STEROIDS: V. THE SYNTHESIS OF 4,4-Dimethyl-3α,5-Cyclocholestan-6-One (XI)

Abstract

The synthesis of the title compound is described.By analogy with cholesteryl derivatives, one of the expected products of the solvolysis of 4,4-dimethyl-cholesteryl tosylate should be 4,4-dimethyl-3cr,5-cyclocholestan-6~-ol (IIa) (1). Since the nature of this compound is disputed (2-4), we were interested in synthesizing it in an unambiguous fashion. This paper describes the synthesis of its immediate precursor, 4,4-dimethyl-3a,5-cyclocholestan-6-one (XI). FLOWSHEET IThe parent compound, 3a,5-cyclocholestan-6-one (11) ( 5 ) had been synthesized by Windaus by the action of potassium hydroxide on 3P-chlorocholestan-6-one (I). Our first objective therefore was the preparation of a 4,4-dimethylsteroid bearing a carbonyl function a t Ca. Nitration (6) and other methods (7-11) for introducing functional groups a t the 6 position of the readily available 4,4-dimethylcholesteryl acetate (111) (12) did not result in the formation of the desired product. However, cis-hydroxylation with osmium tetroxide gave 4,4-dimethylcholestane-3P,5a,Ga-triol acetate (IVa) in good yield. The stereochemistry is assigned in conformity with the "rule of rear-attack" (13) and is corroborated by the positive Cotton-effect (14) shown by the oxidation product of the trio1 monoacetate (IVa), 3~-acetoxy-4,4-dimethyl-5a-hydroxy-cholestan-6-one (V).The 5a-hydroxy group was not removed by the action of zinc in acetic acid (15). However, treatment with calcium in liquid ammonia (16, 17), followed by alkaline hydrolysis of the reaction product, resulted in the formation of the desired 3P-hydroxy-4,4-dimethylcholestan-6-one (VII) in 40-45y0 yield. Its structure and stereochemistry follow from its

An Approach toward the Triquinane-Type Skeleton via Reagent-Controlled Skeletal Rearrangements. A Facile Method for Protection−Deprotection of Organomercurials, Tuning the Selectivity of Wagner−Meerwein Migrations, and a New Route to Annulated Lactones

“…The “iso-steroid” rearrangement, a textbook example of the kinetically controlled solvolysis with neighboring group participation, occurs readily under buffered conditions and can be regarded as an expedient construction of a cyclopropane ring. Thus, solvolysis of cholesteryl mesylate 1 , carried out in the presence of NaHCO 3 and Et 3 N in boiling butanone, , affords the corresponding, acid-sensitive 13 3α,5-cyclo-6β-hydroxy derivative which, without proper isolation, can be directly oxidized with Jones reagent 14,15 to give the cyclopropyl ketone 2 , in 70% overall yield (Scheme ). Reduction of 2 with LiAlH 4 is known to proceed with complete stereoselectivity to produce the equatorial alcohol 3 , which is less acid-sensitive than its axial epimer.…”

“…Thus, solvolysis of cholesteryl mesylate 1 , carried out in the presence of NaHCO 3 and Et 3 N in boiling butanone, , affords the corresponding, acid-sensitive 13 3α,5-cyclo-6β-hydroxy derivative which, without proper isolation, can be directly oxidized with Jones reagent 14,15 to give the cyclopropyl ketone 2 , in 70% overall yield (Scheme ). Reduction of 2 with LiAlH 4 is known to proceed with complete stereoselectivity to produce the equatorial alcohol 3 , which is less acid-sensitive than its axial epimer. Accordingly, the deuterium-labeled alcohol 6 was obtained on reduction of 2 with LiAl 2 H 4 .…”

“…Accordingly, the deuterium-labeled alcohol 6 was obtained on reduction of 2 with LiAl 2 H 4 . By analogy, reaction of 2 with MeMgI or MeLi−CeCl 3 (THF, 0 °C, 1 h; 73%) furnished exclusively the tertiary alcohol 7 17 as a result of axial attack from the sterically more hindered β-side, which appears to be a common behavior in this class of compounds, presumably dictated by stereoelectronic effects. 16b, While 3 − 5 and their axial epimers have most often been utilized as a means of protection in the AB segment of the steroid skeleton , and for solvolytic studies, 13c, we intended to employ the cyclopropane ring as a synthetic building block in a conceptually different way.

1

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“…Method A. Thallium(III) nitrate trihydrate (190 mg; 428 μmol) was added to a solution of cyclopropyl alcohol 3 (165 mg; 427 μmol) in dioxane (20 mL) containing 2 drops of 10% aqueous HClO 4 and the solution was stirred at room temperature for 5 h. A 10% aqueous HClO 4 solution (5 mL) was then added and the mixture was stirred for a further 5 h, then diluted with ether (20 mL), and worked up. The crude product was chromatographed by elution with a petroleum ether−ether mixture (9:1), to afford lactol 11 (103 mg; 256 μmol; 66%), identical to an authentic sample: 21,26 mp 156−158 °C (acetone); IR ν max (OH) 3620 and 3395 cm -1 ; 1 H NMR δ 0.64 (s, 3 H, 18-H), 0.865 (d, J = 6.6 Hz, 3 H, 26-H or 27-H), 0.867 (d, J = 6.6 Hz, 3 H, 26-H or 27-H), 0.91 (s, 3 H, 19-H), 2.27 (dd, J 7 α - H,7 β - H = 12.8 Hz, J 7 β - H,8 β - H = 6.0 Hz, 1 H, 7β-H), 2.40 (m, 1 H, 3α-H), 2.76 (s, 1 H, 6α-OH), 3.41 (dd, J 4 α - H,4 β - H = 8.7 Hz, J 3 α - H,4 β - H = 4.7 Hz, 1 H, 4β-H), 4.18 (dd, J 4 α - H,4 β - H = 8.7 Hz, J 3 α - H,4 α - H = 9.1 Hz, 1 H, 4α-H), 5.18 (s, 1 H, 6β-H); 13 C NMR δ 12.22 (C-18), 18.53 (CH 3 ), 18.76 (CH 3 ), 22.19 (CH 2 ), 22.54 (C-26 or C-27), 22.80 (C-26 or C-27), 23.82 (CH 2 ), 24.48 (CH 2 ), 27.98 (CH), 28.45 (CH 2 ), 28.56 (CH 2 ), 35.65 (CH), 36.08 (CH 2 ), 36.21 (CH 2 ), 37.88 (CH 2 ), 39.47 (CH 2 ), 39.73 (CH 2 ), 40.92 (CH), 43.67 (C-13), 49.24 (CH), 53.03 (C-10), 55.08 (CH), 55.67 (CH), 56.56 (CH), 66.46 (C-5), 71.93 (C-4), 101.17 (C-6); MS (EI) m / z (%) 402 (18, M + ).…”

Synthesis of 6-METHYLCHOLESTA-3.5-DIENE; Solvolysis of 6-Methylcholesteryl Iodide

“…The minor product of this reaction was 6-methylcholesteryl iodide (1116). 'l'he assignlnent of the stereochemistry of alcohol VIII a t C-6 was based on arguments similar to those used to explain the stcrcocliemistry of the lithium aluminium hydride reduction oi V (5). The fornlation of 6-methylcholesteryl iodide is easily rationalized, since the reaction inediu111 contained iodide ions and a Lenis acid.…”