Concise syntheses of the natural products cavicularin (ten steps) and riccardin C (seven steps) are reported. Key features of the new synthetic route are a convergent strategy to assemble acyclic precursors and a sequence of regioselective reduction and halogenation steps to facilitate Wittig macrocyclisation and transannular ring contraction reactions.

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.

A transannular ring contraction induced by the addition of an aryl radical intermediate to a proximal arene facilitated the construction of the highly strained macrocyclic core of cavicularin (1). The precursor, an iodinated derivative of another natural product, riccardin C, was prepared from four commercially available arenes in a highly convergent sequence. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z500466_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

ChemInformVolume 36, Issue 43 Natural Products Total Synthesis of Cavicularin (I) and Riccardin C (II): Addressing the Synthesis of an Arene that Adopts a Boat Configuration. David C. Harrowven, David C. Harrowven Sch. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorTimothy Woodcock, Timothy Woodcock Sch. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorPeter D. Howes, Peter D. Howes Sch. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this author David C. Harrowven, David C. Harrowven Sch. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorTimothy Woodcock, Timothy Woodcock Sch. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorPeter D. Howes, Peter D. Howes Sch. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this author First published: 29 September 2005 https://doi.org/10.1002/chin.200543228Read the full textAboutPDF 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 Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References David C. Harrowven, Timothy Woodcock, Peter D. Howes, Total Synthesis of Cavicularin (I) and Riccardin C (II): Addressing the Synthesis of an Arene that Adopts a Boat Configuration., Angew. Chem., Int. Ed., 2005, 44, 3899–3901. 10.1002/anie.200500466 CASPubMedWeb of Science®Google Scholar Volume36, Issue43October 25, 2005 ReferencesRelatedInformation