Transcript Diapositive 1 - University of Ottawa

ASYMMETRIC EPOXIDATION OF OLEFINS
BY SHI’S CATALYST AND
SYNTHESIS OF CRYPTOPHYCIN 52
1st seminar
Patrick Beaulieu
October 30, 2003
OUTLINE
REAGENTS FOR EPOXIDATION
PERACIDS
O
O
H
O
O
H
O
O
OMg
Cl
O
mCPBA
MMPP
Prilezhaev reaction
O
R
H
O
O
R
R
O
O
+
R
R
HO
R
Stereospecific syn addition
EPOXIDATION CATALYZED BY METAL
1- Peroxide metal complex
R
O M
O
R
O M
O
O
+ MOR
+
Metal most frequently used : V, Ti
R3
RO
High enantioselectivity with allylic alcohols
O
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765
RO
E O
O
Ti
EO
O
R2
E O
OR
Ti
O
O
t-Bu
R1
2- Oxo-based catalysts (M=O)
H
H
Jacobsen-Katsuki catalyst
Ph
R
Catalyst 3 mol%
N
N
Mn
O
O
Cl
Ph
O
mCPBA, NMO
69%, 93% ee
Excellent for cis and trisubstituted olefins
Poor ee obtained with trans substrates
Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378
R
DIOXIRANES
R
O
R1
Oxone
R2
NaHCO3 buffer
R2
O
R1
O
R
R
O
O
+
R
R1
R2
byproduct
Stereospecific syn addition
Oxone : KHSO5.KHSO4.K2SO4
R
O
O O
Me
Me
DMDO
O O
Me
O
O
CF3
TFDO
O
R
Yang's catalyst
Yang, D. J. Am. Chem. Soc. 1996, 118, 11311
O
generator
Generation of Dioxiranes
→ Isolated species
water/acetone
He
0.1M solution for DMDO
0.8M solution for TFDO
→
to trap
NaHCO3
water
acetone
In situ generation
dioxiranes
oxone
magnetic stirrer
Excess of oxone, NaHCO3 buffer
at pH 7-8, in biphasic (CH2Cl2/H2O)
or monophasic (CH3CN/H2O) conditions
Organic syntheses, CV 9, 288
-78oC
MECHANISM OF GENERATION AND
REACTION WITH OLEFINS
O
R1
R1
R2
O
HSO5-
R2
SO42-+O2
O
HO
O
O
-
SO42-
O
O
O
Edwards, J. O. Photochem. Photobiol. 1979, 30, 63
Shi, Y. J. Org. Chem. 1998, 63, 6425-6426
SO3-
OH-
O
SO3-
NOVEL METHODOLOGIE
Hydroden peroxide as primary oxidant
N
CH3CN + H2O2
H 3C
H
OOH
H
N
H3C
H
O
+
OOH
CF3
N
H
O
O
O
CF3
→ 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
F3C
O
O
O
+
NH2
MECHANISTIC BACKGROUND
FMO
TRANSITION STATE
O
R
O
R
O
R
O
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
Top view
R
O
O
R
H
H
Me
Me
R
R
O
O
R
H
Me
O
H
R
Me
Me
Me
Trans alkene
Me
O
R
O
R
R
O
O
Me
R
H
H
H
Me
H
Me
3- Computer calculation
Stabilization with the oxygene electron
lone pairs and the LUMO
O
O
R
R
7.4 Kcal/mol
more stable
H
H
H
H
Houk. K. N. J. Am. Chem. Soc. 1997, 119, 10147
ASYMMETRIC EPOXIDATION WITH DIOXIRANES
First examples
CF3
O
Stoichiometric
use of ketones
O
O
Low conversion
Days to 1 week reaction
9-12.5% ee
Curci, R. J. Chem. Soc; Chem. Commun. 1984, 155
Curci, R. Tet. Lett. 1995, 36, 5831
High conversion
24h-48h reaction
13-20% ee
MAJOR BREAKTROUGH
THE SHI’S CATALYST
Epoxidation of olefins mediated by a fructose-derived ketone
→ Preparation of the D-enantiomer
O
HO
O
OH
O
OH
OH
OH
D-Fructose
27$/Kg
HClO4, 0oC
53%
O
O
O
PCC
O
O
OH CH2Cl2, rt
93%
O
O
O
O O
Commercially available : 106$ / 5g
The enantiomer is prepared from a 5 steps procedure from L-sorbose
Sugai, S. Tetrahedron, 1991, 47, 2133
→ Preparation of the L-enantiomer
O
HO
OMe
OH
OH
OH
O
OMe
DME, 0.23% SnCl2
O
O
OH
L-Sorbose
150$/ 500g
O
H2SO4 - NaOH - H2SO4
One pot
85%
HO
O
OH
OH
O MsCl, pyridine
CH2Cl2
60%, 2 steps
1) acetone, HClO4, 0oC
OH 2) PCC, CH Cl
2 2
OH
OH
L-Fructose
Whistler, R. L. Carbohydr. Res. 1988, 175, 265-271
O
O
O
O
O
O
Ms
O
O
O
O
O
O
PRELIMINARY RESULTS
O
O
O
O
3 eq
O O
oxone 5 eq
R1
R2
NaHCO3/H2O
CH3CN/EDTA
R1
O
R2
pH 7-8, 2 hours
Substrate
OTBS
Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806
Yield (%)
ee (%)
81
90
84
87
OPTIMIZATION TOWARDS A ROBUST CATALYTIC CYCLE
O
R2
HSO4-
R2
OH
R1
R2
R1
O
O
R3
HSO5
HO
R1
R1
R2
HSO5-
SO52-
SO42-
+
HSO4-
+
-
O2
R2
SO42-
R1
R3
+
O2
O O
R2
R1
HO
R2
SO52-
-
SO4
2-
R2
O
O
O
SO3
R1
-
OH-
O
O
SO3BayerVilliger
R1
KETONE CONFIGURATION
O
O
O
O
O
O
O
O
X
O
O
O
Curci
O
O
O
OH
OH
O
O
O
O
O
F
O
O
O
O
O
Potentially epimerized
Low conversion 3-23%
Hydrate form ?
Added steric hindrence?
pH EFFECT
→ Autodecompositon of oxone
→ Catalyst stability
O
O
O
HSO5-
SO52-
+
O2
O
O
O
O
O
O
O
O
O
O
O
OHO
SO4
O
O
O-
2-
O
O
O
SO3O
+
HSO4-
O
O
SO42-
O
O
BayerOH Villiger
O O
SO3-
pH EFFECT
oxone 1.4 eq
catalyst 0.2 eq
O
K2CO3 / solvent
1.5 hours
% of conversion
Epoxidation of trans methylstyrene
100
90
80
70
60
50
40
30
20
10
0
7,5
8
8,5
9
9,5
10 10,5 11 11,5 12 12,5 13
pH
water - ACN - DMM
water - ACN
Acetone 3 eq - water - ACN
Shi, Y. J. Am. Chem. Soc. 1997, 46, 11224
KETONE REACTIVITY
→ Background reaction with oxone
→ Catalyst decomposition with oxone
HSO4-
R2
O
R3
HSO5-
O
O
O
O
R1
O
O
R2
SO42-
R1
R3
+
O2
O
O
O
O
O
SO52-
O
O
THE BAYER-VILLIGER
O
O
O
O
O
O H
O
O
O
B.V.
hydrolysis
+
O
O
O3S
O
O
O
O
-
O
O
O
O
O
O
O
O
THE BAYER-VILLIGER
O
O
O
mCPBA
O
O
O
O
O
O
O
O
O
O
Major
O
O
O
mCPBA
O
O
+
O
O
O
O
O
O
O
O
O
57%
Shi, Y. J. Org. Chem. 2001, 66, 521
O
O
43%
O
OPTIMIZED RESULTS
O
O
O
Trans- disubstituted
O
O O
R1 O
R1
R2
Substrate
Ph
CH3CN - DMM - H2O
R2
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
OTBS
O
61%, 94% ee
OEt
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
OPTIMIZED RESULTS
trisubstituted alkenes
catalyst 0.3 eq,
oxone 1.4 eq, pH 10-11
R1
CH3CN - DMM - H2O
R1
R2
R3
R2
o
-10 C
O
R3
O
OEt
82%, 95% ee
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
Ph
94%, 98% ee
C10H21
94%, 89% ee
CONJUGAISON EFFECT ON ENANTIOSELECTIVTY
FMO
ORIGINE OF THE ENANTIOSELECTIVITY
O
H
O
R3
R3
O R
1
O
O
O
O
R2
H
R2
R2
O R
3
O
O
O
R1
H
O
R3
O
Major
R1
R1
H
O
O
O O
O
O
O
R2
O
R1
O
O
O
O
O
R2 O
O O
H
R3
ORIGINE OF THE ENANTIOSELECTIVITY
O
O
R3
O R
2
O
O
O
R2
H
O
H
R3
O
O
O
O
R2
O
H
R2
O
R1
O
R
O 3
O
H
R1
Minor
O
H
R1 O
O O
O
R1
R3
O
R
O 1
O
O
O
R3 O
O O
R2
ENERGY OF THE SPIRO TRANSITION STATE
O
O
Ph
O Ph
O
O
O
Spiro
Ph
0oC
O
O
Ph
78%, 98% ee
O
O
Ph
O
O
O
Ph
O O
Ph
Planar
Ph
0oC
G = -RTlnK = -8.314 x 273 x ln (2/98) = 2.4 kcal mol-1
O
barely observed
DRAWBACK
→
Low enantioselectivity with cis and terminal olefins
R1
CH3CN - DMM - H2O
R2
-10oC
R1
R2
O
O
O
Catalyst 0.3 eq
oxone 1.4 eq,
pH 10-11
95%, 20% ee
90%, 24% ee
→ Competition between spiro and planar transition state
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224
43%, 61% ee
A LOOK AT THE TRANSITION STATE
cis-alkenes
O
O
R1
R2
O
R2
O
O
O
O
O
O
R1
O
O R1
O
O
O
O R2
O
→ The poor differentiation in the TS results in lower ee
→ A different approach or catalyst was then required
R1
R2
SOLUTION #1
Access to disubstituted geminal alkenes via
2,2-disubstituted vinylsilanes
TMSI, (R1)2Zn
Pd(PPh3)4
Ph
61%
1) Shi epoxidation
2) TBAF
Me
Ph
TMS
49 : 1 dr
Me
Ph
O
61%, 94% ee
O
49% (2 steps) , 93% ee
Murai, S. J. Org. Chem. 1995, 60, 1834
Shi, Y. J. Org. Chem. 1999, 64, 7675
SOLUTION #2
Improvement through catalyst design
Effect of the spiro
Five membered ring
ketal
O
Electronic attraction
Evidence #1
O
Ph
O
O
O
Ph
64% conversion, 3% ee
O
Ph
O
Electronic attraction between
Ph and NBOC group
O
NBOC
Ph
O
O
Ph
100% conversion, 78% ee
O
Ph
Shi, Y. J. Org. Chem. 2002, 67, 2435
O
AN INTRIGUING REVERSE IN
STEREOSELECTIVITY!
O
Electronic attraction
Evidence #2
O
O
Ph
O
O Ph
O
O
O
O
O
O
O
O
O
Ph
Ph
O
O
O
O
98% ee
(R,R)
O
NBOC
NBOC
Ph
O
O Ph
O
O
O
O
O
O
O
O
O
23% ee
(S,S)
Electronic attraction
Evidence #3
FURTHER RESULTS
O
O
O
Me
O
O
N
Ph
O
Ph
O
R
O
O
O
N
Me
O
O Me
O
R
O
Me
O Ph
O
Effect the substituent
ee (%)
-OMe
-Me
-SO2Me
p-NO2
83
84
90
90
Shi, Y. Org. Lett. 2003, 5, 293
o-NO2
78
Ph
SYNTHESIS OF 2ND GENERATION SHI’S CATALYST
Bn2NH
HOAc/EtOH
OH
O
OH
(MeO)3CH
NBn2 acetone, HCl
O
NBn2
OH
O
OH
OH
OH
O
OH
HO
OH
HO
O
OH
D-Glucose
23$/500g
O
O
H2, Pd/C
HOAc
OH
NH3OAc COCl /NaHCO
3
2
O
O
NH 1)PDC
2)(Boc)2O/DMAP
CH2Cl2
OH
O
O
OH
O
O
O
O
NBoc
O
O
Shi, Y. J. Org. Chem. 2003, 68, 4963
O
O
21% overall
SUMMARY
TOTAL SYSTHESIS OF CRYPTOPHYCIN 52
O
O
O
O
O
O
HN
N
R H
Cl
O
OMe
Cryptophycin 1 R = H
Cryptophycin 52 R = Me
•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
RETROSYNTHESIS
O
O
O
O
O O
O
HN
Cl
N
H
O
O
O
HN
O
O
OMe
Cl
O
FmocHN
O
OMe
CCl3
O
OH
HO
OO
O
+
HN
O
NHFmoc
O
Cl
O
CCl3
OMe
OH
OMe
+
H 2N
O
Cl
O
CCl3
OMe
BLUE FRAGMENT SYNTHESIS
Cl
Bu4NHSO4,
40% NaOH
OH
O
n-BuLi
86%
71%
1) TBSCl, Imidazole
2) [(CH3)CHCHCH3]2BH
3) H2O2
OTBS
73%
O
O
OTBS
O
OMe
OH
1) (CH3O)2P(O)CH2CO2CH3
2) O3, pyridine
75%
PhCH2PPh3Cl, n-BuLi
80%
O
OTBS
OMe
COUPLING OF BLUE AND RED FRAGMENTS
O LiOH, acetone
OTBS
OMe
O
95%
OTBS
OH
+
1) FDPP, DIPEA
2) HF
O
OH
Cl
O
HN
O
H2N
O
O
Cl
O
CCl3
OMe
CCl3
chloro-O-methyl-D-tyrosine
F
O
F
Ph2P O
F
F
FDPP
F
SHI EPOXIDATION
O
O
O
O
OH
O
HN
O
Cl
O
OMe
2 eq
O O
oxone 4 eq, K2CO2
n-Bu4NHSO4, CH3CN
pH 10.3-10.7
CCl3
O
O
OH
HN
O
6.5 : 1 / : epoxide
Cl
O
CCl3
OMe
TRANSITION STATE OF EPOXIDATION
O
O
R
O Ph
O
O
H
O
Me
O
O
O
O
O
R
O
Ph
O O
O
HN
O
Me
O
O
OH
O
H
Cl
O
CCl3
OMe
OH
HN
O
Cl
O
CCl3
OMe
BLACK FRAGMENT SYNTHESIS
1) (Boc)2O, Et3N
2) RuCl3, NaIO4
HO
NH2
61%
O
O
HO
NHBoc
O
+
DCC, DMAP
OH
L-Leucid acid
O
O
O
THF, morpholine
Pd(PPh3)4
O
95%
NHBoc
O
OH
O
O
NHBoc
75%
O
OH
O
O
O
NHBoc
O
OH
HN
DCC, DMAP, CH2Cl2
Cl
O
O
OMe
CCl3
O
O
O
O
HN
Piperidine, DMF
Cl
O
O
FmocHN
O
O
OMe
CCl3
O
O
O
O
O
HN
Cl
O
N
H
O
Cryptophycin 52
OMe
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