Functionalization of steroid 18-methyl groups

Lactones from alcohols Functionalization of steroid 18-methyl groups... 

Oximinoalcohols from nitrous acid esters Functionalization of steroid 18[Pg.98]

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

In earlier work it has been found that the C-18 methyl group of the c-nor-D-homo-steroid (23) could be functionalized by photolysis in the presence of iodine, lead tetra-acetate, and sodium carbonate, when (24) was produced.The usefulness of the hypoiodite reaction " for the derivatization of c-nor-D-homo-steroids... 

Among the numerous results reported by the Swiss group, two typical examples of remote functionalization with this reagent are outlined in Schemes 16 and 17. The products of the remote functionalization of steroids by the hypoiodite reaction are either the five-membered oxide (Scheme 16) or the a-lactol acetate (Scheme 17), depending on the relative disposition between the relevant alkoxyl radical and the iodine attached to CIS or C19 of a conformer of the first-formed intermediate monoiodide. Thus, the five-membered oxide is an exclusive product in the example outhned in Scheme 16, because the iodo-methyl group can adopt an orientation that is appropriate for an S 2 or S 2 displacement of the iodine by the 6P-alkoxyl radical or ion, to give the observed oxide, as shown in Scheme 18. On the other hand, the a-lactol acetate is an exclusive product in the example outlined in Scheme 17, because the preferred orientation of the iodomethyl group with respect to the 4P-hydroxyl in the first-formed intermediate... 

The required nitrite esters 1 can easily be obtained by reaction of an appropriate alcohol with nitrosyl chloride (NOCl). The 3-nitroso alcohols 2 formed by the Barton reaction are useful intermediates for further synthetic transformations, and might for example be converted into carbonyl compounds or amines. The most important application for the Barton reaction is its use for the transformation of a non-activated C-H group into a functional group. This has for example been applied for the functionalisation of the non-activated methyl groups C-18 and C-19 in the synthesis of certain steroids. ... 

In the steroid series photochemical rearrangement of hypochlorites of the type A - B (X = halogen) were first used successfully at the Institute to functionalize the 18- and 19-methyl groups.51-63 Thus the hypochlorite (5) on irradiation gave the corresponding chlorohydrin which was smoothly cyclized to the ether (6, X = H2) oxidation of the ether to the lactone (6, X = O) constituted a formal proof of its structure. 

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