New method for the asymmetric hydroboration of ketophosphonates and the synthesis of phospho-carnitine

The reduction of α- or β-ketophosphonates with a chiral reactant 1, prepared from sodium borohydride and (R)- or (S)-tartaric acids, led to the formation of both (S)- and (R)-α- or β-hydroxyphosphonates in high yields. The stereoselectivity of the reaction depended on the absolute configurations of 1 and the ketophosphonates. The reduction of di(1R,2S,5R)-menthyl ketophosphonates with (R)-1 proceeded with matched double asymmetric induction to give high diastereomeric excesses of hydroxyphosphonates (up to 96% de). This methodology was used for the preparation of enantiomerically pure phosphonate modified carnitine on a multigram scale.

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(2S)-[Bis(1R,2S,5R)-menthyl]-3-chloro-2-hydroxypropylphosphonateC23H44ClO4PDe ∼100% (NMR)[α]D = −97.2 (c 3, CHCl3)Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (R,R)-tartaric acidAbsolute configuration: S

(R)-3-(Trimethylamonium)-2-hydroxypropylphosphonic acidC6H16NO4PEe ∼99% (NMR)[α]D = +25 (c 1, H2O)Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (R,R)-tartaric acidAbsolute configuration: R

(1S)-Bis[(1R,2R,5S)-menthyl] hydroxy(phenyl)methylphosphonateC27H45O4PDe 99% (NMR)[α]D = −70.0 (c 1, CHCl3)Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (S,S)-tartaric acidAbsolute configuration: S

(1R)-Bis[(1R,2R,5S)-menthyl] hydroxy(phenyl)methylphosphonateC27H45O4PDe 99% (NMR)[α]D = −87.6 (c 2, CHCl3)Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (R,R)-tartaric acidAbsolute configuration: R

(1S)-Bis[(1R,2R,5S)-menthyl] (2-fluorophenyl)(hydroxyl)methylphosphonateC27H44FO4PEe > 98% (NMR)[α]D = −83.7 (c 2, CHCl3)Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (R,R)-tartaric acidAbsolute configuration: S

(1S)-Bis[(1R,2R,5S)-menthyl] hydroxy(2-methoxyphenyl)methylphosphonateEe > 98% (NMR)[α]D = −75.2 (c 1, CHCl3)Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (R,R)-tartaric acidAbsolute configuration: S

(1R)-Bis[(1R,2R,5S)-menthyl] (benzo[d][1,3]dioxol-5-yl)(hydroxy)methylphosphonateEe > 98% (NMR)[α]D = −74 (c 1, CHCl3).Source of chirality: double asymmetric synthesis with (−)-(1R,2S,5R)-menthol and (R,R)-tartaric acidAbsolute configuration: R