Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical Cyclizantion Approach

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Título

Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical Cyclizantion Approach

Tema

MORFINA
DIOXIGENASA
PRODUCTOS NATURALES
QUIMIOENZIMATICA
QUIMICA ORGANICA
BIBLIOGRAFIA NACIONAL QUIMICA
1998

Abstract

A radical cyclization approach to the complete skeleton of morphine was investigated in several iterations. The first attempt at a radical cascade via a Bergman-type intermediate derived from ene-diyne 10 failed during a model study in which 10-membered silicon-tethered ene-diyne 17 proved inert to Bergman cyclization conditions. A second model study involving ene-diyne 27 , functionalized with an allyl group, underwent Claisen rearrangement to 32 in preference to a Bergman-type cyclization. Several simple model studies were performed with bromophenols appended to protected diols 40 and 50 , respectively, to determine the feasibility of C12–C13 bond formation in the former case and the cascade closure C12–C13/C14–C9 in the latter via radical species generated from the aryl halides. The second-generation approach employed the diene diol 7a derived biocatalytically from b -bromoethylbenzene via oxidation with E. coli JM109(pDTG601), its conversion to cyclization precursor 55 , and the radical cyclization to 56a , b . The conditions and the outcome of this process are discussed in detail along with the rationalization of stereochemistry of the cyclization, which furnished C14- epi configuration in 56a in low yield. The third-generation synthesis relied on stepwise radical cyclization of vinyl bromide 67 derived from obromo- b -ethylbenzene (also by biocatalytic means) and equipped with an oxazolidone as the radical acceptor group. Isoquinoline derivatives 68a and 68b were obtained as a mixture of isomers, the major of which, 68a , was converted via a second tin-mediated cyclization to the pentacyclic compound 78 , also possessing C14- epi configuration. The stepwise radical cyclization proceeded in higher yields, produced cleaner reaction mixtures, and was also performed with the more flexible alcohol 87 , whose tin-mediated closure produced a 1:1 mixture of C14 epimers, tetracyclic compounds 81 and 89 . Finally, tetracycle 80 or pentacycle 79 was converted to oxo aldehyde 83 and cyclized to the complete morphinan skeleton, 84 , in the ent -C14- epi series. Additionally, preliminary studies were performed on direct closures of chloride 82 to 85 , via a C10/C11 alkylation of a sp 3 -hybridized center. The three generations of synthetic effort are discussed in detail and physical and spectral data are provided for all new compounds. The relative merits of tandem vs . stepwise radical cyclization are evaluated and projections for future work are indicated. Key words: enzymatic dioxygenation, radical cyclization, isoquinoline alkaloids, approach to (+)-morphine, ent -morphinans

Autor

Butora, G
Hudlicky, T
Fearnley, S
Stabile, M
Gum, A
Gonzalez, D

Fuente

Synthesis no. 1998, 1998. -- p. 665-681

Editor

Researchgate

Fecha

1998

Derechos

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PDF

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Inglés

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Artículo

Identificador

http://www.researchgate.net/publication/212931184

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PDF
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August 7, 2015
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Bibliografía Nacional Química
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Citación
Butora, G, “Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical Cyclizantion Approach,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed October 20, 2020, http://riquim.fq.edu.uy/items/show/3338.
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