Steroids, Ethynyl

Lithium acetyhde also can be prepared directly in hquid ammonia from lithium metal or lithium amide and acetylene (134). In this form, the compound has been used in the preparation of -carotene and vitamin A (135), ethchlorvynol (136), and (7j--3-hexen-l-ol (leaf alcohol) (137). More recent synthetic processes involve preparing the lithium acetyhde in situ. Thus lithium diisopropylamide, prepared from //-butyUithium and the amine in THF at 0°C, is added to an acetylene-saturated solution of a ketosteroid to directly produce an ethynylated steroid (138). 

Toluene is a useful co-solvent in metal-ammonia reductions as first reported by Chapman and his colleagues. The author has found that a toluene-tetrahydrofuran-ammonia mixture (1 1 2) is a particularly useful medium for various metal-ammonia reductions. Procedure 8a (section V) describes the reduction of 17-ethyl-19-nortestosterone in such a system. Ethylene dibromide is used to quench excess lithium. Trituration of the total crude reduction product with methanol affords an 85% yield of 4,5a-dihydro-17-ethyl-19-nortestosterone, mp 207-213° (after sintering at 198°), reported mp 212-213°. For the same reduction using Procedure 5 (section V), Bowers et al obtained a 60% yield of crude product, mp, 196-199°, after column chromatography of the total reduction product. A similar reduction of 17-ethynyl-19-nortestosterone is described in Procedure 8b (section V). The steroid concentration in the toluene-tetrahydrofuran-ammonia system is 0.05 M whereas in the ether-dioxane-ammonia system it is 0.029 M. 

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. 

The preparation of other 6-aIkylated steroids has also been accomplished with 5,6-epoxides. Thus treatment of 3,3-ethylenedioxy-5a,6a-epoxy steroids (6) with acetylenedimagnesium bromide,propargylmagnesium bromide " or phenylmagnesium bromide, gives the corresponding 6 -ethynyl-, 6j5-propargyl- and 6/ -phenyl-3,3-ethylenedioxy-5a-ols. 

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... 

The stereochemistry of the product resulting from the reaction of a 17-keto steroid with ethylidenetriphenylphosphorane is different from that of the 17-ethylidene steroids obtained by dehydration of 17a-ethyl-17/ -hydroxy compounds, Wolff-Kishner reduction of A -20-keto steroids or by sodium-alcohol or sodium-ammonia " reductions of 17-ethynyl carbinols. These latter products have generally been assumed to possess the trans configuration (C-21 methyl away from the bulk of the ring system) because of anticipated greater stability. The cis configuration for... 

Both sodium acetylide in xylene (Air Reduction Corporation) and lithium acetylide-ethylenediamine complex (Foote Mineral Co.) are now commercially available, and have been used successfully for the ethynylation of 17-keto steroids. 

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. 

Alkylallenes are obtained by the reaction of 1-ethynylcycloalkanol acetates with organocopper reagents, lithium dimethyl- and dibutylcuprates643 (see Section B.l). Even in the case of the presence of a substituent at the acetylenic terminus, SN2 displacement takes place, giving tetra-substituted allenes. Reaction of the steroidal 17-acetoxy-17-ethynyl derivative la shows that the... 

Elaboration of a commercially viable route for total synthesis of 19-nor steroids led to the introduction of the totally synthetic product norgestrel (71) as the progestational component of an oral contraceptive. As was observed in the "natural" 19-nor-compounds, reduction of the 17-ethynyl group to 17-ethyl affords compounds with androgenic/anabolic... 

Norgestrel Norgestrel, ( )-13-ethyl-17a-17)3-hydroxyestr-4-en-3-one (28.3.13), differs from norethindrone in the presence of an ethyl group at C13 of the steroid system. It is synthesized by ethynylating 18-Methylestr-4-ene-3,17-dione [86-92]. 

Ethisterone Ethisterone, 17-ethynyl-17-hydroxyandrosten-4-en-3-one (28.4.14), is made by ethynylation of the androstenolon with acetylene and successive oxidation of the hydroxyl group at Cj of the steroid system [93,94],... 

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. 

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