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Synthesis 2009(17): 2905-2914  
DOI: 10.1055/s-0029-1216920
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereodivergent Approach to Both C2,8a-syn and C2,8a-anti Relative Stereochemical Manifolds in the Lepadin Family via a TiCl4-Promoted Aza-[3+3] Annulation

Gang Li, Lauren J. Carlson, Irina K. Sagamanova, Brian W. Slafer, Richard P. Hsung*, Claudio Gilardi, Heather M. Sklenicka, Nadiya Sydorenko
Division of Pharmaceutical Sciences and Department of Chemistry, Wisconsin Center for Natural Products Research, School of Pharmacy, Rennebohm Hall, University of Wisconsin, Madison, WI 53705, USA
Fax: +1(608)2625345; e-Mail: rhsung@wisc.edu;
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Publication History

Received 23 May 2009
Publication Date:
30 July 2009 (online)

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Abstract

Details in developing a stereodivergent approach to the lepadin family and establishing an entry to both C2,8a-syn and C2,8a-anti relative stereochemical manifolds through a common intermediate are described here. This works paves the foundation for constructing all members of the lepadin family, which consists of three subsets based on an array of interesting relative configurations. These efforts underline the prominence of aza-[3+3] annulation as a unified strategy in alkaloid synthesis.

Key words

titanium(IV) chloride - aza-[3+3] annulation - vinylogous amides - iminium ions - alkaloid synthesis - lepadin alkaloids - stereodivergent approach - episulfide contraction

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17

This particular dihydroxylation was very difficult and required a stoichiometric amount of OsO4, and Scheme  [4] reveals our best conditions. Other conditions examined were: (i) 5-60 mol% OsO4 with NMO, or with K2Fe(CN)6, or with t-BuOOH; bases were K2CO3, MeSO2NH2, or DABCO; (ii) cat. to 1.1 equiv of K2OsO4˙2 H2O with K2Fe(CN)6; bases were K2CO3, or TMEDA, or pyridine; (iii) MCPBA or MMPP or AcOOH; (iv) NBS, DMSO; (v) DMDO or Ozone; (vi) KMnO4 in H2O-EtOH or with TEBACl in CH2Cl2; (vii) 9-BBN or BH3˙SMe2 and then H2O2, MeOH; (viii) RuCl3, NaIO4; (ix) Hg(OAc)2, NaBH4, NaOH; (x) O2, hν, rose Bengal. However, none of these conditions led to any synthetically useful outcome.

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Vinylogous amide 18 is again the same as Ma’s mid-stage intermediate. However, in their beautiful studies en route to lepadins A-E and H, hydrogenation of the C4a-8a olefin took place prior to homologation of the C5 carbonyl group via Wittig-type olefinations (see ref. 13).

26

Wittig olefination employing Ph3P=CHCHO in toluene did not lead to any desired homologation product.