Steroidal Side-Chain Formation

Deoxycholic acid (DCA) (17) and apoeholic acid (ACA) (18) are typical examples of the bile acid family of materials, but with the unique property of forming inclusion compounds with a wide variety of guest molecules 92). Partly due to the cis ring junction between rings A and B, and partly due to the conformation of the steroidal side chain these compounds present a convex hydrophobic P-face and a concave hydrophilic a-face, as shown for DCA (19), a classical aid to the formation of inclusion compounds 93). 

Bjorkemd, I., 1992, Mechanism of degradation ofthe steroid side chain in the formation of bile acids, 7. Lipid Res. 33 455-471. 

Further exploration125 of the stereochemistry associated with modification of the steroidal side-chain into that of steroidal alkaloids such as solanidine (139) and tomatidine (140) has revealed that on formation of the furan ring in (140) tritium in the 16/8-configuration of cholesterol [as (143)] is retained but appears now in the 16a-configuration. Retention of the tritium excludes a C-16-oxo-intermediate, and the fact that an inversion of configuration is observed excludes hydroxylation with normal retention of configuration. Examination of the fate of the cholesterol 16/S-proton on incorporation into solanidine (139) revealed that during solanidine biosynthesis this proton is lost. 

An impressive application, where the stereochemical consequences of unsaturated sulfoxide-sulfenate rearrangements are convincingly utilized, provides an efficient and stereoselective method for the corticosteroid side chain formation, starting from 17-keto steroids (Scheme 21). ... 

Reactions of the same type involving steroid side-chains include the conversion of cholan-24-ol into isomeric 20,24-ethers and their 22-iodo-derivatives, the formation of the 17j8,23-ether from norcholan-23-ol, and synthesis of a y-lactone in the c-nor-D-homo-series. All these reactions illustrate the usual need for a six-membered transition state for hydrogen abstraction, leading to a five-membered heterocyclic ring. 

An exception to the formation of equatorial alcohols is in the reduction of certain 12-oxo-steroids with lithium/ammonia or sodium/alcohol. These reductions provide predominantly the slightly less stable, axial alcohol (Table 3). Apparently, the direction of reduction is influenced by the nature of the side chain substituent at carbon-17 and may be associated with a shielding of the oxygen in the 12-position by the carbon-21 methyl group of the steroidal side chain. Furthermore, MMX calculations suggest that the equatorial 12/i-alcohol is only marginally more stable than the a-alcohol (12/1/12a 55 45). 

From the fact that in the reaction catalyzed by 2 also internal alkynes 24 can react to give ketones 25 (Scheme 8), the authors conclude that in this case no vinylidene complex acts as an intermediate. Apparently, its formation is favored by the presence of phosphane ligands, and in their absence other reaction paths are followed. The regioselectivity of the reaction as well as its yield can be increased if a mixture of water and DMF is used as solvent. The reaction functions also with alkynes whose triple bond is conjugated to an ester group. The chemoselectivity of the reaction was demonstrated by the coupling of a steroid side chain with an allyl alcohol one a,y0-unsa-turated carbonyl functionality present in the steroid part remained unaltered. 

Unhindered aliphatic carboxylic acids such as those found in steroidal side-chains can be degraded by three carbons by a four-step procedure (Scheme 11), via dihydro-oxazole formation, dehydrogenation, and ozonolysis,which should be applicable to a good range of (saturated) substrates. 

The regio- and stereoselective hydride attack on the more substituted terminus of ( 7r-allyl)palladium complexes derived from allylic formates has been applied to the palladium acetate- -Bu3P-catalyzed formation of ring junctions in hydrindane, decaUn, and steroid systems, and to stereospecific generation of steroidal side-chain epimers. ... 

In order to study the resolution of the stereogenic center present in the side chain, the synthesis of racemic 156 was required and was started from the 22-iodo derivative 161 obtained as previously described (Scheme 3) [35]. Following a straightforward chemical procedure the steroid ( )-156 was obtained. The (25i ,5)-3,26-diol 156 underwent a reaction with PSL and vinyl acetate in chloroform/THF at room temperature. H-NMR analysis of (he crude detected only (255)-26-acetate 165, showing that the enzymatic reaction was highly regio- and enantioselective. This reaction is faster than the formation of the (205)-acetate 164 (Scheme 4) [37]. However, it should be remembered that, due to different steric hindrance, the C-26 alcohol is more accessible than the C-22 analog. These results offer new approaches to the stereoselective construction of steroid side chains. 

Classical syntheses of steroids consist of the stepwise formation of the four rings with or without angular alkyl groups and the final construction of the C-17 side-chain. The most common reactions have been described in chapter 1, e.g. Diels-AIder (p. 85) and Michael additions (p. 

Step 5—Formation of Cholesterol The formation of cholesterol from lanosterol takes place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus and side chain (Figure 26-3). The methyl groups on C,4 and C4 are removed to form 14-desmethyl lanosterol and then zymosterol. The double bond at 03—C9 is subsequently moved to Cj-Cg in two steps, forming desmosterol. Finally, the double bond of the side chain is reduced, producing cholesterol. The exact order in which the steps described actually take place is not known with certainty. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

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