Enantioselective Syntheses of -Estrone

Reagents (i) CH2 CHCOMe, base, (ii) L-proline,(iii) NaBH4 iMejC GHj, H3P04,MeMgcarbonate,DMF Pd-BaS04,H2 HCHO,DMF 

Equally, derivatives of this compound, notably an a-methylenic ketone (ref.138) have led to simplifications by the Hoffmann-La Roche group in the synthesis of (+)-estrone methyl ether (ref. 139). For example 3-methoxybenzyl chloride (ref. 140) was reacted with this a-methylenic compound, readily available from A, and afforded in the presence of Cu(l) a 1,4-addition product in 88% yield with little accompanying 1,2-addition. Electrophilic cyclisation with methanolic HCI afforded the tetracyclic product by way of the protonated ketone in 77% yield. Hydrogenation, in which some 9p epimer also resulted, followed by treatment of the crude product with trifluoroacetic acid and Jones oxidation gave estrone methyl ether in 63% yield. 

Reagents (i) 3-OMeC6H4CH2CI,Mg,THF, (ii) aq.HCI,MeOH,(iii) Pd-C,H2,EtOAc,Civ) CFgCOjH Jones oxidn. 

(vi) Jones oxidn. MejCO, (vii)MeOH,HCI, (viii)Pd-C.Hj HCl.dioxane 

The continous search for high yielding syntheses and the elusive 100% yield has inspired several quite distinct novel enantioselective approaches to (+)-estrone following the outstanding industrial work of the sixties and early seventies. 

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Qi-Ying Hu, P.D. Rege, E.J. Corey, Simple, catalytic enantioselective syntheses of estrone and desogestrel,... 

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