Dalian Zhao

Synthesis of Vaniprevir (MK-7009): Lactamization To Prepare a 22-Membered Macrocycle

Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.

Practical chemoenzymatic synthesis of a 3-pyridylethanolamino β3 adrenergic receptor agonist

Abstract A chemoenzymatic synthesis of β 3 agonist 1 suitable for large scale preparation is described. The key chiral 3-pyridylethanolamine intermediate ( R )- 7 was prepared via an improved Neber rearrangement and a yeast-mediated asymmetric reduction. The tetrazolone fragment of the molecule was constructed via a dipolar cycloaddition between 1-(cyclopentyl)-3-propylazide and p -chlorosulfonyl phenylisocyanate. Sulfonamide coupling of these two intermediates under Shotten-Baumann conditions, followed by a borane reduction of the amide afforded 1 in 20–32% overall yield from 3-acetylpyridine.

A practical synthesis of fibrinogen receptor antagonist MK-383. selective functionalization of (S)-tyrosine

Abstract A practical 4-step synthesis of fibrinogen receptor antagonist MK-383, N-(n-butanesulfonyl)-O-(4-(4-piperidinyl)-butyl)-(S)-tyrosine, is accomplished in 48% overall yield from (S)-tyrosine. Highlights include: (1) the dual use of 4-picoline as a masked form of piperidine, and as a nucleophile precursor for a 3-carbon homologation with 3-bromo-1-chloropropane; (2) the use of trimethylsilyl groups for temporary protection of phenolic and carboxylate oxygens of (S)-tyrosine that enable selective N-sulfonylation to be carried out in high yield; (3) the selective phenolic O-alkylation of the tyrosine derivative in high yield with no racemization using aqueous KOH/DMSO; and (4) the selective hydrogenation of the pyridine ring in the presence of the tyrosine ring using Pd/C in acetic acid.

Practical enantioselective synthesis of a COX-2 specific inhibitor

Abstract Two synthetic strategies to the COX-2 specific inhibitor 1 have been described that allowed its preparation in large quantities in 79% overall yield from (S)-2-hydroxy-2-methylbutyric acid. These studies have led to the identification of an efficient resolution of (±)-2-hydroxy-2-methylbutyric acid and a novel thionyl chloride aided formation of amide 11 from acid 6 .

Efficient syntheses of 2-(3′,5′-difluorophenyl)-3-(4′-methylsulfonylphenyl)cyclopent-2-enone, a potent COX-2 inhibitor

Abstract 2-(3′,5′-Difluorophenyl)-3-(4′-methylsulfonylphenyl)cyclopent-2-enone (1) displays high selectivity and potency against COX-2. Three efficient syntheses of this diarylcyclopentenone are described. The first approach employs a Suzuki coupling reaction as the key step while the second synthesis features an intramolecular Friedel-Crafts acylation. The third, and preferred route to this compound involves a sequential malonate alkylation and acylation and ring-closure sequence.

Asymmetric hydrogenation of 3-alkylidene-2-piperidones using Noyori's catalyst. Effect of N-substituents on the enantioselectivity

Abstract The enantioselectivity in the asymmetric hydrogenation of 3-alkylidene-2-piperidones catalyzed by BINAP-Ru(II) complex was found to be significantly effected by the internal substituents on the lactam nitrogen, affording the corresponding 3-alkyl-2-piperidones in 52–92% ee.