Morpholine from alkaloids

L. Hough and A. C. Richardson, From sugars to morpholines, spiro-acetals and alkaloids, in H. Ogura, A. Hasegawa, and T. Suami, (Eds.), Carbohydrates Synthetic Methods and Applications in Medicinal Chemistry, Kodansha, Tokyo, 1992, pp. 108-119. 

The above mentioned reactions are widely used in alkaloid modification. A good example of alkaloid modifications for clinical curation purposes are opioides. Morphine and codeine are natural products of Papaver somniferum. However, the codeine is naturally produced in small amounts. This is one reason why it is produced synthetically from morphine by modification. As codeine is the 3-0-methyl ether of morphine, the mono-O-methylation occurs in the acidic phenolic hydroxyl. Pholcodine is obtained by modification of morphine through alkylation with A-(chloroethyl)morpholine. Moreover, dihydrocodeine, hydro-morphone and heroine are also obtained from morphine through modifications. 

Mescaline has been synthesized in 42% overall yield in five steps from 2,6-dimethoxyphenol.1 Analogues of mescaline with the NH2 group replaced by a pyrrolidine, a piperidine, a morpholine, and a jV-methylpiperazine group have been prepared from 3,4,5-trimethoxybenzyl chloride.2 A process for the determination of mescaline in plasma by g.l.c.-mass spectrometry has been described,3 and behavioural effects of the alkaloid have been studied.4-11... 

The saturated heterocyclic rings are shown in black, and names for the most important ring types are given some (like piperidine, morpholine)you will need to remember others (tetrahydrofuran, pyrrolidine) are more obviously derived from the names for aromatic heterocycles that we wi II. discuss in the next chapter. Someef -these compounds (nicotine, coniine, cocaine) are plant products fall the class called alkaloids. Alkaloids are discussed in Chapter 51. Another important class of saturated heterocycles, sugars, will reappear rt Chapter 49. 

The Knorr oxazine theory of morphine structure led to the preparation of a series of bases derived from morpholine [xxxm], so called on account of its supposed relationship to morphine [49-50]. In particular it was found that N-methylnaphthalanmorpholine [xxxrv] undergoes Hofmann degradation to a methine base [xxxv] that can be degraded further to naphthalene and /3-dimethylaminoethanol. The extraordinary ease with which this last stage takes place led Knorr to believe that an ort/to-attacbment of the nitrogen side-chain to the phenanthrene residue in the morphine alkaloids was improbable, and he accordingly advanced the structure [xxxvi] [51]). 

---