11. Asymmetric Synthesis of Stereoisomers of 2-(2,3-Dihydroxypropyl) piperidine Employing Double Asymmetric Dihydroxylation

Nobuo Ikota and Hidehiko Nakagawa

Keywords: piperidine alkaloid, asymmetric dihydroxylation, hydroquinine, regioselective cleavage, chiral synthesis

Optically active piperidine alkaloids show interesting biological activities and their synthesis has been a subject of recent research. From our continuing studies on synthesis of optically active polyhydroxylated pipertdine alkaloids, we describehere the new asymmetric synthesis of both enantiomers of 2-(2-propenyl) piperidine via Sharpless asymmetric dihydroxylation of 5-hexenyl azide as the starting material, which was then converted into 2-(2,3-dihydroxypropyl) piperidine bya second asymmetric dihydroxylation. Asymmetric dihydroxylation of 5-hexenyl azide (1) using (DHQ)₂ PYR (hydoquinine 2,5-diphenyl-4,6-pyrimidinediyl diether) or (DHQD)₂PYR (hydoquiniidine 2,5diphenyl-4,6-pyrimidinediyl diether) afforded the diols 2 and ent-2 shown in Fig.7. These diols were converted into the epoxides 3 and ent-3 by one-pot procedure (1:CH₃(COCH₃)₃;2:CH₃COBr;3:K₂C0₃) The regioselective cleavage of the epoxide ring in 3 and ent-3 with vinylmagnesium bromide in combination with bromide-dimethyl sulfide complex was per formed to yield the alcohol 4 and ent-4 in 75-86% yield, respectively. The treatment of 4 and ent-4 with mesyl chloride provided the corresponding mesylate, which was reacted with triphenylphosphine followed by hydrolysis in aqueous tetrahydrofuran to release the free amines, which immediately cyclized under inversion of configuration into the 2-propenylpiperidine 5 and ent-5 in 72 and 77% yields, respectively. The structure and optical purity of 5 were confirmed by conversion of 5 into the known (+) -coniine 6. Next, N-Z-protection of 5 and ent-5 (benzyl chloroformate/ K₂C0₃) gave 7 and ent-7 in 96% and 88% yields, respectively. Then, the second asymmetric dihydroxylation of the terminal olefin in 7 was car ried out using (DHQ)₂ PYR to afford a readily separable mixture of the major diastereomer [2R-(2S)] -8 (>98% ee, 70% yield) and the minor diastereomer ([2R-(2R)]-8 (54% ee, 21% yield). On the other hand, the reaction of 7 using (DHQD)₂ PYR as the ligand gave [2R-(2R)]-8 (>98% ee, 69% yield) and [2R-(2S)]-8 (54% ee, 22% yield). Almost the same results were obtained in the double asymmetric dihydroxylation of ent-8 using (DHQ)₂ PYR ( (2 [R (2fi)]-8 (>98% ee, 70% yield), [2S-(2R)]-8 (72%ee, 22% yield) and (DHQD)₂-PYR ([2,S(2R)]-8 (98% ee, 74% yield), [2S-(2S)]-8 (47% ee, 14% yield)).

Thus, all four stereoisomers of 2-(2,3-dihydroxypropyl) piperidine were prepared efficiently using the double asymmetric dihidroxylation reaction. The diols 8 could be useful intermediates for the naturally occurring piperidine alkaloids.

Fig.7. Synthetic Scheme for Optically Active 2(2,3-dihydroxypropyl) piperidines.

Publication:
Takahata, H, Kubota, M. and Ikota, N.: J. Org. chem., 64, 8594-8601, 1999.