Complementary and Stereodivergent Approaches to the Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids from Enantiopure Hydroxylated Lactams

We describe two complementary and stereodivergent routes from commercial and inexpensive starting material for the synthesis of 4,5-dihydroxy- and 5-hydroxypipecolic acids based on the chemistry of lactam-derived enol phosphates. The synthesis of the 4,5-cis 4,5-dihydroxypipecolic acids required the preparation from 2-deoxy-D- and L-ribose of the enantiopure cis (4S,5R)- and (4R,5S)-4,5-dihydroxy-delta-valerolactam, respectively, new chiral synthons potentially useful for the synthesis of other natural products. The key step in our approach was the Pd-catalyzed methoxycarbonylation of the enol phosphates generated from these lactams, which provided enecarbamate esters easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5-trans 4,5-dihydroxypipecolic acid, as well as of 5-hydroxypipecolic acids, was instead realized starting from a known (S)-5-hydroxy-delta-valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. As we report the preparation of the (4R,5S) enantiomer of the cis 4,5-dihydroxy-d-valerolactam from 2-deoxy-L-ribose and because (R)-5-hydroxy-d-valerolactam can be prepared from (R)-(-)-g-hydroxymethyl-g-butyrolactone, our approach allows the synthesis of all of stereoisomers of these compounds which can be employed as conformationally constrained scaffolds in medicinal chemistry for drug discovery.