J. Krysiak, W. Midura, W. Wieczorek
Jun 23, 2010
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Influential Citations
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Journal
Tetrahedron-asymmetry
Abstract
Abstract 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.