Remote functionalization reactions in steroids: discovery and application

Abstract

Research published between 2001 and 2022 on the functionalization of remote positions of steroids, as well as the use of this technique in the generation of biologically active compounds has been reviewed. In the first section of the analysis established and novel methods for activation of sites deemed to be remote were reported. A series of manganese- (mainly), rhodium-, ruthenium- and osmium-centered porphyrins as catalysts in the presence of PIDA as oxidant have effected hydroxylation at C-1, -5, -6, -7, -11, -14, -15, -16, -17, -20, -24 and -25. Dioxiranes have been utilized in inserting hydroxyl groups at the 5, 12, 14, 15, 16, 17, 20, 24 and 25 positions (tertiary centers for the most part). Alcohols at C-12 and -16 were oxidized further to ketones. The Schönecker oxidation, discovered and developed during the period, has revolutionized the selective functionalization at C-12 of steroids possessing a 17-keto group. In the presence of iron-centered PDP- and MCP-based catalysts, hydrogen peroxide and acetic acid, substrates tended to be hydroxylated at C-6 and -12, with further oxidation to ketones often accompanying this reaction. The hypohalite reaction, utilizing the more modern Suarez conditions (irradiation in the presence of iodine and PIDA), was reported to facilitate the insertion of a hydroxyl moiety five atoms away from an existing alcohol oxygen. Steroidal-3β-diazoacetates tend to decompose on heating with di-rhodium-centered catalysts while activating carbons four or five atoms away. Chromium- and iron-based acetates were observed to functionalize C-5 and -25. Other reactions involving ring cleavage and halogenation, ketone irradiation and α-hydroxylation of ethers were also covered.

The syntheses of compounds with marked biological activity from readily available steroids is described in the second section of the study. Cyclopamine, cephalostatin-1, ritterazine B and three polyhydroxypregnanaes (pergularin, utendin and tomentogenin) were generated in sequences in which a key step required hydroxylation at C-12 using the Schönecker reaction. A crucial stage in the preparation of cortistatin A, the saundersioside core, eurysterol A, 5,6-dihydroglaucogenin C, as well as clinostatins A and B involved the functionalization of C-18 or -19 utilizing hypohalite chemistry. The synthetic route to xestobergsterol A, pavonin-4-aglycone and ouagabagenin included a transformation where ketone irradiation played a part in either producing a Δ¹⁴ or a C-19 activated steroid. The radical relay reaction, where a 17α-chloro-steroid was formed, was central in the generation of pythocholic acid. The lead tetraacetate reaction was pivotal in the functionalization of C-19 during the synthesis of cyclocitrinol.