Mukaiyama Aldol Reaction - Peking University PDF
Preview Mukaiyama Aldol Reaction - Peking University
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 4 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 5 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. 6 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. 7 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 8 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. 9 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. 10
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