chem.201405790. [DOI] [PubMed] [Google Scholar]
  35. Kim I. S.; Ngai M.-Y.; Krische M. J. Enantioselective Iridium-Catalyzed Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level via Transfer Hydrogenative Coupling of Allyl Acetate: Departure from Chirally Modified Allyl Metal Reagents in Carbonyl Addition. J. Am. Chem. Soc. 2008, 130, 14891–14899. 10.1021/ja805722e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. The absolute configuration of the newly formed stereocenter was confirmed by Mosher-ester analysis according to:Hoye T. R.; Jeffrey C. S.; Shao F. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat. Protoc. 2007, 2, 2451–2458. 10.1038/nprot.2007.354. [DOI] [PubMed] [Google Scholar]; For details, see the Supporting Information
  37. Morra B.; Morra N. A.; MacDonald D. G.; Pagenkopf B. L. Gram-Scale Synthesis of the Co(nmp)2 Catalyst to Prepare trans-2,5-Disubstituted Tetrahydrofurans by the Aerobic Oxidative Cyclization of Pent-4-en-1-ols. Synthesis 2020, 52, 847–852. 10.1055/s-0039-1690730. [DOI] [Google Scholar]
  38. Palmer C.; Morra N. A.; Stevens A. C.; Bajtos B.; Machin B. P.; Pagenkopf B. L. Increased Yields and Simplified Purification with a Second-Generation Cobalt Catalyst for the Oxidative Formation of trans-THF Rings. Org. Lett. 2009, 11, 5614–5617. 10.1021/ol9023375. [DOI] [PubMed] [Google Scholar]
  39. Gemal A. L.; Luche J. L. Lanthanoids in organic synthesis. 4. Selective ketalization and reduction of carbonyl groups. J. Org. Chem. 1979, 44, 4187–4189. 10.1021/jo01337a038. [DOI] [Google Scholar]
  40. Gaunt M. J.; Yu J.; Spencer J. B. Rational Design of Benzyl-Type Protecting Groups Allows Sequential Deprotection of Hydroxyl Groups by Catalytic Hydrogenolysis. J. Org. Chem. 1998, 63, 4172–4173. 10.1021/jo980823v. [DOI] [Google Scholar]
  41. A TBS group would have saved one step but proved incompatible with the iodo-desilylation as the final transformation en route to the eastern fragment.
  42. Coombs J. R.; Haeffner F.; Kliman L. T.; Morken J. P. Scope and Mechanism of the Pt-Catalyzed Enantioselective Diboration of Monosubstituted Alkenes. J. Am. Chem. Soc. 2013, 135, 11222–11231. 10.1021/ja4041016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. For an early application in natural product synthesis, see ref (30d) and the following:Zhuo C.-X.; Fürstner A. Concise Synthesis of a Pateamine A Analogue with In Vivo Anticancer Activity Based on an Iron-Catalyzed Pyrone Ring Opening/Cross-Coupling. Angew. Chem., Int. Ed. 2016, 55, 6051–6056. 10.1002/anie.201602125. [DOI] [PubMed] [Google Scholar]
  44. Fürstner A.; Larionov O.; Flügge S. What is Amphidinolide V? Report on a Likely Conquest. Angew. Chem., Int. Ed. Engl. 2007, 46, 5545–5548. 10.1002/anie.200701640. [DOI] [PubMed] [Google Scholar]
  45. For an example of iododesilylation in the presence of an alcohol group in vicinity, see:Löffler L. E.; Wirtz C.; Fürstner A. Collective Total Synthesis of Casbane Diterpenes: One Strategy Multiple Targets. Angew. Chem., Int. Ed. 2021, 60, 5316–5322. 10.1002/anie.202015243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ilardi E. A.; Stivala C. E.; Zakarian A. Hexafluoroisopropanol as a Unique Solvent for Stereoselective Iododesilylation of Vinylsilanes. Org. Lett. 2008, 10, 1727–1730. 10.1021/ol800341z. [DOI] [PubMed] [Google Scholar]
  47. Inoue M.; Wang J.; Wang G.-X.; Ogasawara Y.; Hirama M. Divergent synthesis of the tetracyclic ethers of 6-X-7-6 ring systems. Tetrahedron 2003, 59, 5645–5659. 10.1016/s0040-4020(03)00913-x. [DOI] [Google Scholar]
  48. Frantz D. E.; Fässler R.; Carreira E. M. Facile Enantioselective Synthesis of Propargylic Alcohols by Direct Addition of Terminal Alkynes to Aldehydes. J. Am. Chem. Soc. 2000, 122, 1806–1807. 10.1021/ja993838z. [DOI] [Google Scholar]
  49. Hickmann V.; Kondoh A.; Gabor B.; Alcarazo M.; Fürstner A. Catalysis-based and Protecting-Group-free Total Syntheses of the Marine Oxylipins Hybridalactone and the Ecklonialactones A, B, and C. J. Am. Chem. Soc. 2011, 133, 13471–13480. 10.1021/ja204027a. [DOI] [PubMed] [Google Scholar]
  50. Yokoyama H.; Matsuo M.; Miyazawa M.; Hirai Y. Stereoselective Construction of Polyether trans-Pyran Ring System by Gold(I)-Catalyzed Cyclization. Synlett 2016, 27, 2731–2733. 10.1055/s-0035-1562525. [DOI] [Google Scholar]
  51. Hoveyda A. H.; Gillingham D. G.; Van Veldhuizen J. J.; Kataoka O.; Garber S. B.; Kingsbury J. S.; Harrity J. P. A. Ru complexes bearing bidentate carbenes: from innocent curiosity to uniquely effective catalysts for olefin metathesis. Org. Biomol. Chem. 2004, 2, 8–23. 10.1039/b311496c. [DOI] [PubMed] [Google Scholar]
  52. For the first RCM reactions of methacrylates to form trisubstituted unsaturated lactones with the aid of second generation Grubbs-type catalysts, see:Furstner A.; Thiel O. R.; Ackermann L.; Schanz H. J.; Nolan S. P. Ruthenium Carbene Complexes with N,N′-Bis(mesityl)imidazol-2-ylidene Ligands: RCM Catalysts of Extended Scope. J. Org. Chem. 2000, 65, 2204–2207. 10.1021/jo9918504. [DOI] [PubMed] [Google Scholar]
  53. Omura K.; Swern D. Oxidation of alcohols by “activated” dimethyl sulfoxide. a preparative, steric and mechanistic study. Tetrahedron 1978, 34, 1651–1660. 10.1016/0040-4020(78)80197-5. [DOI] [Google Scholar]
  54. Barnett D. S.; Schaus S. E. Asymmetric Propargylation of Ketones Using Allenylboronates Catalyzed by Chiral Biphenols. Org. Lett. 2011, 13, 4020–4023. 10.1021/ol201535b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. For an application to a challenging double-diastereoselective propargylation of a ketone en route to a marine natural product, see:Mailhol D.; Willwacher J.; Kausch-Busies N.; Rubitski E. E.; Sobol Z.; Schuler M.; Lam M.-H.; Musto S.; Loganzo F.; Maderna A.; Fürstner A. Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide. J. Am. Chem. Soc. 2014, 136, 15719–15729. 10.1021/ja508846g. [DOI] [PubMed] [Google Scholar]
  56. It is pointed out that the choice of the acetate is critically important; TBS-protection of the homopropargylic −OH group entailed massive problems in the global deprotection step, as the then axially disposed and sterically hindered −OTBS ether on the C-ring of prorocentin could not be cleaved under a variety of conditions.
  57. Fürstner A.; Radkowski K.; Grabowski J.; Wirtz C.; Mynott R. Ring-Closing Alkyne Metathesis. Application to the Total Synthesis of Sophorolipid Lactone. J. Org. Chem. 2000, 65, 8758–8762. 10.1021/jo0012952. [DOI] [PubMed] [Google Scholar]
  58. Inoue M.; Iwatsu M.; Yamashita S.; Hirama M. A Concise Route to Two Distinct E-Ring Structures of Ciguatoxins. Heterocycles 2007, 72, 327–338. 10.3987/com-06-s(k)16. [DOI] [Google Scholar]
  59. Rummelt S. M.; Preindl J.; Sommer H.; Fürstner A. Selective Formation of a Trisubstituted Alkene Motif by trans-Hydrostannation/Stille Coupling: Application to the Total Synthesis and Late-Stage Modification of 5,6-Dihydrocineromycin B. Angew. Chem., Int. Ed. 2015, 54, 6241–6245. 10.1002/anie.201501608. [DOI] [PubMed] [Google Scholar]
  60. Schaubach S.; Michigami K.; Fürstner A. Hydroxyl-Assisted trans-Reduction of 1,3-Enynes: Application to the Formal Synthesis of (+)-Aspicilin. Synthesis 2017, 49, 202–208. 10.1055/s-0035-1562381. [DOI] [Google Scholar]
  61. Wu J.; Panek J. S. Total Synthesis of (−)-Virginiamycin M2. Angew. Chem., Int. Ed. 2010, 49, 6165–6168. 10.1002/anie.201002220. [DOI] [PubMed] [Google Scholar]
  62. Fang Z.; Wills M. Asymmetric Transfer Hydrogenation of Functionalized Acetylenic Ketones. J. Org. Chem. 2013, 78, 8594–8605. 10.1021/jo401284c. [DOI] [PubMed] [Google Scholar]
  63. Sommer H.; Fürstner A. Hydroxyl-Assisted Carbonylation of Alkenyltin Derivatives: Development and Application to a Formal Synthesis of Tubelactomicin A. Org. Lett. 2016, 18, 3210–3213. 10.1021/acs.orglett.6b01431. [DOI] [PubMed] [Google Scholar]
  64. Gu X.; Zhao J.; Chen L.; Li Y.; Yu B.; Tian X.; Min Z.; Xu S.; Gu H.; Sun J.; Lu X.; Chang M.; Wang X.; Zhao L.; Ye S.; Yang H.; Tian Y.; Gao F.; Gai Y.; Jia G.; Wu J.; Wang Y.; Zhang J.; Zhang X.; Liu W.; Gu X.; Luo X.; Dong H.; Wang H.; Schenkel B.; Venturoni F.; Filipponi P.; Guelat B.; Allmendinger T.; Wietfeld B.; Hoehn P.; Kovacic N.; Hermann L.; Schlama T.; Ruch T.; Derrien N.; Piechon P.; Kleinbeck F. Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696. J. Org. Chem. 2020, 85, 6844–6853. 10.1021/acs.joc.0c00473. [DOI] [PubMed] [Google Scholar]
  65. For a previous use of this building block in natural product synthesis, see:Fürstner A.; Bouchez L. C.; Morency L.; Funel J.-A.; Liepins V.; Porée F.-H.; Gilmour R.; Laurich D.; Beaufils F.; Tamiya M. Total Syntheses of Amphidinolides B1, B4, G1, H1 and Structure Revision of Amphidinolide H2. Chem.—Eur. J. 2009, 15, 3983–4010. 10.1002/chem.200802067. [DOI] [PubMed] [Google Scholar]
  66. Nicolaou K. C.; Postema M. H. D.; Claiborne C. F. Olefin Metathesis in Cyclic Ether Formation. Direct Conversion of Olefinic Esters to Cyclic Enol Ethers with Tebbe-Type Reagents. J. Am. Chem. Soc. 1996, 118, 1565–1566. 10.1021/ja9534866. [DOI] [Google Scholar]
  67. Nicolaou K. C.; King N. P.; He Y. Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products. Top. Organomet. Chem. 1998, 1, 73–104. 10.1007/3-540-69708-x_3. [DOI] [Google Scholar]
  68. Nicolaou K. C.; Frederick M. O.; Aversa R. J. The Continuing Saga of the Marine Polyether Biotoxins. Angew. Chem., Int. Ed. 2008, 47, 7182–7225. 10.1002/anie.200801696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Z-Configured internal alkenes tend to be better substrates than the corresponding terminal alkenes in such ester olefination/metathesis sequences, see:Fujimura O.; Fu G. C.; Grubbs R. H. The Synthesis of Cyclic Enol Ethers via Molybdenum Alkylidene-Catalyzed Ring-Closing Metathesis. J. Org. Chem. 1994, 59, 4029–4031. 10.1021/jo00094a002. [DOI] [Google Scholar]
  70. Cannizzo L. F.; Grubbs R. H. In situ preparation of (μ-chloro)-(μ-methylene)bis(cyclopentadienyl)(dimethylaluminum)-titanium (Tebbe’s reagent). J. Org. Chem. 1985, 50, 2386–2387. 10.1021/jo00213a040. [DOI] [Google Scholar]
  71. Nicolaou K. C.; Gelin C. F.; Seo J. H.; Huang Z.; Umezawa T. Synthesis of the QRSTU Domain of Maitotoxin and Its 85-epi- and 86-epi-Diastereoisomers. J. Am. Chem. Soc. 2010, 132, 9900–9907. 10.1021/ja103708j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Fürstner A. Olefin Metathesis and Beyond. Angew. Chem., Int. Ed. 2000, 39, 3012–3043. . [DOI] [PubMed] [Google Scholar]
  73. Lehmann U.; Awasthi U.; Minehan S.; Minehan T. Palladium-Catalyzed Cross-Coupling Reactions between Dihydropyranylindium Reagents and Aryl Halides. Synthesis of C-Aryl Glycals. Org. Lett. 2003, 5, 2405–2408. 10.1021/ol0345428. [DOI] [PubMed] [Google Scholar]
  74. Boeckman R. K.; Shao P.; Mullins J. J. The Dess-Martin Periodinane: 1,1,1-Triacetoxy-1,1-dihydro-1,2-Benziodoxol-3(1H)-one. Org. Synth. 2000, 77, 141. 10.15227/orgsyn.077.0141. [DOI] [Google Scholar]
  75. For precedent, in which the use of this complex was decisive for determining the regiochemical outcome, see:; a Benson S.; Collin M.-P.; Arlt A.; Gabor B.; Goddard R.; Fürstner A. Second-Generation Total Synthesis of Spirastrellolide F Methyl Ester: The Alkyne Route. Angew. Chem., Int. Ed. 2011, 50, 8739–8744. 10.1002/anie.201103270. [DOI] [PubMed] [Google Scholar]; b Brewitz L.; Llaveria J.; Yada A.; Fürstner A. Formal Total Synthesis of the Algal Toxin (−)-Polycavernoside. Chem.—Eur. J. 2013, 19, 4532–4537. 10.1002/chem.201204551. [DOI] [PubMed] [Google Scholar]
  76. The Brønsted acid also facilitates the (turnover-limiting) protodeauration of the alkenylgold intermediate primarily formed and prevents off-cycle gem-diauration from occuring, see:; a Seidel G.; Lehmann C. W.; Fürstner A. Elementary Steps in Gold Catalysis: The Significance of gem-Diauration. Angew. Chem., Int. Ed. 2010, 49, 8466–8470. 10.1002/anie.201003349. [DOI] [PubMed] [Google Scholar]; b Fürstner A. Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products. Angew. Chem., Int. Ed. 2018, 57, 4215–4233. 10.1002/anie.201707260. [DOI] [PubMed] [Google Scholar]
  77. As the proposed intermediates could not be observed by NMR, we cannot exclude that protonation of 60 occurs at the endocyclic double bond with formation of an oxocarbenium ion with the exocyclic methylene still in place; in this case, double bond migration would occur after the spirocyclic acetal has been locked in. Since the crude product does not contain any trace of (exo or endo) double bond isomers of 62, however, we favor the mechanism via 61 as shown in Scheme 9.
  78. Joung S.; Kim R.; Lee H. Y. Total Synthesis of (−)-Phorbaketal. Org. Lett. 2017, 19, 3903. 10.1021/acs.orglett.7b01797. [DOI] [PubMed] [Google Scholar]
  79. Johnson R. A., Sharpless K. B.. Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima I., Ed.; Wiley-VCH: New York, NY, 2000; pp. 231–285. [Google Scholar]
  80. For related sulfone alkylations, see the following for leading references:; a Rainier J. D.; Smith A. B. Polyene cyclizations to indole diterpenes. The first synthesis of (+)-emindole SA using a biomimetic approach. Tetrahedron Lett. 2000, 41, 9419–9423. 10.1016/s0040-4039(00)01528-8. [DOI] [Google Scholar]; b Ohtawa M.; Matsunaga M.; Fukunaga K.; Shimizu R.; Shimizu E.; Arima S.; Ohmori J.; Kita K.; Shiomi K.; Omura S.; Nagamitsu T. Design, synthesis, and biological evaluation of air-stable nafuredin-γ analogs as complex I inhibitors. Bioorg. Med. Chem. Lett. 2015, 23, 932–943. 10.1016/j.bmc.2015.01.030. [DOI] [PubMed] [Google Scholar]; c Ji M.; Choi H.; Jeong Y. C.; Jin J.; Baik W.; Lee S.; Kim J. S.; Park M.; Koo S. Allylic Sulfones Containing Triene Moieties as Key Synthons for Carotenoid Synthesis. Helv. Chim. Acta 2003, 86, 2620–2628. 10.1002/hlca.200390211. [DOI] [Google Scholar]; d Baj A.; Wałejko P.; Kutner A.; Kaczmarek Ł.; Morzycki J. W.; Witkowski S. Convergent Synthesis of Menaquinone-7 (MK-7). Org. Process Res. Dev. 2016, 20, 1026–1033. 10.1021/acs.oprd.6b00037. [DOI] [Google Scholar]
  81. For deacetylation with LiBHEt3 in the presence of epoxides, see:Danishefsky S. J.; Armistead D. M.; Wincott F. E.; Selnick H. G.; Hungate R. The total synthesis of avermectin A1a. J. Am. Chem. Soc. 1989, 111, 2967–2980. 10.1021/ja00190a034. [DOI] [Google Scholar]
  82. Mohri M.; Kinoshita H.; Inomata K.; Kotake H. Palladium-Catalyzed Regio- and Stereoselective Desulfonylation of Allylic Sulfones with LiHBEt3. Application to the Synthesis of Squalene. Chem. Lett. 1985, 14, 451–454. 10.1246/cl.1985.451. [DOI] [Google Scholar]
  83. For desulfonations in the presence of epoxides, see:Meimetis L. G.; Nodwell M.; Yang L.; Wang X.; Wu J.; Harwig C.; Stenton G. R.; Mackenzie L. F.; MacRury T.; Patrick B. O.; Ming-Lum A.; Ong C. J.; Krystal G.; Mui A. L. F.; Andersen R. J. Synthesis of SHIP1-Activating Analogs of the Sponge Meroterpenoid Pelorol. Eur. J. Org. Chem. 2012, 2012, 5195–5207. 10.1002/ejoc.201200631. [DOI] [Google Scholar]
  84. For pertinent examples, see ref (34a)(34b)(44)(45)(65), and the following:; a Meng Z.; Fürstner A. Total Synthesis Provides Strong Evidence: Xestocyclamine A is the Enantiomer of Ingenamine. J. Am. Chem. Soc. 2020, 142, 11703–11708. 10.1021/jacs.0c05347. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Meng Z.; Spohr S. M.; Tobegen S.; Farès C.; Fürstner A. A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I. J. Am. Chem. Soc. 2021, 143, 14402–14414. 10.1021/jacs.1c07955. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Meng Z.; Fürstner A. Total Syntheses of Scabrolide A and Nominal Scabrolide B. J. Am. Chem. Soc. 2022, 144, 1528–1533. 10.1021/jacs.1c12401. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Preindl J.; Schulthoff S.; Wirtz C.; Lingnau J.; Fürstner A. Polyunsaturated C-Glycosidic 4-Hydroxy-2-Pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene is Likely Identical with Epipyrone A. Angew. Chem., Int. Ed. 2017, 56, 7525–7530. 10.1002/anie.201702189. [DOI] [PubMed] [Google Scholar]; e Willwacher J.; Heggen B.; Wirtz C.; Thiel W.; Fürstner A. Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships. Chem.—Eur. J. 2015, 21, 10416–10430. 10.1002/chem.201501491. [DOI] [PubMed] [Google Scholar]; f Micoine K.; Persich P.; Llaveria J.; Lam M.-H.; Maderna A.; Loganzo F.; Fürstner A. Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics. Chem.—Eur. J. 2013, 19, 7370–7383. 10.1002/chem.201300393. [DOI] [PubMed] [Google Scholar]; g Larivée A.; Unger J. B.; Thomas M.; Wirtz C.; Dubost C.; Handa S.; Fürstner A. The Leiodolide B Puzzle. Angew. Chem., Int. Ed. 2011, 50, 304–309. 10.1002/anie.201005850. [DOI] [PubMed] [Google Scholar]; h Buchgraber P.; Snaddon T. N.; Wirtz C.; Mynott R.; Goddard R.; Fürstner A. A Synthesis-Driven Structure Revision of Berkelic Acid Methyl Ester. Angew. Chem., Int. Ed. 2008, 47, 8450–8454. 10.1002/anie.200803339. [DOI] [PubMed] [Google Scholar]; i Fürstner A.; Radkowski K.; Wirtz C.; Goddard R.; Lehmann C. W.; Mynott R. Total Syntheses of the Phytotoxic Lactones Herbarumin I and II and a Synthesis-Based Solution of the Pinolidoxin Puzzle. J. Am. Chem. Soc. 2002, 124, 7061–7069. 10.1021/ja020238i. [DOI] [PubMed] [Google Scholar]
  85. For reviews, see:; a Nicolaou K. C.; Snyder S. A. Chasing Molecules That Were Never There: Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Elucidation. Angew. Chem., Int. Ed. 2005, 44, 1012–1044. 10.1002/anie.200460864. [DOI] [PubMed] [Google Scholar]; b Maier M. E. Structural revisions of natural products by total synthesis. Nat. Prod. Rep. 2009, 26, 1105–1124. 10.1039/b809658a. [DOI] [PubMed] [Google Scholar]; c Shen S.-M.; Appendino G.; Guo Y.-W. Pitfalls in the structural elucidation of small molecules. A critical analysis of a decade of structural misassignments of marine natural products. Nat. Prod. Rep. 2022, 39, 1803–1832. 10.1039/d2np00023g. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ja2c12529_si_001.pdf (20.7MB, pdf)

Articles from Journal of the American Chemical Society are provided here courtesy of American Chemical Society

RESOURCES