Total syntheses of arenamides A, B and C

Total syntheses of the three arenamides A–C, NFκB inhibitors, are described for the first time. The key steps involved in the synthesis are a Crimmin’s aldol, Wittig olefination and a macrolactamization reaction.

Figure optionsDownload as PowerPoint slide

(2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(benzyloxy)-3-hydroxy-2-methylpentan-1-oneC23H27NO3S2[α]D20=+78.1 (c 0.44, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (2R,3S,S)

(2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(benzyloxy)-3-(tert-butyldimethylsilyloxy)-2-methylpentan-1-oneC29H41NO3S2Si[α]D20=+19.5 (c 0.44 CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (2R,3S,S)

(2R,3S)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-2-methylpentanalC19H32O3Si[α]D28=-38.9 (c 1.0, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (2R,3S)

(3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-methyloctan-1-olC15H34O2Si[α]D28=-23.2 (c 0.62, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S)

(3S,4S)-4-Nitrobenzyl 3-hydroxy-4-methyldecanoateC18H27NO5[α]D30=-19.5 (c 1, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S)

(3S,4S)-4-Nitrobenzyl 3-(tert-butyldimethylsilyloxy)-4-methyldecanoateC24H41NO5Si[α]D28=-20.8 (c 1.0, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S)

(3S,4S)-4-Nitrobenzyl 3-(tert-butyldimethylsilyloxy)-4-methyloctanoateC22H37NO5Si[α]D23=+7.5 (c 0.7, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S)

(3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-methyldecan-1-olC17H38O2Si[α]D28=-17.6 (c 0.80, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S)

(3S,4S)-4-Nitrobenzyl 3-hydroxy-4-methyloctanoateC16H23NO5[α]D28=+12.0 (c 0.3, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S)

(3S,4S)-4-Nitrobenzyl 3-((R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)-4-methyldecanoateC32H44N2O8[α]D28=-6.9 (c 0.5, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S,R)

(3S,4S)-4-Nitrobenzyl 3-((R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)-4-methyloctanoateC30H40N2O8[α]D28=+7.6 (c 0.75, CHCl3)Source of chirality: l-(+)-PhenylalanineAbsolute configuration: (3S,4S,R)

(3S,4S)-4-Nitrobenzyl 3-((R)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanoyloxy)-4-methyldecanoateC28H44N2O8S[α]D28=-13.4 (c 0.75, CHCl3)Source of chirality: l-(+) Phenylalanine, l-(+)-methionineAbsolute configuration: (3S,4S,R)

(8S,11S,14S)-Methyl 11-iso-butyl-8-isopropyl-14-methyl-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oateC25H38N4O7[α]D23=-55.6 (c 1.0, CHCl3)Source of chirality: l-(+)-Leucine, l-(+)-valine and l-(+)-alanineAbsolute configuration: (8S,11S,14S)

(8S,11S,14S,17S,20S)-11-Isobutyl-8-isopropyl-14-methyl-17-(2-(methylthio)ethyl)-20-((S)-octan-2-yl)-3,6,9,12,15,18-hexaoxo-1-phenyl-2,19-dioxa-4,7,10,13,16-pentaazadocosan-22-oic 4-nitrobenzoic anhydrideC47H68N6O13S[α]D28=-16.9 (c 2 CHCl3)Source of chirality: l-(+)-Leucine, l-(+)-valine, and l-(+)-alanine, l-(+)-metheonineAbsolute configuration: (8S,11S,14S,17S,20S,S)

(3S,6S,9S,12S,19S)-3-Benzyl-9-isobutyl-12-isopropyl-6-methyl-19-((S)-octan-2-yl)-1-oxa-4,7,10,13,16-pentaazacyclononadecane-2,5,8,11,14,17-hexaoneC36H57N5O7[α]D28=-65 (c 0.07, CH3OH)Source of chirality: l-(+)-Leucine, l-(+) valine and l-(+)alanineAbsolute configuration: (3S,6S,9S,12S,19S,S)