Angewandte Reviews Chemie International Edition:DOI:10.1002/anie.201507549 ContiguousQuaternary CAtoms German Edition:DOI:10.1002/ange.201507549 Synthetic Strategies toward Natural Products Containing Contiguous Stereogenic Quaternary Carbon Atoms Martin B¸schleb,Stÿphane Dorich, Stephen Hanessian,* Daniel Tao, Kyle B. Schenthal, and Larry E. Overman* Keywords: Dedicated to Professors Elias J. Corey, biomimetic synthesis · Albert Eschenmoser,Rolf quaternary carbon atoms · Huisgen, Jack D. Roberts, natural products · and Gilbert Stork synthetic methods Angewandte Chemie 4156 www.angewandte.org ⌫2016Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Angew.Chem.Int. Ed. 2016, 55,4156 –4186 Angewandte Reviews Chemie Strategies for the total synthesis of complex natural products that From the Contents contain two or more contiguous stereogenic quaternary carbon atoms in their intricate structures are reviewed with 12 representative exam- 1. Introduction 4157 ples.Emphasis has been put on methods to create quaternary carbon 2. Sordaricin 4158 stereocenters,including syntheses of the same natural product by different groups,therebyshowcasing the diversity of thought and 3. Vannusals Aand B 4161 individual creativity.Acompendium of selected natural products containing two or more contiguous stereogenic quaternary carbon 4. Acutumine 4162 atoms and key reactions in their total or partial syntheses is provided in 5. Bukittinggine 4164 the Supporting Information. 6. Daphmanidin E 4165 1. Introduction 7. Calyciphylline N 4166 Long before the accidental synthesis of urea by Friedrich 8. Bilobalide 4167 Wçhler,which is historically considered to be the first recorded synthesis of a“natural product”,[1,2] humankind 9. Maoecrystal V 4169 had already recognized the beneficial effects of plant extracts as remedies for its physical ills.[3] Anecdotal accounts of 10. Hyperforin 4172 miraculous cures in the form of potions and the likes within some cultures,now known as nontraditional or alternative 11. Scopadulcic Acids Aand B 4175 medicines,continue to perpetuate our fascination with natural products.[4] Formillennia, nature has been the 12. Crinipellins Aand B 4178 provider, the healer, and the enticer.[4,5] Thevariety of known chemical structures today is indeed overwhelming. 13. Chimonanthines 4180 Of these,only aminuscule number has been studied for their biological properties,[6] while only amere fraction has been 14. Epilogue 4182 synthesized or chemically manipulated.[7] Thechoice of target molecules to synthesize has been justified, among other reasons,for their promise as potential therapeutic agents, astatement that is often found in the introductory paragraphs of published manuscripts.The total synthesis of many highly which when embedded within the core structure of an complex natural products had already been achieved during intended target molecule presents aformidable challenge to the second half of the twentieth century,thanks to continually asynthetic chemist. Creative solutions to such problems have evolving methods of stereoselective reactions,[8] separation been successfully addressed for natural products that only techniques,and spectroscopic analyses.The incentive to afew years ago would have been considered as beyond undertake the total synthesis of architecturally challenging reach.[10] natural products continues to prevail to this day,asour In this Review,wepresent aselection of such successful understanding of the biological effects at the molecular level syntheses by focusing on natural products that contain two becomes more and more evident thanks to ground-breaking and three quaternary carbon atoms,ofwhich at least two are advances in genetics and molecular biology.More than ever, contiguous.Nature’singenuity (and reasons) to create func- synthetic organic chemists are engaging in fruitful collabo- tionally and architecturally complex molecules that may rations with scientists in other disciplines as aresult of newly contain up to four contiguous quaternary carbons atoms,none discovered activities of known natural products.Thus,biol- of which are methyl bearing, such as in the neo-clerodane ogy-inspired and chemistry-driven projects also relying on diterpenoid musabalbisiane A,[11] illicits awe and fascination. structure-based organic synthesis is becoming widely Whether or not such molecules are biosynthesized for defense acknowledged.[6] In this regard, the “what” and “why” of total synthesis[4] may no longer need to be justified, especially when the target molecules are expected to provide important [*] Dr.M.B¸schleb, Dr.S.Dorich, Prof. Dr.S.Hanessian answers to biologically relevant questions.Having decided on Department of Chemistry UniversitÿdeMontrÿal, Station Centre-Ville agiven target molecule to synthesize,weare confronted with [4] C. P. 6128 Montrÿal, Qc, H3C 3J7 (Canada) the highly subjective task of “how”. Past and present E-mail:[email protected] accomplishments have demonstrated the ingenuity,creativity, D. Tao, K. B. Schenthal,Prof. Dr.L.E.Overman and resolve of synthetic organic chemists to initiate and Department of Chemistry,University of California complete the total synthesis of aplethora of natural prod- 1102 NaturalSciencesII, Irvine, CA 92697-2025 (USA) [4,9] ucts. Among these are asmall number that encompass Supportinginformation for this article is available on the WWW quaternary carbon atoms on one or more stereogenic centers, under http://dx.doi.org/10.1002/anie.201507549. Angew.Chem. Int.Ed. 2016, 55,4156 –4186 ⌫2016 Wiley-VCH Verlag GmbH &Co. KGaA,Weinheim 4157 Angewandte Reviews Chemie mechanisms against other natural predators may forever 2. Sordaricin remain amystery.However,the apparent facility with which nature constructs molecules of such high complexity is at first Sordarin is aditerpene glycoside that was isolated from sight misleading. In fact, in many cases nature uses highly Sordaria araneosa and has been shown to possess antifungal functionalized precursors that are “preorganized” to undergo properties with aunique mode of action.[13, 14] It was estab- intra- and intermolecular cyclizations,asinenzyme (and non- lished that sordaricin, the aglycone,isderived from the enzyme) catalyzed Diels–Alder reactions,toachieve its biosynthetic precursor cycloaraneosene,and it was proposed objectives.[12] These late-stage transformations in biosynthetic that the quaternary carbon centers arise from an intra- pathways take place in atimeframe that greatly contrasts the molecular [4+2] cycloaddition.[15] Sordaricin is characterized often much slower reaction times when similar cyclizations by acomplex and richly functionalized tetracyclic architec- are attempted in the laboratory.Nevertheless,elegant “bio- ture that features an unprecedented presence of three mimetic” total syntheses under extremely mild reaction contiguous quaternary centers,one being abridgehead conditions have been reported which also rely on preorgani- carbon atom. Key steps in the three total syntheses of zation and proximity effects of reacting partners. sordaricin are highlighted below.[16] Abrief introduction to each natural product is followed by adiscussion of relevant and key reactions,especially when quaternary carbon atoms are introduced. Syntheses of one 2.1. The Kato Synthesis and the same natural product by more than one research group are presented to demonstrate different methods and In 1993, Kato et al. completed the first total synthesis of strategies for creating stereogenic quaternary carbon atoms optically pure sordaricin as its methyl ester (Scheme 1).[17] embedded in the structures of highly complex natural Thekey reactions for the synthesis of the polycycliccore products.Aparticular challenge presents itself when the containing three contiguous quaternary centers were aCope hindered quaternary stereocenters in atarget molecule are rearrangement and abio-inspired intramolecular Diels–Alder adjacent. We have limited our discussion to atotal of 12 cycloaddition. It was envisaged that two separate cyclo- natural products,which in our opinion combine the criteria of pentane units,diol 1 and (3S)-1-iriden-7-al 2 (obtained by diversity of strategies with individual creativity.Acompen- chemical resolution of an iridoid menthyl ester[18] originally dium of selected natural products containing two or more synthesized from isoprene and methyl 2,4-dioxopentanoate), contiguous stereogenic quaternary carbon atoms and key may be used as chiral building blocks for the synthesis of reactions in their total or partial syntheses is provided in the rings Aand B(Scheme 1). Supporting Information. Thus, 3 and 4 (available from 1 and 2,respectively) were coupled through aNozaki–Hiyama–Kishi reaction to gener- Martin B¸schleb, born in Leinefelde (Ger- Stephen Hanessian was born in Alexandria many), obtained his diploma (2008) and (Egypt) in 1935 and graduated from the PhD (2012) in organic chemistry from University of Alexandria in 1956. After Georg-August University in Gçttingen under ayear at the Starch Products Co., he the supervision of Prof. Christian Ducho, obtained his PhD in 1960 with Prof. Melville where he studied the synthesis and applica- Wolfrom (Ohio State University).From tion of epicapreomycidine in natural product 1961 to 1968, he worked at Parke-Davis synthesis. He pursued postdoctoral studies Research Laboratories in Ann Arbor,Michi- with Prof. Stephen Hanessian at Universitÿ gan. He became Associate Professor at the de Montrÿal (Canada), working in the field Universitÿde Montrÿal in 1969,