Methyl 3-Phenyl-2H-azirine-2-carboxylate

Cycloaminoalkylnaphthalene 3 shows interesting opioid-like analgesic properties. It possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with receptors is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (2R,3S/2S,3R) racemate and the (2R,3S) and (2S,3R) enantiomers of the 1,2-dimethyl-3-[2-(6-hydroxynaphthyl)]-3-hydroxypyrrolidine 3 is considered and the determination of absolute configuration is described. The (2R,3S/2S,3R)-3 racemate and the (2R,3S)-3 and (2S,3R)-3 enantiomers were prepared by reaction of the racemic and optically active 1,2-dimethyl-3-pyrrolidone 2, respectively, with the lithiation product obtained from 2-bromo-6-tetrahydropyranyloxy-naphthalene 1 and acidic hydrolysis. The above-mentioned enantiomers of 3 were also obtained by optical resolution via fractional crystallization of the salts with D- and L-tartaric acids. The configuration of the optically active compounds was determined by X-ray analysis of a crystal of (-)-(2S,3R)-3.HCl.H2O. The pharmacological test HPT showed that (-)-(2S,3R)-3.HCl.H2O enantiomer is able to induce opioid-like analgesia with a relative potency 1.5 times that of (2R,3S/2S,3R)-3 and approximately 1.5 times that of morphine.

Glutathione conjugation of the four 2-bromo-3-methylvaleric acid (BMV) stereoisomers was studied in vitro (rat liver cytosol) and in the rat in vivo (by monitoring biliary excretion of the glutathione conjugates). Rat liver cytosol catalyzed the formation of the corresponding glutathione conjugates in a ratio of 28:7:1:0 for the isomers 2S,3S-, 2S,3R-, 2R,3R- and 2R,3S-BMV, respectively. In the rat in vivo, a similar rank order was found: no conjugation of the 2R,3S isomer, whereas the biliary excretion half-lives of the GSH conjugates of the 2S,3S-, 2S,3R- and 2R,3R-isomers were 11, 36 and 70 min, respectively. These results show that isomers with the C2 carbon in the S configuration are more rapidly conjugated than those with the R configuration, and that the chiral center at the C3 carbon atom affects the conjugation rate at the C2 carbon. In addition to the SN2-type glutathione conjugates, from three substrates the glutathione conjugate of the corresponding diastereomer was formed, indicating bidirectional chiral inversion at the C2 carbon atom of the isomer. For instance, 2S,3R-BMV yielded both 2R,3R-MV-G and 2S,3R-MV-G. The biliary excretion half-lives of the "inverted" conjugates formed from the 2R,3S-, 2R,3R- and 2S,3R-isomer were 54 +/- 3, 75 +/- 3 and 38 +/- 3 min, respectively.

Dehydroxymethylepoxyquinomicin (DHMEQ, 1a) is a specific and potent inhibitor of NF-κB, and it is now being developed as an anti-inflammatory and anticancer agent. While previously only the (2S,3S,4S)-form had been available from the racemate by using lipase-catalyzed enantioselective resolution, in the present study a new route for production of the (2R,3R,4R)-form was established by use of a chemoenzymatic approach. (1R*,2R*,3R*)-2,3-Epoxy-5-N-[(2-hydroxybenzoyl)amino]-4,4-dimethoxycyclohex-5-en-1-ol (2a) was hexanoylated on both secondary and phenolic hydroxy groups, and subjected to Burkholderia cepacia lipase-catalyzed hydrolysis. The reaction proceeded in a highly enantioselective manner (E >500) to give (1S,2S,3S)-2a in an enantiomerically pure state. Several chemical steps of transformation from the enzyme reaction product gave (2R,3R,4R)-DHMEQ (1a) without any loss of stereochemical purity. Moreover, we newly found that (2R,3R,4R)-DHMEQ activated Nrf2, which is a transcription factor that induces the expression of multiple antioxidant enzymes. It activated Nrf2 in a promoter reporter assay. It also increased the expression of target antioxidant proteins and cancelled ROS-induced cell death in a neuronal cell line. Thus, (2R,3R,4R)-DHMEQ was efficiently prepared by a newly designed route using lipase, and it may be useful as a new anti-inflammatory agent.