Studies on the synthesis of cardiotonic steroids. 4. Synthesis of strophanthidin

Abstract

T h e synthesis of strophanthidin (4) starting w i t h pregnenolone acetate (1) is described. 19-Hydroxylation and introduction of a 14 double bond afforded 9, which was then transformed i n t o the cardatrienolide 13. By stepwise introduction of 50and 140-hydroxy groups, strophanthidol (22) was obtained. Conversion o f strophanthidol t o strophanthidin was successfully carried out by the oxidation w i t h chromic trioxide in hexamethylphosphoric triamide. Scheme IHo @ OH -e HO 4 3 Preparation of the 3-acetate of the dihydroxy ketone 2 is outlined in Chart I. 5-Bromo-6,19-oxidopregnenolone acetate (5) prepared from pregnenolone acetate (1) by an established methodl was brominated with 2 equiv of bromine to give the 17,21-dibromo compound 6 in 63% yield. It was then subjected to lithium bromide catalyzed dehydrobromination in N,Ndimethylformamidea to furnish the conjugated dienone 7 in 70% yield. Treatment of 7 with zinc dust in weakly acidic 2propanol at reflux temperature generated the 5 double bond? yielding the trienone 8 in 89% yield. Selective hydrogenation of the 16 double bond of 8 leading to the dienone 9 was accomplished in 82% yield by heating with triphenylstannane in toluene, a convenient method for the partial reduction of conjugated dienones developed in our laboratory.9The next task-construction of the cardatrienolide structure 13-was then performed by the reaction sequence (Chart 11) which had been developed during our digitoxigenin synthesis.9 First, the 21-methylthio derivative 10 was obtained in 44% yield by the base-catalyzed reaction of 9 with diethyl oxalate followed by the reaction of the resulting 21-oxalyl derivative with methyl thiotosylate in the presence of excess Chart I 1 -Br 5 6 c-d &LL & AcO ACO A c O Br 9 6 I a Br,, AcOH. b LiBr, DMF. C Zn, i-PrOH-AcOH. d Ph,SnH, PhMe.A new route to the unsaturated oxo ester 16, an intermediate in the Raphael synthesis of steganone (4) and its companion antileukemic lignans steganacin (1) and steganangin (2), is described. Key reactions utilized in the synthetic sequence were photochemical ring closure of a stilbenecarboxylic acid to a phenanthrene, the trimethylsilyl azide modification of the Curtius rearrangement of carboxylic acids, and a two-carbon ring expansion of a 9-phenanthrylamine with dimethyl acetylenedicarboxylate.

Development of a Concise Synthesis of Ouabagenin and Hydroxylated Corticosteroid Analogues

“…Semisynthesis campaigns for the preparation of the cardenolides and the related bufadienolides date back to the early 1970s with the landmark synthesis of batrachotoxinin 8 by Werhli and co-workers. Since then, numerous synthetic efforts have resulted in the semisynthesis of strophanthidol and its parent glycoside (strophanthidin) by Yoshii, 9 the semisynthesis of digitoxigenin by Wiesner 10 and Kabat, 11 and bufalin by Wiesner 12 and Yoshii. 13 In addition, the first total synthesis of digitoxigenin 14 was reported by Stork and co-workers in 1996, and the total synthesis of rhodexin A 15 was achieved by Jung and co-workers in 2011.…”

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

“…As illustrated in Fig. 4B, previous approaches to the semisynthesis of cardenolides (5,6,37) and related steroids (batrachatoxin) used indirect means to install crucial oxidized functionality at C19 and C14. In all three cases, this resulted in lengthy routes, compromising both the brevity and scalability of the syntheses.…”

Control of the stereochemistry of C14 hydroxyl during the total synthesis of withanolide E and physachenolide C

“…This was in contrast to a previous report that indicated that a similar reduction was stereoselective. 36 Unfortunately, the two isomers, 14 and 15, were not separable in our hands. This isomeric mixture was reduced with NaBH 4 , affording a mixture of the four possible stereoisomers.…”