Estrone asymmetric synthesis

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolare (29) to the scalemic sulfoxide (30). Direct treatment of the crude Michael adduct with mew-chloroperbeuzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (31) X — a and ftH R = H in over 90% yield. 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone applies a tandem Claisen rearrangement and intramolecular ene-reaction. Most 19-nonsteroid contraceptive agents are produced by total synthesis from nonsteroidal starting materials. 

By the use of the chiral bromo precursor of the bicycioheptane (at step i) an asymmetric synthesis of estrone was envisaged by the authors, in a highiy novel approach an alkylation reaction of a diyne with a vinyicyciopentene derivative has given an intermediate which by cobalt-mediated... 

A photochemical route to racemic estrone commencing with 2-bromo-5-methoxytoluene depended upon the generation of a quinodimethane intermediate incorporating an enolic component (ref. 129). Subsequently the method was adapted to furnish an asymmetric synthesis of (+)-estrone as described in the ensuing section. The cyclopentanone component was derived by the reaction of dimethyl malonate with E-1,4-dibromobut-2-ene to give racemic dimethyl 2-vinylcyclopropane-1,1-dicarboxylate which was then transformed by reaction with dimetyl methylmalonate followed by hydrolysis into racerruc 2-methyl-3-vinylcyclopentanone. 

This efficient asymmetric synthesis was used to convert (3) into (4) with an optical purity of 86%. In this case L-phenylalanine proved to be much more efficient than L-proline. The optically active product (4) was converted into optically active estrone (6) in overall yield of 13% from (2). The intermediate... 

Scheme 5.43 illustrates three applications of this methodology to total synthesis. The first exeunple is taken from Posner s synthesis of estrone and estradiol [211], the second from Posner s synthesis of methyl jasmonate [212], and the third from Holton s synthesis of aphidicolin [213]. The latter is particularly noteworthy in that two contiguous quaternary centers are created in the asymmetric addition with excellent selectivity. In the estrone synthesis, the chirality sense of the product is consistent with the nonchelate model, but the other two examples adhere to a chelate model. Note that the difference is the degree of substitution at the a-position of the enolate. 

Chiral malonate esters have been used successfully in asymmetric cyclopropanations, as shown by the example in Scheme 6.39, part of a total synthesis of steroids such as estrone [143,144]. The key step in this sequence is an intramolecular Sn2 alkylation of the monosubstituted malonate. The rationale for the diastereoselec-tivity is shown in the illustrated transition structure. Note that the enolate has C2 symmetry, so it doesn t matter which face of the enolate is considered. The illustrated conformation has the ester residues syn to the enolate oxygens to relieve Al>3 strain, with the enolate oxygens and the carbinol methines eclipsed. The allyl halide moiety is oriented away from the dimethylphenyl substituent, exposing the alkene Re face to the enolate. The crude selectivity is about 90% as determined by conversion to the dimethyl ester and comparison of optical rotations [143], but a single diastereomer may be isolated in 67% yield by preparative HPLC [144], This reaction deserves special note because it was conducted on a reasonably large scale ... 

The chiral sulphoxide, (S)-(+)-2-(4-tolylsulphinyl)-2-cyclopentenone, has been used as a ring D component to effect an asymmetric Michael addition with 91-94% diastereoselectivity by reaction in the chelated form with the a,a-disubstituted lithium enolate from 2-bromo-6-methoxytetral-1-one while the (R)-(-) antipode reacts in a non-chelated form with the a-monosubstituted lithium enolate of 6-methoxytetralone (ref. 147). This synthesis makes use of earlier experience in the use of a-mono and a,a-disubstituted lithium enolates in the ethyl acetoacetate series with the non-chelated and chelated forms respectively of a p-ketosulphoxide (ref. 148). Eight futher steps were involved to produce (+)-estrone methyl ether in an overall yield of 6.3%. 

Asymmetric cyclization (6, 410-411). The use of optically active amines as catalysts for asymmetric cyclizations, as well as an application for synthesis of optically active estrone, has been mentioned previously. This cyclization has now been used in construction of the asymmetric aldehyde (4), a known precursor to 12-methylprostaglandin (5). Thus cyclization of the trione (I) in DMF with i>-proline as catalyst gave the aldol (2), which was dehydrated to the enedione (3), obtained with 96% optical purity. ... 

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