Homosteroid

A valuable extension of the diazomethane reaction for the preparation of A-homosteroids was discovered by Johnson, Neeman and Birkeland " who found that a,j5-unsaturated ketones are homologated by reaction with diazomethane in the presence of either fluoroboric acid or boron trifluoride. The main product is formed by the insertion of a methylene group between the carbonyl group and the unsaturated a-carbon to give a / ,y-unsaturated ketone. 

B-Homosteroids were first reported by Ringold in the course of an investigation of the relationship of structural changes to biological activity of anabolic agents. The Tiffeneau rearrangement sequence described earlier for the preparation of A-homosteroids was used to synthesize 17/ -hydroxy-B-homo-5a-androstan-3-one (56a). 

In a study of the stereochemistry of the B-homosteroid ring system, Kohout, Fajkos and Sorm prepared 3 -hydroxy-B-homo-5a-cholestan-7-one acetate... 

B-Homosteroids have also been prepared by acid-catalyzed reaction of diazomethane with a,/5-unsaturated ketones. 3/ -Hydroxycholest-5-en-7-one acetate (57) reacts with diazomethane in the presence of concentrated fluoroboric acid, boron trifluoride etherate or aluminum chloride to give 3yS-hydroxy-B-homo-cholest-5-en-7a-one acetate (67). The 7a-keto group is reported to be chemically less reactive than an 11-keto group. 

For the preparation of 19-nor-B-homosteroids Tadanier s acetolysis procedure appears to be the method of choice. The mild reaction conditions employed with each of these procedures allows the maintainance of a variety of functional groups, e.g., double bonds, ethers, hydroxyls and the like during the homologation process. 

Tiffeneau ring enlargement is a route to D-homosteroids. Goldberg and Monnier" treated the 17i5-hydroxy-20-amine (91) prepared by hydrogenation of 17a-cyano-5a-androstane-3)3,17j5-diol (90a) with nitrous acid and obtained 3i5-hydroxy-5a-D-homo-androstan-17a-one (92). 

An advantage of Tiffeneau ring enlargement and rearrangement of 17a-hydroxy-20-keto steroids for preparing of D-homosteroids is the ready availability of the starting 17-ketones. Both procedures involve mild conditions which allow a wide variety of suitably protected functional groups to be present. 

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. 

D-homosteroids, 382 Hydrazoic acid, 27, 145 Hydriodic acid, 172 Hydroboration, 165, 166 Hydrogen peroxide, 221 Hydrogen transfer, 239 17 i3-Hydroxy-2-acety l-5a-androstan-3 -one acetate, 342... 

A-nor-5a-cholestan-2-one, 419 B-norcholestenone, 430 19-Norcholestenone, 281 B-norcholesterol acetate, 429, 430 D-nor-11-dehydrocorticosterone acetate, 441 D-nordesoxycorticosterone acetate, 441 A-nor-B-homosteroids, 395 C-nor-D-homo steroids, 400 C-nor-1U- (a-hydroxyethyl) -pregnane-... 

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. 

On the other hand, in the synthesis of cholesterol (30) by Woodward and CO workers [10] the less stable fran -configuration between rings C and D is attained through a homosteroid (29). i.e. a steroid analogue in which the C/D indane system is substituted by a decalin in which the rran -configuration is the thermodynamically favoured (Scheme 8.7). The conversion of the six-membered ring into one of five members is carried out at a later stage, under conditions that do not affect the preformed tran -junction. 

Expansion of the D-ring of steroids to produce azasteroids is very common. Usually, the nitrogen is inserted between C(17) and the C ring and this kind of transformation was very popular in the search for new active pharmaceutical ingredients. Schonecker and colleagues performed the D ring expansion of 380 in-route to 17-aza-D-homosteroids (equation 152). 

Irradiation of the A-homosteroid 5 leads first, by a ring contraction, to the vinyl-A-norsteroid, which on further irradiation loses carbon monoxide to form the A-bis-norsteroid 6.159... 

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. 

This orientation also obtains in cycloaddition with citraconic anhydride (6). These results arc difficult to rationalize in any case the reaction of 1 with quinones such as 2 provides a route to D-homosteroids with substituents at either C,j or C14. In fact, the adduct 5 was converted to (//-estrone methyl ether. 

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