Syntheses of - -Morphine

The first reaction was involved in a synthesis of morphine, the starting ketone being made by reduction of a substituted naphthalene O. Amer. Chem. Soc., 1950, 72, 3704). No doubt an epoxide could have been used as the electrophile. 

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.

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

Parker, K.A. Fokas, D. (2006) Enantioselective Synthesis of (—)-Dihydrocodeinone A Short Formal Synthesis of (—)-Morphine. Journal of Organic Chemistry, 71,449 55. 

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. 

Ogasawara and coworkers have also published a complete series of threefold anionic domino reactions, all of which are based on an initial retro-aldol process. For instance, starting from chiral bicyclo[3.2.1]octenone 2-437, a formal total synthesis of (-)-morphine (2-445) [233] has been successfully performed (Scheme 2.103) [234]. Transformation of 2-437 into the substrate 2-488, necessary for the domino reaction, was achieved in seven linear steps. The domino process was then initiated by simply refluxing a solution of 2-438 in benzene in the presence of ethy-... 

This intramolecular etherification approach has successfully been applied to the syntheses136 of siccanin137 and clusifoliol,136 and a formal synthesis of morphine.138 Examples of tandem inter- and intramolecular etherification reactions have also been reported which convert catechol and o-aminophenol derivatives into benzodioxins (Equation (24)),139-141 benzodioxepines,142 and morpholines.139,140... 

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). 

Morphinans came about from early attempts at the total synthesis of morphine by a german chemist named R. Grew. Containing the complete carbon-nitrogen skeleton of morphine they are the closest chemical relatives which have been obtained by total synthesis. 

Morphine is presently the standard analgesic by which all the others are compared, and whose alternative methods of synthesis are still being developed [3-6], Nevertheless, synthesis of morphine is not economically practical, since it is much cheaper to obtain from natural resources. 

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. 

The first total synthesis of morphine [115] involves hydration of a tetracyclic intermediate. The attack of water from the more hindered face of the double bond could hardly have been predicted. However, the donor nitrogen atom of the molecule may have been responsible for the protonation at C-7 in favor of C-6 via a polarity alternation mechanism. 

The structure of morphine was first determined in 1925 by Sir Robert Robinson (1886— 1975) and John Masson Gulland (1898-1947). A total synthesis of morphine was achieved in 1952 at the University of Rochester by Marshall D. Gates (1915—2003) and his co-worker Gilg Tschudi. Since its first synthesis, a number of other processes have been used to synthesize morphine in the laboratory, but none of these is economically viable. Therefore morphine continues to be obtained through biosynthesis from poppy plants. 

Trauner, D., Porth, S., Opatz, T., Bats, J.W., Giester, G., Mulzer, J. New ventures in the construction of complex heterocycles. Synthesis of morphine and hasubanan alkaloids, Synthesis 1998, 653-664. 

SCHEME 23. Synthesis of morphine, codeine, and other opiates. 

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

In the total synthesis of (-)-morphine, the pivotal tetracyclic intermediate was generated as depicted below. Thus, this core structure was synthesized by reduction of the enone to afford an allylic alcohol, which was then briefly exposed to BBr, to give the desired skeleton in 64% yield <02JA12416>. 

Evans and Mitch( 101 elaborated this synthesis to afford a general approach to morphinans and to include a total synthesis of ( )-morphine (Scheme 3.7). The diastereomerically pure aziridinium salt, 43, was prepared as illustrated and converted to the aldehyde (44) in 95% yield simply by dissolving in anhydrous DMSO at ambient temperature (Kornblum oxidation). Lewis acid catalyzed ring closure occurred in high yield (80%) to the isomorphinan-10-ol... 

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... 

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