Drospirenone synthesis

The synthesis of drospirenone (see Fig. 17.1) was unusually complicated, with the new structural elements being methylene groups at positions 6)5,7)5 and 15)5,16)5. Originally, in 1966, the 15)5,16)5-methylene group [9,10] had been introduced into the steroid skeleton in the process of another Schering project, and good yields were obtained. The major problem in the synthesis was stereoselective 6)5,7)5-methylenation the key compound for this was the 5)5-hydroxy-6-ene structure A, from which the 6j8,7)5-methylene compound B was synthetized stereoselectively by means of a Simmons-Smith reaction (Zn-Cu/CH2Br2) (Fig. 17.6). 

The synthetic studies were therefore concentrated on a rational synthesis of 5yS-hydroxy-6-ene structure A. The result was the synthesis briefly outlined in Fig. 17.7, which led to drospirenone (9.6% yield) in a 12-step process from andros-tenolone (3j8-hydroxyandrost-5-en-17-one). These investigations were carried out at Schering s pharmaceutical chemistry unit, under the supervision of H. Laurent. 

The synthesis of Drospirenone 41 (Scheme 1-15) [83] starts with the inexpensive androstenolone 66, which can be converted microbiologically (Colletotrichum lini) into the 7a,15a-dihydroxy derivative 67. A selective epimerization at C(7) proceeds by way of the acetal 68. Methylenation of the intermediate (C=C) bond appearing between C(15) and C(16) is successfully accomplished with the aid of dimethylsulfoxonium methylide to provide 71, and that of the (C=C) bond between C(6) and C(7) through a Simmons-Smith reaction. The conversion of 76 into 41 can be carried out in a one-pot procedure, with a Pd-catalyzed hydrogenation being followed by a Ru-catalyzed oxidation and a hydrochloric acid-induced dehydration. 

Scheme 1-15 Collection of formulae relevant to a synthesis of (-)-drospirenone 41 starting from the easily accessible androstenolone 66.

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