Amino steroids ‐ functionalization of position 20 from position 18 in a pregnane system through a Hofmann‐Löffler process. predominant formation of 5α‐heteroconan‐3β‐ol

Abstract

The Hofmann-Loffler sequence of reactions applied t o 18-methylamino-5a-pregnan-36-olled t o 5a-heteroconan-38-01 ill, 206 (12, 2Oa 8 t o I , go the ezclusion of any other nitrogen containing c y c l i c system. or 2OR configuration) and t o 50.-conan-38-01 or 205 c o n f i g u r a t i o n , as i n natural conanine d e r i v a t i v e s ) in a r a t i o of F Intramolecular functionalization in steroidal compounds, especially at the 18 and 19 angular methyl groups, is a well-known fact1. The Hofmann-LEffler reaction' (see mechanism outlined in Scheme I) has found application in that field although not very frequently : there is essentially the functionalization of C-18 starting with 20-N-chloroaminopregnanes (I and 11) in the synthesis of conanine (111) and heteroconanine (IV) derivatives3 and further that of position 168 induced from the 22-positioned N-atom in the side chain in the synthesis of demissidine4 ( V ) .5a-conanine 5a-heteroconanine V ' demi s s i dineOther functionalization reactions involving more readily available alcohol derivatives, such as nitrites and hypohalites, have been more extensively studied5; it is thought that these reactions proceed easily if a transitional six membered chair-like ring can be formed, the distance between the 0-atom and the C-atom acquiring functionality should be 2.5-2.7 1. Probably analogous steric requirements apply t o the Hofmann-LEffler reaction (step B). Taking this into account in the case of a 18-N-chloroaminopregnane we examined on a Dreiding model the possibility of attacking a position neighbouring the 18 angular site : a competition for H-abstraction could exist on the level of C-Il(@), C-8(8), C-15(6) and C-20 (both diastereotopic H's) provided that the side chains at 13 and 17 adopt suitable conformations. The experiment, however, ruled out the three first possibilities and confirmed the latter double hypothesis.