An efficient and practical enantiospecific synthesis of methyl chromanone- and chroman-2-carboxylates

Chromanone-2-carboxylates and chroman-2-carboxylates are useful building blocks for the synthesis of a variety of bioactive compounds, such as repinotan, fidarestat, and nebivolol. An efficient and practical enantiospecific synthesis of chromanone-2-carboxylates and chroman-2-carboxylates has been accomplished using intramolecular Mitsunobu etherification of methyl (S)-2-hydroxy-4-oxo-4-(2′-hydroxy)phenylbutanoates derived from l-malic acid.

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Methyl (S)-4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-oxo-butanoateC11H11FO5ee >99.7%[α]D20 = +13.8 (c 2.0, CHCl3)Source of chirality: the precursor (l-malic acid)Absolute configuration: (2S)

Methyl (S)-4-(5-chloro-2-hydroxyphenyl)-2-hydroxy-4-oxo-butanoateC11H11ClO5ee >99.9%[α]D20 = +16.8 (c 1.0, CHCl3)Source of chirality: the precursor (l-malic acid)Absolute configuration: (2S)

Methyl (S)-4-(5-bromo-2-hydroxyphenyl)-2-hydroxy-4-oxo-butanoateC11H11BrO5ee >99.9%[α]D20 = +15.4 (c 1.0, CHCl3)Source of chirality: the precursor (l-malic acid)Absolute configuration: (2S)

Methyl (S)-4-(2-hydroxy-4-methoxyphenyl)-2-hydroxy-4-oxo-butanoateC12H14O6ee >99.8%[α]D20 = +26.5 (c 0.3, CHCl3)Source of chirality: the precursor (l-malic acid)Absolute configuration: (2S)

Methyl (S)-4-(2-hydroxy-5-methoxyphenyl)-2-hydroxy-4-oxo-butanoateC12H14O6ee >98.8%[α]D20 = +8.8 (c 0.14, CHCl3)Source of chirality: the precursor (l-malic acid)Absolute configuration: (2S)

Methyl (R)-6-fluoro-4-oxochroman-2-carboxylateC11H9FO4ee >99.9%[α]D20 = −38.3 (c 0.85, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-chloro-4-oxochroman-2-carboxylateC11H9ClO4ee >99.9%[α]D20 = −50.2 (c 1.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-bromo-4-oxochroman-2-carboxylateC11H9BrO4ee >99.9%[α]D20 = −47.8 (c 1.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-7-methoxy-4-oxochroman-2-carboxylateC12H12O5ee >99.6%[α]D20 = +12.5 (c 2.2, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-methoxy-4-oxochroman-2-carboxylateC12H12O5ee >99.9%[α]D20 = −67.3 (c 0.1, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-fluorochroman-2-carboxylateC11H11FO3ee >99.5%[α]D20 = −10.3 (c 0.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-chlorochroman-2-carboxylateC11H11ClO3ee >99.3%[α]D20 = −6.9 (c 3.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-bromochroman-2-carboxylateC11H11BrO3ee >98.8%[α]D20 = −7.1 (c 0.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-7-methoxychroman-2-carboxylateC12H14O4ee >99.8%[α]D20 = +11.6 (c 1.8, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-6-methoxychroman-2-carboxylateC12H14O4ee >99.5%[α]D20 = −5.6 (c 0.2, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

Methyl (R)-chroman-2-carboxylateC11H12O3ee >99.1%[α]D20 = −6.9 (c 3.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

(R)-6-Fluorochroman-2-carboxylic acidC10H9FO3ee >99.1%[α]D20 = −12.6 (c 1.0, DMF)Source of chirality: the precursorAbsolute configuration: (2R)

(R)-6-Chlorochroman-2-carboxylic acidC10H9ClO3ee >98.3%[α]D20 = −15.5 (c 1.0, MeOH)Source of chirality: the precursorAbsolute configuration: (2R)

(R)-6-Bromochroman-2-carboxylic acidC10H9BrO3ee >99.1%[α]D20 = −7.8 (c 0.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

(R)-7-Methoxychroman-2-carboxylic acidC11H12O4ee >98.7%[α]D20 = +54.5 (c 1.25, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

(R)-6-Methoxychroman-2-carboxylic acidC11H12O4ee >99.4%[α]D20 = −11.2 (c 1.35, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R)

(R)-Chroman-2-carboxylic acidC10H10O3ee >99.9%[α]D20 = −6.3 (c 1.05, MeOH)Source of chirality: the precursorAbsolute configuration: (2R)