Estrone methyl ether, synthesis

The reaction provides the key step in a stereoselective synthesis of estrone methyl ether (6) from 5.b... 

Several applications in total syntheses exemplify the value of this methodology 11-oxoequiienin methyl ether (101 Scheme 38),105 107 (+)-a-cuparenone,109 (-)-podorhizon,112 (-)-methyl jasmonate (102 Scheme 39),114 (+)-estrone methyl ether,116 and the so called (+)-A-factor (103 Scheme 40)117 were all prepared in high enantiomeric purity. Other applications constitute preparations of 2-alkylchro-man-4-ones,118 and of 3-vinylcyclopentanones, highly valuable intermediates for steroid total synthesis.106,107... 

The synthesis of (+)-estrone methyl ether (36) illustrates the enantioselective construction of a polycyclic target by the use of chiral auxiliary control to establish the first cyclic stereogenic center [14], In this case, the specific design of the naphthyldiazoester 32 directed Rh-mediated intramolecular C-H insertion selectively toward one of the two diastereotopic C-H bonds on the target methylene. The new ternary center so created then biased the formation of the adjacent quaternary center in the course of the alkylation. The chiral skew in the product cyclo-pentanone (35) controlled the relative and absolute course of the intramolecular cycloaddition, to give the steroid (+)-estrone methyl ether (36). 

The functionally and stereochemistry provided by aldehyde (100) have led to the use of the tandem Cope-Claisen rearrangement for the synthesis of estrone methyl ether (117) and steroid synthons. Thermolysis of triene (115 Scheme 8) provides aldehyde (116) as the major component of a 2/1 mixture ... 

Ito and coworkers developed a mild and efficient procedure for generating o-quinodimethanes" as reactive intermediates in [4 -I- 2] cycloadditions. The key step in the sequence, illustrated here by the synthesis of Estrone methyl ether (146 Scheme 53) involves a fluoride-induced fragmentation of the o-[a-(trimethylsilyl)alkyl]benzyltrimethylammonium iodide (144) to give the o-quinodimethane (145), which underwent stereoselective intramolecular [4 + 2] cycloaddition to give the desired tetracyclic framework in (146). The entire process was conducted at room temperature. The annulation reaction is not limited to intramolecular cycloadditions intermolecular versions of the reaction proceed equally well. 

The (S)-diphenylprolinol-derived oxazabotohdine with an ethanediolated boron atom is a new catalyst for the as3fmmetric reduction of ketones with BH3 SMe2- 1,3-Cyclo-alkanediones undergo CBS-reduction to provide (3if)-hydroxycycloalkanones. Based on this method a very short synthesis of chiral estrone methyl ether is completed. ... 

Quinodimethanes have been employed in a stereoselective synthesis (ref. 128) of estrone. A silicon-stabilised benzylic carbanion was obtained, avoiding lithiation of the methoxy-substituted ring, from the intermediate [2-[(trimethylsilyl)methyl]-5-methoxybenzyl]dimethylamine and after alkylation with the requisite cyclopentano component, generation of the quinodimethane structure with CsF afforded racemic estrone methyl ether. 

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. 

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%. 

Based on this methodology, syntheses of ( )-estrone methyl ether and ( )-6P-methylestra-l,3,5(10)-triene-17-one were then developed.In the estrone synthesis (Scheme 20), the aromatic component 149 was obtained in high yield from 3-methyl-4-chlorophenol. The trimethylsilylmethylene moiety was introduced in >90% yield by nickel catalyzed cross-coupling of trimethylsilylmethyl magnesium chloride and aryl chloride 148. 

In another application of borane chemistry to steroid synthesis, Bryson developed a synthesis of ( )-estrone methyl ether in which ring C is constructed by hy-droboration-carbonylation of an appropriate l 4-diene (Scheme 25). The basic methodology was demonstrated earlier in a route to 17-desoxyestrone methyl ether. ... 

Reactions of Oi anoborates with Electrophiles.—Several new applications of the cyanoborate reaction for conversion of thexyldialkylboranes into dialkyl ketones (see ref. 55 for a review) have appeared. In particular, it has been employed as a key step (Scheme 4) in the synthesis of ( )-estrone methyl ether, and for the preparation of 1-hydrindanone and perhydrophenanthrene derivatives with specific or labels. ... 

The third route for the synthesis of estrone methyl ether (133) passes through the ethylene ketal (393), the synthesis of which has been described in Scheme 38. Selective hydrogenation of the ketal (393) leads to the trans-C/D ketal (401), which can also be obtained in two stages by the hydrogenation and ketalization of the ketone (395). The reduction of the A -bond with lithium in liquid ammonia and hydrolysis of the ketal grouping gives the desired product (133) [489, 511]. 

A comparison of the various methods of synthesizing estrone methyl ether (133) has shown that the best is the route through (395) and (403), giving (133) with a yield of 25% on the methoxytetralone (8) [511]. Taking into account the improvements achieved in the synthesis of (395) [497], this yield can be raised to 42%. 

A related approach to the generation of intermediate o-quinodimethanes is showcased in a synthesis by Saegusa (Equation 6) [58]. Treatment of 95 with fluoride led to 1,4-elimination and formation of quinone methide 96. This reactive intermediate participated in a diastereoselective cycloaddition reaction to furnish estrone methyl ether (97) as a single diastereomer in 86% yield. 

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). 

Soon after returning to the Shionogi Research Laboratories from the University of Basel, he became Section Manager to pursue the total synthesis of steroids. This work led to total or partial synthesis of the racemic form of many steroids and steroidal alkaloids, such as estrone 3-methyl ether, 3a-acetoxy-5/3-pregna-9(ll), 16-dien-20-one, aldosterone, latifoline, and cones-sine (1961-1963). With extensive support and encouragement from the late... 

Synthesis. Ssmthesis of 2,4-bis(bromomethyl) estradiol-17 3-methyl ether (BBEzM) is accomplished by reducing 2,4-bis (bromomethyl) estrone... 

Synthesis. The synthesis of 4-bromoacetamidoestrone methyl ether involves four steps the nitration of estrone to 4-nitroestrone, the con-... 

Corbocyclic - The synthesis of 8a, 9p-estrone 3-methyl ether,87 the elusive boat C-ring Isomer, and 8a and 8a, 10a-19-nortestosterone88 have been reported. Recent approaches to the transformation of steroids to their A-homo derivatives include the... 

The methyl ether of 14-isoestrone (485), with an IR spectrum identical with that of the d-enantiomer obtained by partial synthesis from natural estrone was synthesized by an analogous method from the 14)S carboxy-diester (476) cyclization to (480), hydrogenolysis to (482), extension of the side chain, and pyrolysis over lead carbonate [225, 241]. 

On being heated with pyridine hydrochloride, the methyl ethers (33)-(38) were demethylated to the corresponding isomers of estrone [83, 84]. The constants of all eight theoretically possible racemates of estrone obtained by this and other methods of synthesis and also the arbitrary designations given to them by various authors are shown in Table 8. The racemates of the isomeric estrones are arbitrarily shown in this table by the formulas of the corresponding -enantiomers. 

The synthesis of an analog of (403) with a methyl group at Cjo has also been described [Z. G. Hajos, D. R. Parrish, and E. P. Oliveto, Tetrahedron Letters, 1966 6495]. By the method of constructing ring A with l,3-dichloro-2-butene, compound (403) was converted into 4,9-estra-diene 3,17 dione, the acid isomerization of which led to the methyl ether of racemic estrone [O. I. Fedorova, G. S. Grinenko, and V. I. Maksimov, Dokl. Akad. Nauk SSSR, 171 880 (1966)]. 

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