C-nor-D-homosteroids

The C-nor-D-homosteroid rearrangement was discovered by Hirschmann and co-workers at the time that Wintersteiner and his collaborators established that the steroid alkaloids jervine and veratramine incorporate a 14 (1312) abeo-nng system. This was the predecessor of the family of simultaneous ring contraction-expansion reactions. Solvolysis of the 12j5-methanesulfonate (144a) gives mainly the kinetic reaction product, the C-nor-D-homo exocyclic olefin (145) along with some 13(17)-ene (146a). 

In the preparation of C-nor-D-homosteroid hormone analogs Mitsuhashi and Harada extended the Bamford-Stevens rearrangement to the cholanic acid series. Treatment of 3a-hydroxy-12-oxocholanic acid /j-toluene-... 

Since alkaline decomposition of p-toluenesulfonylhydrazones of steroid 12-ketones leads directly to 14(13 I2) jr e >-13(17)-enes whereas solvolysis of 12j5-mesylates gives mixtures of 13(18)- and 13(17)-enes, the former approach is preferred for the preparation of C-nor-D-homosteroids. If the particular system under consideration is not stable to base at elevated temperatures, the milder solvolysis method could be used. Either approach starts with a 12-oxygenated steroid. Additional base-stable functional groups should be compatible under the conditions for the rearrangement process. 

Chart 2.1 C-nor-D-homosteroids and the first two Hedgehog antagonists in clinical trials... 

The unique molecular skeleton of the C-nor-D-homosteroids represents significant challenges for organic chemists. The structure elucidation and the total synthesis of cyclopamine (3, also known as 11-deoxojervine), jervine (ll-oxo-3), and veratramine (4) are important milestones in steroid chemistry. Many synthetic strategies were developed in the 1960s-1970s for these targets. Notably, Masamune... 

The biomimetic approach to the core skeleton of C-nor-D-homosteroid was first developed by the Merck research group (Scheme 2.1) [16]. In the Merck procedure,... 

Johnson has developed two linear approaches to synthesize the C-nor-D-homosteroid skeleton (Scheme 2.2). In his first approach [21], tetralone 19, obtained from reduction of 2,5-dimethoxynaphthalene, was used as the source of the C,D-rings. The B- and A-rings were constructed by sequential Robinson annulations (19 —> 20 —> 21). The Cl 1,12 olefin was then introduced to provide 22. Ozonolysis of 22 followed by an aldol reaction of the resulting dialdehyde gave 23. Subsequent deformylation and deoxygenation afforded the cyclopamine skeleton 24. 

Teruya, T., Nakagawa, S., Koyama, T., Suenaga, K., Kita, M., and Uemura, D. (2003). Nakiterpiosin, a novel cytotoxic C-nor-D-homosteroid from the Okinawan sponge Terpios hoshinota. Tetrahedron Lett. 44,5171-5173. 

Teruya T, Nakagawa S, Koyama T, Suenaga K, Kita M, Uemura D (2003) Nakiterpiosin, a Novel Cytotoxic C-nor-D-Homosteroid from the Okinawan Sponge Terpios hoshinota. Tetrahedron Lett 44 5171... 

Unlike 12)S-sulphonyloxy-derivatives of conanine which afford rearranged c-nor-D-homosteroids, the 12a-epimers undergo reductive fragmentation d with dichloroaluminium hydride to give the 18-nor-l2-ene (331). 

The skeleton of verticine, peiminoside, and fritillarine is a C-nor-D-homosteroid, which possesses a five-membered C-ring and a six-membered D-ring. This skeleton is also common to the Veratrum alkaloids of the Lili-aceae plants. 

In Veratrum and Fritillaria (Lihaceae) C-nor-D-homosteroid alkaloids with 27 C-atoms are found. These substances are linked to sugars at the C-3 hydroxy group and many carry acyl residues attached to other OH-groups. Two typical representatives are veratr amine and ver ace vine. 

T. Masamune has reviewed recent progress in the chemistry of C-nor-D-homosteroids [Kagaku To Kogyo (Tokyo) 19, 500 (1966) CA 65, 3925 (1966)]. T. Masamune and co-workers have also (1) described the details of the structural elucidation of 11-deoxojervine (CXVII) (Bull. Chem. Soc. Japan 38, 1374 (1965)] (2) advanced corroborative evidence for... 

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