The Structure and Function of Estrogens. XI. Synthesis of (±)-7(8→11α)abeo-Estradiol and Its 9,11-Didehydro Derivative

Abstract

Two approaches to the synthesis of (�)-7(8→11α)abeo-estra-1,3,5(10)-triene-3,17 β- diol (2a) from (�)-1 β-t-butoxy-7a β-methy1-2,3,3a α,6,7,7a-hexahydro-1H-inden-5(4H)-one (11) were studied. A pathway involving 6-alkylation of (11) with 2-(3′-methoxyphenyl)ethyl halides or sulfonate esters was unsuccessful, but conjugate addition of 3-methoxybenzyl nucleophiles with (�)-1β-t-butoxy-7a β-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-inden-5(4H)-one (18), prepared from (11), led to ( �)-1β-t-butoxy-6 α-[2′-(3″-methoxyphenyl)ethy1]-7a β α,6,7,7a-hexahydro-1H-inden-5(4H-one (10a). Acid-catalysed cyclization of (10a) afforded (�)-17β-t-butoxy-3-methoxy-7(8 →11)abeo-estra-l,3,5(10),9(11)-tetraene (29) which upon lithium/ammonia reduction in the presence of diphenylmethane gave ( �)-17 β- t-butoxy-3-methoxy-7(8 →11α)abeo-estra,1,3,5(10)- triene (31). Deprotection of (31) and (29) afforded (�)-7(8 →11 α)abeo-estra-1,3,5(10)-triene-3,17 β- diol (2a) and (�)-7(8 →1l)abeo-estra-1,3,5(10),9(11)-tetraene-3,17β-diol (32), respectively. Alternatively, reaction of (�)-1β-t-butoxy-7a β-methyl-6-methylene-2,3,3a α,6,7,7a-hexahydro-1H-inden-5(4H)-one (18) with 3-methoxybenzyl phenyl sulfoxide (23a) gave (1RS,3′SR,2RS,-3a′SR,7a′SR)-3′-t-butoxy-2-(3″-methoxyphenyl)-3a′-methyl-2′,3′,3a′,4′7′,7a′-hexahydrospiro- [cyclopropane-1,5′-[5H]inden ]-6′(1′H)-one (26), reductive cleavage of which with lithium/ammonia afforded (10a). The relative stereochemistries of (31) and of the spiro cyclopropyl ketone intermediate (26) were established unambiguously by X-ray crystallography.

An Asymmetric Route to the Conanine BCDE Ring System. A Formal Total Synthesis of (+)-Conessine

“…The tethered arylethyl side chain to be affixed to lactam 1 was prepared routinely from commercially available 3-methoxyphenylacetic acid. Reduction to the alcohol 2 , followed by transformation to the iodide 3 with triphenylphosphine and iodine, gave the necessary precursor for aromatic bromination. The latter took place using bromine in CH 2 Cl 2 at −10 °C and produced the aryl bromide 4 in 95% yield.…”

First Synthesis of Enantiopure 1,6-Difunctionalized Dodecahydrobenz[f]indenes

“…We utilized part of the reaction sequence reported by Collins et al (Scheme ) for the synthesis of racemic abeo estradiol . In our instance, however, the unsaturated carboxylic acid 1 was prepared from the Hajos−Parrish ketone (7a S )-2,3,7,7a-tetrahydro-7a-methyl-1 H -indene-1,(5,6 H )-dione in optically pure form as previously described. , Hydrogenation over 10% Pd/BaSO 4 and decarboxylation of intermediate 2 yielded the enantiomerically pure indanone 3 (67%) .…”

A facile total synthesis of ent-17β-estradiol and structurally related analogues

“…Indenone 4 [33], the C,D-ring synthon, was treated with NaH in ethylene glycol dimethyl ether and reacted with tosylate 5b [29] to afford compound 6 (60%). Hydrogenation of compound 6 gave a 52% yield of the indenones 7a (major isomer) and 7b (minor isomer).…”

“…The synthesis of several structurally related analogues (Scheme 3, 12a,b; Scheme 4, 14a,b; Scheme 5, 17a,b; Scheme 6, 20; Scheme 7, 22) that were part of a previously published structure-activity study [27] is also reported. [29]-To a solution of m-methoxyphenylethanol (5a, 3 g, 19.7 mmol) in anhydrous pyridine (16 ml), was added p-toluenesulfonyl chloride (4.15 g) at 0 °C. After 30 min, the reaction flask was placed in a cold room (5 °C) and stirred overnight.…”