Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

We herein report an asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 3, key intermediates of a novel immunomodulator, using enzymatic desymmetrization of 2-alkyl-2-tert-butoxycarbonylamino-1,3-propanediols 1a and 1b. This method makes it possible to prepare a chiral analogue of FTY720 4. These synthetic procedures allow for a broad structure variation in order to evaluate structure–activity relationships and the mechanism of action for sphingosine 1-phosphate-1 (S1P1) receptor agonist.

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(2R)-Amino-2-methyl-4-(thiophen-2-yl)butan-1-ol 1/2 d-(−)-tartrateC9H15NOS·0.5C4H6O6Ee = >99%[α]D24=-14.0 (c 1.0, H2O)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 2R

(2R)-Amino-2-methyl-4-(furan-2-yl)butan-1-ol 1/2 d-(−)-tartrateC9H15NO2·0.5C4H6O6Ee = >99%[α]D24=-11.9 (c 1.0, H2O)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 2R

(2R)-Amino-2-methyl-4-(1-methylpyrrol-2-yl)butan-1-ol 1/2 d-(−)-tartrateC10H18N2O·0.5C4H6O6Ee = >99%[α]D24=-13.3 (c 1.0, H2O)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 2R

(4R)-Ethyl-4-[2-(furan-2-yl)ethyl]-1,3-oxazolidin-2-oneC11H15NO3Ee = 93%[α]D24=+13.9 (c 3.1, CHCl3)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 4R

(4R)-Ethyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-oneC12H18N2O2Ee = 94%[α]D24=+10.3 (c 1.0, CHCl3)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 4R

(4R)-Ethyl-4-[2-(thiophen-2-yl)ethyl]-1,3-oxazolidin-2-oneC11H15NO2SEe = 93%[α]D24=+11.9 (c 1.0, CHCl3)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 4R

(2R)-Amino-4-[4-(heptyloxy)phenyl]-2-methylbutan-1-olC18H31NO2Ee = >99%[α]D24=-5.6 (c 0.21, CHCl3)Source of chirality: enzymatic desymmetrizationAbsolute configuration: 2R