Recent Developments and Applications in Enantioselective Desymmetrisation

1
Recent Developments and Applications in
Enantioselective Desymmetrisation

• Xin Linghu
• Department of Chemistry
• University of North Carolina, Chapel Hill

2
Outline

• Introduction
• Enantioselective Desymmetrisation
• of Different Functional Groups
• Cyclic anhydrides
• Epoxides
• Aldehydes and Ketones
• Alkenes
• Diols
• Summary
• Acknowledgement

3
Introduction to Enantioselective Desymmetrisation
4
Enantioselective Desymmetrisation in Total
Synthesis
1987, Schreiber
1992, Harada
5
Enantioselective Desymmetrisation of Cyclic
Anhydride Previous Work
1985, Oda
configuration
R C-8 C-9
H R S cinchonine
H S R cinchonidine
OMe S R quinine
OMe R S quinidine
1999, Bolm
 
 
1995, Seebach
6
Formation of C-X Bond via Anhydrides
Chen, Y. Tian, S.-K. Deng, L. J. Am. Chem. Soc.
2000, 122, 9542-9543.
7
Formation of C-C Bond via Anhydrides
Bercot, E. A. Rovis, T. J. Am. Chem. Soc. 2002,
124, 174-175.
8
Formation of C-C Bond via Anhydrides
entry ligand ee yield ()
1 ()-1 1 76
2 ()-2 12 76
3 ()-3 32 66
4 (-)-4 39 77
5 (-)-5 88 63
Shintani, R. Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 1057-1059.
9
Formation of C-C Bond via Anhydrides
entry ArMgX ee yield ()
1 PhMgCl 92 91
2 p-MeOC6H4MgBr 89 88
3 p-FC6H4MgBr 78 82
4 o-TolMgCl 37 66
Shintani, R. Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 1057-1059.
10
Enantioselective Desymmetrisation of Epoxides
Previous Work
11
Enantioselective Desymmetrisation of Epoxides
Previous Work
Cat. (10 mol), 4A MS
12
Enantioselective Ring Opening Catalyzed by
Planar-Chiral Pyridine N-Oxides
entry R yield () ee
1 Ph 88 94
2 4-FC6H4 97 91
3 4-CH3C6H4 94 93
4 4-CF3C6H4 93 98
5 2-naphthyl 84 94
6 CH2OBn 91 50
catalyst temp ee
A rt 11
B rt 25
B -78C 60
C rt 68
C -78C 92
Tao, B. Lo, M. M. C. Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 353-354.
13
Enantioselective Ring Opening Catalyzed by
Chiral Bipyridine N,N-Dioxide Derivatives
entry R yield () ee (confgn)
1 Ph 95 90
2 CH2OCH2Ph 98 74
3 CH2O(CH2)3Ph 95 70
4 -(CH2)4- 83 0
Nakajima, M. Saito, M. Uemura, M. Hashimoto,
S. Tetrahedron Lett. 2002, 43, 8827-8829.
14
Asymmetric Ring Opening with TMSCN Catalyzed by
(pybox)Yb Complexes
entry substrate ligand temp (C) time (d) yield () ee (confgn)
1 (S,S)-b -45 4 90 91 (1S, 2R)
2 (S,S)-a -10 7 83 92 (1R, 2S)
3 (S,S)-b -40 7 80 90 (2S, 3R)
4 (S,S)-a 0 7 86 83 (1R, 3S, 4R)
5 (S,S)-a -10 7 72 87 (3R, 4R)
Schaus, S. E. Jacobsen, E. N. Org. Lett. 2000,
2, 1001-1004.
15
Enantioselective Alkylation of Vinyloxiranes
1 2 1 2 1 1
yield () 92 86 80 68 78 90
ee 66 37 85 76 71 97
SN2/SN2 gt99/1 98/2 87/13 75/25 93/7 98/2
Bertozzi, F. Crotti, P. Macchia, F. Pineschi,
M. Arnold, A. Feringa, B. L. Org. Lett. 2000,
2, 933-936.
16
Desymmetrisation by Enantioselective Deprotonation
Hodgson, D. M. Gibbs, A. R. Lee, G. P.
Tetrahedron 1996, 52, 14361-14384.
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Enantioselective a-Deprotonation of Epoxides
Previous Work
1996, Hodgson
1996, Hodgson
18
Enantioselective b-Deprotonation of Epoxides
Previous Work
1980, Whitesell and Felman
1993, Milne and Murphy
1998, Andersson
19
Enantioselective Alkylative Double Ring Opening
of Epoxides
Hodgson, D. M. Maxwell, C. R. Miles, T. J.
Paruch, E. Stent, M. A. H. Matthews, I. R.
Wilson, F. X. Witherington, J. Angew. Chem.
Int. Ed. 2002, 41, 4313-4316.
20
Enantioselective Alkylative Double Ring Opening
of Epoxides
Hodgson, D. M. Maxwell, C. R. Miles, T. J.
Paruch, E. Stent, M. A. H. Matthews, I. R.
Wilson, F. X. Witherington, J. Angew. Chem.
Int. Ed. 2002, 41, 4313-4316.
21
a-Deprotonated Epoxides as Nucleophiles
entry E yield () ee
1 TMS 72 74
2 SnBu3 60 79
3 PhCH(OH) 80 76
4 PhCO 68 77
5 Et2C(OH) 75 77
6 EtCH(OH) 74 76
7 EtCO 67 78
8 EtOCO 58 81
Hodgson, D. M. Gras, E. Angew. Chem. Int. Ed.
2002, 41, 2376-2378.
22
First Desymmetrisation of Centrosymmetric
Diepoxide in Natural Product Synthesis
Holland, J. M. Lewis, M. Nelson, A. Angew.
Chem. Int. Ed. 2001, 40, 4082-4084.
23
First Desymmetrisation of Centrosymmetric
Diepoxide in Natural Product Synthesis
Holland, J. M. Lewis, M. Nelson, A. Angew.
Chem. Int. Ed. 2001, 40, 4082-4084.
24
Enantioselective Desymmetrisation of Ketones and
Aldehydes Previous Work
1984, Hanessian
1998, Arai and Shioiri
1990, Roush
1998, Takemoto
25
Enantioselective Desymmetrisation of Ketones and
Aldehydes Previous Work
1998, Ward
1995, Aubé
1997, Bolm
26
Enantioselective Baeyer-Villiger Oxidations by
Transition Metal Catalysis
Uchida, T. Katsuki, T. Ito, K. Akashi, S.
Ishii, A. Kuroda, T. Helv. Chim. Acta 2002, 85,
3078-3089. Watanabe, A. Uchida, T. Ito, K.
Katsuki, T. Tetrahedron Lett. 2002, 43,
4481-4485.
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Enantioselective Baeyer-Villiger Oxidations by
Organocatalysis
entry R yield () ee
1 4-MeOC6H4 67 61()
2 4-MeC6H4 53 62()
3 Ph 67 63(S)
4 4-BrC6H4 28 68()
5 4-ClC6H4 34 66(S)
6 4-FC6H4 55 65()
Murahashi, S.-I. Ono, S. Imada, Y. Angew. Chem.
Int. Ed. 2002, 41, 2366-2368.
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Rhodium-Catalyzed Desymmetrisation of 4-Alkynals
entry R yield () ee
1 n-C5H11 95 92
2 Cy 94 95
3 (CH2)3Cl 91 91
4 CH2OMe 93 82
Tanaka, K. Fu, G. C. J. Am. Chem. Soc. 2002,
124, 10296-10297.
29
Enantioselective Reduction of 2-Alkyl-1,3-diketon
es
Ohtsuka, Y. Koyasu, K. Ikeno, T. Yamada, T.
Org. Lett. 2001, 3, 2543-2546.
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Synthesis of a Potential Intermediate for
Pseudomonic Acid B
Honda, T. Kimura, N. Org. Lett. 2002, 4,
4567-4570.
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Enantioselective Desymmetrisation of Alkenes
Previous Work
1987, Schreiber
1996, Landais
1990, Ito
32
Enantioselective Desymmetrisation of Alkenes
Previous Work
1985, Whitesell
1992, Mikami
1994, Martin
33
Enantioselective Desymmetrisation of Alkenes
Previous Work
1998, Schrock and Hoveyda
34
Preparation of Cyclic Amines Through Mo-Catalyzed
Asymmetric RCM
entry Ar cat. yield () ee
1 Ph a 78 98
2 p-OMePh a 81 97
3 p-BrPh a 81 98
4 o-OMePh b 77 84
5 o-BrPh b 90 82
Dolman, S. J. Sattely, E. S. Hoveyda, A. H.
Schrock, R. R. J. Am. Chem. Soc. 2002, 124,
6991-6997.
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Enantioselective Ru-Catalyzed RCM
Seiders, T. J. Ward, D. W. Grubbs, R. H. Org.
Lett. 2001, 3, 3225-3228.
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Enantioselective Ru-Catalyzed RCM
Seiders, T. J. Ward, D. W. Grubbs, R. H. Org.
Lett. 2001, 3, 3225-3228.
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Tandem Catalytic Asymmetric ROM/RCM
Weatherhead, G. S. Ford, J. G. Alexanian, E.
J. Schrock, R. R. Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 1828-1829.
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Tandem Catalytic Asymmetric ROM/RCM
Weatherhead, G. S. Ford, J. G. Alexanian, E.
J. Schrock, R. R. Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 1828-1829.
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Desymmetrisation of Meso Bicyclic Hydrazines by
Enantioselective Hydroboration
entry R yield () ee
1 CO2Et 49 83
2 CO2Bn 90 84
3 CO2Bu 58 80
4 -CONPhCO- 78 60
Luna, A. P. Ceschi, M. A. Bonin, M. Micouin,
L. Husson, H. P. Gougeon, S. Estenne-Bouhtou,
G. Marabout, B. Sevrin, M. George, P. J. Org.
Chem. 2002, 67, 3522-3524.
40
Desymmetrisation of Meso Bicyclic Hydrazines by
Enantioselective Hydroboration
Luna, A. P. Ceschi, M. A. Bonin, M. Micouin,
L. Husson, H. P. Gougeon, S. Estenne-Bouhtou,
G. Marabout, B. Sevrin, M. George, P. J. Org.
Chem. 2002, 67, 3522-3524.
41
Asymmetric Synthesis of Polyhydroxylated
Celastraceae Sesquiterpene Cores
Spivey, A. C. Woodhead, S. J. Weston, M.
Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40,
769-771.
42
Enantioselective Desymmetrisation of Meso-Decalin
Diallylic Alcohols by Zr-Based SAE
Spivey, A. C. Woodhead, S. J. Weston, M.
Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40,
769-771.
43
Enantioselective Desymmetrisation of Diols
Previous Work
1998, Oriyama
1998, Fu
1996, Trost
44
Enantioselective Desymmetrisation of Diols
Previous Work
1997, Fujioka
1997, Harada
45
Pd-Catalyzed Enantioselective Oxidation
Jensen, D. R. Pugsley, J. S. Sigman, M. S. J.
Am. Chem. Soc. 2001, 123, 7475-7476.
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Asymmetric Oxidation of Meso-Diols under
Photo-Irradiation
entry substrate yield () ee confign
1 a 49 59 1R, 4S
2 b 57 65 1R, 5S
3 c 64 63 -
4 d 66 66 1R, 6S
Shimizu, H. Nakata, K. Katsuki, T. Chem. Lett.
2002, 1080-1081.
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Enantioselective Desymmetrisation of Meso Cyclic
Allylic Bisdiethylphosphate
entry R1 R2 R3 a/b yield ()
1 iBu CHPh2 3-Ph 946 54
2 iBu CHPh2 3,5-Cl2 946 47
3 iBu CHPh2 3,5-tBu2 8713 42
4 Me CHPh2 3,5-Cl2 8614 62
5 iBu CHPh2 H 8416 54
6 iBu CHPh2 5,6-(CH)4- 8317 49
7 Me CHPh2 H 3169 13
8 iPr CHPh2 H 3070 12
9 tBu (R)-CH(Me)Cy H 2476 26
Piarulli, U. Daubos, P. Claverie, C Roux, M
Gennari, C. Angew. Chem. Int. Ed. 2003, 42,
234-236.
48
Pd-Catalyzed Enantioselective Ring Opening with
Dialkylzinc
entry R R1 R2 yield () ee
1 Me H F 87 90
2 Me Me Br 67 90
3 Me Me H 76 89
4 Me H O(CH2)O 85 91
5 Et H F 89 92
6 Et H O(CH2)O 91 92
Lautens, M. Renaud, J.-L. Hiebert, S. J. Am.
Chem. Soc. 2000, 122, 1804-1805.
49
Rh-Catalyzed Enantioselective Ring Opening with
Organoboronic Acids
entry X yield () ee
1 4-Me 88 95
2 None 91 95
3 2-Me n.r. -
4 4-Cl 95 95
5 3-Cl 73 99
6 2-Cl n.r. -
7 3-I 85 95
8 4-Ac 71 94
9 4-OMe 87 96
10 3-OMe 91 95
Lautens, M. Dockendorff, C. Fagnou, K.
Malicki, A. Org. Lett. 2002, 4, 1311-1314.
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Desymmetrisation of Diols with a Dinuclear Zinc
Asymmetric Catalyst
Trost, B. M. Mino, T. J. Am. Chem. Soc. ASAP
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Summary

• Previous works on the enantioselective
  desymmetrisation have been introduced briefly
  according to different functional groups
• Recent developments in the enantioselective
  desymmetrisation have been surveyed based on
  different functional groups
• Recent applications of enantioselective
  desymmetrisation in natural products synthesis
  have been shown

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Acknowledgement
Dr. Jeffrey Johnson
Johnson group