Abstract
The synthesis of (–)-Indolizidine 167B has been achieved from optically active (R)-3-(pyrrol-1-yl)hex-1-ene. The key step is a highly regioselective hydroformylation reaction and a one-pot intramolecular cyclization providing a general approach to the indolizine nucleus.
Highlights
Indolizidine alkaloids are widely diffused in nature and have attracted considerable attention because of their varied range of pharmaceutical application
We recently reported the synthesis of Indolizidine 167B both in racemic and optically active form; [7,8] the crucial key was the cyclodehydration of 4-carboxyethyl-4-(pyrrol1-yl)butanal, obtained via selective reduction of pyrrole masked glutamic acid diethyl ester hydrochloride,[9] to the corresponding 5,6-dihydroindolizine bearing the carboxyethyl group in position five
While at room temperature and high pressure the 2a/2b ratio is largely favorable to the branched aldehyde (29/71),[21] under the above conditions a highly regioselective hydroformylation into the linear aldehyde takes place; this is a consequence of the isomerization of the branched alkyl-rhodium intermediate b, precursor of 2b, into the linear one l, precursor of 2a, via a β-elimination process with formation of olefin 1 (Scheme 2).[22]
Summary
Indolizidine alkaloids are widely diffused in nature and have attracted considerable attention because of their varied range of pharmaceutical application. In the synthesis of Indolizidine 167B depicted here the construction of the bicyclic core still occurs via a pyrrolylbutanal; unlike the previous case, the aldehyde comes from rhodium-catalyzed hydroformylation of optically active (R)-3-(pyrrol-1-yl)hex-1-ene (1) (Scheme 1).
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