Stereoselective total synthesis of cis- and trans-3-hydroxypipecolic acid.

[reaction: see text] 3-Hydroxypipecolic acid, a nonproteinogenic cyclic alpha-amino acid, is a common structural moiety found in a large number of natural and synthetic compounds of medicinal significance. Utilizing D-serine as a chiral template, the present research describes efficient and straightforward routes to cis- and trans-3-hydroxypipecolic acids in enantiopure form. The key steps in the syntheses involve chelation-controlled addition of a homoallyl Grignard reagent to a protected serinal derivative toward stereoselective formation of the corresponding syn-amino alcohol adduct 3. On the other hand, zinc borohydride-mediated chelation-controlled reduction of a serine-derived alpha-aminoketone precursor leads to the formation of the corresponding anti-amino alcohol adduct 4 with high stereoselectivity. Following an efficient sequence of reactions, the above amino alcohol derivatives were subsequently transformed to the corresponding cis- and trans- title compounds, respectively.