Absolute configuration morphine

Scheme 11). The specific optical rotation of compound (-)-2a derived from the chiral ketone (-)-2a agreed with the reported rotation of 73 [43], showing that the absolute configuration of 73 was (4aS, 8aR) and corresponded to that of natural (-)-morphine [42]. 

Morphine, (+)-codeine, and (+)-heroin are all devoid of MHP (sc) antinociceptive activity/119 although (+)-morphine did show some central actions in rats when administered intracerebrally.(120) Compounds of the (+)-morphine series are related configurationally to (-)-sinomenine (53 of Chap. 3),(m) the absolute configuration of which has been demonstrated to be enantiomeric with that of natural (-)-morphine. 

Circumstantial evidence suggested that levorphanol ((-) 49, R = OH R = Me), because its pharmacodynamic profile is similar to that of morphine, has the same absolute configuration. Proof of absolute configuration came from Hellerbach s group,<35) who subjected it to Hofmann degradation, followed by oxidative steps to the dicarboxylic acid, 52, identical to that obtained from thebaine and abietic acid. 

A comparison of the absolute configurations of (-)-5b and morphine is not possible because of the difference in the orientation of their aromatic rings. Cochran<7) investigated the absolute configuration of (—)-5-(3-hydroxyphenyl)-2-methylmorphan by single-crystal, X-ray analysis of the HBr salt and found it to be 1R, 5S. He discovered that both rings of the morphan-fused system existed in chair conformations with the 2-methyl and 5-aryl substituents equatorial. 

The model adequately accommodates most structural variants of morphine and the morphinan and benzomorphan groups of analgesic. All such ligands are closely related in the molecular shape and absolute configurational relationships of the more active antipodal forms. Additional receptor sites are required to interact with ... 

With the advances in organic chemistry in the early decades of the century the more complex drugs began to yield their chemical structures. For example, the structure of morphine was proposed in 1923 [64] the drug was synthesized in 1952 [65], and its absolute configuration was determined in 1955 [66]. (+)-Morphine was synthesized in 1960 and was shown to differ significantly from the natural (-)-morphine in that it lacks analgesic activity, (-t)-Morphine does possess antitussive activity, albeit to a lesser extent than (-)-morphine [67]. 

Reticuline labeled with tritium was used in experiments to show 29) that thebaine (and consequently also codeine and morphine) arises from (— )-reticuline, which is in agreement with the known absolute configuration of these morphinane bases. Its intermediate is salutaridinol-I (not its epimer II) where the absolute configuration of the hydroxyl group was determined by isolation of L-glyceric acid (after degradation). 

In 1955, Hodgkin18 published a crystallographic study of morphine hydroiodide dihydrate, thus revealing important conformational information while verifying the structure. The absolute configuration was later established by Kartha,19 via a study of codeine hydrobromide dihydrate. 

The morphine-fragment type of compound has continued to attract interest. An improved synthesis and new pharmacological data on the analgesic morphan (102) have been described and its IR,5S absolute configuration has been established by X-ray crystallography. Of two series of benzazocine derivatives which were... 

The generally depicted structure for morphine is however a less satisfactory representation for retrosynthetic analysis than the absolute configuration which more truly indicates the steric problems to be surmounted. 

Norreticuline is not a precursor for papaverine. The problem of the ease of A -demethylation in Papaver species is still not completely solved since labeled ( )-reticuline was not incorporated in papaverine while (+)-laudanosoline, which possesses the same absolute configuration as (—)-nor-laudanosoline, was incorporated. It is known that in some cases iV-demethyla-tion definitely does occur since morphine is metabolized to normorphine. ... 

I Strong Analgesics A. Morphine-like compounds -The absolute configuration of morphine has been elucidated and is shov/n (1). The methoxymethyl ether of morphine proved less active than the parent while the essential inactivity of morphine N-oxide has been confirmed. ... 

Knowledge of absolute configurations is also needed in the pharmaceutical industry, both for compounds which are the organic chemist s attempts to improve on nature, for example, analogues of oestrone, morphine or oxytocin, and for totally artificial structures. The suggestion might be seriously considered that no chiral pharmaceutical product should be used without (a) resolution of a racemate into its components, and (b) determination of the absolute configuration of the active enantiomer. 

The stem and root of Sinomenium acutum are used in Chinese medicine. Sinomenine (10) was isolated from this plant and the structure, when elucidated, was found to be similar to that of morphine. The absolute configuration of the structure of sinomenine, however, is antipodal to that of morphine. 

Assign the absolute configurations of the chiral centres of dextropropoxyphene and levopropoxyphene. These drugs are morphine analogues. Can you guess which is the antitussive and which is the narcotic analgesic List all (+) (dextro-) and (—) (levo-) drugs which you can find in the BNF ... 

Morphinan alkaloids are the pharmaceutically most important class of isoquinoline alkaloids. Codeine and morphine are found only in Papaver somniferwn and closely related species. Both alkaloids are derived from (R)-reticuline, the absolute stereochemistry of which corresponds with the configuration of morphinan alkaloids. Re-ticuline is therefore an important branch point in isoquinoline bio nthesis. However, either enantiomer of reticulme, when fed separately, is incorporated into morphinan alkaloids essentially to the same extent. The question therefore arises by which mechanism (R)-reticuline is formed within the plant. 

---