(+)-Biotin (
1) was synthesized from readily accessible L-aspartic acid (
4). The contiguous asymmetric centers at C-3a and C-6a were formed through a diastereoselective aldol reaction of
N-Cbz-3-amino-4-butanolide
5 to provide
trans-disubstituted lactone
6 with high stereoselectivity (
trans/cis=12 : 1). The imidazolidin-2-one moiety of
1 was constructed by a stereoselective Hofmann rearrangement of β-substituted asparagine derivative
7 to provide cyclic urea
8. This reaction proceeds with complete retention of stereochemistry. Removal of the protective groups of
8 and subsequent dibenzylation and thionation provided thiolactone
2. The installation of the C-4 side chain of
1 was performed through a Pd/C-catalyzed coupling reaction of
2 with ethoxycarbonylbutylzinc iodide
14a (Fukuyama coupling reaction), which permitted the synthesis of
1 from
2 under industrially applicable mild conditions in three steps.
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