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Organocatalytic OxidationOrganocatalytic OxidationCatalytic Asymmetric Epoxidation of Olefins Catalytic Asymmetric Epoxidation of Olefins with Chiral Ketones and Synthetic Applicationswith Chiral Ketones and Synthetic Applications
Frédéric ValléeProf. Charette’s laboratoriesLiterature Meeting 20th January 2009
2
Outline
-Introduction
-Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones
-Synthetic Applications
3
Introduction Optically active epoxides are highly useful intermediates and building blocks for the total synthesis of biologically active compounds.
OH
OO
Leukotriene A
O
O
O
O
OH
O
H
Fumagilin
NNH
HN
NH
O
O
OOH
O
O
O
Epoxomicin
4
Introduction Various effective systems have been developed over the years for enantioselective epoxidations.
-Sharpless (epoxidation of allylic alcohols with chiral titanium catalyst)
-VO(acac)2 (epoxidation of allylic and homoallylic alcohols)
-Jacobsen (epoxidation of unfunctionalized, cis and terminal olefins)
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 2000; Chapter 6A.Hoshino, Y.;Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 10452. Zhang, W.;Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem.,Int. Ed. 2005, 44, 4389. Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 941. Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286.Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.Ed.; VCH: New York, 1993; Chapter 4.2. Collman, J. P.; Zhang, X.; Lee, V. J.; Uffelman, E. S.; Brauman, J. I. Science 1993, 261, 1404.
5
Introduction Among the many powerful methods for the epoxidation of olefins, three-membered ring compounds containing two heteroatoms are very versatile oxidation reagents.
Murray, R. W. Chem. Rev. 1989, 89, 1187. Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205.Adam, W.; Saha-Moller,C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499.
N+
Me
Me
O
Ph
BF4-
ON
H
R1R2 O
O
DioxiranesOxaziridines
Oxaziridinium Salts
6
Introduction
More rencently asymmetric epoxidations catalyzed by chiral ketones have received much attention.
Significant progress has been made in this field towards the epoxidation of various types of olefins such as
R
R'
RR'
Unfunctionalyzed
R3 R1
R2
cis
trans
Trisubstituted
7
Introduction
R R'
O
OHO
R R'O
SO3-
O-O
R R'O
SO3-
OH-
R R'
OO
HSO5-
SO42-
R3R2
R1
OR3
R3
R1
Ketone-Catalyzed Epoxidation of Olefins
The dioxiranes are generated in situ from ketone and Oxone(2KHSO5 KHSO4 K2SO4)
Edwards, J. O.; Pater, R. H.; Curci, R.; Di Furia, F. Photochem. Photobiol. 1979, 30, 63. Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R. H. J. Org. Chem. 1980, 45, 4758. Gallopo, A. R.; Edwards, J. O. J. Org. Chem. 1981, 46, 1684.
8
Outline
-Introduction
-Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones
-Synthetic Applications
9
Early Ketones
OMe Me
Me
1
Ph
Me O
Me
H
2
Biphasic
Me Me
O
CF3
O
Me
3
F3C OCH3
Me
O
4
Curci, R.; Fiorentino, M.; Serio, M. R. Chem. Commun. 1984, 155.Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995, 36, 5831.
1984 Curci and co-workers
Yields from 60-92% Up to 12% ee (2, 50 mol%)
1995 Curci and co-workers
Yields from 80-82% Up to 20% ee (4, 1 equiv.)
R
R'
RR'
Unfunctionalyzed
R3 R1
R2
Cis
trans
Trisubstituted
10
C2-Symmetric Binap-Based Ketones
O
O
O
O
X
O
X
8a, X = H8b, X = Cl8c, X = Br
8d, X =O
O
R
R'
RR'
Unfunctionalyzed
R3 R1
R2
cis
trans
Trisubstituted
RTerminal
R
R'1,1'-DIsubstituted
Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491. Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem.Soc. 1996, 118, 11311. Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J.-H. J. Am. Chem. Soc. 1998, 120, 5943.
Yields from 70-95%Up to 95% ee
Best resultsCatalyst 8d, 10 mol%Substrate (E)-Stilbene
Note : As the X going larger from H (47% ee), to Cl (76% ee), to Br (75% ee), to I (32%ee).
1996 Yang and co-workers
11
Other C2-Symmetric Ketones
RR'
R3 R1
R2
trans
Trisubstituted
O
OO
OO
O
5 6
RR'trans
1997 Song and co-workers
1997 Adam and co-workers
Yields from 61-95%Up to 59% ee (6, 1 equiv)
O
O
O
OO
OO
7
O
O
PhPh
Ph Ph
Me
MeO
8
Yields from 67-80%Up to 81% ee (8, 1 equiv)
Song, E. C.; Kim, Y. H.; Lee, K. C.; Lee, S.-g.; Jin, B. W. Tetrahedron: Asymmetry 1997, 8, 2921. Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry 1997, 8, 3995.
12
Other C2-Symmetric Ketones
OMeMe
9a
OMeMe
9b
F
OMeMe
9c
F
F
OMeMe
9d
FF
1998 Denmark and co-workers
Conversion from 6-100% Enantioselectivity up to 94% ee (9c, 30 mol%)
And many others….
RR'
R3 R1
R2
trans
Trisubstituted
RTerminal
Unfunctionalyzed
Denmark, S. E.; Wu, Z. Synlett 1999, 847.Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479.
13
Bicyclo3.2.1octan-3-ones
N
CO2Et
O
X
O
O
XAcO OR
OAcO
10a, X = F10b, X = OAc
11a, X = F11b, X = OAc
12a, R = Ac12b, R = Piv12c, R = Bz
O
O
13
F
OAc
O
O
14a, R = CO2Et14b, R = CH2OC(O)Me
F
R
O
O
X
15a, X = SO2Me15b, X = OAc15c, X = F
1998 Armstrong and co-workers
Conversion from 47-100% Up to 98% ee
Best resultsCatalyst 11b, 20 mol%Substrate
RR'
R3 R1
R2
trans
Trisubstituted
RTerminal
Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621. Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67, 8610.Sartori, G.; Armstrong, A.; Maggi, R.; Mazzacani, A.; Sartorio, R.; Bigi, F. J. Org. Chem. 2003, 68, 3232.
14
Outline
-Introduction
-Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones (The Work of Shi)
-Synthetic Applications
15
Carbohydrate-Based Ketones
Yian Shi was born in Jiangsu, China, in 1963 and obtained his B.Sc. degree in chemistry from Nanjing University in 1983. Upon receiving his M.Sc. degree from University of Toronto with Professor Ian W. J. Still in 1987, he pursued his doctoral studies at Stanford University with Professor Barry M. Trost and obtained his Ph.D. degree in 1992. Subsequently, he carried out his postdoctoral studies at Harvard Medical School withProfessor Christopher Walsh from 1992 to 1995. He joined Colorado State University as assistant professor in 1995 and was promoted to associate professor in 2000 and professor in 2003.
16
Carbohydrate-Based Ketones
1996 Shi and co-workers
OOH
OH
HO
OH
OH
OO
O
O
OHHClO4
OO
O
O
O
O
OO
D-Fructose
16
L-Sorbose Ent-16
PCC
Overall Yield = 49%
Overall Yield = 41-60%
CH2Cl2, rt
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
17
Carbohydrate-Based Ketones
Selectivity and Reactivity; Basic General Considerations
(Catalyst Developement)
1) Stereogenic center must be close to the reacting center which favor the ‘’chiral communication’’ between substrates and catalyst.
2) Fused ring and/or a quaternary center to the carbonyl minimizes the epimerization of de stereogenic centers.
3) C2- or pseudo C2 symmetric element inducing steric discrimination as olefin approaches to the
reacting dioxirane.
4) Inductive activation of the carbonyl with the presence of many closed oxygen atoms.
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
O
O
O
O
OO
1
3
3
2
18
Catalyst DevelopmentWhy use carbohydrate-derived ketone ?
Y
X
O
Y
X
Y
X
O
R1
R2nO
O
O
O
OO
(a) Carbohydrates are chiral, readily available and inexpensive.
(b) They are highly substituted with oxygen groups, (inductive effect of oxygen).
(c) Carbohydrate-derived ketones can have rigid conformations due to the anomeric effect, which is desirable for selectivity.
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
19
Catalyst DevelopmentImpact of the pH on the epoxidation with in situ generated dioxiranes
- At high pH, Oxone autodecomposes rapidly- At pH 7-8, 16 give high enantioselectivity but… need an excess!- Raising the pH, to avoid B-V favoring 19 formation and hoping that the reaction of the ketone with Oxone will be faster than its decomposition
OH-
HSO5-
SO42-
R3R2
R1
OR3
R3
R1 O
O
O
O
OO
16
O
O
OO
OO
17O SO3
-
Baeyer-V illiger (pH 7-8) 20
O
O
OO
O
OO
21
O
O
O
O
OO
O
O
O
OO
OO
18
O SO3-
OH
O-
O
O
OO
OO
19
O
not been isolated
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
20
Catalyst DevelopmentA dramatic pH effect led to a catalytic asymmetric process
Plot of the conversion of trans--methylstyrene against pH using ketone 16 (0.2 equiv) as catalyst in two solvent systems, H2O-CH3CN (1:1.5 v/v) (A) and H2O-CH3CN-DMM (2:1:2 v/v) (B)
Plot of the conversion of trans--methylstyrene against pH using acetone (3 equiv) as catalyst in H2O-CH3CN (1:1.5 v/v). Samples were taken at different reaction times for the determination of conversion: 0.5 (A), 1.0 (B), 1.5 (C), and 2.0 h (D)
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
DMM : Dimethoxymethane
21
Reaction OptimizationSolvent effects
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
Temperature effects
22
Scope and Substrates
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
O
OO
O
OO
30 mol%
Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), MeCN-DMM-0.05 M, Na2B4O7 10 H2O of Na2EDTA
R'R
O
(1:2:2 v/v)
R'R
PhPh Ph Ph Cl OTBS
n-C6H13n-C6H13
OO PhOMe
O
PhPh Ph
PhC10H21
Ph
Ph
PhC10H21
C10H21
COOEt
OO
83%95% ee
89%95% ee
92%92% ee
85%98% ee
94%96% ee
49%96% ee 78%
96% ee
68%92% ee
89%96% ee
94%98% ee
98%95% ee
92%79% ee
83%95% ee
97%87% ee
94%89% ee
89%94% ee
41%97% ee
trans and Trisubstituted olefins
23
Scope and Substrates
Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.
O
OO
O
OO
65 mol%
Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), MeCN-DMM-0.05 M, Na2B4O7 10 H2O of Na2EDTA
R'R
O
(1:2:2 v/v)
R'R
PhTMS
PhTMS TMSPh
TMS
TBDMSO TMS TMSHO
TMS
74%94% ee
82%94% ee
66%93% ee
51%90% ee
67%84% ee
67%92% ee
71%93% ee
TBDPSO
(30 mol% of theketone was used)
2,2-Disubstituted Vinylsilanes
24
Scope and Substrates
Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.
O
OO
O
OO
30 mol%
Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), MeCN-DMM-0.05 M, Na2B4O7 10 H2O of Na2EDTA
R'R
O
(1:2:2 v/v)
R'R
85%94% ee
45%91% ee
68%91% ee
87%94% ee
93%94% ee
85%92% ee
75%74% ee
Ph OH PhOH OH
Ph OH
Ph
OHOH OHPh OH
82%90% ee
Hydroxyalkenes
25
Scope and Epoxides
O
OO
O
OO
20-30 mol%
Oxone (1.12-1.38 equiv.), K2CO3 (5.0-6.2 equiv.), MeCN-DMM-0.05 M, Na2B4O7 10 H2O of Na2EDTA
R'R
O
(1:2:2 v/v)
R'R
77%97% ee
54%95% ee
41%96% ee
68%96% ee
68%95% ee
82%95% ee
61%94% ee
Ph
89%94% ee
O Ph
O
O COOEt OOTBS
O
OH
68%90% ee
O
COOEt
O COOEt O COOEtO COOEt
O
TMS
60%92% ee
Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.
Conjugated Dienes
26
Scope and Substrates
Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.
O
OO
O
OO
30 mol%
Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), MeCN-DMM-aq K2CO3/AcOH
R'R
O
(1:2:2 v/v)
R'R
78%93% ee
71%93% ee
97%77% ee
98%96% ee
59%96% ee
71%89% ee 84%
95% ee
60%93% ee
COOEt
OTBS
OTBS
Ph
TMS TMS TMS
Conjugated Enynes
27
Scope and Substrates
Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 4080. Feng, X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999,121, 11002. Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.
O
OO
O
OO
30 mol%
Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), org solv/aq buffer-aq (3:2 v/v), 0oC
R'R
OR'
R
82%93% ee
79%80% ee
87%91% ee
82%95% ee
92%88% ee
66%91% ee
46%91% ee
OBz OBz OBz
OBz
Ph
OAc
PhPh
OAc
OBz
Method Limitation : cis and terminal olefins
Enol Esters
28
Understanding
3D
29
Understanding
Two mechanistic extremes for disubstituted olefins
O
O
R
R'
Spiro
O
O
R
R'
Planar
Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311-3314. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437-3439.
R1
H HR2
O
O
Me
Me
Spiro-trans
O
O
Me
Me
HR2
H R1
Planar-trans
H
R1H
R2
O
O
Me
Me
Spiro-cis
O
O
Me
Me
HH
R2 R1
Planar-cis
30
Understanding
Mechanistic studies of disubstituted olefins
Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311-3314. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437-3439.
R1
H HR2
O
O
Me
Me
Spiro-trans
O
O
Me
Me
HR2
H R1
Planar-trans
H
R1H
R2
O
O
Me
Me
Spiro-cis
O
O
Me
Me
HH
R2 R1
Planar-cis
- The cis-hexenes is more reactive- The reactivity is dependent on the size of the alkyl groups of the olefin
cis-hexenes vs. trans-hexenes
31
Understanding
Mechanistic studies disubstituted olefins
Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437.Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.
R1
H HR2
O
O
Me
Me
Spiro-trans
O
O
Me
Me
HR2
H R1
Planar-trans
H
R1H
R2
O
O
Me
Me
Spiro-cis
O
O
Me
Me
HH
R2 R1
Planar-cis
vs.
vs.
- The trans-isomers is slightly more reactive (Ph is planar)- Calculation show that the Spiro TS is favored for the epoxidation on ethylene
32
Understanding
Mechanistic studies disubstituted olefins
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.
-The spiro orientation could benefits from a stabilizing interaction of an oxygen lone pair with the * orbital of the alkene
OO
RR'
Spiro
OO
RR'
Planar
O
O
R
R'non-bondingorbital
orbital
O
O
R
R'non-bondingorbital
orbital
33
Stereochemical analysis
OOO
O O
R3
OO
R2
R3
FavoredSpiro (A)
OOO
O O
R3
OO
R2
R1
Favored
OOO
O O
R1
OO
R3
R2
Disfavored
R3R1
R2
O
OOO
O O OO
R2
R3
Disfavored
R1
OOO
O O
R2
OO
R1
Disfavored
R3
R3R1
R2
O
Spiro (A) Spiro (B) Spiro (C) Spiro (D)
OOO
O O OO
DisfavoredPlanar (E)
R2
R1
R3O
OO
O O OO
R3
R1
R2
OOO
O O OO
R2
R1
R3
Disfavored DisfavoredPlanar (G)Planar (F)
OOO
O O OO
R3
R1
R2
FavoredPlanar (H)
Major ( I) Minor (J)
OOO
O O OO
R1
R1
R1
FavoredPlanar (H)
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.
No benef itf rom secondarystabilizing interactions
34
Stereochemical analysis
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
-Due to steric repulsion B-C-D-F-G are disfavored (for disubstituted, where R2=H, B is similar to A and G to H
-Favored spiro A and planar H TS result in the opposite stereochemistry
-For trans-disubstituted and trisub-stituted olefin the spiro TS is favored since the epoxide I is formed predominately
General TS analysis OO
O
O O
R3
OO
R2
R1
Favored
OOO
O O
R1
OO
R3
R2
Disfavored
R3R1
R2
O
OOO
O O OO
R2
R3
Disfavored
R1
R3R1
R2
O
Spiro (A)
Spiro (B)
Spiro (C)
OOO
O O OO
DisfavoredPlanar (E)
R2
R1
R3
OOO
O O OO
R3
R1
R2
FavoredPlanar (H)
Major (I)
Minor (J)
OOO
O O OO
R3
R1
R2
DisfavoredPlanar (F)
OOO
O O OO
R2
R1
R3
DisfavoredPlanar (G)
OOO
O O
R2
OO
R1
Disfavored
R3
Spiro (D)
35
Stereoelectronic Effect
B
G
Reaction Coordinate
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
98% ee0oCO
2.5 kcal mol-1
~2.5 kcal mol-1 beetweenthe two different TS
(Ph are planar)
OO
O
O O
Ph
OO
HPh
Spiro (A)
OOO
O O OO
Ph
Ph
H
Planar (H)
+~2.5 kcal mol-1
O
O
R
R'non-bondingorbital
orbital
The energy difference between the two TS will vary with the substituents, since the energy level of the * is affected by those…
36
Steric Effect…
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
OO
O
O O
R3
OO
R2
R1
Spiro (A)
OOO
O O OO
R3
R1
R2
Planar (H)
vs.
-Decreasing the size R1 → high ee (spiro A favored)-Increasing the size of R3 → high ee (spiro A favored)
The case of the trisubstituted olefin
37
Steric Effect…
OO
O
O O
R3
OO
R2
R1
Spiro (A)
OOO
O O OO
R3
R1
R2
Planar (H)
vs.
Ph
26% ee 79% ee 81% ee 98% ee
Ef fect of the size of R1 (decreasing)
Ef fect of the size of R3 ( increasing)
Ph C10H21
76% ee 87% ee 91% ee
Ef fect of the size of R1 and R3 (decreasing R1 and increasing R3 )
PhPh
76% ee 97% ee
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
Major competitingpathway
38
What about cis and Terminal Olefins?
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
For cis, electronic and steric factors should favor the spiro TS
OO
O
O O
R3
OO
R2
Spiro (A)
OO
O
O O
R2
OO
R3
Spiro (D)
a b
- a and b are the main interaction and furthermore, the ee depends on the energy difference between them.
- The greater the size difference between R2 and R3 the higher the ee is.
39
What about cis and Terminals olefins?
OOO
O O OO
R3
Spiro (A)
OO
O
O O
R3
OO
Spiro (D)
OOO
O O OO
R3
Planar (F)
OOO
O O OO
R3
Planar (G)
O
OO
O
NO SO2Me
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
Terminals olefins
-The energy difference between these TS seems too small
ON
O
O O OO
Spiro (Z)Favored
O
R
SO2Me
ON
O
O O OO
SO2Me
O
R
Spiro (AA)
-ee’s up to 97% with great conversions
Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293.Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115.Wong, O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973.
40
Ketone Structures
O
OO
O
OO O
OO
O
OO
Et Et
EtEt
O
OO
O
OO O
OO
O
OHO
ClO
OO
O
MeO
OO
O
OO
16 22 23 24 25 26
Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.
- The catalytic properties are dependant on the precise nature of the ketone.
- The pyranose oxygen is beneficial for catalysis (16 vs. 26).
-16 is still the best ketone for the epoxidation and for the enantioselectivity compared to all (TS issues).
41
Ketones StudiesO
OO
O
OO O
OO
O
OO
Et Et
EtEt
O
OO
O
OO O
OO
O
OHO
ClO
OO
O
MeO
OO
O
OO
16 22 23 24 25 26
Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.
-The rigid 5-6 spiro ring of 16, is superior in controlling the enantioselectivity.
- 16 is also superior with regard to the yield.
- 16 is more stable under the optimal epoxidation conditions.
OO
O
O O
R2R1
R3R4
R
OO
R
Spiro (A)
OO
O
O O
R2R1
R3R4
OO
R
Spiro (B)
RO
OO
O O
R3R4
OO
R
R
Planar (C)
R2R1
42
Pyranose Oxygen EffectO
OO
O
OO
OO
O
OO
16 26
Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.
Entry Substrate Catalyst Yield (%) ee (%)
1
2
3
4
5
6
7
8
Ph 16 93 92
26 61 87
16 75 97
26 10 88
16 100 15
26 88 15
16 53 51
26 17 61
PhPh
Ph
O
O
43
Pyranose Oxygen Effect
O
O
O
O
OO
16
O
O
O
OO
26
mCPBA
O
O
OO
16a
OO
O O
O
OO
16b
O
OO
major
mCPBA
O
O
OO
26a
O
O O
O
OO
26b
O
O
43% 57%
trace
Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.
44
Outline
-Introduction
-Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones
-Examples of Synthetic Applications Using 16 as Catalyst
45
First Synthesis of (+)-Aurilol
O
OSEMO
O
OHHHO H
16
Oxone
83%
O
OSEMO
O
OHHHO H
O
(15:1)
OHHO H
(10:1)
OO
O
OHH
ent-16
Oxone67%
OHHO H
OO
O
OHH
O
OH H
OOH
OH
OHHO
Br
H
(+)-Aurilol
Morimoto, Y.; Nishikawa, Y.; Takashi, M. J. Am. Chem. Soc. 2005, 127, 5806.
O
OO
O
OO
16 =
46
Enantioselective Total Synthesis of (+)-Nigellamine A2
OH
OH
H
O
Ph
16Oxone
51% two steps
1)
2) Nicotinic acid DCC, DMAP
O
O
H
O
Ph
O
ON
ON
(+)-Nigellamines A2
(7:1 favoring C7-8)
3
4
7
8
Macrocyclic epoxydation
Same diast. with ent-16
Bian, J.; Van Wingerden, M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 7428.
O
OO
O
OO
16 =
47
Total Syntheses of Nakorone, and Abudinol B via Biomimetic Oxa- and Carbacyclizations
TMS
SO2Tol
16
Oxone76% TMS
SO2Tol
O O
(20:1)
O
OH
H
HOH
ent-Nakorone
OH
H
HOH
ent-Abudinol
O
OH
H
H
Tong, R.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X.; Hardcastle, K. I. J. Am. Chem. Soc. 2007, 129, 1050.
O
OO
O
OO
16 =
48
Biomimetic
Nakanishi, K. Toxicon 1985, 23, 473.Shimizu, Y.; Chou, H.-N.; Bando, H.; Van Duyne, F.; Clardy, J. C. J. Am. Chem. Soc. 1986, 108, 514. Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 588.
O
O
O
O
O
O
O
OO
OO
O
H
H H H H H HH
H
H
HO
H H
H
H H
O-O
R
HO
O O OO O O O
O
O
O
H
O
H+
O-
R
O
HO
Biosynthetic Pathway of Brevitoxin B
Proposed all-fused epoxide-opening cascade
49
Epoxide-Opening Cascades Promoted by Water
MeO
TBSOH
16Oxone
50% (two steps)
MeO
TBSOH
O
O
O
H
1) TBAF/THF2) H2O 70oC, 72h
(71%)
O
O
O
O
HHHHMe
HHO
H H H
O
TBSOH
H
Lio, NH3
(3:1 dr)
Stereoselective Epoxidation of a Skipped-Triene
Me
H
Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.
O
OO
O
OO
16 =
50
Conclusion
The Shi’s epoxidation is a powerful selective and efficient way to make enantioselective epoxides and it is a wonderful tool for the synthesis of building blocks involved in modern total synthesis.
51
Thank you!
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