Diapositive 1

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ASYMMETRIC EPOXIDATION OF OLEFINS BY SHIS
CATALYST AND SYNTHESIS OF CRYPTOPHYCIN 52
1st seminar Patrick Beaulieu
October 30, 2003
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OUTLINE
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REAGENTS FOR EPOXIDATION
PERACIDS
Prilezhaev reaction
Stereospecific syn addition
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EPOXIDATION CATALYZED BY METAL
1- Peroxide metal complex
Metal most frequently used V, Ti
High enantioselectivity with allylic alcohols
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765
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2- Oxo-based catalysts (MO)
Jacobsen-Katsuki catalyst
Excellent for cis and trisubstituted olefins Poor
ee obtained with trans substrates
Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378
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DIOXIRANES
byproduct
Stereospecific syn addition
Oxone KHSO5.KHSO4.K2SO4
Yang, D. J. Am. Chem. Soc. 1996, 118, 11311
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Generation of Dioxiranes
?
Isolated species
0.1M solution for DMDO 0.8M solution for TFDO
?
In situ generation
Excess of oxone, NaHCO3 buffer at pH 7-8, in
biphasic (CH2Cl2/H2O) or monophasic (CH3CN/H2O)
conditions
Organic syntheses, CV 9, 288
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MECHANISM OF GENERATION AND REACTION WITH OLEFINS
Edwards, J. O. Photochem. Photobiol. 1979, 30,
63 Shi, Y. J. Org. Chem. 1998, 63, 6425-6426
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NOVEL METHODOLOGIE
Hydroden peroxide as primary oxidant
?
The solvent must be a nitrile
?
Big advantages for process chemistry
Less solvent required
Less salts introduced
Bach, R. D. J. Org. Chem. 1983, 48, 888
Shi, Y. Tetrahedron 2001, 57, 5213
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MECHANISTIC BACKGROUND
FMO
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TRANSITION STATE
Planar
Spiro
Evidence for spiro mode
1- Experimental observation
Epoxidation of cis alkene is 8.3 times faster
Peracids have the same reactivity for both alkenes
Baumstark, A. L. J. Org. Chem. 1988, 53, 3437
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2- Steric hindrence
Cis alkene
Trans alkene
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3- Computer calculation
Stabilization with the oxygene electron lone
pairs and the LUMO
7.4 Kcal/mol more stable
Houk. K. N. J. Am. Chem. Soc. 1997, 119, 10147
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ASYMMETRIC EPOXIDATION WITH DIOXIRANES
First examples
Low conversion Days to 1 week reaction 9-12.5 ee
High conversion 24h-48h reaction 13-20 ee
Curci, R. J. Chem. Soc Chem. Commun. 1984, 155
Curci, R. Tet. Lett. 1995, 36, 5831
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MAJOR BREAKTROUGH
THE SHIS CATALYST
Epoxidation of olefins mediated by a
fructose-derived ketone
?
Preparation of the D-enantiomer
Commercially available 106 / 5g The enantiomer
is prepared from a 5 steps procedure from
L-sorbose
Sugai, S. Tetrahedron, 1991, 47, 2133
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?
Preparation of the L-enantiomer
Whistler, R. L. Carbohydr. Res. 1988, 175, 265-271
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PRELIMINARY RESULTS
Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806
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OPTIMIZATION TOWARDS A ROBUST CATALYTIC CYCLE
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KETONE CONFIGURATION
Hydrate form ? Added steric hindrence?
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pH EFFECT
?
Autodecompositon of oxone
?
Catalyst stability
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pH EFFECT
Shi, Y. J. Am. Chem. Soc. 1997, 46, 11224
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KETONE REACTIVITY
?
Background reaction with oxone
?
Catalyst decomposition with oxone
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THE BAYER-VILLIGER
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THE BAYER-VILLIGER
Shi, Y. J. Org. Chem. 2001, 66, 521
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OPTIMIZED RESULTS
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
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OPTIMIZED RESULTS
82, 95 ee
94, 98 ee
94, 89 ee
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
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CONJUGAISON EFFECT ON ENANTIOSELECTIVTY
FMO
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ORIGINE OF THE ENANTIOSELECTIVITY
Major
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ORIGINE OF THE ENANTIOSELECTIVITY
Minor
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ENERGY OF THE SPIRO TRANSITION STATE
0oC
78, 98 ee
0oC
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DRAWBACK
?
Low enantioselectivity with cis and terminal
olefins
95, 20 ee
90, 24 ee
43, 61 ee
?
Competition between spiro and planar transition
state
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
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A LOOK AT THE TRANSITION STATE
?
The poor differentiation in the TS results in
lower ee
?
A different approach or catalyst was then required
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SOLUTION 1
Access to disubstituted geminal alkenes
via 2,2-disubstituted vinylsilanes
Murai, S. J. Org. Chem. 1995, 60, 1834
Shi, Y. J. Org. Chem. 1999, 64, 7675
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SOLUTION 2
Improvement through catalyst design
Effect of the spiro Five membered ring ketal
Electronic attraction between Ph and NBOC group
Shi, Y. J. Org. Chem. 2002, 67, 2435
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AN INTRIGUING REVERSE IN STEREOSELECTIVITY!
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FURTHER RESULTS
Effect the substituent
Shi, Y. Org. Lett. 2003, 5, 293
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SYNTHESIS OF 2ND GENERATION SHIS CATALYST
Shi, Y. J. Org. Chem. 2003, 68, 4963
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SUMMARY
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TOTAL SYSTHESIS OF CRYPTOPHYCIN 52

• Natural product isolated from blue-green algae
• Cryptophycin 1 exhibits a broad spectrum of
  antitumor activity in mice
• First synthezised by Kitigawa in 1994 and than by
  Moore and Tius in 1995
• Cryptophycin 52 is in advanced clinical
  evaluation for the treatment of solid tumors
• An improve synthesis done by the Eli Lilly
  research group in 2002

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RETROSYNTHESIS
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BLUE FRAGMENT SYNTHESIS
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COUPLING OF BLUE AND RED FRAGMENTS
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SHI EPOXIDATION
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TRANSITION STATE OF EPOXIDATION
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BLACK FRAGMENT SYNTHESIS
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ACKNOWLEDGEMENTS
Bill Ogilvie Livia Aumond Myra Bertrand Val
Charbonneau Ami Jun-Yee Chin Josée
Cloutier Heather Foucault Joseph Jebreen Marc
Lafrance Alison Lemay Mathieu Lemay Joseph Moran