Codeine total synthesis

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. 

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. 

Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T (2007) Chemoenzymatic Total Synthesis of (+)-Codeine by Sequential Intramolecular Heck Cyclizations via C-B-D Ring Construction. Synlett 2859... 

For example, the fermentation of (2-bromoethyl)-benzene with recombinant E. coli furnished excellent yields of the corresponding c/.v-diol. enantiopure 3-(2-bromoethyl)-benzene-l,2-diol. The latter was used as a building block in the total synthesis of (+)-codeine (Fig. 29). Besides a Mitsunobu inversion of one of the stereogenic centers, two successive Heck cyclizations led to the enantiomer of the natural product [173]. Slight modifications of the reaction sequence, generating an epoxide intermediate, also furnished access to the naturally occurring enantiomer (—)-codeine [28]. 

Omori AT, Finn KJ et al (2007) Chemoenzymatic total synthesis of (+)-codeine by sequential intramolecular Heck cyclizations via C-B-D ring construction. Synlett 2007 2859-2862... 

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. 

During total synthesis studies on ( )-3-deoxy-7,8-dihydromorphine and ( )-4-methoxy- N-methylmorphinan-6-one, a series of racemic mixtures with both 2- and 4-oxygen substituents (76) was isolated and characterized.(69) 2,4-Dihydroxy-3-methoxymorphinan-6-ones were isolated in an investigation of the Grewe codeine synthesis/78 ... 

A total synthesis of ( )-codeine also utilized the aziridinium salt 94 as a key intermediate, which was converted to 100 via epidihydrothebainone methyl ether (98) according to Evans s procedure. Specific ether cleavage reaction of 100 with NaSEt afforded dihy othebainone (101) in 100% yield. Since dihydrothebainone (101) had already been transformed into codeine (102), this synthesis constitutes a formal synthesis of 102 (Scheme 19). 

In the laboratory of J.D. White, the asymmetric total synthesis of (+)-codeine was accomplished. The Robinson annulation was the method of choice to build a phenanthrenone precursor starting from a substituted tetralone derivative. As it is usuaiiy the case, the isolation of the Michael adduct allowed the intramolecular aldol reaction to proceed cleanly and to afford a higher yield of the annulated product. 

The asymmetric total synthesis of (+)-codeine, the unnatural enantiomer, was accomplished by J.D. White and coworkers using an intramolecular carbenoid insertion as the key step. The first stereogenic center that directed all subsequent stereochemical events was installed by the asymmetric hydrogenation of an alkylidene succinate that was obtained using the Stobbe condensation. Dimethyl succinate and isovanillin were reacted in the presence of excess sodium methoxide at reflux and the resulting reaction mixture was acidified to obtain the monomethyl ester. 

White, J. D., Hrnciar, P., Stappenbeck, F. Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion. J. Org. Chem. 1999,64, 7871-7884. 

Keywords Chiral synthesis Codeine Morphine Total synthesis... 

In 2008 the Guillou group disclosed the total synthesis of racemic codeine [29]. The key features in their synthesis are (1) a construction of the C-ring including a quaternary carbon by the intramolecular Heck reaction, (2) an oxy-Michael... 

In 2002, Trost and Tang reported the chiral total synthesis of (-)-codeine in short reaction steps using a palladium-catalyzed asymmetric allylic alkylation (AAA) [53] as the key transformation [54], In 2005, a detailed full account of their synthesis was published [55]. The key features of their synthesis are (1) a preparation of an aryl ether with high optical purity by the Pd-catalyzed AAA reaction, (2) the intramolecular Heck reaction to generate the A-C-E benzofuran skeleton, (3) the second intramolecular Heck reaction of Z-vinyl bromide providing the phenan-throfuran core, and (4) the intramolecular hydroamination for the construction of D-ring by the action of LDA and visible light. 

The correct structure of morphine was proposed in 1925. Ultimate proof of its correct structure had to await its total synthesis, accomplished three decades later. The lack of the correct structure of morphine did not discourage the synthesis of several morphine congeners and derivatives by chemical reaction with the known peripheral functional groups, specifically the phenolic hydroxyl (C-3), and allylic alcohol (C-6), and the double bond (C-7-8) (Fig. 5-8). Among the derivatives introduced before 1930 and still in common usage today are codeine,6 ethylmorphine (Dionin), diacetylmorphine (heroin), hydromor-phone (Dilaudid), hydrocodone (Dicodid), and methyldihydromorphinone (Metopon). 

A study directed at the total synthesis of (-)-codeine and (-)- morphine synthesis via a novel asymmetric intramolecular Diels-Alder reaction Costanzo, Michael John... 

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]. 

The summary of accomplishments in the total synthesis of morphine alkaloids is depicted in Table 3. Most authors target codeine as the ultimate S3mthetic target its attainment represents a formal total synthesis of morphine as Rice demonstrated its conversion to morphine by O-demethylation with BBr3 [55]. Such a strategy has... 

Another possibility for practical synthesis could come from the combination of fermentation for attaining specific steps with semisynthesis to complete the preparation. Currently, we are fully dependent on natural sources of morphine and all medicinally useful derivatives are made by semisynthesis. Perhaps more important goals for the future generations of chemists would be to focus on the de novo total synthesis of the derivatives themselves rather than morphine or codeine. Perhaps we will see some effort devoted to this most worthwhile task in the near future. 

After the manuscript has been accepted for publication, a synthesis of codeine was published featuring a Claisen-rearrangement and a 1,3-dipoloar nitrone cycloaddition as key steps Erhard T, Ehrlich G, Metz, P (2011) A Total Synthesis of (-1-/—)-codeine by 1,3-Dipolar Cycloaddition. Angew Chem Int Ed doi 10.1002/ anie.201007448. 

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... 

White JD, Caravatti G, Kline TB, Edstrom E, Rice KC, Brossi A (1983) Biomimetic total synthesis of (—)-codeine. Tetrahedron 39 2393-2397... 

Moos WH, Gless RD, Rapoport H (1983) Codeine analogs - synthesis of 4a-aryldecahy-droisoquinolines containing nitrogen ring functionality and of octahydro-1 h-indeno[l,2,3-ef]isoquinolines - a total synthesis of codeine. J Org Chem 48 227-238 Toth JE, Euchs PL (1987) Syntheses via vinyl sulfones. 21. Total synthesis of dl-morphine. 

Varin M, Barre E, lorga B, Guillou C (2008) Diastereoselective total synthesis of (+/—)-codeine. Chem Eur J 14 6606-6608... 

Reserpine a challenge for total s5mthesis of natural products 05CRV4671. Stereo-controlled construction of quaternary carbon stereocenters in total synthesis of complex cydotiyptamine alkaloids 07AG(E)5488. S5mtheses of morphine and codeine (1992-2002) 06COS99. 

The literature of organic chemistry is replete with attempts to synthesize morphine and codeine and a number of successes have been achieved. The first total synthesis of codeine and morphine, completed in 1952 (that of Gates and Tschudi ), is shown in Scheme 13.44. 

Scheme 13.44. A representation of the first total synthesis of codeine and morphine (after Gates, M. Tschudi, G. /. Am. Chem. Soc., 1950, 72,228 Gates, M. Tschudi. G. J. Am. Chem. Soc., 1952,74,1109).

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