Solid-phase synthesis of enantio-controlled lactic acid oligomers

A synthetic method for lactic acid oligomers via solid-phase synthesis under mild reaction conditions with up to 99% yield is presented. The fine control of the chirality on each lactic acid unit of the oligomers was easily achieved by the substitution of (R)-THP-protected lactic acid (R)-2 by (S)-2 without alternating the procedure. The overall synthesis of the trimer and tetramer was completed in one and two days, respectively. Intramolecular cyclizations of enantio-controlled lactic acids were also attempted through the Yamaguchi macrolactonization or the Mitsunobu reaction. However, we were unable to isolate single cyclic oligomers but always obtained a mixture of cyclic oligomers.

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(R)-2-(((R)-2-(((R)-2-Hydroxypropanoyl)oxy)propanoyl)oxy)propanoic acidC9H14O7[α]D = +0.2 (c 2.0, CHCl3)Source of chirality: (R)-lactic acidAbsolute configuration: (R,R,R)

(R)-2-(((R)-2-(((S)-2-Hydroxypropanoyl)oxy)propanoyl)oxy)propanoic acidC9H14O7[α]D = +0.1 (c 2.0, CHCl3)Source of chirality: (R)-lactic acid, (S)-lactic acidAbsolute configuration: (R,R,S)

(R)-2-(((S)-2-(((S)-2-Hydroxypropanoyl)oxy)propanoyl)oxy)propanoic acidC9H14O7[α]D = +0.05 (c 2.0, CHCl3)Source of chirality: (R)-lactic acid, (S)-lactic acidAbsolute configuration: (R,S,S)

(R)-2-(((R)-2-(((R)-2-(((R)-2-Hydroxypropanoyl)oxy)propanoyl)oxy)propanoyl)oxy)propanoic acidC12H18O9[α]D = +0.1 (c 2.0, CHCl3)Source of chirality: (R)-lactic acid, (S)-lactic acidAbsolute configuration: (R,R,R,R)

(R)-2-(((R)-2-(((R)-2-(((S)-2-Hydroxypropanoyl)oxy)propanoyl)oxy)propanoyl)oxy)propanoic acidC12H18O9[α]D = +0.1 (c 2.0, CHCl3)Source of chirality: (R)-lactic acid, (S)-lactic acidAbsolute configuration: (R,R,R,S)