anil kumar gupta - michigan state university · 1.06.2007 · anil kumar gupta group meeting june...
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Few Selected Total Synthesis in 2007
Anil Kumar Gupta
Group Meeting June 1, 2007
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Total Synthesis without Protecting Groups
Chemoselectivity !! Solution: Protecting group
BUT……..It adds…. Cost Complexity of synthesis At least 2 steps each to a synthetic sequence Also, sometimes lowers efficiency and yield Difficulty in their removal Unintented Side reactions( sometimes)
Sierra, M. A. & de la Torre, M. C. Dead Ends and Detours, Direct Ways to Successful Total Synthesis (Wiley-VCH, Weinheim, 2004)
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Hapalindole, Fischerindole, Welwitindolinone, and Ambiguine alkaloids
Biological Approach Conventional Approach
cation-olefin cyclization
Baran, P. S. & Richter, J. M. Nature, 2007,446, 404
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Hapalindole, Fischerindole, Welwitindolinone, and Ambiguine alkaloids
Baran’s Approach
Biological Activity:
• Antifungal, Antibacterial, • Antimycotic and Anticancer • Further testing prevented by the paucity of this material (~5 mg).
Baran, P. S. & Richter, J. M. Nature, 2007,446, 404
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Hapalindole, Fischerindole, Welwitindolinone, and Ambiguine alkaloids
Baran, P. S. & Richter, J. M. Nature, 2007,446, 404
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Hapalindole U and Ambiguine H
Cu(II) = Cu(II)-2-ethyl hexanoate
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Direct Coupling of Indoles with Carbonyls Compounds
Baran, P. S. & Richter, J. M. J. Am. Chem. Soc. 2004,126, 7450–7451
Oxidative dimerization of enolates???
Large excess of one of the partners avoids
homocoupling
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Optimization
Optimum Protocol
Baran, P. S. & Richter, J. M. J. Am. Chem. Soc. 2004,126, 7450–7451
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Scope
Baran, P. S. & Richter, J. M. J. Am. Chem. Soc. 2004,126, 7450–7451
• Free Alcohols • Hindered Indoles • Amides • Functionalized Indoles
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Hapalindole U and Ambiguine H contd…. Friedal-Crafts annulation failed!!!
4 2
Cyclization at C-2
6-exo-trig
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Hapalindole U and Ambiguine H contd….
1 2
Previous synthesis: racemic,multiple PGs,20 steps
4 2 6-exo-trig
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Hapalindole U and Ambiguine H contd….
Overall 6 steps Danishefsky, S. J. et.al. J. Am. Chem. Soc. 1999, 121, 11964
Danishefsky’s Protocol Norrish Type
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Fischerindole I and Welwitindolinone A (Revised)
*Previous Synthesis : 6.9 % and 1.7% (from 15) This Time: 13.0 % and 5.7%(from 15)
*Baran, P. S. et.al. J. Am. Chem. Soc. 2005, 127, 15394
Friedel Crafts cyclization
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Fischerindole I and Welwitindolinone A
Other reported synthesis: 25 steps 6 PGs, racemic product
(+)
Fluorohydroxylation
Shellhamer, D. F. et al. J. Chem. Soc. Perkin Trans. II, 1991, 401
1
5
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Guidelines followed……………
Redox reactions that do not form C–C bonds should be minimized
The percentage of C–C bond-forming events within the total number of steps in a synthesis should be maximized
Disconnections should be made to maximize convergency
The overall oxidation level of intermediates should linearly escalate during assembly of the molecular framework (except in cases where there is strategic benefit such as an asymmetric reduction)
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Guidelines followed…………… Where possible, cascade (tandem) reactions should be
designed and incorporated to elicit maximum structural change per step
The innate reactivity of functional groups should be exploited so as to reduce the number of (or perhaps even eliminate) protecting groups
Effort should be spent on the invention of new methodology to facilitate the aforementioned criteria and to uncover new aspects of chemical reactivity
If the target molecule is of natural origin, biomimetic pathways (either known or proposed) should be incorporated to the extent that they aid the above considerations
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Pleocarpene and Pleocarpenone
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Pleocarpene and Pleocarpenone
α-pyrone
RCM using Hoyeda-Grubbs 2nd generation
catalyst
Snapper et.al. JACS,2007, 129, 486
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Pleocarpene and Pleocarpenone
Snapper et.al. JACS,2007, 129, 486
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Pleocarpene and Pleocarpenone
Snapper et.al. JACS,2007, 129, 486
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Mother Nature still provides significant synthetic challenges
Maitotoxin
Thanks
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The Total Synthesis of (±)Barbatusol
Tetrahedron Letters 1993, 34,445
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Danishefsky’s protocol of prenylation
Danishefsky, S. J. et.al. J. Am. Chem. Soc. 1999, 121, 11964
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Preparation of 15
Baran, P. S. et.al. J. Am. Chem. Soc. 2005, 127, 15394
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Fischerindole I and Welwitindolinone A (Previous)
Baran, P. S. et.al. J. Am. Chem. Soc. 2005, 127, 15394
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Burgess Reagent
Baran, P. S. et.al. J. Am. Chem. Soc. 2005, 127, 15394
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Total Synthesis of (±) Welwitindolinone A
Reisman, S. E. et.al. J. Am. Chem. Soc. 2006, 128, 1448
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Total Synthesis of (±) Welwitindolinone A
Reisman, S. E. et.al. J. Am. Chem. Soc. 2006, 128, 1448