Two non-racemic preparations of a piperidine-based NMDA antagonist with analgesic activity.

(2R,3S,1'R)-3-(1-Hydroxy-2-phosphonoethyl)-2-piperidinecarboxyl ic acid 1 has been synthesized by two different methods. The NMDA receptor binding affinities (Ki values) are 74 nM for compound 1, and 64 nM for the corresponding ketone 2. The analgesic effects were evaluated using the mouse hot-plate test and the mouse formalin model. The ED50 values for the racemates of compounds 1 and 2, using the mouse hotplate and intrathecal injection, were 0.53 and 0.51 nmol, respectively.

Studies of the synthesis of sugar phosphonates related to 3-deoxy-D-manno-2-octulosonic acid (Kdo).

In attempting to synthesize the analogue of beta-Kdo (2R)-2-carboxy-6-(1',2'-dihydroxyethyl)-4,5-dihydroxy-D-manno-1,2 lambda 5-oxaphosphorinan-2-one (6) as an inhibitor of the enzyme CMP-Kdo synthetase, which is involved in the biosynthesis of the lipopolysaccharide component of the outer membrane of Gram-negative bacteria, (2R)-6-(1',2'-dihydroxyethyl)-2-ethoxy-3,4,5-trihydroxy-4,5:1', 2'-di-O-isopropylidene-D-glycero-D-talo-1,2 lambda 5-oxaphosphorinan-2-one (8) was converted into (2S)-6-(1',2'-dihydroxyethyl)-4,5-dihydroxy-4,5:1',2'-di-O-isop rop ylidene-2-vinyl-D-manno-1,2 lambda 5-oxaphosphorinan-2-one (16), but alkene cleavage to give the target carboxyphosphonate failed. Reduction-oxidation-Arbuzov reaction on the intermediate (2R)-6-(1',2'-dihydroxyethyl)-2-ethoxy-4,5-dihydroxy-4,5:1', 2'-di-O-isopropylidene-D-manno-1,2 lambda 5-oxaphosphorinan-2-one (11) gave the 2S isomer of the protected target compound, but removal of the protecting groups gave the acyclic product dilithium (D-manno-2,3,4,5,6-pentahydroxyhexyl)phosphinatoformate (24). N.m.r. studies of the intermediates allowed assignment of stereochemistry at P for all compounds via 2JP,H coupling constants.