哈佛大学高等有机化学讲义Lecture19A

O
(S) catalyst
H
Et2Zn
96% ee
OH
O
Lepicidin Application: The reaction functions in complex systems
C5H11 OR Bu Et Zn O Ph O Evans, Black, JACS 1993, 115, 44974513 H
Observations s (S,S) dimer dissociates upon addition of RCHO & effects catalysis s (S,R) dimer is overwhelmingly more stable than (S,S) homodimer s (S,R) dimer is ineffective as a catalyst
25% ee Catalyst affords product in 95% ee.
%ee of catalyst
100
19A-02-Et2Zn-1 1/19/00 1:49 PM
D. A. Evans
Enantioselective C=O Addition: Dialkylzinc Addn Scope
R1-CH2MgX (2 equiv.)
Ohno, Tet. Lett. 1989, 30, 7095
Grignard MeMgI n-BuMgBr
RCHO PhCHO PhCHO PhCHO i-PrCHO C6H11CHO CH2=CH(CH2)3CHO Ph(CH2)2CHO
% Yield 55% 82% 83% 40% 35% 69% 60%
CH2=CH(CH2)2MgBr MeMgBr n-BuMgBr
X
Zn 2
R2Zn
MeMgI n-PrMgBr
Ohno catalyst O t-BuO OH Ph
X = Cl, OAc
O t-BuO Zn 2
Reagent 2 is a more effective catalyst for the addition of Et2Zn to aldehydes Seebach, Angew. Chem. Int. Ed. 1991, 30, 1008, and 1321
aldehyde PhCHO PhCH=CHCHO PhCH2CH2CHO n-C5H11CHO
ligand 0.04 equiv 0.02 equiv 0.01 equiv 0.04 equiv
Ti(OR)4 1.2 equiv. 0.3 equiv 0.6 equiv 0.6 equiv
Temp -20 °C -50 °C 0 °C -20 °C
Problem: Rationalize the stereochemical course of each of the catalysts s Non-linear effects observed with the Noyori Catalyst (DAIB-Zn)
100
(S) catalyst
ee 98% ee 99% ee 92% ee 99% ee
(R,R,R,R)-1 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)-2
OH R2 R1
98% e.e. 91% e.e. 93% e.e. 93% e.e. 96% e.e. 90% e.e. 61% e.e.
s Catalyst must be sterically hindered so that association is precluded
R Zn R' 4 R'O ZnR R Zn R' O Zn O R' R R O Zn O R R' R O O R' Zn Zn Zn Zn O R' R O
Scope of the DAIB Catalyst
(S) catalyst
O H OH
(S) catalyst Et2Zn
Et
98% ee
OH
RCHO
+
Et2Zn
O H
(S) catalyst Me2Zn
O Me
O H
Me
O H
91% ee
OH
n-Bu
88% ee
H
78% ee
95% ee
93% ee
100% e.e. (R)
Li N
95% e.e. (S)
(S,S) dimer
(R,R) dimer
Bu N Et Zn O
Bu Me Me2 N Zn Me O Me2 N Zn Me O
N Li
90% e.e. (R)
Ph
90% e.e. (R)
90% e.e. (R)
+
(Results are cited for the reaction of benzaldehyde and Et2Zn)
+ BH3-THF
9
(S) catalyst
Bu3Sn H
Bu3Sn
(n-Pen)2Zn
Bu N Me Et 21
85% ee
OH
the catalyst
O
Me H
3
O
O
(S) catalyst
H
H
H
Et2Zn
H H
90% ee
OH
O
OR
(S) catalyst
n-Bu H
n-Bu
H
Et
பைடு நூலகம்21
OTIPS
15 OTES
H 21
SnBu3
19A-03-Et2Zn-Scope 1/19/00 1:49 PM
D. A. Evans
Enantioselective C=O Addition: Dialkylzinc Addn Scope
Other Catalysts for Aliphatic Aldehydes
NHSO2CF3 NHSO2CF3 Ti(O-i-Pr)4 toluene-hexane 78 - 95% R OH Et Me Me Ph O O Ph
D. A. Evans, D. M. Barnes
Allyl and Crotyl Metal Species-4: Catalytic Systems
Chem 115
s Three Catalytic Asymmetric Allylations of Aldehydes are Known
iPrO O COOH COOH OH OH Ti(OiPr)4, 4Â sieves O O OiPr Ti OiPr
OTIPS
15 OTES
Et2Zn
60% ee
OH MeO
Me H
3
Et2Zn,
0 °C, hexane
O MeO O
Me H
3
Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49 O
diastereoselection 10:1 (98%)
SnBu3
11
% ee 94% 96% 90% ≥90% 90% 95% ≥90%
s Knochel has described preparation of functionalized R2Zn reagents
R–I + Et2Zn
3-5 equiv distill
Et–I
+
R–Zn–Et – Et2Zn + Et–I
Matthew D. Shair
Friday, November 1, 2002
D. A. Evans
Enantioselective C=O Addition: Noyori Catalyst
The Catalytic Cycle
Me N Me O Zn Et H H Me Me Me N O Me H H Me Zn Et Me H H O H C Me Me
Chem 115
Utilization of Grignard and Alkenyllithium Reagents
Ph O Ti O Ph O Ph O Ph O Ph Ph O Me Me Me Me Ph O O Ph Ph O Ti O Ph O–CHMe2 O–CHMe2
RCHO
+
Et2Zn
Me H H
RDS
Me H H
O
the catalyst
OH Et Ar R’
Zn
Ar–CHO
+
R2’Zn
Et2Zn Me2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn
0°C, toluene 59 - 97%
C6H5CHO " p-ClC6H4CHO p-MeOC6H4CHO Cinnamyl PhCH2CH2CHO n-C6H13CHO
Chem 115
Catalytic Asymmetric Carbonyl Addition
R Zn R H R C O I Zn I Me replace with chiral controller Me Me
Me N O Me Zn O H C Et
the catalyst
Noyori & co-workers, J. Am. Chem. Soc. 1986, 108, 6072. J. Am. Chem. Soc. 1989, 111, 4028. Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49
Chem 115
Other Catalysts for the R2Zn Addition Process
H Ph Ph O N Me Zn Et Me3C N H Ph H O Zn Et H Me N N Me Li O Ph Me
97% e.e. (S)
Me N Me N Me Li O Ph Me
(R) catalyst
There is no correlation between catalyst and product ee.
(S,R) dimer
Product (%ee)
Et2Zn + PhCHO (S) catalyst OH Ph Me
Me2 Me N Zn O O Zn N Me Me 2
Me2 N Zn Me O
Chem 115
Improved Selectivity with Aliphatic Aldehydes
Soai, J. Org. Chem. 1991, 56, 4264
Bu Et Zn O Ph R O H H Me 0 °C, hexane 70 - 100% Bu N Me (6%) OH Et
R'
R' R
s The method is catalytic in aminoalcohol. s Two zinc species per aldehyde are involved in the alkylation step.
s Product is taken out of the picture by aggregation
Chemistry 206 Advanced Organic Chemistry
Handout–19A
Enantioselective Carbonyl Addition Handout
s Enantioselective addition of R2Zn to aldehydes s Enantioselective Reduction of Ketones & Imines
PhCHO
92% ee (90% yield)
2 R–MgX Knochel, J. Org. Chem. 1992, 57, 1956 MgX2 + + ZnCl2 dioxane R2–Zn + MgX2 + MgCl2 MgX2–dioxane complex
19A-04-Et2Zn-Scope-2 1/19/00 1:49 PM
Zn–Et O H
the catalyst
Et
90-98% ee
Et2Zn
Me
Me Me N Me O Zn Et H H
00 00 0000 0000 0000
Me
Me Me N O Me Zn O Et C H Et
Me
Me Me N Me Zn Zn Et O Et C H Et
Me
(DAIB-Zn)
19A-01-Et2Zn-1 1/19/00 1:49 PM
D. A. Evans
Enantioselective C=O Addition: Noyori Catalyst-2
Explanation for Nonlinearity of DAIB Catalyst
Me2 Me N Zn O O Zn N Me Me 2 Me2 Me N Zn O O Zn N Me Me 2