Mukaiyama Aldol Reaction - Peking University

23 Pages·2005·0.31 MB·English

by  Jianbo Wang

Mukaiyama Aldol Reaction
Lu Kui
2005 6.11
Content
• Introduction and history of Mukaiyama aldol
• Lewis acid mediated Mukaiyama aldol reaction
• Lewis base mediated Mukaiyama aldol reaction
• Summary and outlook
1
Content
• Introduction and history of Mukaiyama aldol
• Lewis acid mediated Mukaiyama aldol reaction
• Lewis base mediated Mukaiyama aldol reaction
• Summary and outlook
Mukaiyama aldol reaction
OR'3 O O OH
lewis acid
R1 R3 + R4 R5 R1 R4R5
R2 lewis base R2 R3
•Powerful reaction in carbon-carbon formation
• Widely used in asymmetric synthesis
• Widely used in total synthesis
2
Mukaiyama aldol reaction
• Original idea of Mukaiyama aldol reaction
• Advantage of Mukaiyama aldol reaction
• Disadvantage of Mukaiyama aldol reaction
Original idea of Mukaiyama aldol
reaction
O OH O
H
2 R R
H H
OH R
O LDA OLi R CHO OH O
3
R2 R1 R2 R1 R3 R1
R
2
O Bu2BOTf OBBu2 R3CHO OH O
R2 R1 i-Pr NEt R2 R1 R3 R1
2 R
2
3
Advantage of Mukaiyama aldol reaction
• Mild condition
• Directed donor and acceptor
• Catalytic asymmetric synthesis
Disadvantage of Mukaiyama aldol
reaction
• Indirect
• Many factors decide the stereochemistry of the
product
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History of Mukaiyama aldol
Stoichiometric Enantioselective
Mukaiyama Aldol Mukaiyama Aldol
reaction reaction
. . . . .
1973 1986
1960 1970 1980 1990 2000
1958 1999
Lewis acid catalyzed
Lewis base catalyzed
Prepare the silyl Mukaiyama Aldol
Mukaiyama Aldol
enol ether reaction
reaction
Catalytic Enantioselective
Mukaiyama Aldol
reaction
Content
• Introduction and history of Mukaiyama aldol
• Lewis acid mediated Mukaiyama aldol reaction
• Lewis base mediated Mukaiyama aldol reaction
• Summary and outlook
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Lewis acid mediated Mukaiyama aldol
O OSiMe3 TiCl4 OH O
+
Ph Ph Ph Ph
O OSiMe3 TiCl4 O Ph
H + Ph Me
Ph Me Ph
O OH O
O O OSiMe3 TiCl4 O OHO
+ Ph OMe
OMe Me
Ph
Mukaiyama, T. et al.Chem. Lett.1973, 1011.; Mukaiyama, T. et al.J. Am.
Chem. Soc. 1974,96, 7503.; Mukaiyama, T. et al.Chem. Lett. 1975, 741.
Lewis acid mediated Mukaiyama aldol
RR21 OORR + R3 R4OSRiM5e3 TiCl4 R1RO2RH3RO4R5
O OSiMe3 TiCl4 OH O
R1 R2 + R3 R4 OR5 R1R2R3R4OR5
OMe 1 TiCl4-Ti(Oi-Pr)4 OMe
CHO
OMe + OSiMe3 2 H2O
Mukaiyama, T. et al.Chem. Lett. 1974, 15.; Mukaiyama, T. et al.
Chem. Lett. 1975, 989.; Mukaiyama, T. et al.Chem. Lett. 1975, 319.
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Lewis acid mediated Mukaiyama aldol
O Me3SiO OSiMe3 BF3.Et2O HO OSiMe3O
+
R1 R2 R1
-78C℃H 2tCo l02℃ R2
89%
OMe OSiMe3 BF3.Et2O OMeO
+ OEt OEt
Ph OMe Ph
O -78C℃H 2tCo l02℃ O
86%
OSiMe3
OH O
O SnCl4
+
Ph
Ph H CH Cl -78℃
2 2
83%
Nakanura, E. et al.J. Am. Chem. Soc. 1977, 99, 961.; Sugimura, H. et
al.Synlett. 1991, 153.; Mukaiyama, T. et al. Org. Synth. 1987, 65, 6.
Transitional state of Mukaiyama aldol
O OTMS Lewis Acid OH O OH O
R1 H + R2 R3 R1 R3 + R1 R3
R2 R2
Syn anti
(Z)enolate
RainerMahrwald, Chem. Rev. 1999, 99, 1095.
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Preparation of enol silane
O 1 LDA OTMS OTMS
+
OEt 2 TMSCl OEt OEt
Z E
THF 6 : 94
THF/HMPA 82 : 18
Preparation of enol silane
Pri
H
Pri N Li O
OLi
H
Et
Me O OEt
O
Me
OEt
Pri
Me
Pri N Li O OLi
H OEt
Et
H O
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Lewis acid catalyzed Mukaiyama aldol
O OTMS TrClO4 (cat) TMSO O
R1 H + R2 R3 R1 R3
R2
O OTMS OH O
1 B(C6F5)3 (cat)
R1 H + R2 R4 2 HCl or TBAF R1 R4
R3 R2R3
Mukaiyama, T. et al.Chem. Lett. 1985, 447.
Yamamoto, H. et al.Synlett. 1993, 577.
Lewis acid catalyzed Mukaiyama aldol
OSiMe3 OCH3 Me3SiOTf ( 1-5mol%) O OCH3
+
H3CO -78℃
OSiMe3 O OH
1 SnCl2-Me3SiCl (10 mol%)
Ph
+ PhCHO
2 H3O+
Noyori, R. et al.J. Am. Chem. Soc. 1980. 102, 3248.
Mukaiyama, T. et al.Chem. Lett. 1987, 463.
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Stoichiometric lewis acid mediated
asymmetric Mukaiyama aldol
N
N H
Me
Sn(OTf)2
RCHO + OSSiMEet3 n-Bu2Sn(OAc)2 ROH OSEt ROH OSEt
CH2Cl2 -78℃ syn anti
70-96% yield
syn/anti=100/0
NR2 >98%ee (syn)
R1 N Sn R3O
TfO O S CF3
O O
O Sn nBu
AcO nBu
Mukaiyama, T. et al.J. Am. Chem. Soc. 1991, 113, 4247.
Stoichiometric lewis acid mediated
asymmetric Mukaiyama aldol
i-Pr O
TsN O
B
H
(1 equiv) OH
R1CHO + OTMS CO Et
R 2
OEt CH2Cl2 1 *
-78℃ to rt
77-87% Yield, 83-93% ee
Kiyooka, S.-I.; J. Org. Chem. 1991, 56, 2276.
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