Abnormal Beckmann fragmentation/ring closing metathesis route for preparation of 18-nor-Δ¹³⁽¹⁷⁾-androgens and their 18-nor-13,17-epoxide derivatives

Abstract

The synthesis of Δ^13,(17)-androgens and the structurally related 13,17-epoxides is described. The synthetic route involves cleavage of 17-ketosteroids by an abnormal Beckmann rearrangement, modification of the D-ring cleavage product to obtained an intermediate tricyclic diene and ring closing metathesis of the diene to the Δ^13,(17)-androgen. (3α,5α)-Androst-13(17)-en-3-ol and the derivative 13α,17α- and 13β,17β- epoxides were prepared by this route.

The modification of 3α-hydroxysteroids has attracted considerable attention from medicinal and synthetic organic chemists because many compounds in both the androgen and pregnane series are potent modulators of ion channels in the central nervous system of animals.^1–5 For example, spiroepoxide 1 (Figure 1) potently enhances the actions of γ-aminobutyric acid (GABA) at type-A GABA (GABA_A) receptors and is a general anesthetic in mice.⁶ However, neither the 16α,17α- nor the 16β,17β-epoxides 2a and 2b, respectively, are as potent modulators of GABA_A receptors as spiroepoxide 1.⁶

Figure 1.

Structures of known (1,2a,2b) neurosteroid modulators of GABA_A receptors and the previously unknown modulators (3a,3b) prepared herein.

The actions of the 13α,17α- and 13β,17β-epoxides (3a and 3b) have not been described and, to our knowledge, synthetic routes to 13,17-epoxysteroids are not reported in the literature. To evaluate GABA_A receptor actions of these compounds, a synthetic route for their preparation that proceeds through the intermediate Δ¹³⁽¹⁷⁾-steroid was developed. The retrosynthetic analysis shown in Scheme 1 utilizes alkene-nitrile 6, obtained from an abnormal Beckmann rearrangement of the oxime of the corresponding 17-ketosteroid, as a precursor for the diene intermediate 5. Ring closure via a ring closing metathesis reaction gives regiospecifically the Δ¹³⁽¹⁷⁾-steroid 4, and peracid oxidation of the double bond yields the desired epoxides 3a and 3b.

Scheme 1.

Retrosynthetic analysis for the synthesis of epoxides 3a and 3b.

Thus, the commercially available (3β,5α)-3-hydroxyandrostan-17-one was converted into (3α,5α)-3-(benzoyloxy)androstan-17-one (9, 92% yield) by a Misunobu reaction (Scheme 2).⁷ Using a standard method, oxime 10 was obtained in 98% yield by treating steroid 9 with H₂NOH·HCl and NaOAc. The required alkene-nitrile 6 was conveniently synthesized from oxime 10 in 83% yield using a recently reported method (TFA, CH(OMe)₃, THF) that minimizes production of the lactam product of the Beckmann rearrangement.⁸ Due to the presence of TFA employed in this method, neutralization with 10% Na₂CO₃ during workup to avoid isomerization of the exocyclic double bond to the 12,13 and 13,14 positions in the secosteroid C-ring is crucial. Treatment of carbonitrile 6 with DIBALH at −78 °C yielded carboxaldehyde 7 in 85% yield.⁹ A Wittig reaction employing Ph₃P⁺MeBr⁻/KOBu^t in dry THF in the usual manner provided diene 5 in 70% yield.¹⁰ Ring closure of diene 5 was carried out using a second generation Grubbs’ catalyst.^11,12 The Δ¹³⁽¹⁷⁾-steroid 4 was obtained in nearly quantitative yield (98%) under mild conditions and with a short reaction time.¹³ Epoxidation of steroid 4 in dry benzene using mCPBA at room temperature gave a mixture of 13,17-epoxides 3a and 3b which was easily purified by chromatography to yield the less polar 13β,17β-epoxide (3b) and the more polar 13α,17α-epoxide (3a) (4.8:1, 87% in total yield)^14,15. The overall yield for the synthesis of the epoxides was 38%.

Scheme 2.

Reagents and conditions: (a) BzOH, Ph₃P, DEAD, THF, room temperature, 12 h, 92%; (b) H₂NOH·HCl, NaOAc, EtOH, reflux, 12 h, 98%; (c) TFA, CH(OMe)₃, THF, N₂, 60 °C, 2 h, 83%; (d) DIBALH, N₂, CH₂Cl₂, −78°C, 1 h, 85%; (e) Ph₃P⁺MeBr⁻, KOBu^t, THF, room temperature, 60 min, 70%; (f) Grubbs' catalyst 2^nd generation, CH₂Cl₂, N₂, 45°C, 1 h, 98%; g. mCPBA, benzene, room temperature, 30 min, 87% (3a, 72%; 3b,15%). Total yield of the synthetic route is 38%.

The stereochemistry for the 13,17-epoxide products was established by single crystal X-ray diffraction analysis of steroid 3b (Figure 2).¹⁶ Preliminary biological evaluation of epoxide 3b indicates that the actions of this epoxide at GABA_A receptors are weak. As expected, based on previous structure–activity studies of epoxide 2a,⁶ epoxide 3a has little, if any, effect on GABA_A receptor function. Full pharmacological details will be included in a larger study that includes biological data for additional analogues and will be reported elsewhere.

Figure 2.

Crystal structure shown with 50% thermal ellipsoids of one of two unique forms of epoxide 3b.¹⁶

In summary, a general and practical method for the preparation of 18-nor-Δ¹³⁽¹⁷⁾-steroids has been developed. The sequence features the use of an abnormal Beckmann rearrangement/ring closing metathesis reaction sequence to obtain an 18-nor-Δ¹³⁽¹⁷⁾-steroid. Isomeric 18-nor-Δ¹²-steroids and 18-nor-Δ¹³-steroids are not formed. The synthetic method was used to extend structure–activity studies of neurosteroid modulators of GABA_A receptors.