Stereoselective Synthesis of New Simplified Digitalis-Like Compounds from (+)-(3aS,7aS)-3a-Hydroxy-7a-Methylperhydroinden-1,5-Dione¹

Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese, (MI), Italy. Fax +39 2 33500408; E-mail: MC3405@mclink.it

Received: 11 July 1997 / Uploaded: 21 July 1997

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.

Figure 1

CHEMISTRY

In Scheme 1 the synthetic approach for the synthesis of 9, starting from the known (+)-(3aS,7aS)-3a-hydroxy-7a-methylperhydroinden-1,5-dione 1³ is reported.

Scheme 1. Reagents and condition: (a) CeCl₃, PhLi, THF, -78deg.C ; (b) Raney-Ni, EtOH, reflux ; (c) H₂, Rh/Al₂O₃, 48 psi, MeOH ; (d) (i) NH₂NH₂, TEA, EtOH, reflux ; (ii) I₂, TEA, THF; (iii) NH₂NH₂, O₂, AcOH, EtOH (96 deg.), reflux ; (e) (i) Maleic anhydride, TTMSS, AIBN, PhCH₃, 90deg.C ; (ii) DBU, Et₂O then NaH₂PO₄/ HCl 3N (pH 3.5), Et₂O ; (f) NaBH₄, MeOH, THF, reflux then HCl, pH 1.4 ; (g) (i) LDA, THF, -20deg.C / 0deg.C then, PhSeCl -78deg.C / rt ; (ii) H₂O₂, AcOH, THF.

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 CeCl₃/C=O complex⁴: 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/Al₂O₃ 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 5b-position 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.

REFERENCES and NOTES

1. Presented at ESOC 10, Basel June 22-27, 1997 .
2. Hofman, B. F.; Bigger, J. T. In The Pharmacological Basis of Therapeutics; Goodman Gilman, A.; Nies, A. S.; Rall, T. W.; Taylor, P., Eds.; Pergamon Press, New York, 1990, Section VII, Chapter 34.
3. Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615.
4. T. Imamoto, T. Kusumoto, Y. Tawarayama, T. Mita, Y. Hatanaka, M. Yokoyama, J. Org. Chem., 1984, 49, 3904.
5. N. Almirante and A. Cerri, J. Org. Chem., 1997, 62(10), 3402.