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The Aldol Reaction
General Principles ! ! !
- Reaction can be effected under acidic or basic conditions
• General Reactivity
R
O
R
O
R
OHH
H+H
with acid
R
O
R
O OH
R R
O
R-H2O
R
OH
base
R
O
with base
R
O
R
O O
R R
O
R
-H2O
R
O base or H+
R"CHO R
O
R' R
O OH
R" R"R' R'
The Aldol Reaction
General Principles ! ! !
• Hindered Enolates
- Equilibrium varies with counterion
O M
PhCHOO OH
M = Li MgBr
16%93%
O OM
The Aldol Reaction
Symmetrical Aldol ! ! !
• Self Condensation
H
O NaOHH2O, 4-5°C
H
O OH
CHO
CHO tBuOK (1 equiv)tBuOH
CHO
ONaOEtEtOH O OH
O HCl- H2O
O
The Aldol Reaction
Mixed Aldol ! ! !
• Equilibrium Conditions
CHO
CH3 CHOH
O
CH3
OH
H
O OH
H
O OH
H
O
CH3
OH
base
selfcondensation
mixedaldol
The Aldol Reaction
Mixed Aldol ! ! !
• Equilibrium Conditions
- one component is non-enolizable
- one component is more acidic than the other
H
O H
OKOHEtOH
H
O
+
H
O
H H
O K2CO30°C+
H
O
HO
O O O NaOHrt+
O O
The Aldol Reaction
Mixed Aldol ! ! !
• Equilibrium Conditions
- aldehyde + ketone (Claisen-Schmidt)
• Kinetic Conditions
O CHO
O KOHrt O
O
+
OR
H R'
O
OLiR
LDA O
RR'
OH
-78*C
The Aldol Reaction
Stereochemistry ! ! !
• Z-Enolate syn product
• E-Enolate anti product
R
O
R'R"
OHR
O
R'
+H R"
O
E
anti
generalizations 1. Z-enolates (thermodynamic) give predominately syn aldol products 2. E-enolates (kinetic) give predominately anti aldol products 3. diastereoselectivity is higher with Z-enolates
R
OR' +
H R"
O
R
O
R'R"
OH
Z
syn
The Aldol Reaction
Stereoselective Generation of Enolates ! ! !
conditions E : Z ratio
LDA 77 : 23
LTMP 86 : 14
LDA, HMPA 5 : 95
LTMP, HMPA 8 : 92
O baseTHF, -78°C
O O+
kinetic
thermodynamic
• ketones
The Aldol Reaction
Stereoselective Generation of Enolates ! ! !
• Ireland model
R MeO
O
LiN H
R
H Me O
LiN H
R
Me H
E-enolate Z-enolate
A1,2 strain1,3-diaxialinteraction
favored with bulky bases
The Aldol Reaction
Stereoselective Generation of Enolates ! ! !
• Ireland model
generalizations - Model breaks down in polar solvents no chair TS - Trends in selectivity work well in ketones so long as R is small
R1 R2 E : Z ratio
tBu Me 2 : 98
Me Ph 93 : 7
R1 R2O LDA
THF, -78°C R1
R2
O
R1 R2O
+
The Aldol Reaction
Stereoselective Generation of Enolates ! ! !
• esters
RO
O LDAsolvent, -78°C RO
O
RO
O+
E Z
• amides
Me2N
O LDAMe2N
O
Me2N
O+
3 : >97
R solvent E : Z ratio
Me THF 95 : 5
tBu THF 95 : 5
Me THF / HMPA 16 : 84
tBu THF / HMPA 15 : 85
tBu THF / DMPU 7 : 93
kinetic
thermodynamic
The Aldol Reaction
Aldol Stereochemistry – Zimmerman-Traxler model ! ! !
• Z-enolate syn aldol product
R
OMR1 +
H R2
O
R
O
R1R2
OH
R
OMR1
+
H R2
O
O OM
HH
O OM
R2H
R1
R2
R1
R
R
H
O OM
HH
R2
R1
R
R
O
R1R2
OH
syn(major)
O OM
R2H
R1
R
HR
O
R1R2
OH
anti(minor)
Favored
Disfavored
Z
The Aldol Reaction
Aldol Stereochemistry – Zimmerman-Traxler model ! ! !
• E-enolate anti aldol product
R
O
R1R2
OH
R
OM
R1+
H R2
O
R
OM
R1
+
H R2
O
O OM
HR1
O OM
R2R1
H
R2
H
R
R
H
O OM
HR1
R2
H
R
R
O
R1R2
OH
anti(major)
O OM
R2R1
H
R
HR
O
R1R2
OH
syn(minor)
Favored
Disfavored
E
The Aldol Reaction
Aldol Stereochemistry ! ! !
• M-O bond lengths
generalizations 1. Stereoselectivity generally higher with Z-enolates 2. Diastereoselectivity maximized when R / R2 are large 3. Diastereoselectivity increases as shorten M-O bonds
Li-O 1.92 – 2.00 Å
Mg-O 2.01 – 2.03 Å
Zn-O 1.92 – 2.16 Å
B-O 1.36 – 1.47 Å
Ti-O 1.62 – 1.73 Å
Zr-O 2.15 Å
The Aldol Reaction
Aldol Stereochemistry ! ! !
• M-O bond lengths
generalizations 1. Stereoselectivity generally higher with Z-enolates 2. Diastereoselectivity maximized when R / R2 are large 3. Also: diastereoselectivity increases as shorten M-O bonds
Li-O 1.92 – 2.00 Å
Mg-O 2.01 – 2.03 Å
Zn-O 1.92 – 2.16 Å
B-O 1.36 – 1.47 Å
Ti-O 1.62 – 1.73 Å
Zr-O 2.15 Å
• Diastereoselection B > Li > Na > K
The Aldol Reaction
Aldol Stereochemistry ! ! !
• Boron enolates
R
OM PhCHOR
O
Ph
OH
R
O
Ph
OH+
R M syn : anti ratio
Ph Li 88 : 12
B(C4H9)2 >97 : 3
Et Li 80 : 20
B(C4H9)2 >97 : 3
The Aldol Reaction
Aldol Stereochemistry ! ! !
• Z-Boron enolates
OB(Bu)2O Bu2BOTfiPrNEt2
OiPr
H Me
H
BO
iPrMe H
H
B OiPr
H Me
HBBu
Bu
BuBu
BuBu
small alkylgroup
iPr NiPr
Et
OTf
largebase
disassociatedanion
OBBu2iPr
H Me
Z-boron enolate
The Aldol Reaction
Aldol Stereochemistry ! ! !
• E-Boron enolates
OB(Cy)2O Cy2BClEt3N
OiPr
Me H
H
B OiPr
H Me
HB
large alkylgroups
Et NEt
Et
smallbase
boundanion
OBCy2iPr
Me H
E-boron enolate
Cl ClO
iPrH Me
HB
Cl
note kinetic deprotonation
The Aldol Reaction
Aldol Stereochemistry ! ! !
• Boron enolates
boron aldols are NOT reversible!
OB(Bu)2 PhCHOR
O
Ph
OHO
OB(Cy)2 PhCHOR
O
Ph
OHO
Bu2BOTfiPrNEt2
(Cy)2BClEt3N
>97% (Z)
>99% (E)
syn >99%
anti >97%
The Aldol Reaction
Aldol Stereochemistry ! ! !
• Chiral aldehyde
Ph
O
Ph
O OH
Ph
O OHor
H
OPh+
OMe
Ph Ph
OMe OMe
?
Ph
OM
+
OMO
H
Ph
Ph
O OH
OMO
H
H
H Ph
O OH
Favored
Disfavored
H
OPh
OMe
Ph
OMe
Ph H
PhO
MO
H
H
H
Ph
MeO
PhH
H
MeO
H Ph
H Ph
OMeOMO
H
PhH
MeO
HPh
H
OMe
major
The Aldol Reaction
Aldol Stereochemistry ! ! !
• Chiral aldehyde
Ph
OM
+
OMO
H
Ph
Ph
O OH
OMO
H
H
H Ph
O OH
Favored
Disfavored
H
OPh
OMe
Ph
OMe
Ph H
PhO
MO
H
H
H
Ph
MeO
PhH
H
MeO
H Ph
H Ph
OMeOMO
H
PhH
MeO
HPh
H
OMe
OMO
H
H
H
Ph
H
MeO Ph
major
Ph
O OH
Ph
O OHorPh Ph
OMe OMe
?
The Aldol Reaction
Aldol Stereochemistry ! ! !
• Prochiral enolate and chiral aldehyde
O
O OHO OHor
H
OPh+
Me
PhPh
MeMe
O OHO OHor PhPh
MeMeA B C D
or
The Aldol Reaction
Asymmetric Aldol ! ! !
• Evans aldol
NHO
O
NHO
O
MePh
NHO
O
Bn
NHO
O
BnA B C D
- reaction is highly diastereoselective if R ≠ H (R = Me, dr is >300 : 1) - favors syn product - tolerates broad range of aldehydes - reliable - can access either antipode of aldol product by choice of oxazolidinone auxiliary
NO
OR
O
NO
OR
OnBu2BOTf, iPr2NEt
CH2Cl2, 0°CR'CHO
-78°C to rtNO
O O
R
OH
R'
BBu2
R ≠ H
The Aldol Reaction
Asymmetric Aldol ! ! !
• Evans aldol
- poor selectivity when R = H (dr = 1:1)
acetate aldol equivalent
NO
OSMe
O
NO
O O
SMe
OH
R' NO
O O OH
R'Ra(Ni)
dr = 60 : 1
NO
OH
O
NO
O OnBu2BOTf, iPr2NEt
CH2Cl2, 0°CR'CHO
-78°C to rtNO
O O OH
R'
BBu2
The Aldol Reaction
Asymmetric Aldol ! ! !
• Evans aldol
NO
OR
O
NO
OR
OnBu2BOTf, iPr2NEt
CH2Cl2, 0°CR'CHO
-78°C to rtNO
O O
R
OH
R'
BBu2
selectivity model
!
The Aldol Reaction
Asymmetric Aldol ! ! !
• Evans aldol
auxiliary cleavage
NO
O O OH
NO
O O
-78°C to rt
BBu2OHC R
RNO
O O OH
-78°C to rt
OHC RR
NO
O O OP
N
O OHMe(OMeNH•HCl
AlCl3LiOH
LiOOH, THFHO
O OP
HO
OP Ti(OBn)4
BnO
O OP
MeO
R
O OP
H
O OH
DIBALLiBH4
or LiAlH4
1. protect2. RMgX
(P = H)
The Aldol Reaction
Asymmetric Aldol ! ! !
• Anti aldol from Z-enolates
examples
H
O
H
OO PhH
O
PhH
OH
O
H
O
91% yield(dr = 44 : 1)
80% yield(dr = 6 : 1)
92% yield(dr = 28 : 1)
92% yield(dr = 21 : 1)
77% yield(dr = 16 : 1)
65% yield(dr = 30 : 1)
NO
O
Ph
MeO
NO
O
Ph
OMgCl2 (10 mol %)
R3N, TMSCl (1.2 equiv)R'CHO NO
O
Ph
O OH
R'
MgLn
Me
EtOAc, rt Me
The Aldol Reaction
Asymmetric Aldol ! ! !
• Anti aldol from Z-enolates
selectivity model
NO
O
Ph
MeO
NO
O
Ph
OMgCl2 (10 mol %)
R3N, TMSCl (1.2 equiv)R'CHO NO
O
Ph
O OH
R'
MgLn
Me
EtOAc, rt Me
OMgO
PhMe
HOH2
H2OBr
NO
O Bn
NO
O
Bn
O OH
PhMe
H
The Aldol Reaction
To This Point: ! ! !
• Type I Aldol: Metal Aldol Process
- run in presence of either stoichiometiric or catalytic base
XR
H R' XR
XR
XR
O O O OM
R'
OHO
R'
O
M
B M H B Mslow
The Aldol Reaction
Alternate Process: ! ! !
• Type II Aldol: Mukaiyama Aldol
O OTMS O OHLDA
TMSClTiCl4 (1.02 equiv)
PhCHO-78°C, CH2Cl2
then aq H+ workup
XR
H R' XR
XR
XR
O O O OM
R'
OO
R'
O
TMS
M Mslow
M
XR
O OM
R'X
TMS
TMS X
TMS
MX = Lewis acid
The Aldol Reaction
Mukaiyama Aldol: ! ! !
• examples
H
OTMS
H
O OHTiCl4
-78°C, CH2Cl2Ph
OPhH
86%
O
LDATMSCl
Et3NTMSCl
OTMS
OTMS
PhCHOTiCl4
PhCHOTiCl4
O
O OH
Ph
Ph
OH
81%
58%
Lewis acids: TiCl4, BF3•OEt2, SnCl4, SnCl2
The Aldol Reaction
Mukaiyama Aldol: ! ! !
• stereochemistry
selectivity models
O
R'HC
C
R R
M
R OTMS
O
R'HC
R
C R
MR
TMSOOMO
RR'
R
MeR
Closed TS Open TS
anti-periplanar syn-clinal
Metallate Aldol Mukaiyama Aldol
- complicated by fact that Mukaiyama aldol thought to proceed through open TS - less ordered - two competing open TS do not vary significantly in enegry
The Aldol Reaction
Mukaiyama Aldol: ! ! !
• stereochemistry
selectivity models
O
R'HC
C
R R
M
R OTMS
O
R'HC
R
C R
MR
TMSOOMO
RR'
R
MeR
Closed TS Open TS
anti-periplanar syn-clinal
Metallate Aldol Mukaiyama Aldol
- complicated by fact that Mukaiyama aldol thought to proceed through open TS - less ordered - two competing open TS do not vary significantly in enegry
The Aldol Reaction
Mukaiyama Aldol: ! ! !
• stereochemistry
R1H
TMSO
R1
O
R3
OH
R2R3
O
HR2 + R1
O
R3
OH
R2orLewis
acid
R1
O
R3
OH
R2
R1
O
R3
OH
R2
O
HR3C
C
H R2
M
R1 OTMS
O
HR3C
C
R2 H
M
R1 OTMS
O
HR3C
C
H R2
M
TMSO R1
O
HR3C
C
R2 H
M
TMSO R1
Z-enol ether E-enol ether
syn
anti
The Aldol Reaction
Mukaiyama Aldol: ! ! !
• stereochemistry
tBu
TMSO
MeO
O
Ph
OH
MePh
O
HMe + BF3•OEt2
MeO
O
Ph
OH
Me
+
5 : 95
EtOMe
TMSO
MeO
O
Ph
OH
MePh
O
H+ TiCl4
MeO
O
Ph
OH
Me
+
2 : 1
EtO
TMSO
MeO
O
Ph
OH
MePh
O
HMe + TiCl4
MeO
O
Ph
OH
Me
+
3 : 1
The Aldol Reaction
Mukaiyama Aldol: ! ! !
• related processes
MeO
TMSO
MeO
O OHPh
OPh
94%
+ TiCl4
OTMS O
95%
TiCl4PhPh
OPh O
Ph+
H
TMSO
MeO Ph H Ph
O OMeMeO+
88%
TiCl4
Related Processes
Claisen Condensation: ! ! !
mechanism
EtO
O 1. NaOEt (1 equiv)2. H3O+ EtO
O O
EtO
O
R
O EtO
O
EtO
O OEt
EtO
O O
- EtO-NaOEt O
EtO
O O H3O+
EtO
O ONaOEt
EtOH
• self condensation
Related Processes
Claisen Condensation: ! ! !
• mixed Claisen
Ph
O 1. NaOEt (1 equiv)2. H3O+ Ph
O O+
EtO
O
MeO OMe
O
MeO
O
MeO
OMe
OMe
O
OMe
OMe
N+
H
HH O-
coccinellene
NaHDME
- useful for preparation of simple β-keto esters and diketones
EtO
O
EtO
O
Ph
O+
EtO Ph
O 1. tBuOK (excess), DMF2. H3O+
Related Processes
Claisen Condensation: ! ! ! • Dieckman condensation (intramolecular Claisen)
O O O O
CO2MeO
CO2MeMeO2C
NaOMe (xs);MeI
Me
EtO
O
O
1. NaOEt (xs)2. H3O+
O O
MeO2C
CO2Me
1. NaH, DME2. H3O+
O
MeO2C
Related Processes
Mannich Reaction: ! ! !
R HO O
H R1HN R"2
R
O NR"2
R'CF3CO2Hor pTsOH+ +
enolizablecarbonyl
non-enolizablecarbonyl
1° or 2°amine
β-aminocarbonyl
• tropanone
N
O
Me
CHO
CHOMe NH2
OR R
NMe OHN
OH+
(R = H)
Robinson J. Chem. Soc. 1917, 762.
Related Processes
Mannich Reaction: ! ! !
OH2C=O + Me2NH
CF3CO2H+
O
NMe2
O H
H
Me
N NMe
Me
H
HOHO H
H
Me
NMeH Me
H2C=OΔ, 20h
NBoc
NBn
Cl BrO
OMe
OTMS
CF3CO2H-78°C - rt
NBoc
NBn
BrO
MeO2C
R HO O
H R1HN R"2
R
O NR"2
R'CF3CO2Hor pTsOH+ +
enolizablecarbonyl
non-enolizablecarbonyl
1° or 2°amine
β-aminocarbonyl
Related Processes
Michael Reaction: ! ! !
Ph CO2Et EtO2C CO2Et NaOEtEtOH Ph
CO2Et
CO2EtEtO2C
+
Ph CO2Et EtO2C CO2EtNaOEtEtOH
Ph CO2Et
CO2EtEtO2C+
Michael 1887
NCN
EtOH, Δ
NCN H3O+
OCN
Related Processes
Michael Reaction: ! ! !
Michael acceptors (W) Michael donors
W = electron withdrawing group Nu = heteroatom or highly stabilized carbanion
R ,
O
OR ,
O
NR2 ,
OS R ,
OP OR
OOR
-NO2 , -CN , -SO2Ar , - PR3 -OH , -OR , SH , -SR , -NH2 , -NHR , etc.
R ,
O
OR ,
O
R
O
R
O
OR ,
O
RO
O
base: K2CO3, Et3N, piperidine, KOH, NaOH, KOtBu, NaH, etc.
W+ WNuNu H
base
Related Processes
Michael Addition ! ! !
• Examples
N
O
O O
K2CO3THF, Δ
N
O O
O
98%
OHI
O
O
MeO
CO2Me
Et3NO
I
O
O
MeO
CO2Me89%
NEtO CO2Et
MeEtO2C
NEtO CO2Et
EtO2C
O
NEtO CO2Et
HO
O
LDA;
O
1.2. EtOH
85%
![Multi-Step Application of Immobilized Reagents and ... · application of the asymmetric Mukaiyama aldol reaction de-veloped by Kiyooka (Scheme 3).[33] Aldol reaction, mediated by](https://img.pdfslide.us/doc/110x75/5f07e4017e708231d41f4531/multi-step-application-of-immobilized-reagents-and-application-of-the-asymmetric.jpg)
