- Enantioselective synthesis of (-)-wikstromol using a new approach via malic acid
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The total synthesis of (-)-wikstromol, a bioactive α-hydroxylated lactone lignan, from natural malic acid using a consecutive alkylation strategy is presented. First, alkylation of a malic acid ester provided the monobenzyl derivative, which was then converted to an α-substituted dioxolanone. This derivative was reacted in a second alkylation step to a double benzylated dioxolanone, which was transformed to bis-O-benzyl-protected (-)-wikstromol and subsequently to the natural product. Only six steps were required to produce wikstromol in 30% overall yield. A second approach from malic acid, the double alkylation of dienolates from 5-oxo-1,3-dioxolan-4-yl acetic acid derivatives, was not successful. No reaction conditions were found to afford the dienolates. Instead, rapid fragmentation of the dioxolanones to fumaric acid derivatives and pivalaldehyde occurred even at -105 °C, and aldol reaction products with good stereoselectivity were formed. The relative configuration of the major isomer was determined by X-ray structure analysis. By comparison of NMR data it is shown that a previous assignment of the configuration of one of the described aldol products was incorrect.
- Sefkow
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- New results on the stereoselective alkylations of malic acid derivatives supported by molecular modeling
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The stereoselectivity of the alkylation of dialkyl malates is dependent on steric hindrance of both ester alkyl groups. It was found that the two alkyl groups have opposite effects on diastereoselectivity. Increased steric hindrance at the C(1) carboxy group increases the anti-selectivity, whereas increased steric hindrance at the C(4) carboxy group decreases it. The results are explained by comparing the structures of the enolates, which were obtained by molecular modeling. Alkylation at C(4′) of dioxolanones, derived from benzyl-substituted malic acids, with an additional stereogenic center on the side chain is dependent on the stereogenic centers of the ring acetal and of the side chain. Alkylation at low temperatures occurs only with cis-dioxolanones having an (R)-configured side-chain stereogenic center. The corresponding trans-dioxolanone and the cis-dioxolanone with a (S)-configured side-chain stereogenic center were recovered unchanged. A rationale is presented with models of monolithiated dioxolanones obtained by ab initio calculations.
- Sefkow, Michael,Koch, Andreas,Kleinpeter, Erich
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p. 4216 - 4229
(2007/10/03)
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