Synthesis of Aziridinosteroids

Abstract

11α,12α-aziridinosteroids (2a, b, c) were prepared   from 5β-H-11-pregnene-3, 20-dione (1) using different iminophenyliodinanes and cloramine aziridination reagents.

Introduction

The presence of an heteroatom, either replacing a methylene group of the steroid nucleus or as a substituent gives rise to major changes in the biological activity of steroid derivatives [1]. Thus, many steroidal nitrogen derivatives are pharmacologically important. Furthermore, 12α-amino steroids have recently found application as chiral templates for combinatorial synthesis [2]. As an alternative way to introduce nitrogen functionalities into the steroid nucleus, we have explored the aziridination of steroi-dal double bonds. Aziridine ring opening with a nucleophile would yield aminosteroids with defined stereochemistry [3,4]. We describe the synthesis of 11α,12α-aziridinosteroids (2a, b, c) by reaction of 11-pregnen-3,20-dione (1) with different aziridination reagents.

Experimental

Typical aziridination procedure: Copper (I) triflate (0.065 mmol) and 11-pregnen-3,20-dione (1, 0.65 mmol) were added under argon to a suspension of molecular sieves 4 Å (185 mg) in dry acetoni-trile (1.65 ml). SES-iminophenyliodinane (1.7 eq) was then added in 15 portions every 30 min with vigorous stirring and stirring continued for 24 h at 25°C. The reaction mixture was filtered, evaporated to dryness and purified by column chromatography to yield 2c (53% yield).

Results and Discussion

The aziridination reaction was carried out on several olefins (ciclohexene, styrene, norbornene, methyl acrylate, etc.) with a series of N-sulfonyl iminophenyliodinanes and N-SES chloramine sodium salt and different catalysts (Cu (I) and Cu (II) triflate, PTAB, Py.HBr₃). With ciclohexene and (p-chlorobenzenesulfonyl)-iminophenyl iodinane the aziridine was obtained in 52% yield; cleavage with thiophenol followed by removal of the PhS group gave cycloheylamine in 95% yield.

Steroid 1 was treated with (tosylsulfonyl) and (nosylsulfonyl)-iminophenyliodinane in acetonitrile- dichloromethane 1:1, rendering stereospecifically the 11α,12α-aziridinosteroid (2a, b) with moderate yields (25-30%). Stereochemistry was established from the NOESY spectra (correlations H-19/H-11β and H-18/H-12β).

Attempts to aziridinate the 5,6 double bond in pregnenolone and pregnenolone acetate gave com- plex mixtures. On the other hand, the 4,5 conjugated double bond in progesterone was inert under the reaction conditions used.

To facilitate the deprotection step to give the free aziridine, (N-(2-trimethylsilyl)-ethanesulfonyl)- iminophenyliodinane (PhI=NSES) was used as aziridination reagent. In this case, using acetonitrile as solvent, 1 rendered derivative 2c in 53% yield. Aziridination of 1 with the sodium salt of (N-(2- trimethylsilyl)-ethanesulfonyl)-chloramine in acetonitrile gave 2c in only 27% yield.