Sequence Steroid rearrangement

Perhaps the most spectacular of the natural carbocation rearrangements is the concerted sequence of 1,2-methyl and 1,2-hydride Wagner-Meerwein shifts that occurs during the formation oflanosterol from squalene. Lanosterol is then the precursor of the steroid cholesterol in animals. 

A tandem sequence of double [2,3]-sigmatropic rearrangement-six-electron electro-cyclization-4 + 2-cycloaddition has been shown to convert acyclic ene-bis(propargyl alcohols) such as (71), via the corresponding bis-sulfenic ethers such as (72), into anthracene (with an intermolecular final cycloaddition) or phenanthrene or related (with an intramolecular cycloaddition) skeletons. The sequence is illustrated in Scheme 12 for synthesis of a steroid skeleton, estra-l,3,5(10)-trien-17-one (73).81... 

Pinhey utilized the decarboxylative rearrangement of 2 to the nor-alkyl pyridyl sulfide 3, oxidation to the corresponding sulfoxide and thermal elimination sequence in a simple transformation of podocarpic acid 4 into useful synthons 5 (for example, in vitamin D3 synthesis) for steroid CD-ring systems, as shown in Scheme l.8... 

A one-step allylic rearrangement-of a 17/3-hydroxy-17a-vinyl steroid (21) in acidified acetic acid-acetic anhydride gave the 21-acetoxypregn-17(20)-ene (22) in 60—65% yield,59 improving upon an earlier two-step sequence via the 21-chloro-derivative. 17/8-Hydroxy-17a-vinyl steroids (21) are converted into ( )-pregn-17(20)-enes (24) by reaction first with thiourea and hydrochloric acid to give the rearranged thiuronium salt (23), followed by reduction with sodium-ammonia.60... 

This procedure for inversion of configuration has also been exploited in the area of steroid synthesis. Thus, 3-methoxy-19-nor-17a-pregna-l,3,5(10),20-tetraen-17-ol (1) was epimerized via a sulfoxide rearrangement into a separable 73 27 mixture of the fi- and a-isomers73. Thermal racemization of the intermediate diastereomerically pure sulfoxide to a S-epimeric mixture, before subjecting it to the irreversible treatment with trimethyl phosphite, resulted in a slightly better ratio (86 14). The whole sequence could be carried out as a one-pot procedure. 

In the case of steroidal propargylic alcohols the first rearrangement produced a mixture of allenyl sulfoxides, epimeric at the sulfur atom, which reacted with an added nucleophile to produce substituted allylic sulfoxides. Rearrangement of the sulfoxide resulted in the exclusive formation of a-hydroxy derivatives. This reaction sequence has been applied in a synthesis of hydrocortisone acetate74 (Nu = OCH3) from androstene-3,17-dione and in a transformation of mesantrol75 (Nu = malonate) to a spirolactone. 

The Zurich workers [51] have proposed a reaction sequence for photo-isomerisation of steroidal i,4 dienones which can account for all the major reaction products. In the cyclo-hexa-2,5-dienone (9), rearrangement of an excited triplet (probably n n ) was considered by Zimmerman [55] to... 

Acid-catalysed rearrangements of highly alkylated ketones have been reported outside the steroid field [2go], but only one such steroid reaction seems to be known. It occurred when the 5j3-methyl-A nor-B-homo-6-ketone (i) was allowed to react with boron trifluoride, giving the normal 5 5-methyi-cholestan-4-one (3 [2gi], The initial ketone-BFg complex (i) may rearrange via the epoxide (2), although alternative bond-migration sequences can be formulated with the same end result. 

K., and Jeger, O., 1966, Photoisomerization of 3-oxo-steroids in dioxane solution. Structure identification of the photoisomers and establishing the rearrangement sequence, Helv. Chim. Acta 45, 1049-1105. 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

Methyl-A-nor-5a-steroidal 3-ketones (599) have been obtained from 3a,5a-cyclosteroids (596) by the sequence illustrated. A stereospecific pinacol rearrangement of the 3j3,5/ -diol (598) ensured the configuration of the 5-methyl substituent. "... 

Zard has studied the isomerization/Mislow-Evans rearrangement of vinyl sulfoxides such as 237, arising from enolate addition to alkynyl sulfoxides [Scheme 18.60). Isomerization of 237 to the allylic sulfoxide 238 enabled the [2,3]-sigmatropic rearrangement to a-hydroxy-a-vinyl ketone 239. In this case, diastereoselectivity was low in formation of the carbinol center within a steroid framework. Additions to allenyl sulfoxides provide a similar sequence, leading to 2-propenyl substitution at the tertiary alcohol center (not shown). 

It remains to be seen, however, whether these latter compounds or structural modifications of them will find application chnically. Certainly any earher hopes for useful therapeutic application of the triterpenoid cucurbitacins as founded on the high order of their cytotoxicity in vitro [479-484] have been dashed on account of the very low margins between the active and the toxic doses as revealed in in vivo experiments. Since the earlier review was written the structures of the cucurbitacins have been elucidated in full and they have been found to represent an unusual structural type in which backbone rearrangement in the formal carbonium ion initially formed from the cychsation of squalene epoxide in chair-boat-chair-boat conformational sequence proceeds beyond the stages giving rise to lanosterol and cycloartenol. Thus they can be regarded as overshoots of the biosynthetic pathway giving rise to the steroids in the same way as fusidic acid (LX), cephalosporin and helvolic acid represent undershoots of the same pathway. The structure of cucurbitacin A is as depicted in LXIV [485, 486]. 

---