The Absolute Configuration of the (+)- and (-)-cis- and (+)- and (-)-trans-1-Benzyl-4-hydroxypiperidine-3-methanols: An Unusual Application of the H-1-NMR-Mosher Method

The enantiomerically pure title compounds were prepared and the absolute configurations assigned by the high-field H-1-NMR application of the Mosher method on the bis-MTPA derivatives (MTPA = alpha-methoxy-alpha-(trifluoromethyl)benzeneacetic acid). The final evidence for the adaptability of the procedure was effected by X-ray crystallographic analyses. The absolute configurations of the cis- and trans-1-benzyl-4-hydroxypiperidine-3-methanols are as follows: (+)-(3S,4S) and (-)-(3R,4R) (cis), and (+)-(3R,4S) and (-)-(3S,4R) (trans), respectively (Scheme 2). Nonfermenting bakers' yeast reduction of methyl 1-benzyl-4-oxopiperidine-3-carboxylate afforded (+)-methyl (3R,4S)-1-benzyl-4-hydroxypiperidine-3-carboxylate (de > 97%, ee > 99%) which was further reduced to the (+)-(3S,4S)-diol (Scheme3). The result confirms the stereochemical outcome of the biological reduction with re-face selectivity and cis-diastereoselectivity as predicted for bakers' yeast. The 4-hydroxypiperidine-3-methanols are the key starting compounds for the synthesis of the enantiomerically pure P(3)-axially and P(3)-equatorially substituted cis- and trans-configurated 8-benzyl-2,4-dioxa-8-aza-3-phosphadecalin 3-oxides (= 8-benzyl-2,4-dioxa-8-aza-3-phospha-bicyclo[4.4.0]decane 3-oxides) representing gamma-homo-acetylcholine mimetics.