Steroids remote functionalization

Scheme 2. Remote functionalization of steroids by the Barton reaction.

Generally, hypervalent iodine reagents are often better than traditional reagents of similar reactivity, with respect to efficiency and chemoselectivity - sometimes even stereoselectivity. Unusual reactivity is another interesting feature which has often resulted in unexpected transformation. Examples of such reactions may be found in the oxidation of nitrogen-containing compounds, the Hofmann rearrangement in acidic conditions, the acetalization of carbonyl compounds in alkali, the remote functionalization of steroids, etc. Some unique transformations were effected in the... 

Difluoroiodo)-and (dichloroiodo)arenes Chlorination. Remote Functionalism, of Steroids. Fluorination. Further Transformations. 

Remote chlorination (6, 298-300). Breslow has extended his remote functionalization of steroids to a double functionalization at C, and Cn of cholestanol. Thus the ester (2) of cholestanol, prepared from a p-iodophenylnicotinic acid, when treated with 1 (1.2 equiv.) is chlorinated selectively at C9 chlorination of the same ester with 3 equiv. of C6H5IC12 results in chlorination at C9 and at C17 in quantitative yield. The para-iodo group of the ester plays an important role in this remote chlorination. 

Although epoxidation reactions are treated in detail elsewhere in these volumes, it should be mentioned here that a template ester attached to a steroid alkene can direct epoxidation to remote double bonds using the general concepts of remote functionalization. Steroidal diene (5) underwent the epoxidation shown (Scheme 13) with excellent regiochemical and stereochemical control. The product was formed in quantitative yield, although the reaction was carried through to only 25% conversion. 

The majw work to date on synthetic applications of remote functionalization has involved free radical chlorination. The earliest studies involved the direct attachment of aryliodine dichloride units to the steroid substrates, then intramolecular free radical chain chlorination in benzene or chlorobenzene solution (Scheme 14). Yields were only in the 50% region, but fairly good selecdvities were observed compound (6) afforded chiefly the 9-chloro derivative, while compound (7) produced the 14-chloro steroid. The yields and selectivities were considerably improved when it was realized that aromatic solvents promote intermolecular random processes by forming complexes with C1-, and when the radical relay method was developed. 

The possibility to control the regioselectivity of the attack at non-activated C-H bonds was also validated in further studies that demonstrated opportunities to achieve remote functionalization at several other sites in steroid derivatives, including the valuable case of functionalization on the aliphatic... 

Irradiation of the steroidal nitroxide (56) in toluene solution afforded 39% of (57) and 57% of the unstable iV-hydroxy-derivative (58). This shows the N-hydroxy-group to be a potential tool for remote functionalization in appropriate molecules. These results, along with similar ones obtained in other series,... 

Reese, P. B. Remote functionalization reactions in steroids. Steroids 2001, 66,481-497. 

In sterically constrained cases, hydrogen atom abstraction over long distances has been unequivocally established. In the steroid functionalization work of Bieslow, for instance, irradiation of (120) leads, by 1,13-abstraction, to clean formation of the 12-membered macrolide (121 equation 43). The chapter on Remote Functionalization (Volume 7, Chapter 1.3) contains a full discussion of this family of reactions. 

In the Barton reaction, an alkyl nitrite is converted into an alcohol-oxime. The nitrite is photoexcited to a 1,2-diradical. It fragments to NO and an alkoxy radical (RO-), and the latter abstracts H- from the nearest C-H bond. The resulting alkyl radical then combines with NO to give a nitroso compound, which then tautomerizes to the oxime, probably by a polar stepwise mechanism. The Barton reaction has been used for the remote functionalization of hydrocarbons, especially steroids. 

Remote functionalization of steroids (4,264-265 5,352-353). Breslow et al have modified their earlier procedure for chlorination of steroids at C9 or Ci4 by use of an external source of chlorine radicals, lodobenzene dichloride or sulfuryl chloride. Thus irradiation of the m-iodobenzoate of 3a-cholestanol (1) and lodobenzene dichloride in methylene chloride for 28 min. at 25° followed by saponification and acetylation leads to a mixture of 3a-cholestanyl acetate (18.4%) and the acetate of A -cholestene-3a-ol (2, 66%). Application of the... 

Scheme 6-3 Introduction of double bonds into steroids by remote functionalization.

Section 12.5 in Part A describes some additional reactions that are of synthetic value and involve intramolecular hydrogen abstraction at unactivated groups. Of particular note is a method, known as the Barton reaction, in which nitrite esters of alcohols are photolyzed. Nearby hydrocarbon groups, including methyl groups, can be functionalized by this method, and the reaction has been applied to remote functionalization in 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 application of hypoiodite photolysis for remote functionalization has been mostly in the steroid field. There has been, however, a resurgence of appHcations in the field of spiroacetal-type compounds. The reaction was originally found in 1966 by Mihailovic and collaborators, who described remote functionalization by a thermal reaction of alcohols with lead tetraacetate. ... 

In steroids and other rigid systems, a functional group in one part of the molecule can strongly affect the rate of a reaction taking place at a remote part of the same molecule by altering the conformation of the whole skeleton. 

A common feature of the reactions in this section is that they serve to introduce functionality at a position remote from functional groups already present. As such, they have proved very useful in synthesizing many compounds, especially in the steroid field (see also 19-2 and 19-14). When N-haloamines in which one alkyl group has a hydrogen in the 4 or 5 position are heated with sulfuric acid, pyrrolidines or piperidines are formed, in a reaction known as the Hofmann-Loffier reaction... 

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