184884-49-9Relevant academic research and scientific papers
Toward a practical synthesis of morphine. The first several generations of a radical cyclization approach
Butora, Gabor,Hudlicky, Tomas,Fearnley, Stephen P.,Stabile, Michele R.,Gum, Andrew G.,Gonzalez, David
, p. 665 - 681 (2007/10/03)
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 β-bromoethylbenzene via oxidation with E. coli JM 109(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 o-bromo-β- 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 sp3-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.
