Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzyme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives

We have developed a highly convergent and stereoselective synthesis of BILA 2157 BS, a potent and orally active renin inhibitor. The synthesis proceed s in 15 distinct chemical steps (with several integrated, multistep operati ons) from aminodiol 4. The key step in the synthesis involves the use of an enantiospecific, enzyme-catalyzed hydrolysis of a substituted succinate di ester to provide a homochiral succinic acid derivative in 98% enantiomeric excess (greater than or equal to 2.5 kg scale). Recycling of the unwanted e nantiomer is accomplished through base-catalyzed racemization, leading to a n efficient deracemization of the starting racemic diester. The entire sequ ence proceeds without chromatographic purifications and delivers the produc t with >97% homogeneity. In addition, compared to the previously reported s yntheses of BILA. 2157 BS, this approach avoids the use of expensive chiral auxiliaries and, cryogenics and, thus, should be amenable to the preparati on of large quantities of this peptidomimetic inhibitor.