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ASYMMETRIC EPOXIDATION OF OLEFINS BY SHI’S CATALYST AND SYNTHESIS OF CRYPTOPHYCIN 52 1 st seminar Patrick Beaulieu October 30, 2003
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ASYMMETRIC EPOXIDATION OF OLEFINSBY SHI’S CATALYST AND
SYNTHESIS OF CRYPTOPHYCIN 52
1st seminarPatrick Beaulieu
October 30, 2003
OUTLINE
REAGENTS FOR EPOXIDATION
PERACIDSO
OO
H
Cl
mCPBA
O
OO
H
O
OMg
MMPP
Prilezhaev reaction
OH O
OR
R
R
R
R
O+
O
RHO
Stereospecific syn addition
EPOXIDATION CATALYZED BY METAL
1- Peroxide metal complex
MOO
R
+
MOO
R
O+ MOR
Metal most frequently used : V, Ti
High enantioselectivity with allylic alcohols
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765
Ti
OR
O
RO
O O
RO
E
O
E
E OTi
O
O
O
R3
R2
R1
t-Bu
2- Oxo-based catalysts (M=O)
Jacobsen-Katsuki catalyst
Excellent for cis and trisubstituted olefinsPoor ee obtained with trans substrates
Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378
Ph Catalyst 3 mol% Ph
O
mCPBA, NMO69%, 93% ee
HHN
MnN
O OCl
RR
DIOXIRANES
byproduct
Oxone : KHSO5.KHSO4.K2SO4
Stereospecific syn addition
OO
MeMe
OO
CF3Me
DMDO TFDOR
R
O
O
O
O
O
Yang's catalyst
Yang, D. J. Am. Chem. Soc. 1996, 118, 11311
O
R2R1
Oxone
O
O
R1
R2 R
R
R
R
O+
O
R2R1
NaHCO3 buffer
Generation of Dioxiranes
Isolated species0.1M solution for DMDO0.8M solution for TFDO
Organic syntheses, CV 9, 288
In situ generation
Excess of oxone, NaHCO3 bufferat pH 7-8, in biphasic (CH2Cl2/H2O)or monophasic (CH3CN/H2O) conditions
He
NaHCO3wateracetone
generator
water/acetone
magnetic stirreroxone
dioxiranes
to trap
-78oC
→
→
MECHANISM OF GENERATION ANDREACTION WITH OLEFINS
Edwards, J. O. Photochem. Photobiol. 1979, 30, 63Shi, Y. J. Org. Chem. 1998, 63, 6425-6426
O HSO5-
HO O
OSO3
-
OH-
-O O
OSO3
-
O
O
SO42-
SO42-+O2
R2R1
R2R1
O
NOVEL METHODOLOGIE
Hydroden peroxide as primary oxidant
Bach, R. D. J. Org. Chem. 1983, 48, 888
Shi, Y. Tetrahedron 2001, 57, 5213
CH3CN + H2O2H3C OOH
NH
The solvent must be a nitrile
Big advantages for process chemistry * Less solvent required
* Less salts introduced
→→
H3C OOH
NH
+CF3
O
CF3
O O
ON
H
H
O
O
F3C+
O
NH2
MECHANISTIC BACKGROUND
FMO
TRANSITION STATE
O
O
R
R
O
O
R
R
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
2- Steric hindrence
Cis alkene
Trans alkene
O
O
R
R
MeHH
Me
H
O
O
R
R
H
Me
Me H
O
OR
R
HMe
Me
OO
RR
HH
Me
Me
Me
Me
O
R
R
Top view
3- Computer calculation
7.4 Kcal/molmore stable
Stabilization with the oxygene electronlone pairs and the LUMO
Houk. K. N. J. Am. Chem. Soc. 1997, 119, 10147
H
O
O
R
R
HH
H
ASYMMETRIC EPOXIDATION WITH DIOXIRANES
First examples
O
O
O
CF3
Curci, R. J. Chem. Soc; Chem. Commun. 1984, 155
Curci, R. Tet. Lett. 1995, 36, 5831
Low conversionDays to 1 week reaction9-12.5% ee
High conversion24h-48h reaction13-20% ee
Stoichiometricuse of ketones
MAJOR BREAKTROUGH
Epoxidation of olefins mediated by a fructose-derived ketone
THE SHI’S CATALYST
Preparation of the D-enantiomer
Commercially available : 106$ / 5gThe enantiomer is prepared from a 5 steps procedure from L-sorbose
Sugai, S. Tetrahedron, 1991, 47, 2133
→
OOH
OH
OH
OH
HO
O
HClO4, 0oC53%
O
OH
O
OO
PCC
CH2Cl2, rt93%
O
OO O
OO
D-Fructose27$/Kg
O
Preparation of the L-enantiomer
Whistler, R. L. Carbohydr. Res. 1988, 175, 265-271
→
H2SO4 - NaOH - H2SO4
One pot85%
OOH
OH
OH
OH
HO
1) acetone, HClO4, 0oC2) PCC, CH2Cl2
OO
O
OOO
L-Fructose
OOH
OH
OH
OH
HO
L-Sorbose150$/ 500g
OMe
OMe
DME, 0.23% SnCl2
O OO
O
O OH
MsCl, pyridine
CH2Cl260%, 2 steps
O OO
O
O OMs
PRELIMINARY RESULTS
Substrate Yield (%) ee (%)
81 90
84 87OTBS
Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806
R1
R2
oxone 5 eq
NaHCO3/H2OCH3CN/EDTA
R1
R2
O
OO O
OO
3 eq
O
pH 7-8, 2 hours
OPTIMIZATION TOWARDS A ROBUST CATALYTIC CYCLE
O
R1R2
R1R2
R1R2
SO42-
SO52-
SO42-
+O2
R1
R2
R3
R1
R2
R3
OHSO5
-SO5
2- SO42-
+
+O2
HO O
OSO3
-
R1R2
-O O
OSO3
- OH-
OO
R1R2
OHHOOR1R2
Bayer-Villiger
HSO5-
HSO4-
HSO4-
Hydrate form ?Added steric hindrence?
KETONE CONFIGURATION
O
O
O
O
OO
O O
OO
OH
OH
O
O
OO
OO
Potentially epimerized
Curci
O
O
OO
OO
F
Low conversion 3-23%
X
O
O
pH EFFECT
Autodecompositon of oxone→→ Catalyst stability
SO42-
HSO5-
OH-
O
O
O
OO
O O
OO
O
OH
O
SO3-
O O
OO
O
O-
OSO3
-
O O
OO
OO
SO52- SO4
2-
+
+O2
HSO4-
O
O
O
O
Bayer-Villiger
pH EFFECT
Shi, Y. J. Am. Chem. Soc. 1997, 46, 11224
oxone 1.4 eqcatalyst 0.2 eq
O
1.5 hoursK2CO3 / solvent
Epoxidation of trans methylstyrene
0102030405060708090
100
7,5 8 8,5 9 9,5 10 10,5 11 11,5 12 12,5 13
pH
% o
f co
nve
rsio
n
water - ACN - DMM
water - ACN
Acetone 3 eq - water - ACN
KETONE REACTIVITY
Background reaction with oxone
Catalyst decomposition with oxone→→
SO52-
SO42-
+O2
R1
R2
R3
R1
R2
R3
O
HSO5-
HSO4-
O O
OO
OO
O O
OO
O
O
O
THE BAYER-VILLIGER
O O
OO O
O
O
O
-O3S
HB.V.
O
O
O
O
O
OO
O
O
O
O
OO
O
+Ohydrolysis
Shi, Y. J. Org. Chem. 2001, 66, 521
THE BAYER-VILLIGER
O O
OO
O
O
mCPBA
O
O
O
O
O
OO
Major
O
OO
O
O
mCPBA
OO
O
O
OO
57%
OO
O
OO
+
O
43%
OPTIMIZED RESULTS
Substrate Catalyst 3 eq
Oxone 5 eq, pH 7-8
Catalyst 0.3 eq
oxone 1.4 eq, pH 10-11
81%, 88% ee 94%, 94% ee
84%, 87% ee 85%, 93% ee
61%, 94% ee
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
Ph
OTBS
Trans- disubstituted
OEt
O
R1
R2CH3CN - DMM - H2O
R1
R2
O
O O O
OO
O
OPTIMIZED RESULTS
trisubstituted alkenes
82%, 95% ee 94%, 98% ee 94%, 89% ee
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
OEt
O
Ph C10H21
CH3CN - DMM - H2O
catalyst 0.3 eq,oxone 1.4 eq, pH 10-11
-10oCR2
R1
R2
R1
OR3R3
CONJUGAISON EFFECT ON ENANTIOSELECTIVTY
FMO
ORIGINE OF THE ENANTIOSELECTIVITY
Major
O
OO
OO
O
OR2
R1
R3
O
OO
OO
O
OR3
R1R2
O
O O
OO
O
O
R3R2
R1
H
H
H
O
O O
OO
O
O
R1H
R3R2
HR1
R2 R3O
ORIGINE OF THE ENANTIOSELECTIVITY
Minor
O
OO
OO
O
OR2
R3
R1
O
OO
OO
O
O
R1
R3
R2
H
H
O
O O
OO
O
O
R2R3
HR1
O
O O
OO
O
O
HR1
R2R3
R1H
R3 R2O
78%, 98% ee
ENERGY OF THE SPIRO TRANSITION STATE
0oC
0oC
PlanarO
O O
OO
O
O
Ph
Ph OPh
Ph
barely observed
G = -RTlnK = -8.314 x 273 x ln (2/98) = 2.4 kcal mol-1
O
OO
OO
O
OPh
PhSpiro
O
Ph
Ph
DRAWBACK
→ Low enantioselectivity with cis and terminal olefins
→
Catalyst 0.3 eq
oxone 1.4 eq, pH 10-11
O
O
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
CH3CN - DMM - H2O
R2
R1
-10oCR2
R1
O
A LOOK AT THE TRANSITION STATE
cis-alkenes
→ The poor differentiation in the TS results in lower ee
→ A different approach or catalyst was then required
O
OO
OO
O
O R1
R2 O
OO
OO
O
O R2
R1R1 R2
O
R1 R2
O
SOLUTION #1
Access to disubstituted geminal alkenes via2,2-disubstituted vinylsilanes
Murai, S. J. Org. Chem. 1995, 60, 1834
Shi, Y. J. Org. Chem. 1999, 64, 7675
Ph
TMSI, (R1)2ZnPd(PPh3)4
Me
TMSPh61%
49 : 1 dr
1) Shi epoxidation2) TBAF Me
PhO
61%, 94% ee
O
49% (2 steps) , 93% ee
SOLUTION #2
Improvement through catalyst design
Effect of the spiroFive membered ringketal
Electronic attraction betweenPh and NBOC group
Shi, Y. J. Org. Chem. 2002, 67, 2435
Electronic attractionEvidence #1
O
OO
O
O
Ph
Ph
PhO
64% conversion, 3% ee
O
NBOCO
O
O
Ph
Ph
PhO
100% conversion, 78% ee
O
Electronic attractionEvidence #2
AN INTRIGUING REVERSE IN STEREOSELECTIVITY!
O
OO
OO
O
O
Ph
O
OO
NBOCO
O
O
Ph
Ph
O
23% ee(S,S)
O
O
OO
NBOCO
O
OPh
O
OO
OO
O
OPh
Ph
O
98% ee(R,R)
O
Electronic attractionEvidence #3
Shi, Y. Org. Lett. 2003, 5, 293
O
OO
NO
O
O Me
PhMe Ph
O
RO
O
OO
NO
O
O Ph
Me
RO
Me Ph
O
-OMe -Me -SO2Me p-NO2 o-NO2
ee (%) 83 84 90 90 78
Effect the substituent
FURTHER RESULTS
SYNTHESIS OF 2ND GENERATION SHI’S CATALYST
O OH
OH
HO
OH
OH
O
HO
OH
OH
OHNBn2
O
OH
OHNBn2
OO
O
OH
OHNH3OAc
O
O
O
OHO
O
NHO
O
D-Glucose23$/500g
Bn2NHHOAc/EtOH
(MeO)3CHacetone, HCl
H2, Pd/CHOAc
COCl2/NaHCO3
CH2Cl2
1)PDC2)(Boc)2O/DMAP
21% overall
O
OO
NBocO
O
O
Shi, Y. J. Org. Chem. 2003, 68, 4963
SUMMARY
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
O HN
O
O
O
NH
O
Cl
OMe
O
R
Cryptophycin 1 R = HCryptophycin 52 R = Me
O
RETROSYNTHESIS
O HN
O
O
O
NH
O
Cl
OMe
O
OH HN
O
O O
Cl
OMe
O
O
NHFmoc
HO
CCl3
+
O HN
O
O
O
O O
Cl
OMe
FmocHN CCl3
OH
O
H2N
O O
Cl
OMe
CCl3
OMe
+
OO
O
BLUE FRAGMENT SYNTHESIS
OH
Cl
Bu4NHSO4,40% NaOH O n-BuLi
86% 71% OH
1) TBSCl, Imidazole2) [(CH3)CHCHCH3]2BH3) H2O2
73% OTBS
1) (CH3O)2P(O)CH2CO2CH3
2) O3, pyridine
75%
O
O
OTBS
O
OMe
PhCH2PPh3Cl, n-BuLi
80%OTBS
O
OMe
Ph2P O
O F F
F
FF
FDPP
COUPLING OF BLUE AND RED FRAGMENTS
OTBS
O
OMe
LiOH, acetone
95% OTBS
O
OH
+
O
H2N
O O
Cl
CCl3
chloro-O-methyl-D-tyrosine
OH HN
O
O O
Cl
OMe
CCl3
1) FDPP, DIPEA2) HF
SHI EPOXIDATION
OH HN
O
O O
Cl
OMe
CCl3
O
OO O
OO
2 eq
oxone 4 eq, K2CO2
n-Bu4NHSO4, CH3CN
pH 10.3-10.7
OH HN
O
O O
Cl
OMe
CCl3
O
6.5 : 1 / : epoxide
O
OO
OO
O
OPh H
Me
R
OH HN
O
O O
Cl
OMe
CCl3
O
O
O O
OO
O
OPh
Me
R
H
OH HN
O
O O
Cl
OMe
CCl3
O
TRANSITION STATE OF EPOXIDATION
BLACK FRAGMENT SYNTHESIS
HO NH2 HO NHBoc
O1) (Boc)2O, Et3N2) RuCl3, NaIO4
+
OH
OO
L-Leucid acid
DCC, DMAP
O
OOO
NHBoc
THF, morpholinePd(PPh3)4
61% 75%
95% O
OHOO
NHBoc
O
OHOO
NHBoc
OH HN
O
O O
Cl
OMe
CCl3
O
DCC, DMAP, CH2Cl2
HN
O
O O
Cl
OMe
CCl3
O
O
OOO
FmocHN
Piperidine, DMF
HN
O
NH
O
Cl
OMe
O
O
OOO
Cryptophycin 52
ACKNOWLEDGEMENTS
Bill OgilvieLivia AumondMyra BertrandVal CharbonneauAmi Jun-Yee ChinJosée CloutierHeather FoucaultJoseph JebreenMarc LafranceAlison LemayMathieu LemayJoseph Moran
