Opium alkaloid total synthesis

Another example of a tandem reaction, in this case an intramolecular Heck insertion followed by a r-allylpalladium displacement, comes from our opium alkaloid total synthesis project (Scheme 6-25) L53J. Treatment of diene aryl iodide 142 under forcing Heck cyclization conditions provided 143 in 56% yield in which the two final rings of the opium alkaloid skeleton are constructed in this one key step. 

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. 

Hong, C.Y, Kado, N., Overman, L.E. (1993) Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (—)- and (-f)-Dihydrocodeinone and (—)- and (-F)-Morphine. Journal of the American Chemical Society, 115, 11028-11029. 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

The discovery of morphine s analgesic activity in 1806 started a long series of studies of the alkaloids from the opium poppy, including morphine s first correctly postulated structure in 1925 and its total synthesis in 1952. The depressant action of the morphine group is the most useful... 

In 1803 the German pharmacist Seturner achieved the isolation of morphine as one of the active ingredients of opium. He named the compound after Morpheus, Ovid s god of dreams, the son of sleep. Among the other alkaloids of opium are codeine, isolated in 1832, thebaine, narceine, narcotine, and papaverine. From the isolation of pure morphine to the elucidation of its structure by first Gulland and Robinson(1,2) and later Schopf(3) took another 120 years. A total synthesis by Gates and Tschudi(4,5) confirmed the structure in the early 1950s. 

Morphine (1) and its congeners, codeine (2), thebaine (3), and oripavine (4), Fig. 1, as well as other minor constituents of the opium poppy latex, continue to gamer interest of the chemical community for a number of reasons. The focus on the total synthesis of these alkaloids in the academic sector has not waned and now spans almost 60 years since the seminal disclosure of the first synthesis by Gates in 1952 [1,2]. 

Rice KC (1980) Synthetic opium-alkaloids and derivatives - a short total synthesis of (-1-/—)-dihydrothebainone, (+/—)-dihydrocodeinone, and (-f/—)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners. J Org Chem... 

Hong CY, Kado N, Overman LE (1993) Asymmetric-synthesis of either enantiomer of opium-alkaloids and morphinans - total synthesis of (—)-dihydrocodeinone and (-1-)-dihydrocodeinone and (—)-morphine and (+)-morphine. J Am Chem Soc 115 11028-11029 Mulzer J, Dumer G, Trauner D (1996) Formal total synthesis of (—)-morphine by cuprate conjugate addition. Angew Chem hit Ed 35 2830-2832... 

Mulzer J, Bats JW, List B, Opatz T, Trauner D (1997) The phenanthrenone approach to opium alkaloids formal total synthesis of morphine by sigmatropic rearrangement. Synlett 441 44... 

Hong, C. Y. Overman, L. E. "Preparation of Opium Alkaioids by Paiiadium Cataiyzed Bis-Cyclizations. Formai Totai Synthesis of Morphine" Tetrahedron Lett. 1994, 35, 3453, Aiso see Hong, C. Y. Kado, N. Overman, L. E. "Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (-)- and (+)-Dihydrooodeinone and (-)- and (+)-Morphine" J. Am. Chem. Soc. 1993, 115,11028-11029. Heerdlng, E. A. Hong, C. Y. Kado, N. Look, G. C. Overman, L. E. "Simple Method for Controlling Stereoseleotion in Mannich Cyclization Reactions of Aldehydes" J. Org. Chem. 1993, 58, 6847-6948. 

In this report, a brief overview of the history of the chemistry and pharmacology of the opium alkaloids will be presented in order to place recent progress in opiate total synthesis in proper perspective. After a brief description of how past, present and possible future developments influenced the development of the NIH opiate total synthesis, some recent progress in this area will be described. 

Dobie JJ, Lauder A (1911) Hydroxycodeine A new alkaloid from opium. J Chem Soc 99 34-35 Evans DA, Mitsch CH (1982) Studies directed towards the total synthesis of morphine alkaloids. Tetrahedron Lett 23 285-288... 

Rice KC (1982) Synthetic opium alkaloids and derivatives 2. Efficient total synthesis of (-)-dihy-drocodeinone and derivatives.. In Harris LS (ed) Problems of drug dependence 1981. NIDA Res Monogr 41, Washington DC, p 99 and references cited therein Rice KC, Brossi A (1980) Expedient synthesis of racemic and optically active N-norreticuline and N-substituted and 6 -bromo-N norreticulines. J Org Chem 45 592-601 Rice KC, Ripka WC, Reden J, Brossi A (1980) Pavinan and isopavinan alkaloids. Synthesis of racemic and natural thalidine, bisnorargemonine and congeners from N-norreticuline. J Org Chem 45 601-607... 

A recent extension of the DTS is the concept of collective total synthesis, which has been introduced by MacMillan in 2011 [94]. Collective total synthesis aims for the generation of structurally diverse natural products by transformation of a common synthetic scaffold through biomimetic-like pathways [95]. MacMillan et al. employed the common tetracyclic scaffold 120 for the complex total synthesis of six different opium alkaloids of considerable structural complexity (Scheme 15.25) [94]. 

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