Practical approaches to the matrix metalloproteinase inhibitor Trocade® (Ro 32-3555) and to the TNF-α converting enzyme inhibitor Ro 32-7315

Stereoselective methods were found to efficiently prepare 2- and 3-substituted succinates with anti configuration. In the synthesis of Trocade® 1, the hydantoinmethyl residue was introduced by alkylation of the non-chelated potassium enolate 19 with the bromomethyl hydantoin 9 to give a 92:8 mixture favouring the 2,3-anti configurated succinate 18. The preparation of TNF-α converting enzyme (TACE) inhibitor 2 was accomplished by a highly stereoselective protonation of the dialkylated enolate 23 using CF3CONH2 affording a 98:2 mixture in favour of the 2,3-anti configurated succinate 24.