The yohimbinoid alkaloids have received considerable attention from the synthetic community due to their interesting chemical structures and varied biological activity. Although there have been several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class have been hampered by a lack of complete control in setting the C(3) stereocenter at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on precedent from Stork, which addresses this long standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be effectively controlled in a Pictet-Spengler reaction. This approach has been applied to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.

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A general approach to the tetracyclic core of the neomangicol natural products via a late-stage indene alkylation reaction is presented. This strategy sets the stage for access to the neomangicol family and, in addition, provides a potential biogenetically inspired entry to the mangicol natural products.Historically, the carbon framework of terpenoid natural products has proven to be a synthetic challenge due to the lack of functional groups on these molecules that can direct C-C bond formation. 1 As a result, synthetic chemists must design strategies for terpenoid syntheses that maximize carbon-carbon bond formation. Enolate methodology has been featured prominently in a wide range of C-C bond forming cyclization tactics (e.g., intramolecular aldol and Dieckmann reactions) en route to terpene natural products, which often necessitate the removal of the enolate carbonyl oxygen at a late stage. In the context of [5-6] bicyclic ring-containing terpene natural products, we envisioned that indenes, which possess acidities comparable to carbonyl compounds (e.g., ketones), could serve as enolate equivalents in late-stage bondforming events. In this communication, we present the application of this tactic to the synthesis of the tetracyclic core of the natural product neomangicol C (2, Figure 1). Neomangicol C is a member of a group of rearranged sesterterpenoids isolated from a marine fungus of the genus Fusarium, which possess varied bioactivity. 2 For example, neomangicols A and B (1a and 1b, Figure 1) have shown in vitro cytotoxicity against human colon carcinoma.Furthermore, neomangicol B (1b) has shown potency against the Gram-positive bacterium Bacillus subtilis similar to that of the aminoglycoside gentamycin and may prove to be of general utility as an antibiotic. 2 Preliminary studies have not identified significant bioactivity for neomangicol C (2), and there is evidence that suggests it may be an isolation artifact arising from the net loss of HCl or HBr from 1a or 1b, respectively. 2To date, there have been no reports of synthetic work toward the neomangicols. However, studies by Uemura 3 and Paquette 4 have recently begun to address the synthesis of the related E-mail: rsarpong@berkeley.edu. Supporting Information Available. Experimental details and characterization data for all new compounds are available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 July 16. Published in final edited form as:Org Lett. 2009 July 16; 11(14): 3128-3131. doi:10.1021/ol9010008. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript mangicols 5 (e.g., mangicol A (3) and B (4), Figure 1). Mangicol A is of interest as a unique structural motif that possesses anti-inflammatory activity.A series of feeding studies has demonstrated that the neomangicols may arise from a rearrangement of the mangicol skeleton (see B → A, Figure 1). 5 We envisioned that our model studies on the neomangicols would offer an opport...

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