Current Organic Synthesis, 2006, 3, 99-120 99 Syntheses of Morphine and Codeine (1992 – 2002): Templates for Exploration of Synthetic Tools L. M. Mascavage#, M. L. Wilson and D. R. Dalton* Department of Chemistry (016-00), Beury Hall, 13th and Norris Streets, Temple University, Philadelphia, PA 19122, USA and Department of Chemistry, Arcadia University, Glenside, PA, 19038, USA Abstract: Morphine (1) and its O-methylated analogue codeine (2), analgesic alkaloids of the opium poppy (Papaver Somniferium), have been targets of organic chemists engaged in synthetic activities for at least half a century. The “first” (Gates) and “most efficient” (Rice) syntheses of morphine (1) and codeine (2) are well known and have been reviewed and analyzed extensively numerous times. However, syntheses of the same two alkaloids that have been reported since 1992 and which have been used as devices to advance the art of organic synthesis are not as widely recognized and they have not been as thoroughly reviewed. Here they are analyzed in the spirit of the use of these two compounds as templates. Further, since both racemic and enantiospecific syntheses are important and since all eight (8) approaches (since 1992) are sufficiently different so as to warrant more tha n superficial examination, they are all considered. H HO 7 H 8 15 6 H H 6 14 N 5 CH3 H 13 NCH3 HO 14 13 9 16 9 O 16 12 15 10 O 10 4 4 11 1, R = H 2, R = CH 1 1 3 RO 3 RO 3 2 2 It is nearly two hundred years since the initial report the ubiquitous standard opium poppy or with cultivars that (1806) of the isolation of morphine (1, R = H) from the might be subsequently generated through genetic unripe seed pods of the opium poppy, Papever somniferum, manipulations so as to maximize production of these or by Friedrich Wihelm Adam Setürner [1], seventy five years related bases. Therefore, to the extent that morphine (1) and since the deduction of the correct molecular structure by codeine (2) remain synthetic targets, it is now also clear that John Mason Gulland and Sir Robert Robinson [2] and fifty the syntheses must be directed not only to the bases years since the first synthesis (and structure proof) by themselves but in such a way as to be able to produce Marshall Gates and Gilg Tschudi [3]. Subsequently, relatives (e.g., the enantiomer, diastereomers, products of numerous partial and full syntheses of these alkaloids have “substitution” that cannot be easily made by subsequent been attempted (with varying degrees of success) and reports manipulation of the natural materials, etc.) for testing have been produced and review articles generated [4]. OR HO H OH N NCH3 O HO CH3 O O RO RO CH3 N H Fig. (1). Representations of Morphine (1), R = H, and Codeine (2), R = CH3. It is now widely recognized that it is unlikely that a purposes and to demonstrate the prowess of synthetic purely synthetic process will be able to compete with either organic chemistry. In the decade 1992 – 2002, eight syntheses of (1) and (2) *Address correspondence to this author at the Department of Chemistry were reported. Two of the syntheses resulted in racemic (016-00), Beury Hall, 13th and Norris Streets, Temple University, material while six can be considered “asymmetric Philadelphia, PA, 19122; USA; Tel: 215-204-7138 (office), 215-204-7146 (laboratory); Fax: 215-204-1532; E-mail: [email protected] syntheses”. All eight are considered here and as already #LMM is Associate Professor of Chemistry at Arcadia University. noted, some of the material to be discussed here has been 1570-1794/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd. 100 Current Organic Synthesis, 2006, Vol. 3, No. 1 Dalton et al. included in other reviews and some of the striking features pyridinium p-toluenesulfonate, was protected as the of those syntheses commented upon. Their value is not ethoxyethyl ether (3) (65 % for the three steps); Fig. (2). diminished by recapitulation and their reemphasis may serve With the phenol protected, and without subsequent to spark the imagination! isolation of intermediate steps, reduction of the nitro group could be effected with lithium aluminum hydride in THF, 1992 : MARCUS A. TIUS AND MICHAEL A. KERR the resulting amine protected as the carbamate with methyl [5] chloroformate and the ethoxyethyl protecting the phenol removed with methanolic pyridinium p-toluenesulfonate The synthesis described is directed toward the production (69% for the three steps). Then, in dimethylformamide of isomers of thebainone (vide infra. 13) which had been (DMF), the phenol was oxidized with oxygen in the converted to morphine (1) by Gates and Tschudi [1]. The presence of a 0.1 M quantity of N,N-bis(salicylidene) work of Tius and Kerr begins with the thesis that ethylenediaminocobalt (II) (salcomine) to the corresponding disconnection of “aryl or arylalkyl C-C bonds (could be) quinone (4) in 78% yield (or 35% overall from o-vanillin); strategic(ally) viable” and it is certainly true that this Fig. (3). insightful suggestion presaged the development of many of the current catalytic methods for just such transformations The classical Diels-Alder ring forming process was [6]. utilized next to generate what is destined to become the B ring of the alkaloid system (Fig. 4). Thus, the commercially The work itself began, following precedent, with the available mono-ethylene ketal of 1,4-cyclohexanedione in aldol condensation between 2-hydroxy-3-methoxybenz- THF underwent a Grignard reaction with commercially aldehyde (o-vanillin) and nitromethane to produce the cor- available vinylmagnesium bromide (1 M in THF) to produce ω responding -nitrostyrene and reduction of the carbon- the corresponding allylic alcohol (87 %); the latter was carbon double bond of the latter with sodium borohydride in subsequently induced to lose water (in benzene solution) in methanolic tetrahydrofuran (THF) to produce a nitroalkyl the presence of 5 Å molecular sieves and p-toluenesulfonic phenol which, with ethyl vinyl ether in the presence of OOH OH OEE OC H OCH 3 O2N OCH3 O2 N 3 H a,b c (3) Fig (2). (a) CH3NO2, NH4OAc, HOAc; (b) NaBH4, MeOH/THF; (c) CH2=CHOCH2CH3, CH2Cl2, PyOTs. OEE CH3 O CH3 O OH O O2N OC H3 O / DMF (a ) HN OCH3 2 HN OCH3 N + N (3) 2 Co O O O (4) (sa lcomine) Fig. (3). (a) LiAlH4 in THF; ClCOCH3, CH2Cl2, I-PrNEt2; PyOTs, CH3OH. H3C O CH3O CH3 O HN O OO O OO O O HN OC H3 O O + OCH3 H H H O H NHCOCH (4) O 3 (5) (6) Fig. (4). The Diels-Alder Reaction. Syntheses of Morphine and Codeine (1992 – 2002) Current Organic Synthesis, 2006, Vol. 3, No. 1 101 H3C H C HN O 3 O O O O O O N H OCH 3 OC H3 a, b H O H O H O O CH O 3 O CH3O O O O O O O H H H H N O NHC OCH3 (7) (6) H3C Fig. (5). o (a) C6H5SeCl, CH3OH, 0 C; (b) THF, H2O2 (30%). acid to produce the corresponding diene (5) (34%), written ketal with aqueous hydrogen chloride yielded the here as the Z-isomer. The Diels-Alder reaction between 4 and corresponding ketone and generation of the potassium enol 5 at 100 oC in toluene yielded (86%) a single product (6). of the latter with potassium bis(trimethylsilyl)amide in THF oC followed by oxaziridine oxidation produced the When the dienone (6) was treated with phenylselenium at –78 acyloin (8) in 70 –88% yield as shown in Fig. (6). chloride in methanol at 0 oC [Fig. (5)] an “unusual … (and un)anticipated” tandem selenocyclization involving the Catalytic (10% Pd on C) hydrogenation of the non- carbamate occurred and oxidative elimination of the conjugated carbon-carbon double bond in 8, followed by selenium produced the alkene (7) (80%). Swern type oxidation (dimethyl sulfoxide in CH2Cl2 with trifluoroacetic anhydride) of the dihydroacyloin generated a The structure of the ketal (7) was confirmed by single (presumed) diketone (written here as the enolic tautomer). crystal x-ray diffraction analysis. Then, hydrolysis of the Without purification, the ketoenol was treated (in dichloro- H3C O H3C O O O OH O N N H H OCH3 OCH3 a, b,c O O H O H O O HO CH O CH3O O 3 O O O O O H H H H N N O O H C H3C (7) 3 (8) Fig. (6). + - o (a) aq HCl, THF; (b) K [N(TMS)2] , THF, –78 C; (c) THF, 3-phenyl-2-(phenylsulfonyl)oxaziridine. 102 Current Organic Synthesis, 2006, Vol. 3, No. 1 Dalton et al. H C O 3 H C H C 3 3 H3C OH O O OH O OH OH N O O O H N N O H H N OCH 3 OCH OCH 3 3 OCH3 O (a ) (b) (c ) O O H O H H O O H O (8) (d) OC H3 H3 C OCH3 O O O OCH3 N OC H3 N O H H O CH O 3 (9) Fig. (7). (a) H2 (10% Pd/C) in THF; (b) (CH3)2SO, (CF3CO)2O; (c) BF3 • O(Et)2; (d) K2CO3, acetone, CH3I. methane at –30 oC) with boron trifluoride etherate to effect yield and reduction with sodium borohydride in methanol aromatization and this material (with the dihydrofuran ring produced the corresponding alcohol which was not purified in place, a “fortunate turn of events”) was directly converted but rather dissolved in dry THF and treated with a ten fold to the methyl ether 9 on treatment (in acetone) with excess of methyllithium at 0 oC.