Syntheses from 6-methoxy-2-tetralone

The foregoing chemical conversions of enmein into gibberellins A15 and A37 correspond to a formal total synthesis of the latter compounds, because the total synthesis of enmein has been accomplished. A more direct total synthesis was also carried out. Compound (137) was synthesized from 5-methoxy-2-tetralone and converted into (138) as shown in Scheme 25. 

Syntheses from 5 - Methoxy - 2 Tetralone. These total syntheses, carried out mainly by Johnson and his colleagues, take place in three main stages [98] ... 

A more recent synthesis for (14-9) takes quite a different course. The first step comprises the displacement of one of the halogens in 1,4-dibromobenzene by the alkoxide from A-2-hydroxyethylpyrrolidine (15-2) in the presence of 18-crown ether to afford (15-3). Condensation of the lithium salt from (15-3) with 6-methoxy-tetralone (15-4) followed by dehydration of the initially formed carbinol give the intermediate (15-5), which incorporates the important basic ether. Reaction of that compound with pridinium bromide perbromide leads to the displacement of the vinylic proton by halogen and the formation of bromide (15-6). Condensation of that product with phenylboronic acid in the presence of a tetrakistriphenyl-phosphine palladium catalyst leads to the coupling of the phenyl group by the formal displacement of bromine. The product (14-9) is then taken on to lasoxifene (14-11) as above [16]. 

Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. One notable exception, however, was the first industrial-scale synthesis of optically active steroids performed by workers at Roussel-UCLAF. The linear synthesis began with a suitable B—C-ring synfhon, 6-methoxy-l-tetralone (186). In a series of steps, tetralone (186) was converted to 2-methyl-2-cyanotetralone (270). Condensation of (270) with dimethyl succinate followed by carbonyl reduction, saponification, and resolution produced the optically active tricyclic acid (271). A series of reductions, a decarboxylation, and a hydrolysis produced (272). Appendage of the A-ring functionality by alkylation produced intermediate (273). Compound (273) was used as a common intermediate for the synthesis of 19-norsteroids, estrogens, and corticosteroids (230). 

Ziegler and Wang have achieved a synthesis of ( )-estrone from 6-methoxy-tetralone based on Cope rearrangement and polyene cyclization methodology (Scheme 28). ... 

B. Heterocyclic - A number of ring-aza steroids are conveniently prepared by total synthesis. The 6,7-diaza steroid was prepared from a bicyclic enamine intermediate with m-methoxydiazonium fluoroborate which was used to introduc the adjacent nitrogens prior to completion of the rest of the steroidal skeleton. The enamines of g-tetrolone and 6-methoxy -tetralone were treated with a-bromoacetate and then treated with hydrazine hydrate followed by either malonyl dichloride or propiolactone to give 13,14-diozo steroids. By this sequence the D-homo-diaza steroidal system could also be prepared.The 8,13-diazaestranes were prepared by... 

The desire to avoid the demethylation of the 3-methoxy group in the preparation of estrogens by Schemes 35 and 36 made it necessary to study other possibilities for the synthesis of D-homoestrogens, starting from 6-hydroxy-l-tetralone (383) [458, 482-485] and its tetrahydropyranyl derivative [458, 463,475, 486] (Scheme 37). The initial 6-hydroxy-1-tetra-lone can be obtained either by demethylating the methoxy derivative (8) or by a four-stage synthesis from jS-naphthol with an over-all yield of about... 

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). 

In the first of these sequences, often called the Torgov-Smith synthesis, the initial step consists in condensation of a 2-alkyl-cyclopentane-l,3-dione with the allyl alcohol obtained from 6-methoxy-l-tetralone and vinylmagnesium chloride. Although this reaction at first sight resembles a classic SN displacement, the reaction is actually carried out with only a trace of base. 

Organomagnesium compounds react with imines, prepared from 3-methoxy-2-naphth-aldehydes by a 1.4-addition mechanism. This reaction can be performed with high diastere-oselectivity. The method was applied for the synthesis of optically pure S-tetralones . Vinyhnagnesium bromide reacts as an acceptor with a ketone dimethyl hydrazone zincate 207, yielding a 1,1-bimetallic species, which can be reacted sequentially with two different electrophiles (equations 131 and 132) . The reaction proceeds via a metalla-aza-Claisen rearrangement, where the dimethylhydrazone anion behaves as an aza-allylic system . 

Starting with this hypothesis, several 6-sila-steroids were prepared127-129. As an example, the syntheses of 6,6-dimethyl-6-sila-oestradiol (197) and 6,6-dimethyl-6-sila-mestranol (198) are described in Scheme 25. Not only the synthesis of the key intermediate 4,4-dimethyl-4-sila-6-methoxy-l-tetralone (7 96) but also the well known organic reactions, leading from 196 to 197 and 198, are strongly influenced by the specific properties of the silicon atom. Although known reactions of steroid chemistry could be used for further transformations from 196 to 197 and 198, conditions were not directly transferable because of the chemical behaviour of the Si-Calkyi and Si-Qryl bond. Important differences in the pH- and solvent profile were neces-... 

Arylacetic acids. A new synthesis of phenylacetic acids from aromatic ketones is illustrated for conversion of 6-methoxy-l-tetralone (1) into 6-methoxy-l,2,3,4-tetrahydronaphthalene-1-carboxylic acid (3). 

Imines derived from 3-methoxy-2-naphthaldehydes react with organomagnesium compounds by a 1,4-addition mechanism. This reaction can be performed with high diastereoselectivity by using an apropriate chiral auxiliary. The method was applied for the synthesis of optically pure /3-tetralones.243... 

The substitution pattern in the benzene ring of 1 controls the regioselectivity of this 3-tetralone synthesis. 7-Substituted-2-tetralones arc obtained from precursors substituted in the p-position (CH, OCH, OAc). An -methyl substituent in 1 results in 5-methyl-2-tetralone (86%), whereas a j-methoxyl substituent in 1 results in a one-step direct conversion to 6-methoxy-2-tetralone (86%). 

The first total synthesis of (+)-brasiliquinone B was accomplished by V.H. Deshpande and co-workers starting from 7-methoxy-1-tetralone. The key step of their synthesis was the Friedel-Crafts alkylation of 2-ethyl-7-methoxytetralin with 3-bromo-4-methoxyphthalide in the presence of tin tetrachloride. 

An alternative approach to the tetracyclic systan forms the heterocyclic ring by nucleophilic addition of an amine to a carbonyl group. Application of the Friedlander quinoline synthesis to various methoxy-1-tetralones yields the methoxy-5,6-dihydrobenz-[c]acridines, which are dehydrogenated to the aromatic compound by distillation from palladium-charcoal (M. Croisy-Delcey et al. J. med. Chem., 1983, 26, 303). 

The structure and absolute stereochemistry of hinesol (282) has now been firmly established by an unequivocal synthesis which involved the tricyclic dienone (329) prepared from 6-methoxy-l-tetralone. Treatment of the dienone with lithium dimethylcopper gave a mixture of syn and anti enones (330). By a series of stereoselective reactions this compound was converted to the diol (331) whose mono-mesylate underwent a base-induced cleavage to give the spiro[4,5]-ketone (332). Elaboration of this ketone to hinesol was accomplished along... 

Synthesis of racemic (178) is shown in Scheme 37. Ketoester (177), synthesized from naphthalene-1,6-diol via 5-methoxy-2-tetralone, was converted into compound (180) by successive methylation at C-4, acetali-zation at C-3, reduction of the ester group to hydroxymethyl group, epoxidation of the C-5, C-6 double bond, and ring opening of the epoxide. Birch reduction of diol (180) with 18 equivalents of lithium in liquid ammonia followed by acid hydrolysis and subsequent methyl acetalization... 

A convergent synthesis of SERM 2, a selective estrogen receptor modulator is described. This approach incorporates the acylation of 6-methoxy-2-tetralone with [4-[2-(l-piperidinyl)ethoxy]benzoyl]chloride as a key step. In streamlining the process, 6-methoxy-2-tetralone was prepared in situ from 4-methoxyphenyl acetic acid. 

Two methods of synthesis of the acid (5) from 6-methoxy-l-tetralone (8), formed in two stages from nerolin (7) [139-142], have also been proposed. One of them [143, 144], like that just described above, is based on the introduction of the and 0 2 atoms by the Reformatskii reaction of the ketone (8). The ester formed (10) is converted into the bromide (11) and the 0 3 and 0 4 atoms are introduced by the condensation of the latter with sodiomalonic ester and decarboxylation. Dehydrogenation of the resulting acid (12) gives the acid (5). According to the other method for synthesizing this acid [140], the acids are introduced in one stage... 

The unsaturated ketone (85) has also been obtained by two methods. Dieckmann cyclization of the diester (80) and hydrolysis of the reaction product to (85) [209] is the first method of synthesis. The other method [140, 212, 213] starts from the dienic ester (9), the preparation of which from 6-methoxy-l-tetralone is described in Scheme 1. Selective hydrogenation leads to the monounsaturated acid (86), which cyclizes to (85) under the action of zinc chloride.t... 

The total synthesis of derivatives of 19-norpregnane from the bicyclic ketone (134) has been developed by Nagata et al. [28, 247-249] (Scheme 13). The addition of ring C to 6-methoxy-2-tetralone (134) by Robinson s method gave the tricyclic ketone (135), which is a mixture of the and... 

Syntheses via BCD Intermediates with a Five-Mem-bered Ring D. These syntheses generally start from 6-methoxy-l-tetralone or its 5-methyl derivative, which are used as the BC fragments. All the methods used in Chapter II for the synthesis of estrogenic hormones from 14-oxa compounds are employed for the construction of ring D. It must be mentioned that some of the intermediates illustrated in Schemes 70 and 71 have also been obtained by syntheses of the BD - C type (cf. Section 3 of this chapter). 

The first stage of the synthesis, the preparation of the unsaturated cyclic ketone (140) is illustrated in Scheme 94. Here the starting material is 5-methoxy-2-tetralone (51), which was obtained in two stages from 2, 5-dihydroxynaphthalene with an over-all yield of 73% (Chapter HI, Scheme 56). Condensation of the tetralone (51) with l-diethylamino-3-pentanone methio-dide led to a mixture of the A - and A -tricyclic ketones (138). The next stage, the formation of ring A, can be carried out both with methyl vinyl ketone (yield 75%) and with l-diethylamino-3-butanone methiodide (yield 64%). The isolation of the tricyclic ketones (138) was not necessary, and by successively condensing the tetralone (51) with the diethylaminopen-tanone methiodide and methyl vinyl ketone it was possible to obtain the tetracyclic product (140) with an over-all yield of 34% [915, 916]. 

The synthesis of the initial compound (277) can be effected in three ways (Scheme 106). The first of them consists in the reduction with alkali metals and alcohol of 2,6-dimethoxynaphthalene (280) [79, 950, 951]. The second method starts from 6-methoxytetralin (275) which, on treatment with lead tetraacetate, gives the acetate (276) which forms compound (274) when acetic acid is split out oxidation of the latter with perbenzoic acid and pyrolysis leads to the desired product (277) [952, 953]. The most suitable method for large amounts proved to be the third method, starting from 6-methoxy-1-tetralone (272), the synthesis of which has been described in Chapter II (Scheme 1). The tosylhydrazone (273) obtained from it, on being heated with sodium glycolate and subsequently distilled in vacuum over potassium bisulfate gives the tetraene (274), which, on oxidation with peracetic acid and treatment of the reaction product with hydrochloric acid forms the ketone (277) [954]. 

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