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The Absolute Configuration of the (+)‐ and (−)‐ cis ‐ and (+)‐ and (−)‐ trans‐ 1‐Benzyl‐4‐hydroxypiperidine‐3‐methanols: An Unusual Application of the 1 H‐NMR‐ Mosher Method
Author(s) -
Clerc Christian,
Matarazzo Igor,
Rüedi Peter
Publication year - 2009
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200800270
Subject(s) - chemistry , decane , stereochemistry , absolute configuration , structural isomer , selectivity , bicyclic molecule , proton nmr , enantiomer , organic chemistry , catalysis
The enantiomerically pure title compounds were prepared and the absolute configurations assigned by the high‐field 1 H‐NMR application of the Mosher method on the bis‐MTPA derivatives (MTPA= α ‐methoxy‐ α ‐(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: (+)‐(3 S ,4 S ) and (−)‐(3 R ,4 R ) ( cis) , and (+)‐(3 R ,4 S ) and (−)‐(3 S ,4 R ) ( trans ), respectively ( Scheme 2 ). Nonfermenting bakers' yeast reduction of methyl 1‐benzyl‐4‐oxopiperidine‐3‐carboxylate afforded (+)‐methyl (3 R ,4 S )‐1‐benzyl‐4‐hydroxypiperidine‐3‐carboxylate (de>97%, ee>99%) which was further reduced to the (+)‐(3 S ,4 S )‐diol ( Scheme 3 ). 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 γ ‐homo‐acetylcholine mimetics.