Racemization morphinan

The (—)-morphinans (i.e., those configurationally related to morphine) are responsible for all the antinociceptive properties of the racemate. In addition, such compounds tend to have parallel respiratory depression levels and PDCs. In (+)-series (e.g., dextromethorphan), clinically useful antitussive properties are encountered, again following the separation of biological activities noted in 4,5-epoxymorphinan optical antipodes. 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

The benzomorphans thus far studied were all racemic. In view of the diverse pharmacological properties of the cycloalkylmethyl derivatives it was desirable that the compounds be resolved to ascertain wherein each action resided. Fortunately, for comparison with the morphine and morphinan nuclei we had available from Gates (8) the corresponding cyclopropylmethyl derivatives, 13 and 14. Table IV compares the analgesic antagonist activity of a group of cyclopropylmethyl derivatives with the resolved optically active dimethylallylbenzomorphan, 9. 

Morphinans are basic morphine skeletals without the 4-5 ether bridge. The simplest one illustrating analgesia (although weak) is N-methylmorphinan. This compound was synthesized from 2-carbethoxycyclohexanone. This was soon followed by the racemic... 

The analgesic (-)-levorphanol is obtained by resolution of racemic ( )-3-hydroxy-A/-methyl-morphinane (G) with (+)-tartaric acid. The synthesis of G is accomplished by the following sequence of reactions ... 

With morphinan 20 in hand, the stage was set for the deracemization and functionalization of the D ring of the alkaloid. Resolution of racemic amine 20 with dibenzoyl tartrate (Scheme 2) afforded the isomer with correct configuration at C9 and Cl3 but epimeric at Cl4. The identity of the synthetic material was unambiguously confirmed... 

Two extra variables in the first analysis accounted for (+)-enantiomers (aj = —0.97) and (—)-enantiomers (a = 0.17). While the value for the more active (—)-enantiomers is not too far from the theoretical value of 0.3, which results if the (+ )-enantiomers are absolutely inactive, general experience shows that the less active enantiomers cannot be expected to differ from the active ones (or the racemates) by a constant value (problems associated with QSAR analyses of optically active compounds are discussed below and in chapter 9.1). The group contributions of the benzomorphans could be used to predict the biological activity values of structurally related morphinans (49), which are more active than the benzomorphans by some orders of magnitude (eq. 191) [811]. 

Leimgruber W, Mohasci E (1972) Derivatives of Morphinan. US Pat 3634429 Lie TS, Maat L, Beyerman HC (1979) Chemistry of opium alkaloids, part XI. Synthesis of racemic and chiral codeine and morphine via the dihydrothebainones. Reel Trav Chim Pays-Bas Belg 98(6) 419-420 and references dted therein MacKay M, Hodgkin DC (1955) A crystallographic examination of the structure of morphine. JChem Spe 3261-3267... 

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