Total Synthesis of TMC-95A and -B via a New Reaction Leading to Z-Enamides. Some Preliminary Findings as to SAR

Abstract

A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an α-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.

Cyclodextrin host as a supramolecular catalyst in nonpolar solvents: stereoselective synthesis of (E)-3-alkylideneoxindoles

“…1 H NMR (DMSO-d6) δ 6.86 (d,J = 7.7 Hz,1 H),7.01 (dd,J = 7.7,7.7 Hz,1 H),7.23 (dd,J = 7.7,7.7 Hz,1 H),7.30 (d,J = 12.2 Hz,1 H),4 H),4 H),7.75 (dd,J = 12.2,14.9 Hz,1 H),2 H),7.99 (d,J = 7.7 Hz, 1 H), 10.5 (s, 1 H). 13 C NMR (DMSO-d6) δ 109.8 (d,121.5 (d,122.1 (s,Ar),123.3 (d,124.2 (d,, 125.8 (s, C=CH), 128.1 (d,Ar),128.9 (d,Ar),129.2 (d,129.7 (d,Ar),134.5 (d,, 135.9 (s, Ar), 142.2 (s, Ar), 144.5 (d,168.9 (s,C=O).…”

“…13 C NMR (DMSO-d6) δ 109.8 (d,121.5 (d,122.1 (s,Ar),123.3 (d,124.2 (d,, 125.8 (s, C=CH), 128.1 (d,Ar),128.9 (d,Ar),129.2 (d,129.7 (d,Ar),134.5 (d,, 135.9 (s, Ar), 142.2 (s, Ar), 144.5 (d,168.9 (s,C=O). IR : 1698.19 (C=O).…”

“…1 H NMR (DMSOd6) δ 6.85 (d,J = 8.6 Hz,1 H),7.27 (dd,J = 2.2,8.2 Hz,1 H),7.36 (d,J = 12.2 Hz,1 H),4 H),7.75 (dd,J = 12.2,15. 13 C NMR (DMSO-d6) δ 110. 9, 123.2, 123.6, 123.6, 124.5, 125.7, 128.5, 128.7, 128.9, 129.9, 135.8, 136.6, 140.9, 146.3, 168.7.…”

“…for C17H12BrNO : 325.0102, found 325.0098. (d,J = 4.6 Hz,1H),8.50 (dd,J = 12.6,15.9 Hz, 1 H). 13 C NMR (DMSO-d6) δ 25.…”

Synthesis of reaction-ready 6,6′-biindole and 6,6′-biisatin via palladium(ii)-catalysed intramolecular C–H functionalisation

“…18 Isonitrosoacetanilide 17 was prepared in good yield (74%), and subsequent heating of 17 in concentrated sulfuric acid allowed di-cyclisation to occur, with biisatin 2 isolated in 83% yield after precipitation on crushed ice, without the requirement for chromatography.…”