This article presents studies that illustrate beta-alkoxy methyl ketone-derived boron enolates undergo diastereoselective aldol addition to afford the 1,5-anti diol relationship. The stereochemical outcome of this reaction is documented to be general for a variety of beta-alkoxy methyl ketone analogues and aldehyde partners. The double stereodifferentiating reactions of these enolates with chiral beta-alkoxy aldehydes have also been investigated in conjunction with the possibility of controlling the absolute stereochemistry of the aldol process. With the proper selection of reaction conditions, the proximal alkoxy substituent on either the aldehyde (1,3-induction) or the enolate fragment (1,5-induction) can be employed to control facial selectivity of the aldol addition. Selection of a boron enolate ensures dominant 1,5-anti induction from the beta-alkoxy methyl ketone-derived enolate partner while negating any influence of the beta-alkoxy aldehyde substituent. Conversely, if stereochemical control from the beta-alkoxy aldehyde is desired, a Lewis acid-catalyzed enolsilane addition ensures dominant 1,3-induction from the aldehyde beta-oxygen substituent.

The first total synthesis of a spongipyran macrolide, altohyrtin C, is described. The convergent synthesis strategy relies on a regioselective macrolactonization, a stereoselective Wittig coupling of the two major synthetic fragments, a complex anti aldol reaction to join the C1–C15 and C16–C28 spiroketal regions, and an anomeric sulfone acylation to join the C29–C37 and C38–C43 pyran regions. The incorporation of the C44–C51 sidechain in the final stages of the synthesis establishes a viable route for the construction of variants in this pharmacologically important region. Methodological developments en route to the total synthesis include a 1,5 anti-selective methyl ketone aldol reaction and a diastereoselective approach to Lewis acid mediated β-C-glycosidation. Completion of the synthesis has confirmed the stereochemical assignments proposed in the altohyrtin series and has established the identity of the altohyrtin and spongistatin marine macrolides.

A new method for the synthesis of β-C-allyl glycosides has been developed for use in the synthesis of the spongipyran macrolides. Functionalized dihydropyrans are transformed to cis tetrahydropyrans via a two step process: i) epoxidation using dimethyldioxirane and ii) Lewis acid mediated epoxide opening with allylstannanes as nucleophiles. This protocol, which can be successfully applied to complex systems, augments the limited body of methodology available for the preparation of β-configured C-glycosides.

Angewandte Chemie International Edition in EnglishVolume 36, Issue 24 p. 2741-2744 Communication Enantioselective Synthesis of Altohyrtin C (Spongistatin 2): Synthesis of the EF-Bis(pyran) Subunit†‡ Prof. David A. Evans, Corresponding Author Prof. David A. Evans Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this authorB. Wesley Trotter, B. Wesley Trotter Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this authorDr. Bernard Cǒté, Dr. Bernard Cǒté Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this authorDr. Paul J. Coleman, Dr. Paul J. Coleman Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this author Prof. David A. Evans, Corresponding Author Prof. David A. Evans Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this authorB. Wesley Trotter, B. Wesley Trotter Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this authorDr. Bernard Cǒté, Dr. Bernard Cǒté Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this authorDr. Paul J. Coleman, Dr. Paul J. Coleman Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 (USA), Fax: Int. code + (617) 495–1460, e-mail: [email protected]Search for more papers by this author First published: January 7, 1997 https://doi.org/10.1002/anie.199727411Citations: 96 † Financial support has been provided by the National Institutes of Health (NIH) and the National Science Foundation (NSF). The NIH BRS Shared Instrumentation Grant Program 1-S10-RR04870 and the NSF (CHE 88-14019) are acknowledged for providing NMR facilities. ‡ Dedicated to Professor Dieter Seebach and Professor Yoshito Kishi on the occasion of their 60th birthdays AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract The first total synthesis of a spongipyran macrolide, altohyrtin C (spongistatin 2; see picture below), has been realized. The spongipyrans derived from marine sponges are among the most potent cytotoxic compounds yet isolated, and exhibit subnanomolar activities against a variety of human cancer cell lines. While the structures proposed for the independently isolated altohyrtins and spongistatins are largely homologous, they differ significantly with regard to internal stereochemical relationships. This discrepancy has been resolved by the total synthesis, which verifies the altohyrtin structural assignment and establishes the identity of altohyrtin C and the independently isolated spongistatin 2. Citing Literature Volume36, Issue24January 7, 1997Pages 2741-2744 RelatedInformation

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ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXT1,5-Asymmetric Induction in Methyl Ketone Aldol Addition ReactionsDavid A. Evans, Paul J. Coleman, and Bernard CôtéView Author Information Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138 Cite this: J. Org. Chem. 1997, 62, 4, 788–789Publication Date (Web):February 21, 1997Publication History Received30 December 1996Published online21 February 1997Published inissue 1 February 1997https://pubs.acs.org/doi/10.1021/jo962417mhttps://doi.org/10.1021/jo962417mrapid-communicationACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views1624Altmetric-Citations148LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Aldehydes,Aldol reactions,Enolates,Ketones,Substituents Get e-Alerts

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.