Constrained cycloalkyl analogues of glutamic acid: stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue

A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6-dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-(R)-2-(p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent-4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer–Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9–11 have been obtained by asymmetric cyclopropanation of (−)-(S)-3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)-11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)-endo-2 in 46% overall yield.

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(1S,5R,6R,SS)-Ethyl-1-(p-tolylsulfinyl)-2-oxobicyclo[3.1.0]hexane-6-carboxylateC16H18O4SEe >98%[α]D20 = +31.3 (c 4.7, acetone)Source of chirality: (−)-(1R,2S,5R)-mentholAbsolute configuration: (1S,5R,6R,SS)

(1R,5S,6R,RS)-Ethyl-1-(p-tolylsulfinyl]-2-oxobicyclo[3.1.0]hexane-6-carboxylateC16H18O4SEe >98%[α]D20 = −24.0 (c 3.0, acetone)Source of chirality: (+) (1S,2R,5S) mentholAbsolute configuration: (1R,5S,6R,RS)

(1S,5R,6S)-Bicyclo[3.1.0]hexan-2-one-6-carboxylic acid ethyl esterC9H14O3Ee >98%[α]D20 = +64.2 (c 1.5, MeOH)Source of chirality: (+)-(1S,2R,5S)-mentholAbsolute configuration: (1S,5R,6S)

(1R,5R,6S,SS)-1-(p-Tolylsulfinyl)6-[5,5-Dimethyl-2-oxo-2-(1,3,2)dioxaphosphorinanyl]-bicyclo[3.1.0]hexan-2-oneC18H23O5PSEe >98%[α]D20 = +64.8 (c 3.2, acetone)Source of chirality: (−)-(1R,2S,5R)-mentholAbsolute configuration: (1R,5R,6S,SS)

(1R,5R,6S,SS)-6-Dimethyl-1-(p-tolylsulfinyl)-2-oxobicyclo[3.1.0]hexan-6-ylphosphonateC15H19O5PSEe >98%[α]D20 = +56.4 (c 2.2, acetone)Source of chirality: (−)-(1R,2S,5R)-mentholAbsolute configuration: (1R,5R,6S,SS)

(1S,5S,6S)-6-Diisopropyl 2-oxobicyclo[3.1.0]hexan-6-ylphosphonateC12H21O4PEe >98%[α]D20 = +10.8 (c 2.3, acetone)Source of chirality: (−)-(1R,2S,5R)-mentholAbsolute configuration: (1S,5S,6S)

(1S,2R,5S,6S)-6-(Diisopropyloxyphosphoryl)-2-spirohydantoinbicyclo[3.1.0]hexaneC14H23PN2O5Ee >98%[α]D20 = +92 (c 6.4, acetone)Source of chirality: (−)-(1R,2S,5R)-mentholAbsolute configuration: (1S,2R,5S,6S)

(1S,2R,5S,6S)-2-Amino-6-phosphonobicyclo[3.1.0]hexane-2-carboxylic acidC7H12NO5PEe >98%[α]D20 = +82.5 (c 4.2, methanol)Source of chirality: (−)-(1R,2S,5R)-mentholAbsolute configuration: (1S,2R,5S,6S)