Conjugate addition reductive removal

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92) Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone... 

Conjugate addition to 1 proceeded across the open face of the bicyclic system to give an enolate, condensation of which with the enantiomerically-pure aldehyde 8 gave the enone 9. Conjugate reduction of the enone also removed the benzyl ether, to give the alcohol. Conversion of the alcohol to the azide gave 10. Ozonolysis followed by selective reduction then gave 2. 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

Cerium-mediated conjugate addition of diethyl 1-lithio-l,1-difluoromethylphosphonate to 1-phe-nylsulfonyl-3,4-epoxycyclopentene and -cyclohexene proceeds smoothly at low temperature in THF to give the corresponding adduct in 53% and 65% yields, respectively. The possibility of mild reductive removal of the SOiPh moiety makes these reactions attractive. 

In some examples, the stereochemistry of radical reactions was controlled by chiral carbohydrate auxiliaries. As a radical counterpart to the ionic conjugate additions discussed above, Garner et al. [169] prepared carbohydrate linked radicals that were reacted with a,P-unsaturated esters. The radical precursor, the carboxylic acid 256, generated by the addition of ( Sj-methyl lactate to tri-O-benzyl-D-glucal and subsequent ester hydrolysis, was decarboxylated by Barton s procedure (Scheme 10.84) [170]. Trapping of the chiral radical 258 with methyl acrylate furnished the saturated ester 259 in 61% yield and with high diastereoselectivity (11 1). The auxiliary caused a preferential addition to the si-facQ of radical 258, probably due to entropic effects. The ester 259 was transformed in acceptable yield to the y-butyrolactone 261 by reductive removal of the thiopyridyl group followed by acid hydrolysis. 

Conjugate additions of thiols to N-enoyloxazolidinones E- or Z-7.42 derived from 1.116 [415] or to lactone derivative 1.31 [66] take place with a good selectivity. After removal of the chiral auxiliary, the corresponding adducts are readily obtained. Conjugate additions of amines to lactone 1.36 (G = menthyl) [66, 1396] are also highly selective. Reduction of the resulting adducts with LAH provides... 

There are many methods that can be used to tackle this question. The only snags are protecting the OH group if necessary and care in isolating the Z-compound as it may isomerize easily to the E-compound by reversible conjugate addition. One way to the Z-alkene uses reduction of an alkyne to control the stereochemistry. The OH group is protected as a benzyl ether removed by hydrogenation, perhaps under the same conditions as the reduction of the alkyne. 

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