A Practical Synthesis of (+)‐Biotin from L‐Cysteine

Abstract

Alpha-amino aldehyde 4, which is readily derived from L-cysteine through cyclization and elaboration of the carboxy group, was subjected to the Strecker reaction, which, via sodium bisulfite adduct 16, afforded alpha-amino nitrile 5 with high diastereoselectivity (syn/anti=11:1) and in high yield. Amide 6, derived from 5, was converted to thiolactone 8, a key intermediate in the synthesis of (+)-biotin (1), by a novel S,N-carbonyl migration and cyclization reaction. The Fukuyama coupling reaction of 8 with the zinc reagent 21, which has an ester group, in the presence of a heterogeneous Pd/C catalyst allowed the efficient installation of the 4-carboxybutyl chain to provide 9. Compound 9 was hydrogenated and the protecting groups removed to furnish 1 in 10 steps and in 34 % overall yield from L-cysteine.

Recent Advances in Pd/C-Catalyzed Coupling Reactions

“…In an effort to avoid these pitfalls, Seki and coworkers applied the Fukuyama coupling reaction to introduce the 4-carboxybutyl chain (Scheme 28, Table 4). 50,60,61,[66][67][68][69][70][71] Zinc reagent 60 was allowed to react with 62 to afford, after dehydration, the desired compound 64 carrying the required side-chain. The reaction was initially conducted by the use of a homogeneous palladium catalyst, PdCl 2 (PPh 3 ) 2 .…”

“…As expected, highly reproducible formation of zinc reagent 60 was achieved, and the amount of 63 was reduced by roughly 50% from 2.5 equivalents to 1.4 equivalents to provide 64 in a high yield (Table 4, entry 8). 68,69 This significantly decreased the overall cost of production of 65. In the reaction, palladium remains bound to activated carbon and is recovered quantitatively by simple filtration.…”

Total Synthesis of (+)-18-epi-Latrunculol A

“…12 In turn, (+)- 9 was converted to the Weinreb amide 13 and then treated with vinyl magnesium bromide to yield enone (+)- 7 in 36 % overall yield (4 steps) from D-cysteine.…”

(2R,4R)-3-(tert-Butoxycarbonyl)-2-(3-chlorophenyl)-1,3-thiazolidine-4-carboxylic acid monohydrate

“…The steric course of the reaction between L-cysteine and aldehydes deserved much attention because this reaction had been implicated in several biochemical processes (Kallen, 1971). An analogous condensation reaction constituted the first step in the syntheses of important natural products, such as penicillin and biotin (Seki et al, 2004). Therefore, thiazolidine derivatives have become especially noteworthy in recent years (Song et al 2009).…”