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J Am Chem Soc
J Am Chem Soc
ja
jacsat
Journal of the American Chemical Society
0002-7863
1520-5126
American Chemical Society

39167047
10.1021/jacs.4c09467
Communication
Total Synthesis of the Norcembranoid Scabrolide B and Its Transformation into Sinuscalide C, Ineleganolide, and Horiolide
Lin Davy S.
Späth Georg
Meng Zhanchao †
https://orcid.org/0000-0003-4617-7605
Wieske Lianne H. E.
Farès Christophe
https://orcid.org/0000-0003-0098-3417
Fürstner Alois *
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany
* fuerstner@kofo.mpg.de
21 08 2024
04 09 2024
146 35 2425024256
12 07 2024
16 08 2024
14 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

It was recognized only recently that the sister norcembranoids scabrolides A and B have notably different carbotricyclic scaffolds. Therefore, our synthesis route leading to scabrolide A could not be extended to its sibling. Rather, a conceptually new approach had to be devised that relied on a challenging intramolecular alkenylation of a ketone to forge the congested central cycloheptene ring at the bridgehead enone site; the required cyclization precursor was attained by a lanthanide-catalyzed Mukaiyama–Michael addition. The dissonant 1,4-oxygenation pattern was then installed by allylic rearrangement/oxidation of the enone, followed by suprafacial 1,3-transposition. Synthetic scabrolide B was transformed into sinuscalide C by dehydration and into ineleganolide by base-mediated isomerization/oxa-Michael addition, which has potential biosynthetic implications; under basic conditions, the latter compound converts into horiolide by an intricate biomimetic cascade.

Max-Planck-Gesellschaft 10.13039/501100004189 NA GÃ¶ran Schills Foundation NA NA document-id-old-9ja4c09467
document-id-new-14ja4c09467
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pmcThe final stages of our total synthesis of scabrolide A (1),1−5 an intriguing norcembranoid derived from soft corals of the genus Sinularia,6 capitalized on earlier biosynthetic considerations which had suggested that 1 derives from a sister compound 2 named “scabrolide B” by double-bond isomerization (Figure 1).7−10 While this transformation was indeed achieved in essentially quantitative yield, we noticed a perplexing incongruence:1 synthetic 1 corresponded perfectly to scabrolide A, but its precursor 2 did not match presumed scabrolide B at all. The proposed biosynthesis of 1 might hence be correct, but authentic scabrolide B is not on the pathway; its structure had been misassigned in the original isolation paper.6,11

Figure 1 Selected polycyclic norcembranoid diterpenoids from Sinularia and related soft corals.

The available data did not allow us to firmly revise the structure of scabrolide B. Therefore, we resorted to an in silico screening, in which the spectra of all possible stereomers of types 2 and 3 were computed at the DFT level and compared to the experimental data set of scabrolide B; the match/mismatch was assessed using the DP4+ probabilistic tool.12−14 Since the validity of this approach could be convincingly demonstrated,15 the excellent score for isomer 3 encouraged us to embark on a new total synthesis project to confirm the reassignment.16 This goal, however, became obsolete soon thereafter when scabrolide B was reisolated and its structure established by X-ray diffraction analysis.17 Actually, it seems that the compound was independently obtained a second time but published under the name “sinuscalide D”, the data of which perfectly match those of scabrolide B.18 Suffice it to say that these reisolation campaigns confirmed our computational prediction.

Natural scabrolide B (3) differs significantly from scabrolide A (1) in that it features a 6–7–5 rather than 7–6–5 carbotricyclic skeleton; as such, it is closely related to sinuscalide C (4) as its dehydrated sibling18 as well as to fragilolide A (5),19 in which the C3 ketone is reduced. In addition to this constitutional disparity, it is noteworthy that the C12 stereocenters of 1 and 3 are of opposite configuration. This apparent subtlety has significant (bio)synthetic implications (see below); it also sets scabrolide B (3) apart from ineleganolide (6),20 which otherwise has the same 6–7–5 core structure spanned by an additional tetrahydrofuran ring that could derive from a transannular oxa-Michael addition of the C8–OH group onto C5 of the enone subunit, although the proposed biosynthesis suggests otherwise.21 The remarkable topological complexity and dense functionalization rendered ineleganolide an iconic target within this intriguing family of polycyclic norcembranoides; although it had captured attention of the synthetic community for decades, successful conquests of 6 and its equally demanding relatives were reported only lately.22−26 In light of the new results summarized below, it is relevant to note that control over the C12 stereocenter had thwarted one otherwise seminal approach toward this intricate target.25

Initially, we had hoped that some fairly straightforward adjustments of our successful route to scabrolide A (1) might also bring scabrolide B (3) into reach. Specifically, the central six-membered ring of 1 had been forged by ring-closing metathesis (RCM). The resulting alkene 8 was subjected to hydroxy-directed epoxidation followed by base-induced ring opening to set the dissonant 1,4-dioxygenation pattern (Scheme 1A); a few steps then sufficed to convert compound 10 into the target.1 We had to learn, however, that this strategy could not be extrapolated to scabrolide B (Scheme 1B):12 while diene 11 underwent ring closure without incident, all attempts at selective (hydroxy-directed) oxidation of one or the other double bond of the resulting 1,3-diene 12 met with failure. In stark contrast, the delicate β,γ-unsaturated ketone 13 could not be engaged in RCM even under forcing conditions; poor conversions into complex mixtures were observed, which contained no 14 but traces of an isomeric cycloheptene.12,27

Scheme 1 (A) Literature Precedent, (B) Intelligence Gathering, and (C) Retrosynthetic Analysis

Therefore, a substantial revision of the synthetic plan was mandatory (Scheme 1C). After careful consideration, we opted for enolate alkenylation as the way to form the central ring;28 ideally, it would come along with double-bond isomerization to furnish an enone of type A. This novel strategy based on the formation of the arguably challenging C4–C5 bond29 bore considerable risk: first, both C–H acidic sites flanking the C3 carbonyl group of B are equally well accessible. Hence, the reaction can work only if enolization is reversible; both enolates would form and be able to revert to B, but one of them can also cyclize; in doing so, the desired product A might accumulate in a meaningful yield. However, the failed attempts at making the closely related compound 14 by RCM implied that A comprising a bridgehead alkene is almost certainly highly congested;29 while intramolecular enolate alkenylations, though not particularly widespread, have a good track record in closing five- and six-membered rings,28,30,31 applications to strained and/or hindered products are rare.32−34 If successful, however, only an allylic oxidation would be needed to convert a product of type A into 3. Another argument in favor of the envisaged plan was the fact that the cyclization precursor B should be readily accessible by Michael addition of lactone C to enone D. Since we had previously developed a scalable route to terminal alkene C (X = H),1 the analogous alkenyl halide C (X = I, Br), as required in this project, seemed easy to attain in optically pure form.

(R)-Norcarvone (19) as the envisaged Michael acceptor is known in the literature, but the published synthesis takes at least seven steps;35 therefore, we were prompted to find a shortcut (Scheme 2). To this end, an asymmetric rhodium-catalyzed 1,4-addition of commercial boronate 16 to cyclohexenone (15) was adapted from the literature,36,37 which furnished 17 with excellent optical purity (94% ee) on gram scale.38 Subsequent deprotonation with bulky LiTMP followed by a TMSCl quench gave silyl enol ether 18 as the major isomer (rr ≥ 5:1). The subsequent Saegusa-type oxidation worked best with Pd2(dba)3 as the catalyst in the absence of any extra ligand and diallyl carbonate as the terminal oxidant.39,40 A short-path distillation allowed the resulting product to be separated from (coeluting) dba, thus securing good quantities of analytically pure 19.

Scheme 2 Preparation of the Building Blocks

Lactone 21 was prepared from (R)-linalool as previously described.1,41 Because we had to learn at a later stage of the project that the bulky silyl ether at the tertiary C8–OH position thwarted the envisaged end game but a protecting group was needed, the TBS group was swapped to a TMS ether prior to ozonolytic cleavage of the double bond in 22.42 The resulting aldehyde was instantly subjected to Stork–Zhao olefination to give the required Z-configured alkenyl iodide 23 in good yield.43,44

At the stage of fragment coupling (Scheme 3), we were beneficiaries of earlier work that had shown that Mukaiyama–Michael addition reactions45 to carvone derivatives work well when catalyzed by lanthanum salts.25,46 In fact, the silyl ketene acetal generated in situ from 23 under soft enolization conditions reacted with 19 in the presence of La(OTf)3 to give fragile 24, which was briefly exposed to TBAF at −78 °C to entail selective cleavage of the silyl enol ether without harming the labile −OTMS group; after some optimization,47 the desired product 25 was obtained in 70% yield. As one might expect, the conjugate addition proceeded via axial attack of the nucleophile that transiently formed onto the lowest-energy conformer of 19. The critically important configuration of the newly formed stereocenters at the overcrowded C12–C13 bond was inferred from a set of characteristic NOEs and JH,H coupling constants12 and confirmed by X-ray diffraction analysis (Figure 2).

Scheme 3 Completion of the Total Synthesis

Figure 2 Structure of 25 in the solid state (scabrolide numbering scheme).48

As expected, the subsequent closure of the central seven-membered ring of scabrolide B (3) was challenging in the first place. Attempts at engaging silyl enol ether 24 directly into ring closure resulted in decomposition.49 When using the derived ketone 25, the choice of base and solvent had to meet the boundary conditions outlined above; therefore, a number of common procedures for palladium-catalyzed enolate alkenylations were sorted out as nonviable in the present case. This included the use of tBuOK or TBAF,28,31,50,51 which caused dehydrohalogenation with formation of alkyne 26; K2CO3 in MeOH (with or without Bu4NBr) also failed.31b−31f A first hit was obtained with PhOH/tBuOK,52,53 although 28 was only one of several products formed in low yield (≤20%). However, this result was deemed encouraging. Upon careful optimization, it was found that sterically hindered 2,6-diisopropylphenol (27) (3.5 equiv) in combination with tBuOK (3 equiv) in toluene (2 mM) at 60 °C was an adequate promoter in combination with Pd(PPh3)4 as catalyst. Under these conditions, the congested tricyclic enone 28 was formed in respectable yield (∼60%) together with dimeric side product 29 (29%) formed by a second, now intermolecular alkenylation at the vinylogous C6 of 28. Since separation required HPLC, it was best to engage crude 28 in allylic γ-oxidation. While several standard oxidants failed to effect this seemingly straightforward transformation, the method used by the Sarlah group in their total synthesis of scabrolide A (1) proved to be viable.3,54 Thus, stirring of a solution of crude 28 in MeCN under an O2 atmosphere in the presence of P(OMe)3 and DBU resulted in allylic rearrangement/oxidation with formation of 30 as a single diastereomer without affecting the olefin branching off the cyclohexane ring. For the then necessary oxidative transposition of the allylic alcohol into the desired 1,4-diketone, Sarlah and co-workers had used PCC,3 which failed in our case. Therefore we had to resort to a stepwise procedure, commencing with a suprafacial 1,3-allylic rearrangement of 30 into 31 catalyzed by MeReO3, which led to concomitant cleavage of the tertiary −OTMS ether (and also afforded a first small crop of 3).55,56 Finally, 31 was oxidized with MnO2 to give the targeted compound (−)-3. The analytical and spectral data of the synthetic material were in full accord with those of authentic scabrolide B (“sinuscalide D”);17,18 an X-ray structure analysis excluded any doubt (Figure 3).

Figure 3 Structure of 3 in the solid state.

Treatment of 3 with Burgess reagent57 afforded sinuscalide C (4) in good yield, the data of which also nicely matched the literature.18 Finally, an attempt was made to transform synthetic 3 into ineleganolide (6) (Scheme 4). Although the proposed biosynthesis of 6 does not pass through scabrolide B,21 this foray was inspired by an observation previously made en route to scabrolide A (1) that certain compounds featuring a cis,trans-annelated butenolide ring could be epimerized to the corresponding cis,cis isomers under basic conditions.1 Indeed, stirring of a solution of 3 in Et3N/MeOH/MeCN at 60 °C triggered a cascade comprising an oxa-Michael addition of the C8–OH group onto the enone with formation of the signature tetrahydrofuran ring of ineleganolide (6) and epimerization of the C12 stereocenter; this observation has potential biosynthetic implications.58 Somewhat unfortunately, 6 turned out to be only metastable under the chosen conditions (see below); therefore, the reaction was stopped at incomplete conversion, and unreacted 3 was recovered. While the net yield of ineleganolide (6) per round was low,59 the recorded data matched nicely.20,22

Scheme 4 Syntheses of Ineleganolide and Horiolide

When the reaction was left stirring, a new product slowly emerged at the expense of 6, which was identified as horiolide (34).60 Its formation implies that the ether ring of 6 can be cleaved in a retro-oxa-Michael fashion under the chosen conditions but the resulting compound 32 does not revert to 3 by epimerization of C12;61 rather, it adopts a conformation that allows the C7–C8 σ orbital to overlap with the C6–O π* orbital. The ensuing retro-aldol reaction affords 33, which instantly succumbs to a proximity-driven intramolecular Michael addition to form the new C5–C9 bond.62 The involved course of this step mirrors the proposed biosynthetic pathway.7

In summary, we describe the first conquest of scabrolide B (3) in 19 steps (longest linear sequence) and its elaboration into sinuscalide C (4), ineleganolide (6), and horiolide (34). Key to success was a challenging intramolecular alkenylation of an almost symmetrical ketone, which allowed the congested seven-membered ring with the inscribed bridgehead olefin to be forged; in this embodiment, the reaction has arguably no precedent but obviously much potential. Of equal relevance is the fact that the successful conversion of scabrolide B into ineleganolide might emulate a previously unrecognized biogenetic link between these emblematic marine norcembranoids that merits further study.21,58,61,63

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c09467.Experimental Section including characterization data and NMR spectra of new compounds as well as a crystallographic abstract (PDF)

Supplementary Material

ja4c09467_si_001.pdf

Author Present Address

† Lingang Lab, Shanghai 200031, China

Open access funded by Max Planck Society.

The authors declare no competing financial interest.

Acknowledgments

Generous financial support by the Max-Planck-Gesellschaft is gratefully acknowledged. L.H.E.W. thanks the Swedish Pharmaceutical Society for support through the Göran Schills Foundation. We thank Prof. J.-H. Sheu (National Sun Yat-Sen University, Taiwan) for an exchange of information, Y. Sell for the preparation of starting materials, S. Tobegen for help with numerous structure assignments by NMR, Dr. M. Leutzsch for discussion about structure elucidation strategies, S. Klimmek for excellent HPLC service, J. Rust and Prof. C. W. Lehmann for solving the X-ray structures, Dr. F. Bohle for support in setting up input files for CREST and CENSO, and all analytical departments of our Institute for excellent service.
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c Yu J. ; Wearing X. Z. ; Cook J. M. A General Strategy for the Synthesis of Vincamajine-Related Indole Alkaloids: Stereocontrolled Total Synthesis of (+)-Dehydrovoachalotine, (−)-Vincamajinine, and (−)-11-Methoxy-17-epivincamajine as Well as the Related Quebrachidine Diol, Vincamajine Diol, and Vincarinol1. J. Org. Chem. 2005, 70 (10 ), 3963–3979. 10.1021/jo040282b.15876085
d Cao H. ; Yu J. ; Wearing X. Z. ; Zhang C. ; Liu X. ; Deschamps J. ; Cook J. M. The first enantiospecific synthesis of (−)-koumidine via the intramolecular palladium-catalyzed enolate driven cross coupling reaction. The stereospecific introduction of the 19-(Z) ethylidene side chain. Tetrahedron Lett. 2003, 44 (43 ), 8013–8017. 10.1016/j.tetlet.2003.08.072.
e Zhao S. ; Liao X. ; Cook J. M. Enantiospecific, Stereospecific Total Synthesis of (+)-Majvinine, (+)-10-Methoxyaffinisine, and (+)-Na-Methylsarpagine as Well as the Total Synthesis of the Alstonia Bisindole Macralstonidine. Org. Lett. 2002, 4 (5 ), 687–690. 10.1021/ol010222h.11869102
f Wang T. ; Cook J. M. General Approach for the Synthesis of Sarpagine/Ajmaline Indole Alkaloids. Stereospecific Total Synthesis of the Sarpagine Alkaloid (+)-Vellosimine. Org. Lett. 2000, 2 (14 ), 2057–2059. 10.1021/ol000095+.10891229
g Solé D. ; Urbaneja X. ; Bonjoch J. Synthesis of the 4-Azatricyclo[5.2.2.04,8]undecan-10-one Core of Daphniphyllum Alkaloid Calyciphylline A Using a Pd-Catalyzed Enolate Alkenylation. Org. Lett. 2005, 7 (24 ), 5461–5464. 10.1021/ol052230u.16288531
a Utsugi M. ; Kamada Y. ; Nakada M. Synthetic studies on the taxane skeleton: effective construction of eight-membered carbocyclic ring by palladium-catalyzed intramolecular α-alkenylation of a methyl ketone. Tetrahedron Lett. 2008, 49 (32 ), 4754–4757. 10.1016/j.tetlet.2008.05.105.
b Hirai S. ; Utsugi M. ; Iwamoto M. ; Nakada M. Formal Total Synthesis of (−)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation. Chem.—Eur. J. 2015, 21 (1 ), 355–359. 10.1002/chem.201404295.25346263
a Watanabe T. ; Oga K. ; Matoba H. ; Nagatomo M. ; Inoue M. Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization. J. Am. Chem. Soc. 2023, 145 (47 ), 25894–25902. 10.1021/jacs.3c10658.37972241
b Matoba H. ; Watanabe T. ; Nagatomo M. ; Inoue M. Convergent Synthesis of Taxol Skeleton via Decarbonylative Radical Coupling Reaction. Org. Lett. 2018, 20 (23 ), 7554–7557. 10.1021/acs.orglett.8b03302.30452272
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Reference (36) describes that this transformation worked well even on 130 kg scale.

Tsuji J. ; Minami I. ; Shimizu I. ; Kataoka H. Enone Formation from Allyl 2-Keto Esters, Alkenyl Allyl Carbonates, Silyl Enol Ethers, and Enol Acetates by the Phosphine-Free Palladium Catalyst. Chem. Lett. 1984, 13 , 1133 10.1246/cl.1984.1133.
For applications in total synthesis by our group, see:

a 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 (35 ), 14402–14414. 10.1021/jacs.1c07955.34448391
b Meng Z. ; Fürstner A. Total Synthesis Provides Strong Evidence: Xestocyclamine A is the Enantiomer of Ingenamine. J. Am. Chem. Soc. 2020, 142 (27 ), 11703–11708. 10.1021/jacs.0c05347.32544329
Brill Z. G. ; Condakes M. L. ; Ting C. P. ; Maimone T. J. Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products. Chem. Rev. 2017, 117 (18 ), 11753–11795. 10.1021/acs.chemrev.6b00834.28293944
A TMS-ether instead of the TBS-ether cannot be chosen at the outset because it is incompatible with the Lewis acid-catalyzed countersteric Diels–Alder reaction en route to compound 21 (see ref (1)); the tert-OH group needs to be protected for the intramolecular enolate alkenylation to proceed.

Stork G. ; Zhao K. A stereoselective synthesis of (Z)-1-iodo-1-alkenes. Tetrahedron Lett. 1989, 30 (17 ), 2173–2174. 10.1016/S0040-4039(00)99640-0.
Morin M. ; Rothe S. ; Elgindy C. ; Sherburn M. Preparation of a Z-Iodoalkene through Stork-Zhao-Wittig Olefination, Stereo-retentive Lithium-Iodine Exchange and Z-Boronic acid Pinacol Ester Synthesis. Org. Synth. 2020, 97 , 217–231. 10.15227/orgsyn.097.0217.
Narasaka K. ; Soai K. ; Mukaiyama T. The New Michael Reaction. Chem. Lett. 1974, 3 (10 ), 1223–1224. 10.1246/cl.1974.1223.
For pioneering work on the use of lanthanide derivatives as catalysts in Mukaiyama–Michael reactions, see:

Giuseppone N. ; Collin J. Tandem Mukaiyama Michael–aldol reactions catalysed by samarium diiodide. Tetrahedron 2001, 57 (43 ), 8989–8998. 10.1016/S0040-4020(01)00902-4.
Only the use of TIPSOTf resulted in meaningful yields of the Mukaiyama–Michael adduct, whereas other silyl triflates proved inadequate. This is all the more surprising since NMR inspection showed that treatment of 23 with TIPSOTf and TMP furnished mixtures of the expected silyl ketene acetal and unreacted 23, independent of the reaction time. It was this mixture that reacted well with 19. It is therefore not entirely clear whether the 1,4-addition follows the traditional mechanism of Mukaiyama–Michael reactions.

Disorder not shown for clarity; the full structure is contained in the Supporting Information.

For precedent, see ref (50) and the following:

Shigehisa H. ; Jikihara T. ; Takizawa O. ; Nagase H. ; Honda T. An exceptional palladium-catalyzed alkenylation of silyl enol ether in the absence of a fluoride additive. Tetrahedron Lett. 2008, 49 (25 ), 3983–3986. 10.1016/j.tetlet.2008.04.104.
Solé D. ; Peidró E. ; Bonjoch J. Palladium-Catalyzed Intramolecular Coupling of Vinyl Halides and Ketone Enolates. Synthesis of Bridged Azabicyclic Compounds. Org. Lett. 2000, 2 (15 ), 2225–2228. 10.1021/ol005973i.10930249
Solé D. ; Diaba F. ; Bonjoch J. Nitrogen Heterocycles by Palladium-Catalyzed Cyclization of Amino-Tethered Vinyl Halides and Ketone Enolates. J. Org. Chem. 2003, 68 (14 ), 5746–5749. 10.1021/jo034299q.12839475
Solé D. ; Urbaneja X. ; Bonjoch J. Palladium-Catalyzed Intramolecular Coupling of Amino-Tethered Vinyl Halides with Ketones, Esters, and Nitriles Using Potassium Phenoxide as the Base. Adv. Synth. Catal. 2004, 346 (13–15 ), 1646–1650. 10.1002/adsc.200404148.
For a discussion of the effects that phenols may exert in related ketone arylations, see:

Rutherford J. L. ; Rainka M. P. ; Buchwald S. L. An Annulative Approach to Highly Substituted Indoles: Unusual Effect of Phenolic Additives on the Success of the Arylation of Ketone Enolates. J. Am. Chem. Soc. 2002, 124 (51 ), 15168–15169. 10.1021/ja0288993.12487580
For further precedent, see:

Schuppe A. W. ; Newhouse T. R. Assembly of the Limonoid Architecture by a Divergent Approach: Total Synthesis of (±)-Andirolide N via (±)-8α-Hydroxycarapin. J. Am. Chem. Soc. 2017, 139 (2 ), 631–634. 10.1021/jacs.6b12268.28001380
Jacob J. ; Espenson J. H. ; Jensen J. H. ; Gordon M. S. 1,3-Transposition of Allylic Alcohols Catalyzed by Methyltrioxorhenium. Organometallics 1998, 17 (9 ), 1835–1840. 10.1021/om971115n.
Volchkov I. ; Lee D. Recent developments of direct rhenium-catalyzed [1,3]-transpositions of allylic alcohols and their silyl ethers. Chem. Soc. Rev. 2014, 43 (13 ), 4381–4394. 10.1039/c4cs00036f.24759893
Atkins G. M. Jr ; Burgess E. M. The reactions of an N-sulfonylamine inner salt. J. Am. Chem. Soc. 1968, 90 (17 ), 4744–4745. 10.1021/ja01019a052.
The exact timing of the events and the reason why the epimerization is apparently irreversible (see ref (61)) are currently unclear. In addition to a simple deprotonation/reprotonation of C12 α to the lactone, more involved scenarios triggered by cleavage of the C7–C11 bond by a base-induced retro-Michael reaction can also be envisaged.

With yields of 11.5% (+35% isomeric sinulochmodin C) and 45%, the final steps of the reported total syntheses of 6 are also rather low-yielding (cf. ref (22)); likewise, the key step of the biomimetic semisynthesis had a yield of only ca. 26% (cf. refs (8) and (21)).

Radhika P. ; Subba Rao P. V. ; Anjaneyulu V. ; Asolkar R. N. ; Laatsch H. Horiolide, a Novel Norditerpenoid from Indian Ocean Soft Coral of the Genus Sinularia. J. Nat. Prod. 2002, 65 (5 ), 737–739. 10.1021/np010528x.12027754
Ineleganolide eventually disappeared and horiolide was formed, but scabrolide B was not detected in the crude mixture; hence, either the epimerization of the C12 stereocenter that converts 3 into 6 is irreversible or the evolution of 32 into horiolide (34) is kinetically favored. In any case, this observation suggests that scabrolide B might be a biosynthetic precursor of ineleganolide, not vice versa.

The Michael addition seems to be non-stereoselective in the first place, as the crude material showed a 1:1 mixture of 34 and a compound tentatively assigned as 9-epi-horiolide. The latter compound, however, equilibrated upon attempted chromatographic isolation to give 34 as the only distinct product.

For total syntheses by our group of other natural products derived from Sinularia corals, see:

a Meng Z. ; Fürstner A. Total Synthesis of (−)-Sinulariadiolide. A Transannular Approach. J. Am. Chem. Soc. 2019, 141 , 805–809. 10.1021/jacs.8b12185.30572706
b Löffler L. E. ; Wirtz C. ; Fürstner A. Collective Total Synthesis of Casbane Diterpenes: One Strategy, Multiple Targets. Angew. Chem., Int. Ed. 2021, 60 (10 ), 5316–5322. 10.1002/anie.202015243.
c Peil S. ; Bistoni G. ; Goddard R. ; Fürstner A. Hydrogenative Metathesis of Enynes via Piano-Stool Ruthenium Carbene Complexes Formed by Alkyne gem-Hydrogenation. J. Am. Chem. Soc. 2020, 142 (43 ), 18541–18553. 10.1021/jacs.0c07808.33073575
