Chiron based synthesis of isocoumarins: reactivity of α-substituted carboxylic acids

The asymmetric synthesis of a novel (S)-isocoumarin has been attempted in a single step by the coupling of homophthalic acid with (S)-N-protected amino acids and α-chloroacids at high temperature by exploiting a chiral pool methodology. The coupling of homophthalic acid with N-protected (S)-amino acids gave exclusion of the carboxyl/alkyl group. However, coupling of homophthalic acid with α-chloroacids afforded asymmetric isocoumarins in high yield.

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2-[(3′S)-2-Oxothiolan-3′-yl]-2-benzazole-1,3-dioneC12H9NO3S[α]D24 = −4.0 (c 1.0, CHCl3)Absolute configuration: (3S)

(9R)-9-(2′-Methylpropyl)-3H-furo[3,4-c]isochromene-1,11-dioneC15H14O4[α]D22 = +26.0 (c 1.0, CHCl3)Absolute configuration: (9R)

(9R)-9-Benzyl-3H-furo[3,4-c]isochromene-1,11-dioneC18H12O4[α]D22 = −14.0 (c 1.0, CHCl3)Absolute configuration: (9R)

(9R)-9-Methyl-3H-furo[3,4-c]isochromene-1,11-dioneC12H8O4[α]D22 = +18.0 (c 1.0, CHCl3)Absolute configuration: (9R)

(9R)-9-(1′-Methylethyl)-3H-furo[3,4-c]isochromene-1,11-dioneC14H12O4[α]D22 = +10.0 (c 1.0, CHCl3)Absolute configuration: (9R)