6,7-Benzomorphan ring

Although the benzomorphan ring system was first synthesized in 1947 by Barltrop (386), it was the synthesis of 2,5-dimethylben-zomorphan (92, R = R = CHg) by May and Murphy (387) that began the investigation into the synthesis and pharmacology of this structural family. As is the case for the mor-phinans, the benzomorphans are prepared synthetically and therefore are obtained as racemic mixtures. A number of these racemates have been resolved and the activities of the individual isomers examined (see Refs. 283, 388 for reviews, also see Ref. 389). The active isomers are the levo isomers, which have the same absolute configuration at the bridgehead... 

In a continuation of the theme of simplification of the morphine ring, it was found that one of the carbocyclic rings (that which contained the allyl alcohol in morphine proper) can be dispensed with as well, to give compounds that show the full activity of the natural prototype. These agents, the benzomorphans, are of... 

In recent years much attention has been paid to the synthesis of benzomorphane heteroanalogs in which a benzene ring has been replaced by a heteroaromatic one. Syntheses of substituted thieno[3,2-/]morphanes (derivatives of thieno[2,3-d]-azocine) described in Ref. 75JHC651 consists of the condensation of cyanopyri-dines 120 with 2-thienyllithium, reduction of the resulting ketones into thienylmethylpyridines, quaternization and reduction of the quaternary salts with sodium borohydride to form piperidines 124 and 125. Intramolecular cyclization of the latter leads to the formation of thieno[2,3-d]azocines 126 (Scheme 34). 

The double bond of A3-piperideines can be used to activate and control the functionalization of the six-membered ring. For example, studies on the synthesis of the benzomorphans require 2-benzyl-A3-piperideine derivatives. One approach to these compounds has been... 

Treatment of (16-3) with sodium borohydride leads to the selective reduction of the enamine bond to lead to the tetrahydropyridine (16-4). This intermediate undergoes ring closure with a strong acid to give the benzomorphan (16-5) in direct analogy to the more complex morphinans. The product consists predominantly of the isomer that bears the equatorial secondary methyl group [18],... 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Some l-alkyl-2-benzyl-3-piperideines (185) were used in the Grewe synthesis of the benzomorphane-like analgesics (186). The ring closure between the ortho position of the benzyl residue and position 4 of the 3-piperideine nucleus was usually accomplished by heating in 48% hydrobromic acid or 85% phosphoric acid.41,103,188-193... 

Opioid receptor affinity labels have been reported for other narcotic analgesics, for example, piperidines, 293 294 benzomorphans, 295 296 and mor-phinans, 297,298 and the topic is further discussed in Chapter 13 (p. 445). Not only is the oxo-function in the 4,5-epoxymorphinan C-ring available for ready elaboration, but C-6 substituents, although they affect agonist potency, do not impair unduly receptor affinity. 299 301 ... 

Many of the comments in this section are reflected in structure-activity discussions on morphinans and benzomorphans. In the case of 4,5-epoxymorphinans, variation of the N-substituent and changes in the form (rigidity and conformation) of the ring system and the nature of substituents bring about dramatic qualitative and quantitative changes in biological responses. 

Removal of the 4-OH was mediated by the Ullmann formation of the phenyl ether, which could be removed reductively by Na/NH3. To facilitate clean removal of the C-4 oxygen function, it was necessary to protect the ketone functions as ketals. A mixture of ketals (123 and 124) was isolated and both could be used in subsequent steps. Cleavage of the C-ring was effected by peroxide oxidation and recyclization of the benzomorphan 6,11-methylcar-boxylates (125) to the C-cyclopentanone (126) occurred in acetic anhydride. 

Ozonolysis of thebaine<216) has been found to give three products. In two of these the unsaturated epoxymorphinan C-ring has been cleaved to give, as the major product (34%), the benzomorphan dicarboxylic acid (2c), and a furanobenzomorphan (14%) (2b). The minor component (3%) proved to be 14-hydroxycodeinone (2d) by comparison with an authentic sample. Compounds related to 2b have also been derived by a codeine degradation.(220)... 

Beckmann rearrangement of C-ring ketones (26 and 27) prepared via a 2-tetralone (Scheme 4.3) afforded a route to 6,7-benzomorphans that were otherwise difficult to synthesize. (13"14a) The 11a- and 11/3-methylnorbenzomor-phans (29) were prepared in this way. 

Other substituted piperidines, particularly piperidinols, have been exploited as benzomorphan precursors. The first 6,7-benzomorphan lacking a 6-alkyl substituent, the parent heterocycle, was reported by May et al. in 1968<43,44) in a synthesis from 2-cyano-4-phenylpyridine (102) (Scheme 4.15). The 2-carbomethoxypiperidine (103) was prepared readily, but it proved resistant to direct cyclization to 3-methylbenzomorphan-l-one (105) with polyphosphoric acid, presumably because the more stable 2,4-diequatorial isomer is not favorable for ring closure for geometric reasons. Hydrolysis to the corresponding acid (104), however, gives an intermediate that closes to 105 in 94% yield. The parent heterocycle 106 is produced by standard techniques. 

Benzomorphans bearing an 8-OH substituent are readily synthesized by conventional tetralone, Grewe and Stevens rearrangement routes described earlier, but in addition, conversions of benzomorphans unsubstituted in the aromatic ring to corresponding 8-OH derivatives have been described.(24,33)... 

Numerous compounds analogous(3,I34a) to benzomorphans with changes in the rings or the position of the hetero-atom have been reported. Few possess significant analgesic properties. Table 4.1 lists examples of such structures. 

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