17a-ethynyl-steroid

Because of the important biological effects observed with 17a-methyl and 17a-ethynyl steroids, alkylation at the 17-position is of particular interest and many examples have been reported. 

Acetoxy-17a-ethynyl steroids rearrange to 21-acetoxy-17,20,21-allenes under the influence of Ag+ catalysis, with equal amounts of both possible isomers being formed.19 Acid or base hydrolysis then gives the trans-21-aldehyde in high overall yield. 

With carbon-carbon triple bonds, oxygen insertion yields an oxirene which opens by heterolytic C — O bond cleavage to form a highly reactive intermediate which binds covalently to the enzyme. In the case of 17a-ethynyl steroids, the reaction can also result in an extension of ring D (Fig. 31.12). 

Fig. 31.12 The triple bond in a 17a-ethynyl steroid is first epoxidated to an oxirene which then undergoes a rearrangement and an extension of ring D.

The methylenation of A -3 -hydroxy-5a-H steroids (5) proceeds analogously to give 1 ) ,2i3-methylene steroids in solvent mixtures of glyme and diethyl ether at reflux. The yields for various examples incorporating additional functionality, i.e., 17j -acetoxy, 17-keto, 20j9-hydroxy, 1-methyl-17j5-acetoxy-19-nor and 17j5-acetoxy-17a-ethynyl-19-nor are about 25 to 60... 

Since 17a-ethynyl-17 -hydroxy steroids are so readily prepared, they represent attractive starting materials for conversion to 20-ketopregnanes. Standard methods for the hydration of aliphatic acetylenes (e.g, mercuric salts alone, with aniline, or with BF3) give variable results, and sometimes no product at all, due to D-homo rearrangement. 233,235,265-7 mercury... 

Metbyl-A<5-cortisone, 60 4, 5/3-Metbylene-5/3-cbolestan-3 8-ol, 112 l, 2/3-Methylene-3fJ-hydroxy-A 5-steroids, 110 5a, 1 Oa-Metbylene-A-norestran-3-one, 429 Methylenetripbenylpbospborane, 129 16a,17a-Metbylene steroids, 102 1-Metbylestradiol 17-acetate, 338 7 c-18-metbyl-17a-ethynyl-3-metboxyestra-... 

Reaction of estrone with a metal acetylide affords 17a-ethynyl-173-hydroxy-estradiol (etbynylestradiol, 30a EE). This compound is equipotent with estradiol by subcutaneous administration, but it is 15 to 20 times as active when administered orally. Ethynylation of the methyl ether of estradiol analogously affords mestranol (30b), It should be noted that the same factors apply in these reactions as in previously discussed reductions at 17 almost the sole products of these reactions are those which result from attack of reagent from the least hindered a side of the steroid. Ethynylestradiol and mestranol are of special commercial significance since the majority of the oral contraceptives now on sale incorporate one or the other of the compounds as the estrogenic component. 

A high degree of stereoselectivity is also observed in the reaction of 17a-ethynyl-17/ -hydroxy-4,9(1 l)-androstadien-3-one with phenylsulfenyl chloride, which affords a single diastereomer of the steroidal allenyl sulfoxide 18110. 

It remains to consider the role of 17a-alkyl substituents in the attachment to the receptor. We can see that the steroid-receptor attachment can accommodate a 17a-methyl or 17a-ethyl group but there is a sharp decrease in activity when a 17a-propyl, or ethynyl group is introduced and the importance of the third-dimensional attachment becomes immediately evident. Inspection of molecular models reveals that a 17ar propyl or 17a-ethynyl substituent protrudes well beyond the molecular dimensions of steroids in the a and in the planar direction. In order to obtain the molecular dimensions of steroids we draw a plane perpendicular to the a- and /S-faces, which connects along the equatorially oriented substituents at carbons 1,2, 11, and 12 on one side, 16 and 17 on the other, and 6 and 7 on the third side. We postulate, therefore, that the steric requirements of the steroid-receptor attachment can accommodate 17a-methyl and 17a-ethyl substituents and the attachment of Ha-alkyl group is two-dimensional at the /3-face and in the third dimension as defined above. 

The difluorocarbene addition reaction to the steroidal 17a-ethynyl side-chain ° has been investigated further. By analogy with results obtained in the... 

The propadienyl-steroid (273) has also been obtained, but in lower yields, either by dibromocarbene addition to the 17-methylene derivative, followed by methyl-lithium fragmentation of the mixture of dibromocyclopropanes, or by treatment of 17a-ethynyl-17jS-hydroxy-steroid with lithium aluminium hydride in the presence of aluminium trichloride. ... 

Tris(triphenylsilyl) vanadate with triphenylsilanol is an efficient catalyst for the rearrangement of a 17a-ethynyl-17/3-hydroxy-steroid (140) to give the pregn-17(20)-en-21-al (142). A vanadate ester (141) is assumed to transfer oxygen as illustrated. 

Androsta-l,4-diene-3,17-dione reacted selectively at C-17 with potassium acetylide to give the 17a-ethynyl-17/8-alcohol the dihydroxyacetone side-chain was then elaborated by use of known transformations, without interference from the l,4-dien-3-one system/ Ethynylation of a [16- H]- or [16- H2]-17-oxo-steroid proceeds without loss of label/ ... 

Djerassi, C., Miramontes, L., Rosenkranz, G., Sondheimer, F. and Steroids, LIV. (1954) Synthesis of 19-nor-17a-ethynyl-testosterone and 19-nor-17a-methyl-testosterone. Journal of the American Chemical Society, 76, 4092 1094. 

X-Ray crystal structures are reported for the first 9a-fluoro-A -steroid (10), and for 17a -ethynyl-17/8 -hydroxy-13/3-(3-hydroxypropyl)gon-4-en-3-one... 

Ene-21-al steroids. 17a-Ethynyl-17/3-hydroxy steroids (1) are rearranged to this key system (2) for the synthesis of corticosteroids by tris-... 

Covey, D.F., W.F. Hood, and P.C. McMullan (1986). Studies of the inactivation of human placental aromatase by 17a-ethynyl-substituted lOP-hydroperoxy and related 19-nor steroids. Biochem. Pharmacol. 35, 1671-1674. 

Two metabolic pathways have been identified for 17a-acetylenic steroids, namely de-ethynylation and D-ring homoannulation. Although both detoxification pathways are only of overall minor importance, they seem to be unique for this class of synthetic estrogens and progestins and therefore deserve special consideration. 

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