Enantiodivergent synthesis of steroidal side chains. Stereocontrol via SN1 vs. SN2 type cleavage of acetal templates

Abstract

The chiral steroidal acetals 2(S–R, R isomer) and 3(S–S, S isomer) were prepared from the reaction of the steroidal aldehyde 1 with (2R, 4R)-(–)-pentane-2,4-diol and with (2S, 4S)-(+)-pentane-2,4-diol, respectively. The TiCl₄ mediated reaction of 2 and 3 with organometallic reagents, such as allylsilane, allyltin, allyl-9-BBN, 1-tributylstannylalk-1-ynes, and 1-trimethylsilylhex-1-yne gave a mixture of the Cram, 4 and 6, and anti-Cram, 5 and 7, adducts. The organometallic compounds with lower nucleophilicity (the Me₃Si and 9-BBN derivatives) gave the Cram isomer predominantly or exclusively regardless of the chirality of the acetal, whereas the reagents with higher nucleophilicity (the tributylstannyl derivatives) produced the anti-Cram isomer with good diastereoselectivity in the case of the S–S, S isomer 3. This synergistic or countervailing effect of the acetal template and Cram rule is understood by considering that the chiral induction is controlled by the timing of bond breaking and bond making in the acetal template. This stereodivergent synthetic method was applied to the preparation of an α-ecdysone type steroid 17.