The Total Synthesis of the Sex Hormone Equilenin and Its Stereoisomers

Molecular Chirality in Chemistry and Biology: Historical Milestones

“…12 -20 times more potent than the dextro-enantiomer in a variety of physiological or pharmacological effects, e.g., mydriasis in the cat, salivary secretion in the dog, and at cardiac myoneural junctions, but, interestingly, (þ)-hyoscyamine was the more potent enantiomer in CNS-excitatory effects [146]; in 1940, significant biological differences between the enantiomers of sex hormones, e.g., those of the steroid equilenin (Fig. 10), were reported [147]; natural (À)-morphine was synthesized in 1952 [148] and its absolute configuration determined in 1955 [149]; (þ)-morphine was synthesized in 1960 and was shown to differ significantly from (À)-morphine in that the former was found to lack analgesic activity [150]; the b-adrenergic-antagonist activity of propranolol (Fig. 10), the first commercially successful such drug, was determined to be lopsidedly in the (À)-(S) enantiomer, and a similar dependence of the activity on configuration was found in several other, related, b-blockers [151].…”

Acylation of Esters, Ketones and Nitriles

“…175 The mechanism of this reaction has been examined; 176 labeling studies showed that it was the ester carbonyl that was eliminated. Reaction may occur with ester:ketone ratios of I: I, 2: 1, or I :2, but only the 1: 1 case finds substantial use in modem synthetic practice.…”

Ab → Abc → Abcd

“…Demethylation of rZZ-equilenin methyl ether with hydrochloric acid and acetic acid afforded dZ-equilenin (23). Resolution was easily effected via the Z-menthoxy ester according to the method of Bachmann, Cole, and Wilds [2]. Similarly, demethylation of cZZ-isoequilenin methyl ether (36) led to dZ-isoequilenin (24).…”

“…The latter compound had been previously obtained by Wilds [6] from the bromide 44 via the acid 45. A number of other methods for the synthesis of 46 have been described in the literature [2,11,[22][23][24]. Condensation of this ketone with succinic ester resulted in the formation of the unsaturated ester 48.…”