Dimeric and Oligomeric Steroids.

The steroid nucleus is one of the largest rigid units readily available with multiple chiral centers and the biological importance of this structural entity is well documented.1 While dimeric steroids were first observed as synthetic byproducts2,3 and then discovered in nature,4 up to very recently, dimeric steroid systems were considered more of a novelty than anything else. With the discovery of a second dimeric steroid class,5 it may be conjectured that eventually other naturally occurring dimeric steroids will be identified. This belief is further reinforced by the reported microbial transformation of dehydrocholic acid into steroid dimers in which carbon atoms 4,4′,5,5′,6,6′ comprise a benzene nucleus.6 Evidence that the dimerization of the steroid skeleton leads to unique characteristics and applications gradually began to emerge in different areas. A standard color test for the presence of cholesterol is the formation of a green color in concentrated sulfuric acid, and this was shown to be due to a polyenyl steroidal dimer carbocation.7-9 Many dimeric and oligomeric steroids exhibit micellular, detergent, and liquid crystal behavior.10-12 Steroidal dimers have been used as catalysts for some types of reactions13 and may lead to new pharmacologically active steroids.14 For example, the cephalostatins is a group of dimeric steroids that are among the most potent natural cytotoxins.5 This exceptional activity of cephalostatins has led to interest in the synthesis of these compounds and analogues as potential antitumor agents.5 Some time ago, during our synthetic studies of bile acid derivatives and their conversion to seco analogues and dinorquassinoids, we invariably observed trace amounts of polar side products via TLC analysis which, at the time, we believed might be oligomeric (polymeric) derivatives.15,16 Also, we were intrigued by the possibility that cholic acid dimers and ester dimers with cholesterol might occur in the gastrointestinal/liver system of mammals. Gallstone dissolution therapy might actually involve a mechanism whereby cholesterol forms a dimer with deoxycholic acid, with or without a spacer group. While all this was conjectural, it nevertheless piqued our interest in these systems. This led us to briefly study the dimerization of cholestanol and 3-oxocholanoic acid.17 Recent progress involving dimerization and oligomerization of the cholic acid skeleton as an architectural building block has renewed our interest in this area. Oligomeric steroids with and without spacer groups can be used as chiral building blocks to construct artificial receptors and as architectural components in biomimetic/molecular recognition chemistry.1 Davis has briefly reviewed his work in this area directed toward construction of enzyme mimics.1 However, no comprehensive review for this topic has been published. Therefore, it is appropriate to fully review this emerging area of steroid chemistry. Our review covers the synthesis of all bisand oligosteroid derivatives and isolation of these steroids from natural products. A list of these bisand oligosteroids and a brief report on some of their properties are also included. As will be evident, the cholic acid steroidal skeleton plays a pivotal role in this area. Cholic acid is an ideal building block for artificial 283 Chem. Rev. 1997, 97, 283−304