ChemInform Abstract: Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical Cyclization Approach.

Butora, Gabor; Hudlický, Tomáš; Fearnley, Stephen P.; Stabile, Michele R.; Gum, Andrew G.; González, David

doi:10.1002/chin.199830253

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“…A regioselective epoxide opening led to aryl ether 16, whose Heck cyclization provided the pentacyclic precursor to 18 [9]. We realized during this particular synthesis that the configuration of the On the other hand, we experienced difficulties in some of our past approaches in executing a second Mitsunobu inversion in order to set up the C-5 center for the natural series [10]. A solution to the problem was envisioned in generating the allylic epoxide 21 and attaching the required aryl residue by the regioselective opening of the epoxide at C-5 (morphine numbering).…”

Section: Morphine Alkaloidsmentioning

confidence: 99%

Recent chemoenzymatic total syntheses of natural and unnatural products: Codeine, balanol, pancratistatin, and oseltamivir

Hudlický

2010

Pure and Applied Chemistry

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Presented here is a short summary of the recent accomplishments in total synthesis in our laboratories. In particular, recent generations of the syntheses of pancratistatin derivatives, codeine, balanol, and oseltamivir (Tamiflu) are described in relation to their common chemoenzymatic origin in toluene-dioxygenase-mediated dioxygenation of aromatic substrates. Perspectives and projections are discussed in the conclusion. RESULTS AND DISCUSSIONThe mainstay of our program in chemoenzymatic synthesis is the whole-cell fermentation of aromatic compounds with recombinant strains of E. coli that over-express toluene dioxygenase. The organisms, such as E. coli JM109(pDTG601) developed by Gibson [1], enjoy widespread use in the provision of many enantiopure diol metabolites such as 5, 6, and 7, Fig. 2. The latest compilation of these metabolites by Johnson lists more than 400 such structures [2], only a few of which have been exploited in total synthesis [3]. Given the diverse functionality in the substrates that the enzyme tolerated, this large number of enantiopure metabolites provides an almost limitless opportunity for applications to asymmetric synthesis of natural products. This paper provides an overview of the latest results from our laboratory. T. HUDLICKÝScheme 1 Synthesis of C-1 derivatives of 7-pancratistatin.ether linkage at C-5 determines the outcome of all subsequent stereochemical events pursued in the assembly of the morphine skeleton.With this recognition, we devised an enantiodivergent approach to codeine from the Boc-protected amine 19, obtained in a few steps from diol 6. A single Mitsunobu inversion with bromoisovanillin at C-5 would provide the aryl ether 20 whose Heck cyclization and further transformations would lead to ent-codeine (2) as shown in Fig. 3. Fig. 7 Symmetry-based design for oseltamivir from cis-dihydrodiols 5 and 7. . The efforts of students and postdoctoral fellows in the author's laboratory are greatly appreciated; their names appear in the cited references. T. HUDLICKÝ

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Section: Morphine Alkaloidsmentioning

confidence: 99%

Recent chemoenzymatic total syntheses of natural and unnatural products: Codeine, balanol, pancratistatin, and oseltamivir

Hudlický

2010

Pure and Applied Chemistry

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show abstract

ChemInform Abstract: Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical Cyclization Approach.

Cited by 1 publication

References 1 publication

Recent chemoenzymatic total syntheses of natural and unnatural products: Codeine, balanol, pancratistatin, and oseltamivir

Recent chemoenzymatic total syntheses of natural and unnatural products: Codeine, balanol, pancratistatin, and oseltamivir

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