Chemistry 206 Advanced Organic Chemistry Handout-21A Supplemental enantioselective Carbonyl Addition Handout Enantioselective addition of r zn to aldehydes Enantioselective Reduction of Ketones imines Matthew d. shair Wednesday, November 6. 2002
Chemistry 206 Advanced Organic Chemistry Handout–21A Supplemental Enantioselective Carbonyl Addition Handout Matthew D. Shair Wednesday, November 6, 2002 ■ Enantioselective addition of R2Zn to aldehydes ■ Enantioselective Reduction of Ketones & Imines
D. A. Evans Enantioselective C=O Addition: Noyori Catalyst Chem 115 Catalytic Asymmetric Carbonyl Addition The Catalytic Cycle place with chiral controller the catalyst Noyori& co-workers, J. Am. Chem. Soc. 1986, 108, 6072 JAm.chem.Soc.1989,111,4028 Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49 E- Et 2Zn the catalyst (DAlB-ZI 59-97% C6H5CHO 98%ee.: Catalyst must be sterically hindered so that association is precluded p-CICBH4CHO EtZ 93%ee 93%ee. n-C6H13CHO 61%ee. 4 RO-ZnR ne method is catalytic in aminoalcohol a Two zinc species per aldehyde are involved in the alkylation step a Product is taken out of the picture by aggregation 19A01-Et2Zn-11/1900149PM
00 00 0000 0000 0000 Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49 the catalyst ■ Two zinc species per aldehyde are involved in the alkylation step. ■ Product is taken out of the picture by aggregation 4 ■ The method is catalytic in aminoalcohol. D. A. Evans Enantioselective C=O Addition: Noyori Catalyst Chem 115 Noyori & co-workers, J. Am. Chem. Soc. 1986, 108, 6072. replace with chiral controller Catalytic Asymmetric Carbonyl Addition 98% e.e. ■ Catalyst must be sterically hindered so that association is precluded 91% e.e. 93% e.e. 93% e.e. 96% e.e. 90% e.e. 61% e.e. Et2Zn Me2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn C6H5CHO " p-ClC6H4CHO p-MeOC6H4CHO Cinnamyl PhCH2CH2CHO n-C6H13CHO 0°C, toluene 59 - 97% Ar–CHO + R2’Zn J. Am. Chem. Soc. 1989, 111, 4028. the catalyst the catalyst Et2Zn 90-98% ee RDS The Catalytic Cycle (DAIB-Zn) Zn R Zn I I C O R R H Me Me N H Me Me Me O Zn H Et Me Me N H Me Ar R’ OH Me Me O Zn H Et O C H Zn Et Et Zn Et C Et O H O Zn Et H H N Me Me Me Me Me O C H Et H O Zn Et H H O N Me Me Me Me Me Me Me N H Me Me Me O Zn H Et Zn–Et O C H R' O Zn O Zn Zn O O Zn R R R R'O ZnR R' Zn R R' R' O R R' O R' Zn R O Zn Zn O R R' R' R Zn Et H H O N Me Me Me Me Me 19A-01-Et2Zn-1 1/19/00 1:49 PM
D A. Evans Enantioselective C=O Addition: Noyori Catalyst-2 Chem 115 Other Catalysts for the R2Zn Addition Process Explanation for Nonlinearity of DAlB Catalyst Me3C Et 97%ee.(S) 100%ee.(R) 95%ee.(S) (S, S)dimer (R, R)dimer 90%ee.(R) 90%ee(R) 90%ee.(R) (Results are cited for the reaction of benzaldehyde and Et2Zn) Problem: Rationalize the stereochemical course of each of the catalysts (S)catalyst (R)catalyst Non-linear effects observed with the Noyori Catalyst(DAlB-Zn) There is no corel ion hetween I (S, R)dimer Et2Zn PhCHO (%ee) bservations (S,S)dimer dissociates upon addition of RCHo effects catalys 25%ee Catalyst affords product in 95%ee (s, R )dimer is overwhelmingly more stable than(s,S)homodimer a(S, R )dimer is ineffective as a catalyst %ee of catalyst 19A02Et2Zn11/1900149PM
Other Catalysts for the R2Zn Addition Process D. A. Evans Enantioselective C=O Addition: Noyori Catalyst-2 Chem 115 ■ Non-linear effects observed with the Noyori Catalyst (DAIB-Zn) Product (%ee) 100 %ee of catalyst 100 25% ee Catalyst affords product in 95% ee. There is no correlation between catalyst and product ee. Et2Zn + PhCHO (S,S) dimer (R,R) dimer + (S) catalyst (R) catalyst (S) catalyst 90% e.e. (R) 90% e.e. (R) 90% e.e. (R) (Results are cited for the reaction of benzaldehyde and Et2Zn) 97% e.e. (S) 100% e.e. (R) 95% e.e. (S) Problem: Rationalize the stereochemical course of each of the catalysts Explanation for Nonlinearity of DAIB Catalyst (S,R) dimer Observations ■ (S,S) dimer dissociates upon addition of RCHO & effects catalysis ■ (S,R) dimer is overwhelmingly more stable than (S,S) homodimer ■ (S,R) dimer is ineffective as a catalyst Ph Me OH O Zn Me2 N Me Zn Me Me2 N O Zn Me Me2 N O O Zn N Me2 Me Zn O O Zn Me NMe2 Me2 N Me Zn O O Zn Me NMe2 N Zn O Me Ph Ph Et Zn Et Ph H N O Me3C Me2 N Me Li O N Me Me N Me H H Ph H Ph N O N Li N Me Me Me Me N Zn N Bu Me O Et Li Li Bu Ph 19A-02-Et2Zn-1 1/19/00 1:49 PM
D. A. Evans Enantioselective C=O Addition: Dialkylzinc Addn Scope Chem 115 Improved Selectivity with Aliphatic Aldehydes Scope of the DAlB Catalyst Soai, J. Org. Chem. 1991, 56, 4264 (S)catalyst (S)catalyst (6%) Et2Zn 98%ee RCHo+ 0°c, hexane 70-100% (S)catalyst 91%ee 88%ee 78%ee 95%ee93%ee (S)catalyst Lepicidin Application The reaction functions in complex systems Bu3Sn (n-Pen)2Zn 85%ee the catalyst (S)catalyst Evans, Black, JACS 1993, 115, 44974513 OTIPS Et2Zn 60%ee OTES Et24 0°c, hexane Review. Noyon Angew. Chem. Int. Ed. 1991, 30, 49 10.:1(98%) 19A-03-Et2Zn-Scope 1/19/00 1: 49 PM
88% ee 78% ee 95% ee 93% ee Improved Selectivity with Aliphatic Aldehydes Soai, J. Org. Chem. 1991, 56, 4264 (6%) RCHO + Et2Zn 0 °C, hexane 70 - 100% 60% ee Et2Zn (S) catalyst Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49 (S) catalyst Et2Zn 90% ee (S) catalyst (n-Pen)2Zn 85% ee 96% ee Et2Zn (S) catalyst (S) catalyst Me2Zn 91% ee 98% ee Et2Zn (S) catalyst Scope of the DAIB Catalyst (S) catalyst D. A. Evans Enantioselective C=O Addition: Dialkylzinc Addn Scope Chem 115 Lepicidin Application: The reaction functions in complex systems 3 9 Et2Zn, 3 3 15 15 11 diastereoselection 10:1 (98%) 21 the catalyst 21 21 0 °C, hexane Evans, Black, JACS 1993, 115, 44974513 H O OH Et Me OH O Zn Me2 N Me Ph N O Bu Et Zn Me Bu R Et OH O O n-Bu H H O O H Me H Me O OR OR O O Me Et H H H H H MeO OTIPS OTES O O H H O OH H Bu3Sn Me H O Et OH MeO SnBu3 OTIPS OTES O Me C5H11 OH O H H OH O Bu3Sn H n-Bu SnBu3 H H Zn H O OH H N Bu Me O Et Bu n-Bu Ph 19A-03-Et2Zn-Scope 1/19/00 1:49 PM
A. Evans Enantioselective C=O Addition: Dialkylzinc Addn Scope Chem 115 Other Catalysts for Aliphatic Aldehydes Utilization of Grignard and Alkenyllithium Reagents NHSO2 CF3 Ph RCHO Et2Zn ligand Ti(OR)4 Temp (R,R, R, R)- (RR-2 HcHO 0.04 equiv 1.2 equiv. -20C 98%ee 1)ZnCl2, Et20, 23C 2)dioxane; filter PhCH=CHCHo 0.02 equiv 0.3 equiv -50C 99% ee H2MgX3)0.15eq1,78c PhCH2 CH CHo 0.01 equiv 0.6 equiv 0C 92%ee 4)1.2 eq. Ti(OiPr)4 0.04 equiv 0.6 equiv -20C 99%ee 5)R2 CHO to30°c n-CsH11CHO Ohno. Tet. Lett. 1989. 30. 7095 RCHO Yield % MeMg HcHO Knochel has described preparation of functionalized R2Zn reagents 55%94% n-BuMgBr HcHO 82%96% R-l Et2zn CH2=CH(CH2 2MgBr PhC 83%90% distill Et2Zn Et-l 40%≥90% i-PrCHo n-BuMaBl 35%90% RzN C6H11CHO 69%95% MeMg CH2=CH(CH2)3CHO X=CL OAC 60%≥90% n-PrMgBr CHo Ohno Reagent 2 is a more effective or the addition of Et2zn to aldehydes t-BuO t-Buo Seebach, Angew. Chem. Int. Ed. 1991, 30, 1008, and 1321 92%ee(90% yield 2 R-MgX ZnCl2 R2-Zn MgX2 MgCl2 Knochel, J. Org. Chem. 1992, 57, 1956 Mg×2+ dioxane roxane comple 19A-04-Et2Zn-Scope-2 1/19/00 1: 49 PM
MgX MgX2–dioxane complex 2 + dioxane 2 R–MgX + ZnCl2 R2–Zn + MgX2 + MgCl2 D. A. Evans Enantioselective C=O Addition: Dialkylzinc Addn Scope Chem 115 Ohno, Tet. Lett. 1989, 30, 7095 RCHO + Et2Zn Ti(O-i-Pr)4 toluene-hexane 78 - 95% ■ Knochel has described preparation of functionalized R2Zn reagents Knochel, J. Org. Chem. 1992, 57, 1956 Other Catalysts for Aliphatic Aldehydes -20 °C -50 °C 0 °C -20 °C 0.04 equiv 0.02 equiv 0.01 equiv 0.04 equiv 98% ee 99% ee 92% ee 99% ee 1.2 equiv. 0.3 equiv 0.6 equiv 0.6 equiv PhCHO PhCH=CHCHO PhCH2CH2CHO n-C5H11CHO aldehyde ligand Ti(OR)4 Temp ee R–I + Et2Zn 3-5 equiv Et–I + R–Zn–Et distill R2Zn – Et2Zn + Et–I 2 X = Cl, OAc 2 Ohno catalyst PhCHO 92% ee (90% yield) Reagent 2 is a more effective catalyst for the addition of Et2Zn to aldehydes MeMgI n-BuMgBr CH2=CH(CH2)2MgBr MeMgBr n-BuMgBr MeMgI n-PrMgBr PhCHO PhCHO PhCHO i-PrCHO C6H11CHO CH2=CH(CH2)3CHO Ph(CH2)2CHO 55% 82% 83% 40% 35% 69% 60% 94% 96% 90% ≥90% 90% 95% ≥90% R1-CH2MgX (2 equiv.) 1) ZnCl2, Et2O, 23°C 2) dioxane; filter 3) 0.15 eq. 1, -78°C 4) 1.2 eq. Ti(OiPr)4 5) R2CHO to -30°C (R,R,R,R)-1 (R,R)-2 Utilization of Grignard and Alkenyllithium Reagents Seebach, Angew. Chem. Int. Ed. 1991, 30, 1008, and 1321 Grignard RCHO % Yield % ee X Zn O t-BuO Zn t-BuO O Ph OH O Ti O O O O Me O Ph Me Ph Ph Ph O O Me Ph Me Ph Ph Ph OH R Et NHSO2CF3 NHSO2CF3 O Ti O O O O–CHMe2 Me Ph Me Ph Ph Ph O–CHMe2 R2 OH R1 19A-04-Et2Zn-Scope-2 1/19/00 1:49 PM