Development of a Novel Pd-Catalyzed N-Acyl Vinylogous Carbamate Synthesis for the Key Intermediate of ICE Inhibitor VX-765

Abstract

A novel Pd-catalyzed coupling of Cbz-protected proline amide with 4-bromo-5-ethoxyfuran-2(5H)-one was developed for the synthesis of the P1-P2 unit (5) of VX-765. The process afforded quantitative coupling in the presence of water, providing a 1:1 mixture of 5 and its ethoxy epimer epi-5. Compound 5 was isolated as a single diastereomer via fractional crystallization, which was stereoselectively converted to 17 via hydrogenation, and subsequently transformed to VX-765. Nine examples of the Pd coupling are presented with yields ranging from 76-98%.

(E)-MethylN′-[(1H-indol-3-yl)methylidene]hydrazinecarboxylate 0.25-hydrate

“…For chemical, pharmaceutical and agrochemical applications of 3,4-amino-2(5H)-furanones, see: Tanoury et al (2008); Kimura et al (2000). For the synthesis of optically pure 5-(l-menthyloxy)-3,4-dichloro-2(5H)-furanones, see: Song et al (2009).…”

“…Recently, owing to their specific activity and high stereoselectivity, chiral 5S-(l-menthyloxy)-2(5H)-furanones have emerged as significant synthetic intermediates (Hoffmann et al, 2006;Song et al, 2009). At the same time, 4-amino-2(5H)-furanone (or 3-amino-2(5H)-furanone) is a kind of attractive moiety in chemical, pharmaceutical and agrochemical research (Tanoury et al, 2008;Kimura et al, 2000). Therefore we were interested in the tandem Michael addition-elimination reaction of the chiral synthon 3,4-dichloro-5(S)-(l-menthyloxy)-2(5H)-furanone and diallylamine in the present of potassium fluoride which yielded the title compound, C 20 H 30 ClNO 3 , illustrated in Fig.…”

(E)-Methyl 2-chloro-4-dicyclohexylamino-4-oxobut-2-enoate

“…For the biological activity of 2(5H)-furanones, see: Lattmann et al (2005); Rowland et al (2007); Kim et al (2002). For chemical, pharmaceutical and agrochemical applications of 3,4-amino-2(5H)furanones, see: Kimura et al (2000); Tanoury et al (2008). For related structures, see: Lattmann et al (1999Lattmann et al ( , 2006.…”

Methyl 2-[(4-chloro-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino]acetate

“…For biologicallly active 4-amino-2(5H)-furanones, see: Kimura et al (2000); Tanoury et al (2008). For related furanone structures, see: Song et al (2009b); Li et al (2009).…”

“…At the same time, 4-amino-2(5H)-furanone is an attractive moiety in chemical, pharmaceutical and agrochemical research. Many 4-amino-2(5H)-furanones have been patented as prodrugs or insecticides and herbicides (Kimura et al, 2000;Tanoury et al, 2008). Attracted by versatile 4-amino-2(5H)-furanones, we synthesized the title compound with 3,4-dichloro-5-methoxyfuran-2(5H)-one and glycine methylester in the presence of triethylamine via the tandem Michael addition-elimination reaction.…”