Divergent synthesis of conidiogenones B–F and 12?-hydroxyconidiogenone C

•Expedient assembly of the conidiogenone core via nitrile-assisted TMM diyl cycloaddition•Regio- and diastereoselective decorations D-ring scaffold•Divergent synthesis six (?)-conidiogenones•First total (?)-conidiogenones E, F, 12?-hydroxyconidiogenone C Herein, we constructed fused tetracyclic natural products by single-step tandem cyclizations diazo, allene, olefin moieties in linear precursor trimethylenemethane intermediate. Our synthetic approach also features regio- stereoselective oxidations carbon–carbon bond formations on to access different conidiogenones a divergent manner. Given that published pharmaceutical activity data reveal subtle alterations oxidation state lead profoundly profiles, such as antitumor or antibiotic addition conidiogenesis-inducing properties for which family is named, these compounds (which are incredibly hard secure through isolation from source fermentation) critical their further exploration. Since initial discovery 2002, over 20 highly congested 6/5/5/5-fused cyclopianes have been isolated served an arena development new strategies. While with distinct oxidative serves fingerprint region products, most approaches focused construction structure, amenable modifications remains unknown. describe strategy enabled conidiogenones, including three first syntheses. Trimethylenemethane (TMM) diyl-mediated cycloaddition expediently forged core. The moiety was formed result TMM-based handle subsequent diversifications. Conidia asexual non-motile spores fungus responsible its aerial aquatic dispersal. In Sterner co-workers Penicillium cylopium showed it potent selective inducer conidiogenesis.1Roncal T. Cordobés S. Ugalde U. He Y. O. Novel diterpenes conidiation inducing activity.Tetrahedron Lett. 2002; 43: 6799-6802Crossref Scopus (58) Google Scholar this discovery, B–L,2Du L. Li D. Zhu Cai Wang F. Xiao X. Gu Q. New alkaloids deep ocean sediment derived sp.Tetrahedron. 2009; 65: 1033-1039Crossref (132) Scholar,3Gao S.-S. X.-M. Zhang C.-S. B.-G. Conidiogenones H I, two cyclopiane class marine-derived endophytic chrysogenum QEN-24S.Chem. Biodivers. 2011; 8: 1748-1753Crossref PubMed (57) Scholar,4Niu Fan Z. Tang Liu Shao G. Yang X.-W. Cyclopiane-type deep-sea-derived commune MCCC 3A00940.Tetrahedron 2018; 59: 375-378Crossref (22) Scholar,5Cheng Xu W. Kang Luo Three cyclopiane-type deep-sea sp. YPGA11 effects against human esophageal carcinoma cells.Bioorg. Chem. 2019; 91: 103129Crossref (29) 13?-hydroxyconidiogenone C, 12?-hydroxyconidiogenones D6Li Sun Gao Lin B. Chai C. H. J. Hu anti-inflammatory sea sediment-derived TJ403-2.Chin. 2020; 31: 197-201Crossref (20) isolated, additional biological activities secondary metabolites, cytotoxic, anti-inflammatory, anti-microbial, anti-allergic effects, disclosed. From structural point view, diterpenoids feature framework up 8 contiguous stereogenic centers four quaternary carbon centers. Biosynthesis involves cyclization rearrangement phase geranylgeranyl pyrophosphate (GGPP) form skeleton phase.7Mitsuhashi Kikuchi Hoshino Ozeki M. Awakawa Shi S.-P. Fujita Abe I. Crystalline sponge method investigation prenyltransferase-terpene synthase chimeric enzyme, whose product exhibits broadened NMR signals.Org. 20: 5606-5609Crossref (32) Scholar,8Niu Z.-W. Xie C.-L. Z.-H. Spirograterpene A, spiro-diterpene 5/5/5/5 ring system granulatum 3A00475.J. Nat. Prod. 2017; 80: 2174-2177Crossref (52) It important note biogenetic diversifications centered (Scheme 1A). daunting molecular architectures along notable activities, drawn continued interests community elegant syntheses reported. 2016, Tu co-workers9Hou S.-H. Y.-Q. Xi C.-C. F.-M. Y.-T. Total conidiogenone, conidiogenol, B.Angew. Int. Ed. Engl. 2016; 55: 4456-4460Crossref (40) reported ent-conidiogenone B (ent-2, 24 LLS [Longest Linear Sequence]) derivative (ent-8) ent-conidiogenol (ent-9) semi-pinacol-type expansion aldol reaction revised structures 1B). 2019, Snyder group completed (2, 13 LLS), (8), conidiogenol (9) deoxyconidiogenol (10), synthesized impressive intercepted Heck reductive reactions key steps.10Hu P. Chi H.M. DeBacker K.C. Gong Keim J.H. Hsu I.T. S.A. Quaternary-centre-guided complex polycyclic terpenes.Nature. 569: 703-707Crossref (68) Markedly, (3, 16 LLS) D (4, could be accessed repeating whole sequence starting material methoxymethyl (MOM)-protected alcohol at either C20 C19, respectively More recently, Zhai research team another landmark 14 conodiogenol orchestrating Nicholas/Pauson-Khand Danheiser annulation steps stereochemically dense target products.11Xu Xun Su (–)-conidiogenone B, (–)-conidiogenone, (–)-conidiogenol.Angew. 16475-16479Crossref (19) impressive, aforementioned involved stereochemical oxidation-state establishment early stage route were not other E (5), F (6), (7) late-stage D-ring. Hence, complementary prior envisioned develop susceptible 1C). With grand goal mind, planned employ triquinane moiety.12Kang Song S.B. Kim W.-Y. B.G. Lee H.-Y. (–)-crinipellin A.J. Am. Soc. 2014; 136: 10274-10276Crossref (47) Scholar,13Lee mediated reactions: mechanism based design strategies.Acc. Res. 2015; 48: 2308-2319Crossref (30) Scholar,14Kim M.J. Baik M.-H. Unexpected selectivity intramolecular [3+2] toward B.Eur. Org. 2020: 609-617Crossref (5) We anticipated diazo compound 11 would undergo allene yield diazene intermediate 12. Diazene 12 then dinitrogen extrusion 13, go 14. decyanation strain release-promoted migration afford 15. utilize common 15 C–C accesses B–F our previous studies noticed ketone undergoes undesired “6-endo-trig” (C6–C10 formation) 17. Diyl 17 subsequently underwent (C5–C11 1,4-hydrogen atom abstraction bridged tetracycle 18 tricycle 19, 2A).14Kim To address problem, envisaged re-engineering introducing nitrile C10 means increase radical accepting ability C5. commenced previously diketone 2B).14Kim Diketone subjected catalytic asymmetric desymmetrization (R)-Me-CBS, N,N-diethylphenylamine, catecholborane toluene15Yeung Y.-Y. Chein R.-J. Corey E.J. Conversion Torgov’s estrone into enantioselective efficient process.J. 2007; 129: 10346-10347Crossref (102) TBS protection silyl ether 46% (two steps, dr = 40:1, 92% ee). resulting allowed react base-pretreated diethyl (cyanomethyl)phosphonate Horner-Wadsworth-Emmons 21 E-isomer >99% yield. Terminal alkyne transformed presence 22, p-toluenesulfonyl hydrazide, CuI, LiOtBu Cu-carbene migratory insertion developed co-workers.16Hossain M.L. Ye CuI-catalyzed cross-coupling N-tosylhydrazones terminal alkynes: 1,3-disubstituted allenes.J. 2013; 78: 1236-1241Crossref (92) Subsequent alkylative deprotection dithiane produced alleneketone 80% robust 24, next investigated reaction. delight, when treated hydrazide heated sodium hydride, desired obtained 47% steps. Consistent design, installation favored “5-exo-trig” C6 diradical 25 stabilized nearby moiety. pre-installation methyl C16 drastically changed outcomes Either nitriles 28 29 (syntheses depicted supplemental information) cyclized 31 (as mixture diastereomer C12) stereochemistry major 2C). Reductive potassium metal, hexamethylphosphoramide (HMPA), t-BuOH (91% yield)17Torneiro Fall Castedo Mouriño A. An 1?,25-dihydroxyvitamin D3 functionalized C-11.Tetrahedron 1992; 33: 105-108Crossref (33) yielded 26. faced challenge unit C14 forge center. Direct hydromethylation18Dao H.T. Michaudel Maxwell B.D. Baran P.S. Hydromethylation unactivated olefins.J. 137: 8046-8049Crossref (115) Scholar,19Tang Lan Bolte Banwell M.G. Ward J.S. Willis A.C. (+)-viridianol, sesquiterpene embodying decahydrocyclobuta[d]indene framework.J. 83: 14049-14056Crossref (11) attempts 26 inseparable hydromethylation hydrogenation low yield, cyclopropanation/hydrogenation successful. Serendipitously, during attempted functionalizations strained tetrasubstituted 26, found treatment trifluoroacetic acid (TFA) resulted protonation strain-released carbocation intermediate, elimination proton C13 produce trisubstituted 91% This isomerization set foundation C12–C14 C19 positions, making pluripotent conidiogenones. hand, aimed synthesizing (2) (6) 3). gem-dimethyl introduced involving cyclopropanation reduction C13–C14 double bond. On epoxidation alkene introduction (6). subjection Simmons-Smith 32 76% Hydrogenation cyclopropane catalyzed platinum oxide 33 (71% yield). Treatment tetrabutylammonium fluoride (TBAF), followed Dess-Martin periodinane (DMP)-mediated alcohol, 34, enantiomer Tu’s (ent-2),9Hou completing formal 19 LLS). For mCPBA convex face epoxide 35 97% lithium tetramethylpiperidine diethylaluminun chloride allylic 36 achieved subjecting two-step PtO2-mediated hydrogenation. 38 protected MOM (93% yield), C1-ketone treating 39 TBAF DMP steps). functionalization A-ring, adopted endgame strategy.9Hou Ketone 40 enol 41 refluxing methanol solution excess trimethyl orthoformate p-toluenesulfonic acid. As observed partial C13-alcohol transformation, crude reacted chloromethyl (MOMCl), Hünig’s base, 4-dimethylamino-pyridine (DMAP) obtain clean sample (92% Allylic conditions group.20Yu J.-Q. A mild, catalytic, ?,?-enones 1,4-enediones.J. 2003; 125: 3232-3233Crossref (154) Diastereoselective ?-methylation 42 reacting diisopropylamide (LDA) iodide HMPA (80% Finally, aluminum hydride (LAH)-mediated 43, hydrolysis both product, 70% turned attention (4) (5). required identification sets regioselectively oxidize C12 respectively. Selective face, Scheme 4). C12, conjugate methylation pleasure, selenium dioxide oxidized sterically less hindered enal 81% yield.21Lusi R.F. Sennari Sarpong R. nine longiborneol sesquiterpenoids using camphor strategy.Nat. 2022; 14: 450-456Crossref (15) borohydride-mediated aldehyde afforded 44 82% (99% yield) oxide-mediated (61% protection, TBAF-mediated desilylation, DMP-mediated 46. final A-ring complete accomplished employing sequence,9Hou applied (6, Complementary SeO2-mediated oxidation, chromium (III) conjunction 3,5-dimethylpyrazole (3,5-DMP) position enone 49 72% position. initially conversion regular cuprate employed. After extensive experimentations, application Yamamoto protocol situ generation Me2CuLi?BF3 pre-mixing MeLi (4 equiv), CuI (2 BF3?Et2O (1.2 equiv) effective give 50 85% yield.22Yamamoto use Lewis acids organocopper related reagents. methods (61).Angew. 1986; 25: 947-959Crossref (281) consequently confronted problem ketone. Even though 3D model C18 hindering Bürgi-Dunitz angle moiety, cognizant re concave bicyclic system. fact, borohydride cerium ambient temperature, R S configuration 1:1 diastereomeric mixture.23Mehta Murthy A.N. Reddy D.S. A.V. general linearly products. (±)-hirsutene, (±)-coriolin, (±)-capnellene.J. 108: 3443-3452Crossref (126) Delightfully, resolved conducting step lower temperature. ?78°C 51 R-configuration 94% single diastereomer. hydroxyl (97%), desilylation C1 group, free steps) 52. Application described five-step 52 finally (3) 5). C20-hydroxymethyl present vinylation/oxidative cleavage sequence. Efficient vinylation vinylmagnesium bromide (8 copper (I) 56 83% more conventional CuBr?SMe2, HMPA, trimethylsilyl (TMSCl) did product. 2:1 ratio successful transformation. Unlike 4), reactivity upon –78°C. When conducted 0°C, 58 57 65% 32% yields, oxidatively cleaved ozonolysis 95% reduced MOMCl 59. Silyl 59 60 (7). (3), imperative deoxygenate carbon, utilized vinyl C14. Attempted Clemmensen but no reduction. therefore Barton-McCombie deoxygenation alcohols radical-mediated comparable efficiency. Thus, enhance practicality procedure, conditions. 63 61% Reduction (94% 64. 64 65 66% (3). sum up, (3)–F (7).24Han “K-synthesis”: recent advancements unique strategies Korea.Bull. Korean 2023; https://doi.org/10.1002/bkcs.12654Crossref Nitrile-assisted facile TFA-mediated tetrasubsituted ring. By strategically delaying modification late synthesis, exploit bias framework. transformations indeed facilitated convex/concave curvature skeleton. case center-guided overturned convex/concave-based selectivity. Identifications regioselective pivotal approach. chemical technology (or unnatural derivatives, if necessary) diverse enable detailed SAR study metabolites. Those will subject forthcoming reports.