Yao-Jun Shi

Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction with complete inversion of configuration

Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields at elevated temperatures (80–100°C). The SN2 displacement pathway is evident by complete inversion of the (S)-alcohol to (R)-ether.

Asymmetric bioreduction of a β-tetralone to its corresponding (S)-alcohol by the yeast Trichosporon capitatum MY 1890

The yeast Trichosporon capitatum MY 1890 was identified by microbial screening as a suitable biocatalyst for the asymmetric bioreduction of 6-bromo-β-tetralone to its corresponding (S)-alcohol (β-tetralol). This β-tetralol is a precursor to the chiral drug candidate MK-0499, a potassium channel blocker targeted for the treatment of ventricular arrhythmias. Process development studies, employing statistical exploratory designs, yielded a 10-fold increase in the rate of bioreduction and improved the (S)-β-tetralol enantiomeric excess from 71% to 99%. The (S)-β-tetralol enantiomeric excess was found to be highly dependent on glucose catabolism by T. capitatum. Elevated enantiomeric excesses were achieved when switching to a glycerol containing medium. Other process parameters such as pH, temperature and medium composition were found to mostly influence the rate of bioreduction. The developed shake flask process was scaled up to laboratory reactors (23-l scale) and supported the production of gram quantities of highly optically pure (S)-β-tetralol.

THE OXAZABOROLIDINE-BORANE REDUCTION OF KETONES : IDENTIFICATION AND REACTIVITY OF TRANSIENT INTERMEDIATES

Abstract An investigation of the reaction pathway for oxazaborolidine — borane reduction of ketones has revealed a transient intermediate which can competitively reduce ketones.

An improved method for chiral oxazaborolidine-catalyzed reduction of 4-chromanone analogs and MK-0499☆

Abstract Addition of isopropanol to the stoichiometric reduction of ketones 4 – 8 using oxazaborolidine-borane complex 3 or the oxazaborolidine-catalyzed reduction of 4-chromanone analogs ( 1 , 7 – 9 ) enhances the enantioselectivity of the reduction.

Regioselective nucleophilic substitutions of fluorobenzene derivatives

Abstract Regioselective nucleophilic substitutions of tri- and di-substituted fluorobenzoates, fluorobenzonitriles, and fluoronitrobenzenes were accomplished by sequential addition of various nucleophiles, such as, potassium N-Boc-4-piperidinyl oxide, potassium methoxide, and piperidine.

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.

Synthesis of antifungal glucan synthase inhibitors from enfumafungin.

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.

A Practical Synthesis of 2-Butyl-4(5)-chloro-5(4)-hydroxymethyl- 1H-imidazole

Abstract A practical process for the synthesis of 2-butyl-4-hydroxymethyl imidazole (4) followed by chlorination to provide chloroimidazole 1 in an overall 71% yield has been developed.