A-Norsteroids

Oxidation of 17j5-acetoxy-5a-androstan-3-one (1) by chromium trioxide in acetic acid at 55-65° gives the 2,3-seco acid (2). Conversion of the seco acid to its anhydride followed by pyrolysis and distillation gives the A-nor-2-ketone (3) in 45% overall yield. Analogous reactions have been carried 

17)5-Acetoxy-A-nor-5a-androstan-2-one (3) l7 -Acetoxy-2,3-seco-5a-An-drostane-2,3-dioic Acid (2). This an an adaptation of the method of Riill and Ourission.  

17P-Acetoxy-A-nor-5a-androstan-2-one (3). A solution of 50 g of seco acid (2) and 70 ml of acetic anhydride is heated at reflux temperature for 2 hr. 

By converting the A -3-ketone into its 2-hydroxymethylene derivative, selective ozonolysis to the 2,3-seco-2,3-dicarboxylic acid can be carried out in the presence of the A -double bond. Weisenborn has thus prepared A-nortesto-sterone and A-norprogesterone. In the latter case, selective formyla-tion at C-2 was achieved by first reducing the 20-ketone to the 20-ol (4). 

The A -double bond can also be introduced in saturated A-nor-2-ketones by bromination-dehydrobromination. This has been used in an alternate preparation of A-norprogesterone and in a recent synthesis of A-nor-19-nortestosterone.  

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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.). 

Cyanogen azide is a useful reagent for conversion of pyrrolidine enamines of 3-keto steroids to A-norsteroids. " Ring contractions can be carried out in the presence of 17j5-hydroxy, 17j -acetoxy, 20-keto groups and isolated double bonds. In a typical procedure, 17j -hydroxy-5a-androstan-3-one (partial formula 8) is converted into the enamine (9) by pyrrolidine in benzene... 

Cyanoamidines such as (10) are converted into the more useful 2-formyl-A-norsteroids (11) by reduction with lithium in methylamine (buffered with ammonium acetate) followed by hydrolysis on hydrated alumina. This yields a mixture containing approximately 5 parts of the 2j5-aldehyde and 3 parts of the 2a-aldehyde (11). Both aldehydes are smoothly dehydrogenated by 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of acid to the 2-formyl--A-iiorsteroids (12). ... 

Although crude cyanoamidine (10) can be used for many reactions, reduction to the 2-formyl-A-norsteroid (11) is most satisfactory when purified material is employed. The crude cyanoamidine is stirred for about 15 min with boiling toluene (120 ml/g of steroid) to effect dissolution, the hot solution is filtered quickly through fluted paper, and the filtrate is cooled and diluted with an equal volume of petroleum ether. The mixture is cooled for 0.5 hr in ice, affording from 25 g of crude material about 18 g of colorless 2a-(A-pyrrolidinylcyanoiminomethyl)-A-nor-5a-androstan-17 -ol (10) mp 252-255° (anal, sample mp 262-263°, from benzene-hexane 250 m ... 

The ready availability of 2,2- and 4,4-dimethyl-3j5-hydroxy steroids enhances the utility of the retropinacol rearrangement as a method for preparing A-norsteroids (see chapter 14). 

Benzilic rearrangement of diosphenol (44) gives the A-norsteroid (45) in 90 % yield. 

A-norsteroids (59) of the cholestane, androstane, pregnane and hydrocortisone series have been prepared from the diols (61)." However, preparation of these 1,2-diols is complicated by concomitant formation of isomeric 4,5-diols, which are usually difficult to separate. The sequence (58) -> (59) appears to be the most practical route to A-norsteroids (59), provided that diosphenol (58) is readily available. 

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." " ... 

Photolysis of a-diazoketones has also been used to prepare A-norsteroids. Results in the A-nor series support the ketene intermediate invoked for the assignment of the 16) -configuration to the D-nor acids. Thus, irradiation of 2-diazo-5a-cholestan-3-one (99) gives 2/ -carboxy-A-nor-cholestane (100, R = H) in 45 % yield. ... 

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... 

The stereochemistry of the epoxidation of A-norsteroids is less predictable than that of the corresponding steroids in view of the flattened nature of ring A and the preferred cis fusion of the hydrindane it has been shown that epoxidation with peroxy acids proceeds predominantly from the fi-face in some norsteroids294. 

Similarly, many A-norsteroids 244 have been subjected to phenol-dienone rearrangement in HF—SbF5 medium854 [Eq. (5.312)]. 1H NMR spectroscopic studies at low temperature confirms the formation of 0-protonated intermediates (Scheme 5.87), which subsequently rearrange to diprotonated precursors of the dienones 245. 

Reductive cyclization of y-ethynyl ketones to allylic alcohols. This reaction was first reported by Stork et al., who used an alkali metal and liquid ammonia.1 The main by-products, at least in cyclization to A-norsteroids, result from overreduction. This side reaction can be prevented by use of sodium naphthalenide in THF or DME.2... 

Furano-steroids 80 and 3-oxa-A-norsteroids 79 have been prepared by reaction of a-bromoketones with steroid dienamines39,66 (Scheme 39). 

The stereochemistry of the product obtained when 3-2,3-epoxycholestane is treated with MeMgl is in keeping with a mechanism involving initial diaxial opening to form an iodohydrin salt (equation 100), followed by rearrangement with backside displacement of the iodide via a twist boat conformer. Addition of MeMgl to the A-norsteroid aldehyde formed in this manner would then result in the two alcohols (epimeric at the carbinol center), which were isolated. 

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