Stereoselective Synthesis of New Simplified Digitalis-Like Compounds from ( + )-( 3 aS , 7 aS )-3 a-Hydroxy-7 a-Methylperhydroinden-1 , 5-Dione 1

Cardiac glycosides of Digitalis species are well known heart-stimulating drugs, clinically used for treatment of congestive heart failure.2 In the steroidal moiety of the aglycons (cardenolides) the C/D cis ring junction, the 14b-OH and the 17b-butenolide could be recognized as three peculiar features for a potent pharmacological action, while the A/B ring junction can vary from cis (e.g. digitoxigenin) to trans (e.g. uzarigenin) (Fig. 1) without a dramatic loss of activity. As a part of our work aimed at searching new digitalis-like compounds with an improved pharmacological profile, we synthesized compound 9 (Fig. 1) in which the C/D part of the molecule was maintained while the A/B part was simplified in a 5b-cyclohexyl substituent.


INTRODUCTION
Cardiac glycosides of Digitalis species are well known heart-stimulating drugs, clinically used for treatment of congestive heart failure. 2 In the steroidal moiety of the aglycons (cardenolides) the C/D cis ring junction, the 14b-OH and the 17b-butenolide could be recognized as three peculiar features for a potent pharmacological action, while the A/B ring junction can vary from cis (e.g.digitoxigenin) to trans (e.g.uzarigenin) (Fig. 1) without a dramatic loss of activity.As a part of our work aimed at searching new digitalis-like compounds with an improved pharmacological profile, we synthesized compound 9 (Fig. 1) in which the C/D part of the molecule was maintained while the A/B part was simplified in a 5b-cyclohexyl substituent.

CHEMISTRY
In Scheme 1 the synthetic approach for the synthesis of 9, starting from the known (+)-(3aS,7aS)-3a-hydroxy-7amethylperhydroinden-1,5-dione 1 3 is reported.The first problem was to find a reagent and/or reaction conditions permitting a regio-and stereoselective nucleophilic attack of the 5-keto function.
A reaction with an organometallic reagent could do the trick, owing to the higher reactivity of 5-vs.1-keto group and the easier approach from the b-face compared to the more hindered a-face (Fig. 1).
Disappointingly the reaction with PhLi gave an almost 1:1 mixture of 5a and 5b-phenyl derivatives in only 40% yield, probably due to enolization of the ketone.
To overcome the problem we repeated the arylation on the CeCl 3 /C=O complex 4 : this time the yield was 73% and the ratio between the 5b-phenyl 2 and the corresponding 5a-phenyl was 4.6:1 (Scheme 2).

Scheme 2.
The two diastereoisomers were easily separated by flash chromathography and the benzylic 5a-hydroxy group of 2 was eliminated by hydrogenolysis with Raney-Nickel with complete retention of configuration.
The desired cyclohexyl derivative 4 was obtained by hydrogenation with Rh/Al 2 O 3 as a catalyst.
At this point, a b-substituent in position 1 had to be introduced.
First we transformed, with a known, stereospecific reaction sequence, the 1-keto derivative 4 into the 1a-iodo compound 5; then applied a stereospecific free-radical reaction with maleic anhydride, recently published by us, 5 to obtain the advanced precursor 7 of the 1b-butenolide target compound, probably through the anhydride 6.
Chemoselective reduction of the ester function of 7 led to the butanolide derivative 8 which was transformed into the final compound 9 in 7% overall yield.

CONCLUSIONS
The simplified cardenolide 9, with a perhydroindene skeleton, was obtained from the known, enantiopure compound 1 with a simple and versatile reaction sequence.The key steps were the introduction of a cyclohexyl substituent at 5bposition and of the butenolide moiety at 1b-position.The transformations were achieved through few stereo-and regioselective reactions.The free-radical introduction of an advanced precursor of the butenolide ring, performed by us on a 14b-androstane derivative, 5 could thus be successfully exported to a more flexible nucleus.