The Synthesis of Morphine

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

Scheme 3. Overman s intramolecular Heck strategies for the synthesis of (-)-morphine (9).

The principles expounded in Chapter T 39 apply to di-hydropyridlnes, e,g., (23), wanted in their own right in this case for the synthesis of morphine analogues. The 1,5-dlcarbonyl compound needed for (23) is (24), available by a Michael reaction. 

Figure 4.46 Synthesis map showing starting materials used for the synthesis of morphine.

Gates, M. Tschudi, G. (1956) The Synthesis of Morphine. Journal of the American Chemical Society, 78, 1380-1393. 

Zezula, J. Hudlicky, T. (2005) Recent Progress in the Synthesis of Morphine Alkaloids. Synlett, 388 05. 

In Entry 9, the initial reaction involves 5-exo addition of the aryl radical to the more-substituted end of the cyclohexene double bond, followed by a 6-endo addition to the phenylthiovinyl group. The reaction is completed by elimination of the phenylthio radical. The product is an intermediate in the synthesis of morphine. 

Per-O-acylated glycosyl iodides are stable at room temperature and can be purified on a silica gel column and stored at 0 °C. Stachulski and coworkers [202] synthesized methyl 2,3,4-tri-O-pivaloyl-glucopyranuroate iodide, which is a stable solid at 20 °C and can be stored for months at room temperature or for more than a year at 0 °C. The X-ray crystal structure of this compound, the first one of this class, shows a typical chair structure. Importantly, such a disarmed and stable iodide can be coupled with primary and secondary steroidal alcohols using I2 as a promoter, as demonstrated by the synthesis of morphine-6-glucuronide, an analgesic [202], The glycosyl donor ability... 

The plan for a tandem cyclization as the key step in the synthesis of morphine alkaloids has been successfully performed [95]. Three examples are given in Scheme 7.10. Specifically, the initially formed aryl radical, generated by bromine abstraction from compound 74, underwent a tandem cyclization to construct the desired carbocyclic skeleton. Depending on the nature of the Z substituent to the double bond, the product radicals either abstracted hydrogen from silane (Z = C02Me or CN) or eliminated thiyl radical (Z = SPh). 

An intramolecular Heck cyclization of substrate 96 was used in Overman s synthesis of pyridinomorphinans <97TL8439>. Under relatively forcing conditions, the desired cyclization of octahydroisoquinoline 96 led to enantiomerically pure 97, an intermediate for the synthesis of (-)-morphine (98) analogs. 

Thioaldehydes as heterodienophiles in the synthesis of morphine alkaloids 93PS(74)17. 

Is (/ )-reticuline, which is required for the synthesis of morphine in plants (272,273) and formed from the (5 )-enantiomer in benzyliso-quinoline-producing plants (274) by an oxidation-reduction sequence (257), also the crucial intermediate in the biosynthesis of mammalian morphine Confirmation that it is must await its detection. Conversion of... 

This is especially true in the analysis of the synthetic pathways to many natural compounds, where the most effective synthetic ideas can be often borrowed from the arsenal of the most skillful synthetic chemist of all times Mother Nature. A good illustration of the fruitfulness of this so-called biomimetic approach is provided by the synthesis of morphine group of alkaloids (Scheme 3.11). 

One step in the synthesis of morphine by Gates and Tschudi involved elimination of a keto group from an intermediate having two phenolic methoxyl groups, and under usual Huang-Minlon conditions extensive demethylation occurred. A high yield was achieved by operating at 150-155° for 1 hr. 

Recent Advances in the Synthesis of Morphine and Related Alkaloids... 

The dimethylamide function in 27 was reduced by the action of Ti(0/-Pr)4 and phenylsilane [35] to give aldehyde 29, which was then treated with p-TsOH in toluene at room temperature (Scheme 6). Under these reaction conditions, the intramolecular Friedel—Crafts-type cyclization occurred, and the subsequent dehydration of a benzylic alcohol also took place to afford phenanthrofuran skeleton (A-B-C-E ring) 30. The formation of the B-ring by way of intramolecular Friedel—Crafts acylation was first reported by Ginsburg in his synthesis of dihy-drothebainone in 1954 [36]. This transformation was also employed by White in the synthesis of (+)-morphine [37], and by Multzer in the synthesis of dihydrocodei-none [38 -0]. The Friedel—Crafts-type cyclization with an aldehyde function was used by Evans [41] in the formal synthesis of morphine and by Hudlicky in the... 

The first chapter, Recent Advances in the Synthesis of Morphine and Related Alkaloids, by Noritaka Chida, presents the racemic synthesis of morphine and related alkaloids by four research groups, and the chiral synthesis of those alkaloids by four research groups. This work has greatly contributed to progress in Organic Chemistry and Medicinal Chemistry. 

If it is difficult to spot where a product results from a dihydroxylation because there is only one oxygen in the product then it must be even more difficult to spot when there are none. Reticuline 117 is a natural product which can be used in the synthesis of morphine 116. 

Although the synthesis of morphine hoe not yet been accomplished, enough is known of its constitution to indicate that it coniainB the nolio group (OH), and that it ia a derivntim of phenantihreue (see p. 

Eventual biosynthetic postulations and revelations have led several groups over the years to approach the synthesis of morphine as does Nature, choosing to adopt a biomimetic phenolic oxidative coupling as the key step. Unfortunately, the in vitro oxidation of reticuline derivatives to salutaridines tends to proceed with poor regiocontrol and in low yield, despite employment of a variety of novel reagents. This of course... 

New synthetic approaches towards the synthesis of morphine Spoors, Paul Grant... 

A radical cyclization approach to the synthesis of morphine and synthetic approaches to trialkoxyphthalic acid derivatives... 

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