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Synlett 2003(14): 2185-2187  
DOI: 10.1055/s-2003-42071
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Total Synthesis of Attenol A and B

Dieter Enders*, Achim Lenzen
Institut für Organische Chemie, Rheinisch Westfälische Technische Hochschule, Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
Further Information

Publication History

Received 25 August 2003
Publication Date:
07 October 2003 (online)

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Abstract

The asymmetric total synthesis of attenol A (1) and B (2), which possess challenging structures and an interesting biological activity, was accomplished in a convergent and highly stereo­selective manner (de, ee ≥ 96%) with good overall yield. The short total synthesis is based on asymmetric alkylations of SAMP-hydrazones as well as a Sharpless asymmetric dihydroxylation as key steps.

Key words

asymmetric dihydroxylation - dithianes - natural products - SAMP-hydrazone methodology - total synthesis

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12

Experiments towards higher stereoselectivities in the reduction step were not conducted since the newly formed stereogenic center had to be removed afterwards.

13

A large excess of Bu3SnH was necessary to sufficiently reduce the occuring side reactions. Under optimized conditions 10 contained only 3 mol% of an isomerization product in which the terminal double bond had migrated between C-19 and C-20 (the numbering refers to the final natural products).

15

The de of 13 and the ee of 5 were verified by HPLC on chiral stationary phase. In order to do so, the 1:1-epimeric mixture of 13 and the racemate of 5 had to be synthesized which was performed starting from the N,N-dimethyl-hydrazone of 12. Alkylation with MeI and ozonolysis gave the α-alkylated racemic aldehyde which was treated with SAMP and Ph3PCHCO2Et to obtain the desired mixtures of compounds.

17

The ee of 15 was verified by HPLC on chiral stationary phase. For this, ent-15 had to be synthesized analogously to 15 starting from the RAMP-hydrazone ent-7 and performing the Sharpless asymmetric dihydroxylation of ent-5 with the AD-mix α.

18

The reaction sequence leading to 15 was also conducted starting with 5 of much lower enantiomeric purity (i.e. ee = 83%). After HPLC, 15 (obtained in lower yield) was still diastereomerically and enantiomerically pure (de, ee ≥ 98%) which indicates the high stereoselectivity of the Sharpless asymmetric dihydroxylation.

20

Our synthetic material was identical in all respects with physical and spectroscopic data provided for the natural products. Compound 1: [α]D 26 -8.2 (c 0.35, CHCl3) {(ref. [2a] , [α]D 28 -9.7 (c 0.35, CHCl3) and [α]D 28 -8.0 (c 0.38, CHCl3) for natural 1. Compound 2: [α]D 26 37 (c 0.072, CHCl3) {(ref. [2a] , [α]D 29 34 (c 0.073, CHCl3) and [α]D 28 31
(c 0.065, CHCl3) for natural 2}.
All new compounds gave satisfactory spectral data and correct elemental analyses.