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(S)-()-thalidomide
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(R)-()-thalidomide
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http//www.chirality.ouvaton.org/homepage.htm
3
Examples of privileged chiral ligands
Diels-Alder Mukaiyama aldol aldehyde
allylation hydrogenation alkene
isomerization Heck reaction
hydrogenation hydrophosphination hydroacylation hy
drosilylation Bayer-Villager oxidation
Diels-Alder aldehyde allylation ester
alcoholysis iodolactonization
alkene reduction imine reduction Ziegler-Natta
polymerization
Yoon, T. P. Jacobsen, E. N. Science 2003, 299,
1691
4
Examples of privileged chiral ligands
epoxidation epoxide ring-opening Diels-Alder imine
cyanation conjugate addition
Diels-Alder Mukaiyama aldol conjugate
addition cyclopropanation aziridination
dihydroxylation acylation heterogeneous
hydrogenation phase transfer catalysis
Yoon, T. P. Jacobsen, E. N. Science 2003, 299,
1691
5
Thinking
? Catalysts chiral ligands

1. Cost
2. Availability

Our consideration
Readily available catalysts for simplifying
asymmetric reactions
6
Idea for development of chiral ligands

• Development of easily available and readily
  tunable ligands using multicenter and grafting
  strategy
• Derived from readily and commercially available
  chiral starting chemicals

7
Application of Grafting Strategy
Novel Sulfamide-Amine Alcohol Ligands (SAA)
Boshun Wan, J. Org. Chem. 2004, 69, 9123
8
Synthetic route of Ts-Based SAA Ligand
9
Ts-Based SAA ligands
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New Ms,Tf-Based SAA ligands
1. The size of the fluxional group R is a primary
determinant of enantioselectivies ? 2. What is
the difference effect of R1, and X ?
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New Tf-Based SAA ligands
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New Ms-Based SAA ligands
13
Application of Reactions
1 Asymmetric addition of diethylzinc to aldhydes
2 Asymmetric addition of phenylacetylene to
aldehydes
3 Asymmetric addition of phenylacetylene to
ketones
4 Asymmetric hydrogenation transfer reaction
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1. Asymmetric addition of diethylzinc to aldhydes
Figure Chiral sulfonamide-type ligands using
Ti(OiPr)4 for dialkylzinc addition
to aldehyde.
How about SAA ligands?
15
1. Asymmetric addition of diethylzinc to aldhydes
Our idea
Pu, L. Yu, H,-B. Chem. Rev. 2001, 101, 757.
16
1. Asymmetric addition of diethylzinc to aldhydes
(S)
(R)
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1. Asymmetric addition of diethylzinc to aldhydes
Comparisons
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1. Asymmetric addition of diethylzinc to aldhydes
entry ligand R isolated yield ee
1 7b Ph 86 gt99 (R)
2 4 o-Cl-Ph 74 gt99 (S)
3 4 1-naphthyl 70 gt99 (S)
4 7b o-Cl-Ph 92 gt99 (R)
5 7b 1-naphthyl 70 gt99 (R)
6 4 c-C6H11 51 gt99 (S)
7 7b i-C4H9 36 gt99 (R)
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Summary-1
Boshun Wan, J. Org. Chem. 2004, 69, 9123
20
2. Asymmetric addition of phenylacetylene to
aldehydes
Zn Ligand
Characteristics
Ti Zn Ligand
Reviews see (a) Tetrahedron 2003, 59, 9873 (b)
Eur. J. Org. Chem. 2004, 4095
21
2. Asymmetric addition of phenylacetylene to
aldehydes
Amine alcohols species
(a) T. Mukaiyama et al, Chem. Lett. 1979, 447
(b) E. J. Corey et al, J. Am. Chem. Soc.1994,
116,3151 (c) E.M. Carreira et al, J. Am. Chem.
Soc. 2000, 122, 1806 (d) E.M. Carreira et al,
Org. Lett. 2000, 2, 4233. (e) B. Jiang et al,
Chem. Commun. 2002, 1524 (f) B. Jiang et al,
Tetrahedron Lett. 2002, 43, 8323.
22
2. Asymmetric addition of phenylacetylene to
aldehydes
Amine alcohols species
(a) S. Dahmen, Org. Lett. 2004, 6, 2113 (b) R.
Wang et al, Tetrahedron Asymmetry 2004, 15,
3155 (c) R. Wang Tetrahedron Lett. 2005, 46,
863 (d) C. Wolf, J. Am. Chem. Soc. 2006, 128,
10996 (e) B. M. Trost et al, J. Am. Chem. Soc.
2006, 128, 8 (f) B. G. Davis et al, Org. Lett.
2006, 8, 207
23
2. Asymmetric addition of phenylacetylene to
aldehydes
Sulfonamides and Amides ligands
(a) (b) R. Wang et al, Adv. Synth. Catal. 2006,
348, 506 (b) R. Wang et al, Adv. Synth. Catal.
2005, 347, 1659-1665 (c) R. Wang et
al,Org.Lett 2004, 6, 1193 (d) R. Wang et al,
Angew. Chem. Int. Ed. 2003, 42, 5747 (e) X. P.
Hui et al, J. Mol. Catal. A-Chemical 2007, 269,
179. (f) J. X. Xu et al, Org. Lett., 2005, 7,
2081
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2. Asymmetric addition of phenylacetylene to
aldehydes
Binaphthol-based ligands
(a) L. Pu et al, Org. Lett. 2002, 4,
4143 (b) L. Pu et al, Org. Lett. 2002, 4, 1855
(c) A. S. C. Chan et al, J. Am. Chem. Soc.
2002, 124, 12636 (d) A. S. C. Chan et al,
Chem. Commun., 2002, 172 (e) M. Shibasaki et
al, J. Am. Chem. Soc. 2005, 127, 13760
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2. Asymmetric addition of phenylacetylene to
aldehydes
Binaphthol-based ligands
(a) L. Pu et al, Angew. Chem. Int. Ed. 2006, 45,
122 (b) L. Pu et al, J. Org. Chem. 2007, 72,
4340 (c) L. Pu Tetrahedron 2006, 62, 9335 (d)
L. Pu et al, P. N. A. S. 2004, 101, 5417 (e)
A. S. C. Chan et al, Tetrahedron Asymmetry
2003, 14, 449
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2. Asymmetric addition of phenylacetylene to
aldehydes
Origins
How about SAA ligands?
Zn(OTf)2
High e.e.
10 times of ZnEt2
Ti(OiPr)4
High e.e.
Moisture sensitive
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2. Asymmetric addition of phenylacetylene to
aldehydes
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2. Asymmetric addition of phenylacetylene to
aldehydes
Entry Ligand R Isolated yield () ee ()b
1 4 Ph 99 61
2 1 Ph 79 15
3 4 p-F-Ph 72 50
4 4 p-Br-Ph 76 50
5 4 p-MeO-Ph 86 60
6 4 p-Me-Ph 96 56
7 4 p-NO2-Ph 70 84
8 4 o-Me-Ph 99 82
9 4 1-naphthyl 85 81
10 4 cyclohexyl 98 39
11 4 isovaleric 99 24
12 4 pelargonic 39 26
13 1 cyclohexyl 99 26
Boshun Wan, Chirality, 2005, 17, 245
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3. Asymmetric addition of phenylacetylene to
ketones
Lewis acid center
Lewis base center
Zn (salen) as a bifunctional complex
(a) Cozzi, P. G. Angew. Chem. Int. Ed. 2003, 42,
2895 (b) Saito, B. Katsuki, T. Synlett 2004, 9,
1557
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3. Asymmetric addition of phenylacetylene to
ketones
Chiral ligands for aromatic ketones

1. Lu, G. Li, X. S. Jia, X. Chan, W. L. Chan, A.
   S. C. Angew.Chem., Int. Ed. 2003, 42, 5057
2. Zhou, Y. Wang, R. Xu, Z. Yan, W. Liu, L.
   Kang, Y. Han, Z. Org. Lett. 2004, 6, 4147
3. Liu, L. Wang, R. et al, J. Org. Chem. 2005, 70,
   1084-1086..

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3. Asymmetric addition of phenylacetylene to
ketones
Without using zinc reagent or Lewis acid
a. Cozzi, P. G. Alesi, S. Chem. Commun. 2004,
2448. b. Wang, R. et al, Tetrahedron Asymmetry
2004, 15, 3757.
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3. Asymmetric addition of phenylacetylene to
ketones
Expectation
No additional Lewis acid
?
Poor catalysts
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3. Asymmetric addition of phenylacetylene to
ketones
The valuated ligands in the reaction
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3. Asymmetric addition of phenylacetylene to
ketones
Entry Substrate Yield () ee ()
1 acetophenone 66 78
2 2'-chloroacetophenone 83 65
3 2'-fluororoacetophenone 40 53
4 2'-methylacetophenone 33 67
5 3'-chloroacetophenone 75 70
6 1'-naphthacetophenone 50 55
7 2'-naphthacetophenone 65 83
Boshun Wan, J. Mol. Catal. A Chemical 2005,
237, 126.
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4. Asymmetric hydrogenation transfer reaction
iPrOH/ KOH
HCOOH/ (C2H5)3N
RuCl2(p-cymene)2 / ligand
H2O / HCOONa
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4. Asymmetric hydrogenation transfer reaction
Known chiral ligands (H2O/HCOONa)
TsDPEN
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4. Asymmetric hydrogenation transfer reaction
The evaluated ligands

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4. Asymmetric hydrogenation transfer reaction
Successful conversion
cheaper storable
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4. Asymmetric hydrogenation transfer reaction
entry ketone conversion ee
1 16 99.3 75 (R)
2 17 gt99 43 (R)
3 18 gt99 50 (R)
4 19 98.2 48 (R)
5 20 97.4 78 (R)
6 21 97.8 83 (R)
7 22 95.0 81 (R)
8 23 98.5 83 (R)
9 24 98.6 77 (R)
10 25 97.1 74 (R)
11 26 56.9 65 (R)
12 27 97.2 50 (R)
13 28 96.5 62 (R)
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4. Asymmetric hydrogenation transfer reaction
Advantage

• Firstly introducing a new type of chiral
  N,O-ligand hydrochloride into the reaction
  performed in water and air.
• The catalyst is stable, commercially available
  and low-cost.
• The destined products were easily departed from
  the catalytic system by adding some ether in the
  reaction mixture.

Boshun Wan, Tetrahedron Lett. 2005, 46, 7341
41
? Reversal of enantioselectivity
(S)-Chiral Ligand
(R)-Chiral Ligand
(S)- or (R)- Products
(S)-Chiral Ligand
(S)-Chiral Ligand
(S)-Chiral LigandAdditive

(R)-Chiral Ligand
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? Reversal of enantioselectivity
Reversal of enantioselectivity by adding Ti(OiPr)4
Reaction 1
Boshun Wan, J. Mol. Catal. A Chemical 2005,
225, 33
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? Reversal of enantioselectivity
Reversal of enantioselectivity by adding Ti(OiPr)4
Reaction 2
Boshun Wan , J. Mol. Catal. A Chemical 2005,
232, 9.
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? Reversal of enantioselectivity
Relationship between Ti/L and ee
Boshun Wan , J. Mol. Catal. A Chemical 2005,
232, 9.
45
Conclusions

• Design and synthesized the novel chiral
  sulfamide-amine alcohols ligands (SAA) using
  multicenter and grafting strategy
• Applied them into asymmetric addition reactions

? Applied the strategy and novel ligands into
other asymmetric reactions
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Acknowledgements
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