Direct and Sequential Removal of Phenolic Oxygen Functions in S-(+)-Bulbocapnine, S-(+)-Boldine and R-(-)-Apomorphine

Brossi, Arnold; Rahman, Muhammad Arif; Rice, Kenner C.; Gerecke, M.; Borer, R.; O'Brien, Jay; Teitel, S.

doi:10.3987/s-1977-01-0277

Cited by 11 publications

(11 citation statements)

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“…It seemed therefore advisable to first attempt the synthesis of 2-hydroxy substituted 6-ketomorphinans, also needed for our SAR studies, and to eliminate the phenolic 2-hydroxy group afterwards. Elimination of phenolic hydroxy groups has been carried out in several alkaloidal systems and was not expected to give rise to any difficulties (6). This plan has now been accomplished and 'Author to whom correspondence should be addressed.…”

mentioning

confidence: 99%

Synthesis of (−)- and (+)-2-hydroxy-6-keto-N-methylmorphinans, their O-methyl ethers, and 2-deoxy congeners

Schmidhammer¹,

Brossi²

1982

Can. J. Chem.

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HELMUT SCHMIDHAMMER and ARNOLD BROSSI. Can. J. Chem. 60, 3055 (1982).Bischler-Napieralski cyclization of the known phenylacetamide 1, followed by selective ether cleavage of the 3,4-dihydroisoquinoline 2 and sodium borohydride reduction, afforded the tetrahydroisoquinoline 4. Optical resolution of 4 with tartaricacid gave the optical isomers 4a, b , which were converted into the 6-ketomorphinans 9 0 , b and their 0-methyl ethers 100, b by the following reaction sequence: Birch reduction, N-formylation of the dihydro bases, Grewe cyclization, removal of the N-formyl protecting groups, reductive N-methylation, and 0-methylation. The 2-deoxy congeners 1241, b were obtained from 9 a , b by phenyltetrazolylation, and catalytic removal of the heterocyclic ether function. The (-)-enantiomer 1% obtained by this synthesis was identical with material prepared from natural morphine, and exhibited the high antinociceptive potency already reported.HELMUT SCHMIDHAMMER et ARNOLD BROSSI. Can. J. Chem. 60,3055 (1982). La reaction de cyclisation de Bischler-Napieralski de la phenylacetamide 1 suivie du clivage selectif de 1'Cther de la dihydro-3,4 isoquinolCine 2 et de la reduction par le borohydrure de sodium, conduit la tCtrahydroisoquinoleine 4. La rCsolution optique du compose 4 avec I'acide tartrique permet d'obtenir les isomeres optiques 4a ,b que I'on transforme en cCto-6 morphinans 9a,b et en leurs ethers 0-methyliques 10a,b selon les reactions suivantes: la rCduction de Birch, la N-formylation des bases dihydro, la cyclisation de Grewe, le clivage des groupes protecteurs N-formyle, la N-mithylation reductive et 1'0-methylation. On obtient les

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confidence: 99%

Synthesis of (−)- and (+)-2-hydroxy-6-keto-N-methylmorphinans, their O-methyl ethers, and 2-deoxy congeners

Schmidhammer¹,

Brossi²

1982

Can. J. Chem.

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“…Scheme I), and already tested with the synthesis of hartwood constituents [22], olivetol [23], and diphenic acids related to the alkaloid protostephanine [24]. Elimination of undesired phenolic OH groups introduced during the aromatization of 1,3-diones, or by a Bueyer-Villiger oxidation (cJ Scheme 3) was envisaged to be accomplishable by catalytic hydrogenation of phenyl tetrazolyl ethers and investigated earlier [25] [26].…”

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confidence: 99%

Colchicine Models: Synthesis and Binding to Tubulin of Tertamethoxybiphenyls

Itoh¹,

Brossi²,

Hamel³

et al. 1988

Helvetica Chimica Acta

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Synthesis of tetramethoxybiphenyl21 was accomplished from 4-phenylcyclohexane-1,3-dione 13 by aromatization to biphenyl 19 and reductive removal of the phenolic OH group as phenyltetrazolyl ether. Tetramethoxybiphenyls 34 and 40 were obtained from 4-phenylcyclohexenone 26 via ester 27. The tetramethoxybiphenyls 21,34, and 40, and analogs 28, 29, and 31 were evaluated for antitubulin activity and as antimitotic agents with L1210 murine leukemia cells. Compounds 31 and 34 had significant effects on the in-vitro polymerization of tubulin. Compound 31 was the most cytotoxic of the six new biphenyls studied (ICs0 for cell growth, 0 . 6~) and caused the accumulation of cells in metaphase arrest.Introduction. -The antimitotic effect of colchicine and its inhibition of migration and phagocytosis of polymorphonuclear leukocytes are attributed to its binding to tubulin, which disorients the structural organization of microtubules [ 1-41. Data collected from studies of many colchicinoids (compounds chemically related to colchicine) in assays, measuring binding to tubulin in vitro an antitumor activity in vivo [4] [5], and inhibition of

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“…(-)-I-Hydroxy-N-methylmorphinan (6). A mixture of 20 mg (0.074 mmol) of 5, 2 ml of triethylene glycol and 1 ml of 64% hydrazine hydrate was stirred under Ar at 125" (bath temp.)…”

Section: Decahydro-l H-[l]benzopyrano[23-j]isoquinolinementioning

confidence: 99%

“…ether 3 via carbenium ion intermediates and cyclization, possibly involving a dienonephenol rearrangement [5]. The apomorphinan 4 should be an interesting compound for further transformation [6] since the overall yield of 4 from 1 and 2 is quite remarkable.…”

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confidence: 99%

ChemInform Abstract: APOMORPHINANS FROM ISOQUINOLINES: GREWE CYCLIZATION OF 1‐(2‐HYDROXYBENZYL)‐N‐METHYLOCTAHYDROISOQUINOLINE AND ITS O‐METHYL ETHER

Schmidhammer¹,

Brossi²,

Flippen‐Anderson³

et al. 1984

Chemischer Informationsdienst

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SummaryWolff-Kishner reduction of the optically active ketomorphinan 5 afforded the optically active morphinan 6 differing chromatographically and spectroscopically from the material obtained in a Grewe-cyclization of the isoquinoline 1. A single crystal X-ray analysis of a hydrobromide salt of a phenolic amine obtained from 1 and 2 with refluxing hydrobromic acid showed this compound to be the N-methylapomorphinan 4.It was reported that the isoquinoline 1 afforded with refluxing hydrobromic acid the cyclic ether 3, converted on further treatment into a phenolic base of m.p. 232-236" for which a 1-hydroxymorphinan structure was proposed [l]. The same phenolic compound was later prepared elsewhere by a somewhat modified procedure 121. This phenolic base was, however, not identical by TLC and 'H-NMR with (-)-I-hydroxy-Nmethylmorphinan (6), prepared from the ketomorphinan 5 [3] by a Wolff-Kishner reduction (Scheme 1) *). Whereas the structure of the cyclic ether 3 was supported by a chemical degradation, that of the 'so-called' I-hydroxy-N-methylmorphinan was not secured with additional data (s. [ l]), and required in the light of our findings a reexamination of its structure.We now report that the Grewe-cyclization, when repeated with the isoquinoline 2 prepared by the route shown in Scheme 2, afforded compounds 3 and 4 identical with the materials obtained elsewhere [l] from 1.

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Direct and Sequential Removal of Phenolic Oxygen Functions in S-(+)-Bulbocapnine, S-(+)-Boldine and R-(-)-Apomorphine

Cited by 11 publications

References 1 publication

Synthesis of (−)- and (+)-2-hydroxy-6-keto-N-methylmorphinans, their O-methyl ethers, and 2-deoxy congeners

Synthesis of (−)- and (+)-2-hydroxy-6-keto-N-methylmorphinans, their O-methyl ethers, and 2-deoxy congeners

Colchicine Models: Synthesis and Binding to Tubulin of Tertamethoxybiphenyls

ChemInform Abstract: APOMORPHINANS FROM ISOQUINOLINES: GREWE CYCLIZATION OF 1‐(2‐HYDROXYBENZYL)‐N‐METHYLOCTAHYDROISOQUINOLINE AND ITS O‐METHYL ETHER

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