Hydrogenolysis enol acetates

Reductive fission. Use of a mixed hydride was first reported by B. R. Brown, who investigated the action of a 1 1.5 mixture on cholestenone enol acetate (1). The result was a mixture, and the only point of interest is that one product, A -cholestene (2), results from reduction and hydrogenolysis. Reduction of cholestenone... 

Desoxycholic acid (III) is commercially available, but its 7-hydroxy analog, cholic acid (I), is much more abundant in animal bile. One of the best conversions is due to Fieser and Rajagopalan (1949), who oxidized cholic acid (I) with N-bromosuccinimide to the 7-keto derivative (II), which without purification is reduced in 68% over-all yield by the Huang-Minlon modification of the Wolff-Kishner method to desoxycholic acid (III). An alternative reduction, devised by Hirschmann et al. (1951), involves the catalytic hydrogenolysis of the enol acetate of II, but the yield is inferior. 

The 3-deoxyhexoses were obtained crystalline after separation on a column of cellulose, a rather tedious operation recently separation of these sugars by fractional crystallization has been reported (41). From the major unsaturated ester 27, 3-deoxy-D-ribo- and -arabino-hexose were shown to have been produced respectively in the ratio 66 34, and from ester 28 in the ratio 24 76. Saturation of the enol grouping of the esters 27 and 28 gives, therefore, the 1,2-cis products preferentially. However, some hydrogenolysis of the anomeric acetate group accompanies simple saturation of the double bond and poses another separation problem. 

The route used to prepare the unsaturated 2 methyl androgen stenbolone provides yet a further illustration of the propensity for the formation of enolates at the 2 position. Thus reaction of dihydrotestosterone acetate (41-1) with formaldehyde and dimethylamine gives the Mannich product (41-2). Hydrogenolysis of that product gives the 2 methyl derivative (41-3) the relatively elevated temperature used for this last reaction suggests that the reaction may proceed via the methylene product... 

In Fig. (12) keto ester (94) was selected as starting material. It was converted to the formyl derivative (95) which yielded a,P-unsaturated aldehyde (96) by treatment with DDQ. Michael addition of the sodium enolate of tert-butyl- isovalerylacetate to aldehyde (96) afforded the adduct (97) as a mixture of C-ll diastereomers. By fractional crystallization one of the adducts could be separated but for the synthetic purpose the mixture was not separated. Treatment of the adduct (97) with p-toluenesulfonic acid in glacial acetic acid caused t-butyl ester cleavage, decarboxylation and cyclodehydration leading the formation of tricyclic enedione (98) in 80% yield. This approach was previously utilized by Meyer in the synthesis of nimbiol [29], Treatment of (98) with pyridinium bromide perbromide, followed by hydrogenolysis with palladium and carbon caused aromatization of (98) leading the formation of the phenolic ester (99). 

Scheme 13.1 Formation and hydrogenolysis of bicyclic acetals in the hydrogenation of a cyclic enol ether 1.

Enol esters are much more labile to hydrogenolysis than enol ethers. Thus, 1-acetoxy-cyclohexene and ethyl 3-acetoxycrotonate are almost quantitatively hydrogenolyzed over Adams platinum in ethanol or acetic acid (eqs. 13.46 and 13.47).91 92... 

The phosphoric acid ester of an enol ether is even more readily hydrogenolyzed than an enol acylate. When the (Z)-enol phosphate 51 was subjected to hydrogenation in ethyl acetate at 0.3 MPa H2, the hydrogenolysis products were isolated in 95% yield not only over platinum oxide but also over 5% Pd-C and 5% Rh-Al203 (eq. 13.50).94 The hydrogenolysis of an enol phosphate has been utilized in conversion of one of two oxo groups to the methylene as shown in eq. 13.51 95... 

Enamines may be reduced by sodium borohydride to give saturated amines, but only if a protonating species is available to convert the enamine initially into the iminium cation (lo). Steroidal g-amino-g,5-dienes are unreactive to sodium boro-hydride alone, but addition of acetic acid leads to rapid reduction via the iminium ion (10) to give gj -amino-A -steroids [224], The possibility that diborane was the reactive species in the NaBHd/HOAc system was excluded by the virtual non-reactivity of the enamine to externally generated diborane. Reduction of the iminium ion derivative (3) of a 6-formyl enol ether has been exploited in a variant of the Vilsmeier synthesis of 6-methyl steroids [22 ], the reduction product was the 6-aminomethyl enol ether (ii) which suffered hydrogenolysis with Raney nickel to give the 6-methylated enol ether (12). 

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