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A Simple Synthesis of Cardenolides and Their Less Toxic Isomers via Furyl Intermediates

1979; Elsevier BV; Volume: 12; Issue: 11 Linguagem: Inglês

10.3987/r-1979-11-1397

1881-0942

Karel Wiesner, Thomas Y. R. Tsai, Akwasi Minta,

Phytochemistry and Bioactive Compounds

A novel efficient and stereospecific synthesis of digitoxigenine ( 19) and its isomer ( 2 3 ) via the common ---intermediate ( 15) is described.-- DISCUSSIONMany years ago one of us (K.W.) proposed a synthesis of cardiac aqlycones which would start with tertiary carbinols of the type (I) obtainable by the action of 8-furyllithium on suitable steroidal 17-ketones.It was hoped that these compounds could be modified to 17-B,furylsteroids (11).Mechanistic considerations justified the expectation that these furyl intermediates (11) were capable of being oxidized by peracids to normal cardenolides (111) and by N-bromosuccinimide to the cardenolide isomers (IV), respectively.Model experiments performed on isopropyl furan (V) have shown that this last expectation was indeed correct.'The oxidation of a furan may be represented (see formula V) as an attack of an electrophile at the less-hindered a-position, followed by a nucleophilic attack at the remaining a-site.This in the case of NBS lead to the intermediate LIX) which yielded the lactone (X) by elimination of HBr.Peracid oxidation proceeded probably via the intermediate LVI) which underwent further oxidation to the hydroxy lactone LVII).This last compound was reduced with NaBH4 to the unsaturated lactone (VIII).It will be shown in the present communication that the yields of all these reactions are capable of considerable improvement.While the total synthesis of the furyl intermediates 1 from 17-keto steroids was up to the present time never successfully carried out, these compounds were obtained by hydride reduction of natural cardenolides (111).Moreover, the transformation of the furyl derivatives (II), prepared by reduction from natural cardenolides, yielded as predicted selectively the lactones of the type (111) or (IV) .'On pharmacological testing the isolactone derivatives (IV) have turned Out to display "more rapid onset of action, quick reversibility of toxic effects and a greater margin between therapeutic and toxic doses". 2We now wish to disclose a simple and efficient total synthesis of digitoxigenine (A?) and its isomer ( 2 2 ) via the furyl derivative ( t z ) .The starting material was the a.0-unsaturated ketone (11) readily prepared in -high yield from testosterone (1).The simple and essentially known operations which were used in this preparation are portrayed in Scheme 11.The ketone ( 11) was -treated with 8-furyllithium3 in ether and the tertiary carbinol ($?I was obtained in a yield of 93% '[I.R. (CHC13) vmax: 3600 cm-' (OH); N.M.R. (CDCl31 i: 2 . 6 5( s , 5 H , benzyl aromatic), 2 .5 7 , 2 .7 8 , 3.58 (broad s , 1H each, furyl), 3.91 (d.J = 6 , lH, 1 5 -H ) , 4.28 (dd, J = 6, lH, 16-HI, 5 .5 2 ( s , 2H, benzylicl, 6.3 (broad Ill 8" IX X scheme I ...