19- Norsteroids synthesis

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

The 1950s and 1960s saw the development of orally active progestins based on the synthesis of steroids that lack the C19-angular methyl substituent (19-norsteroids). The commercial production of these compounds for the regulation of menstmal disorders began in 1957, and for oral contraception in 1960. 

Interest in the synthesis of 19-norsteroids as orally active progestins prompted efforts to remove the C19 angular methyl substituent of readily available steroid precursors. Industrial applications include the direct conversion of androsta-l,4-diene-3,17-dione [897-06-3] (92) to estrone [53-16-7] (26) by thermolysis in mineral oil at about 500°C (136), and reductive elimination of the angular methyl group of the 17-ketal of the dione [2398-63-2] (93) with lithium biphenyl radical anion to form the 17-ketal of estrone [900-83-4] (94) (137). 

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

The photolytic and thermolytic decomposition of azides in the presence of olefins has been applied to aziridine synthesis. However, only a limited number of steroid aziridines have been prepared in this manner. The patent literature reports the use of cyanogen azide at ca. 50° for 24 hours in ethyl acetate for the preparation of an A-nor- and a B-norsteroidal aziridine. The addition is believed to proceed via a triazoline. The reaction of cholest-2-ene with ethyl azidoformate takes place in a nonselective manner to produce a mixture of substances, including C—H insertion products. 

Recent improvements in the total synthesis of steroids which give as the first tetracyclic products 19-norsteroids bearing a hydroxyl or keto group at C-17 have revived interest in the conversion of androstanes to pregnanes. 

Photochemical Wolff rearrangement of 2-diazo-3-ketones, though not widely used as a source of A-norsteroids, is discussed in section V in connection with the mechanism of the important photochemical synthesis of D-norsteroids. Photochemical rearrangement of epoxy ketones is a source of A-nosteroids these rearrangements are discussed in chapter 13. Other photochemical routes to A-norsteroids are known." " ... 

Ozonization of A -steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol" (or formaldehyde ) improves yields significantly. Thus, Tanabe and Morisawa prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74% by the reaction sequence represented below. 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

This method was employed in the synthesis of 16-acyl-D-norsteroids (see Houben-Weyl, Vol. 4/4, pp 94-119) the product 7 was formed as a mixture of epimers in 50% yield.76... 

Functionalization of Ci from C6 in high yield found a useful application in the synthesis of medically important 19-norsteroids.9-1<> Thus, readily available A6 6-steroids (as exemplified by partial structure 20)... 

An interesting breakthrough in steroid endocrinology occurred with the discovery of a novel class of steroid antihormoncs. Several 11 /(-substituted 19-norsteroids display potent amiprogeslinal activity. For example, RU-486 (33) is marketed in Europe as a contragestive agent. The synthesis of RU-486 demonstrates a unique method for functionalization of the 11/(-position of a steroid nucleus. 

The Danishefsky group reported the use of an organocatalytic intramolecular aldol reaction in the synthesis of a key intermediate, 108, for preparation of optically active estrone and commercially relevant 19-norsteroids [118, 119]. In the presence... 

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