Jess W. Sager

Synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677

Abstract The preparation of the Merck Growth Hormone Secretagogue; MK-677 is described. A Fischer indole/reduction based strategy provides the novel spiroindoline nucleus of this potent compound. This optimized sequence necessitates the isolation of only one intermediate 10 and provides MK-677 in 48% overall yield from isonipecotic acid 3.

Cyclic imidate salts in acyclic stereochemistry: Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides

Abstract Reaction of 2-alkyl-4-enamides with 1 + and aqueous sodium bicarbonate results in the diastereoselective formation of the corresponding iodohydrins with essentially no iodolactone by-product. The reaction appears to proceed through a cyclic imidate type intermediate. This methodology has been successfully employed for the synthesis of the epoxide intermediate of the orally active HIV-1 protease inhibitor MK-639 (indinavir sulfate).

Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673

Abstract A highly convergent, asymmetric synthesis of L-768,673, an I ks Class III antiarrythmic drug candidate, is described. Synthesis of the recemic 1-trifluoroethyl-3-amino-5-phenyl benzodiazepinone [(±)-amine] was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% overall yield. An efficient one-pot resolution-racemization of (±)-amine provided the desired (±)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifluoromethyl)benzene with n-BuLi in the presence of a catalytic amount of 2,2′,6,6′-tetramethylpiperidine afforded its aryl lithium. Subsequent transmetalation and alkylation with allyl bromide produced the corresponding olefin. Ru-catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifluoromethyl)phenylacetic acid in 35% overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.

The enantioselective synthesis of LTD4 antagonist L-708,738

Abstract An efficient, 9-step synthesis of LTD 4 antagonist L-708,738 is described. The asymmetric center is set via a chiral borane reduction.

Observation and quantification of a chiral medium induced difference in rate of enantiomerization

A chiral stationary phase HPLC column has been used both to separate the enantiomers of a γ-lactol and also to observe the rate of enantiomerization of the individual enantiomers; the rate of enantiomerization differed for both enantiomers in the presence of the chiral stationary phase.