Steroids photolysis

By Iodine Mercuric Oxide Photolysis of 5a.-Hydroxy Steroids... 

Alkoxy radicals are also the active hydrogen-abstracting species in a procedure that involves photolysis of nitrite esters. This reaction was originally developed as a method for functionalization of methyl groups in steroids.379... 

Photolysis reactions often are associated with oxidation because the latter category of reactions frequently can be initiated by light. The photooxidation of phenothiazines with the formation of N- and S-oxides is typical. But photolysis reactions are not restricted to oxidation. In the case of sodium nitroprusside, it is believed that degradation results from loss of the nitro-ligand from the molecule, followed by electronic rearrangement and hydration. Photo-induced reactions are common in steroids [36] an example is the formation of 2-benzoylcholestan-3-one following irradiation of cholest-2-en-3-ol benzoate. Photoadditions of water and of alcohols to the electronically excited state of steroids have also been observed [37],... 

Schaifner and co-workers found that steroid (49) upon photolysis gave products (50) in which the —CD3 and —CH3 groups were scrambled. This would be consistent with a stepwise oxa-di-w-methane type mechanism. 

The photolysis of the following steroid system resulted in two products corresponding to the Norrish type II reaction and one product due to a-cleavage (Norrish type I cleavage)<101) ... 

Photolysis of 2-propylnitrite, in which intramolecular hydrogen abstraction cannot occur via a six-membered transition state, results in a 30% yield of 2-propanone. As we shall see, this intramolecular hydrogen abstraction has been extensively applied to steroid syntheses by D. H. R. Barton and hence is commonly referred to as the Barton reaction. 

The photolysis of nitrite esters has been found to be of considerable synthetic utility, particularly in functionalizing steroid methyl groups. The most spectacular application of this reaction has been a three-step synthesis of aldosterone.<59) Irradiation of corticosterone-11-nitrite (30) followed by nitric acid treatment gave aldosterone (32) in a 15% overall yield ... 

Photolysis of nitro-steroids 225 yields the aci-nitronate at 254 nm131. This in turn gives various products, among them are ketone 226 and hydroxamic acid 227 (equation 105) which could be formed from the intermediate anions of the Af-hydroxyoxaziridines, with a possible participation of gem-hydroxynitroso transient (or its anion see Scheme 10). For comparison, IV-butyl spiro-oxaziridine 228 in ethanol is photolysed at 254 nm (equation 106) to give 7V-butyl lactam 229 (50%) and the ketone 230 (25%). The former process is a well-known photoprocess of oxaziridine131. 

For the substitution of the angular methyl groups in steroids five methods are known (a) homolysis of N-chloramines [Loffier-Freytag reaction (only C-18)] (b) oxidation of alcohols with lead tetraacetate (c) photolysis of nitrite esters (d) homolysis of hypochlorites (e) the hypoiodite reaction. ... 

Cyano-20-oxo-steroids (193) are available by photolysis of the a-peracetoxy-nitriles (192). Yields are comparable to those obtained by Kalvoda from the reactions of 20-cyano-20-hydroxy-steroids with Pb(OAc)4-l2. The preparation of the a-peracetoxy-nitriles (192) is outlined in Scheme 5, and attention is drawn to the conversion of the 17-oxo-steroids into the ajS-unsaturated nitrile (191) in a... 

Functionalization of the methyl groups in the photolysis of the nitrites of 6-hydroxy-4,4-dimethyl steroids is used as a probe for conformational analysis. It is confirmed that in the 4,4-dimethyl-19-nor-series ring A has the normal chair... 

It was shown by Barton et al. that the photolysis of steroidal nitrites 50 proceeding by formation of alkoxy radicals could result in hydrogen abstrae-tion from suitably situated methyl groups forming earbon-centered radicals, which then reacted with the NO generated to give oximes (equation 79). This permitted the functionalization of the unaetivated centers. 

Formation of hydroxamic acids has been reported during the photolysis of steroidal C-17 fl-nitrite esters,227 of ether dl-bornyl ether, and of dl-isobornyl nitrite.144... 

Similarly, the products derived from the photolysis of steroidal nitrites (60 and 11/8) in toluene were mainly the result of intramolecular hydrogen abstraction (the Barton reaction). Kxothermicity calculations23 predict intermolecular hydrogen abstraction process (AH = 25 kcal./mole) to predominate over intramolecular hydrogen abstraction (AH = —3 to 5 kcal./mole). 

The ring cleavage behavior of cyclopentyl nitrite has been used in an interesting synthesis of cyclic hydroxamic acids. Thus steroidal 17/8-nitrites (81) on photolysis yield the corresponding hydroxamic acids (82).29 This conversion can be rationalized in the following way (83 to... 

An interesting addition of this type has recently been observed33 in the photolysis of a steroid nitrite ... 

Vitamin D3 is a precursor of the hormone 1,25-dihy-droxyvitamin D3. Vitamin D3 is essential for normal calcium and phosphorus metabolism. It is formed from 7-dehydrocholesterol by ultraviolet photolysis in the skin. Insufficient exposure to sunlight and absence of vitamin D3 in the diet leads to rickets, a condition characterized by weak, malformed bones. Vitamin D3 is inactive, but it is converted into an active compound by two hydroxylation reactions that occur in different organs. The first hydroxylation occurs in the liver, which produces 25-hydroxyvita-min D3, abbreviated 25(OH)D3 the second hydroxylation occurs in the kidney and gives rise to the active product 1,25-dihydroxy vitamin D3 24,25 (OH)2D3 (fig. 24.13). The hydroxylation at position 1 that occurs in the kidney is stimulated by parathyroid hormone (PTH), which is secreted from the parathyroid gland in response to low circulating levels of calcium. In the presence of adequate calcium, 25(OH)D3 is converted into an inactive metabolite, 24,25 (OH)2D3. The active derivative of vitamin D3 is considered a hormone because it is transported from the kidneys to target cells, where it binds to nuclear receptors that are analogous to those of typical steroid hormones. l,25(OH)2D3 stimulates calcium transport by intestinal cells and increases calcium uptake by osteoblasts (precursors of bone cells). 

The photolysis of nitrosopregnone steroid (117) afforded the 18,20-benzo-fused compound (118) as the major product (24%) along with the diol (119) (6%), whilst the expected C(18) rearranged product (120) is not isolated (Scheme 17).277 Reaction proceeds via the C(18) alkyl radical (121), formed in accordance with the accepted C(ll) O—NO bond homolysis and H-abstraction pathway, before either addition of C(11) radical (121) to the aromatic ring to afford (118) or H abstraction to give (119). 

Scheme 76 Barton nitrite photolysis of a steroidal compound 277 to afford an oxime 199.

Schemes 5 and 6 outline the functionalization of a 10/1-Me by a steroidal 6/f-ol [1] and a 2/3-61 nitrite [6], Functionalization of 13/i-Me by a 20a-ol nitrite [7] and functionalization in the terpenoid field [8] are outlined in Schemes 7 and 8. The last example involves a 7-membered cyclic transition state that seldom occurs. Scheme 9 outlines a recent application of the Barton reaction in the synthesis of a biologically active carbacepham [9]. The photolysis of acyclic 5-phenyl-1-pentanol nitrite gives, preferentially, a nitroso dimer arising as a result of the abstraction of a hydrogen attached to the d-carbon, rather than the e-carbon from which the better stabilized benzyl radical can be generated (Scheme 10) [10].

With inflexible substrates, this photochemical functionalization process showed significant selectivity. As our first example, photolysis of steroid ester 70 led to carbonyl insertion into the C-H bonds at C-7 and C-14 [149,150]. Other steroid esters afforded selective functionalizations in various positions [e.g. 151, 152], and compound 71 directly dehydrogenated the steroid to form the product olefin 72 [150]. 

It will be clear that nitrite photolysis is compatible with many of the sensitive functions found in complex steroids. It provides a useful means of molecular manipulation using radical chemistry. 

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