The Synthesis of Thebaine and Northebaine from Codeinone Dimethyl Ketal

Rapoport, Henry; Lovell, Calvin H.; Reist, Helen R.; Warren, Mitchum E.

doi:10.1021/ja00984a032

Cited by 41 publications

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“…For this rea son, both the elimination of HBr from bromide 5d and hydrolysis (acidolysis) of codeinone dimethyl ketal (6c) were studied in detail in the framework of the developed earlier procedure for the preparation of 2a from codeinone (6d), which is readily available from 4a. 7,8 Ketal 6c can be synthesized from bromide 5d by both the prolonged refluxing with potassium tert amylate in tert amyl alcohol 7 and the action of Bu t OK in DMSO at 60 °C. 8 Similar reaction of 8 [(1E) 2 phenylethenyl] substituted bromide 5c with Bu t OK in DMSO proceeded at ambient temperature to give ketal 6a.…”

Section: Resultsmentioning

confidence: 99%

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

2011

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An improved method for the synthesis of 8 [(1E) 2 phenylethenyl]codeinone dimethyl ketal was described. The ability of [(1E) 2 phenylethenyl] substituent to stabilize effectively the π system of the ring C is responsible for the essential difference in both the reactivity and the compositions of products formed in the reactions of the corresponding substituted and unsubsti tuted codeinone and thebaine derivatives. Thevinone (1a) is a key intermediate on the synthetic route from natural alkaloid thebaine (2a) toward orvinols (3a), so called "semi synthetic" opioid derivatives exhibit ing marked affinity to opioid receptors (e.g., buprenor phine, diprenorphine, ethorphine, dihydroethorphine). 1,2 Therefore, compounds 3a for decades are the subjects for intense search for potent analgetics for treatment of severe and chronic pain with decreased level of unwanted side effects. Compound 1a is formed by [4+2] cycloaddition of AcCH=CH 2 to diene system of 2a and serve as the starting compound for the synthesis of large scope of thevinols 3b, O demethylation of the latter leading to compounds 3a. A variety of compounds 3b and 3a resulted mainly from altering the substituents R 2 and R 3 . However, recently, modification of the C(6)-C(14) etheno or ethano bridge of compounds 3 became of interest. Functionalization of these positions can be achieved by either preliminary in troduction of the substituent at the positions 7 or 8 of diene 2a (which correspond to positions 18 and 19 of ad duct 1a) followed by [4+2] cycloaddition 3 or by modifica tion of the ethene bridge in the Diels-Alder adduct. 4,5Recently, in the framework of the design of novel pro cedures for the modification of the C ring of the morphi nan alkaloids, we carried out the Pd catalyzed Heck reac tion of codeine (4a) and PhCH=CHBr to give 7,8 di hydro 8β [(1E) 2 phenylethenyl]codeinone (5a), from which 8 [(1E) 2 phenylethenyl]codeinone dimethyl ket al (6a) was synthesized in four steps. 6 It was found that ketal 6a bearing conjugated diene system reacts with di enophiles to give adducts 7 including 19 [(1E) 2 phenyl ethenyl]thevinone (1b) (in the reaction with AcCH=CH 2 ) instead of the expected 7,8 fused compounds. The use of ketal 6a as "masked" 8 [(1E) 2 phenylethenyl]thebaine (2b) opens the route toward derivatives of compounds 3 substituted at the position 19. Moreover, the hydrolysis of ketal 6a and subsequent reduction of the carbonyl group afforded 8 [(1E) 2 phenylethenyl]codeinone (4b), which in the "ordinary" Diels-Alder reaction gives derivatives with the additional cycle fused to the C ring at the posi tions C(7)-C(8). 6 Thus, ketal 6a is the key intermediate toward both the 7,8 fused derivatives of morphinan alkaloids and de 1, 2: R = H (a), trans CH=CHPh (b) 3: R 1 = H (a), Me (b); Z∼Z = CH 2 CH 2 , CH=CH

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Section: Resultsmentioning

confidence: 99%

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

2011

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“…Thus, the styryl substituent at C(8) of 6 is also in the b-position because the transformation 6 ! 7 proceeds without any rearrangement at C (8). In addition, the 3 J(8,14) value (10.6 Hz) of 8 similarly indicates the presence of H a ÀC(8) both in 8 itself and in its precursor 6.…”

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confidence: 86%

“…Specifically, the aim was to prepare compounds bearing a 1,3-diene moiety formed by the C(6)=C(7) bond of the alkaloid and an exocyclic vinyl substituent at C(8). Here we report on the syntheses of (8b) (8). Thus, the styryl substituent at C(8) of 6 is also in the b-position because the transformation 6 !…”

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confidence: 99%

“…In addition, the 3 J(8,14) value (10.6 Hz) of 8 similarly indicates the presence of H a ÀC(8) both in 8 itself and in its precursor 6. Further, following the Rapoport procedure [8], ether 8 was transformed into the hydrobromide with 48% HBr solution at 08 followed by the reaction with MeOBr in MeOH leading to bromide 9 which has an a-positioned HÀC(7) ( rise to the codeinone derivative 10 which was reduced with NaBH 4 in MeOH [9] yielding the targeted codeine derivative 5. The substituted thebaine 11 was prepared from 4 by refluxing in toluene with concomitant slow distillation of the solvent to remove the MeOH formed as the by-product.…”

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Palladium‐Catalyzed 2‐Phenylethenylation of Codeine: 8‐[(1E)‐2‐Phenylethenyl]codeinone Dimethyl Ketal as the Unexpected ‘Masked’ Diene for the Preparation of 19‐Substituted Diels–Alder Adducts of Thebaine

Калинин

Shishkov

Moiseev

et al. 2006

Helvetica Chimica Acta

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In a search for starting materials for the preparation of 7,8-fused morphine alkaloid derivatives, 8-[(1E-2-phenylethenyl]codeinone dimethyl ketal (4) and 8-[(1E-2-phenylethenyl]codeine (5) were prepared. These dienes were used as substrates in the Diels-Alder reactions. Compound 5 formed the normal adduct 12 with N-phenylmaleimide, while compound 4 behaved in reactions with dienophiles as the masked diene 11, a 8-[(1E)-2-phenylethenyl]-substituted thebaine, yielding the corresponding 19-substituted 6,14-endo-etheno-6,7,8,14-tetrahydrothebaines. Specifically, reaction of 4 with methyl vinyl ketone gave rise to 19-[(1E)-phenylethenyl]thevinone (14) whose structure was elucidated by an X-ray diffraction analysis. The thebaine derivative 11 was also prepared from 4.

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“…The first practical synthesis of 1 was reported by Rapoport and his co-workers in 1956 [33], however the procedure was completely described in 1967 (Scheme 2) [34]. Their objective was the preparation of codeinone dimethyl ketal (9) followed by the conversion of the ketal to enol ether.…”

Section: Synthetic Routes To Thebainementioning

confidence: 99%

Recent Developments in the Chemistry of Thebaine and its Transformation Products as Pharmacological Targets

Berényi¹,

Csutorás²,

Sipos

2009

CMC

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The most practical synthetic routes to the preparation of as important pharmaceuticals as oxycodone, naloxone, naltrexone, nalbuphine and buprenorphine have utilized the alkaloid, thebaine, as a starting material. This review intends to focus on chemical transformations of morphinans which resulted in morphinandiene derivatives with well-established and novel pharmacological potencies. These chemical transformations were mainly associated with the formation and substitution of the unique diene structure of the ring C of the morphinan backbone.

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The Synthesis of Thebaine and Northebaine from Codeinone Dimethyl Ketal

Cited by 41 publications

References 0 publications

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

Palladium‐Catalyzed 2‐Phenylethenylation of Codeine: 8‐[(1E)‐2‐Phenylethenyl]codeinone Dimethyl Ketal as the Unexpected ‘Masked’ Diene for the Preparation of 19‐Substituted Diels–Alder Adducts of Thebaine

Recent Developments in the Chemistry of Thebaine and its Transformation Products as Pharmacological Targets

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