Transcript PowerPoint 프레젠테이션

Carbon-Carbon Bond Forming Reactions
I. Substitution Reaction
R
X
+
R
R'
R
X
R'
II. Addition Reaction
R
X
+
R'
R'
Carbon-Carbon Bond Forming Reactions
II. Addition Reaction : Condensation Reaction
R
X
+
R'
R
X
R'
Aldol condensation : base catalyzed
acid catalyzed
Directed Aldol condensation : usually kinetic control
Base Catalyzed aldol condensation
+
O
Base
+
-
O
-
O
-
+
H:Base
O
O-
O
O
HO
+
H:Base
+
O
Base
O
HO
HO
O
+
Base
-
O
O
Acid Catalyzed aldol condensation
+
O
HA
+
OH+
OH+
OH
+
A-
H+
HO
OH
+
+
OH
OH
H2O
H2O
O
OH
O
+
Mixed aldol condensation
Classical : with non-enolizable carbonyls
O
Ph
O
OH-
O
Ph
H
trans : major
O
Ph
O
H
O H OH
OH
Ph
Ph v.s.
H
H
H
H
base
base
O
O
OH
OH
H
Ph
H
H
v.s.
H
Ph
H
H
O
Ph
Base catalyzed v.s. Acid catalyzed
O
O
+
PhPh
+
H
OH-
O
Ph
H
Under base catalysis
O
OH
Ph
OH-
OH-
O
O
+
Ph
O
OH
Ph
H
slower
O
O
Ph
Ph
O
H+
OH-
O
O
+
Ph
Ph
O
Ph
H
Under acid catalysis
OH
O
OH
major
O
slow
Ph
O
OH
H
O
Ph
OH
Ph
fast
O
Ph
Control of regio- and stereochemistry in aldol condensation
Directed aldol : regioselective, stereoselective
100% single enolate, generally non-equilibirum
O
O
base
O
+
H
O
R
R
LDA
R2BOTf
TiCl4-R3N
OTMS
O
+
H
TiCl4
R
OH
O
OH
R
Stereocontrol in Aldol Condensation
O
O
O
+
R
X
O
OH
O
R
X
X
H
OH
R
OH
R
X
relative control
O
X
OH
O
R
X
OH
R
Syn aldol
anti aldol
absolute control
L
Erythro vs. Threo
L
H
H
started from sugar chem.
H
H
L
L
erythro
threo
Extension (generalization) : following the priority rule for (R, S) configuraiton
If priority eclipses --- erythro
If priority does not eclipse --- threo
OH
H
HO
OH O
COOH
H
threo
syn vs. anti
Proposed by Masamune : ACIE 1980, 19, 557
COOH
OH
OH O
anti
Ph
COOH
OH
anti
anti-syn
Aldol condensation of enolates
For syn, anti selectivity
i) Enolate geometry is important – usually syn is dominant
E,Z-selectivity of enolates depends on substitution, base & additives
Li
O
O
O
LDA
+
R
R
R= Et
3.3 : 1
R= i-Pr
1.7 : 1
R= t-Bu
1
: >50
R
Li
Aldol condensation of enolates
O
OH
R2
1
R
R2
R
O
M
1
R
syn-major
O
R CHO
Z-enolate
1
R
2
R
M
O
O
R2
R2
R
OH
R1
1
R
anti-major
E-enolate
H M
O
O
R2
H
R
R1
Z-enolate
R
O
OH
2
R
1
R
syn-major
R2
H M
O
O
R
1
R
H
E-enolate
R
O
OH
2
R
1
R
anti-major
Aldol condensation of enolates
For syn, anti selectivity
i)
ii)
Enolate geometry is important – usually syn is dominant
Cyclic ketones --- anti aldol is major
-
O
O
+ PhCHO
E-enolate
OH
O
Ph
+
84 : 16
OH
Ph
Aldol condensation of enolates
For syn, anti selectivity
i)
ii)
iii)
iv)
v)
Enolate geometry is important – usually syn is dominant
Cyclic ketones --- anti aldol is major
Kinetically Z-enolate is preferred
Metal plays an important role – size, ligands
In reality, aggregation state is important -- effect of additives
enolates can equilibrate fast – thermodynamic mixture
Aldol condensation of enolates
a. Li enolates
i)
ii)
Can be easily generated with LDA from ketone, ester, amide, etc.
Can chelate to other functional groups
R'
LDA
OR'
Li
O
R'O
R''CHO
R"
O
OR
OH
OR
O
COOR
iii) Regioselective addition
LDA
O
CHO
R
RCHO
OH
CHO
LDA
O
CHO
Ph
O
Al
Ph
3
RCHO
Al
R
CHO
OH
Aldol condensation of enolates
b. Boron enolate
i)
ii)
iii)
iv)
v)
Cyclic transition state
Transition state is compact – amplify steric factor :better selectivity
Two extra ligand can influence the outcome
Z-enolate dominant
With bulky ligand on boron, E-enolate dominates
B
O
O
O
+
B
PhCHO
O
OH
O
Ph
+
(n-Bu)2BOTf
97 : 3
(2-BCO)2BOTf
3
: 97
OH
Ph
Aldol condensation of enolates
c. Ti, Sn, Zr enolate
i)
ii)
Somewhere between B, and Li enolate
Extra chelation available , could have extra ligands
O
O
Mostly syn selective !!!
O
N
Cl 3
Ti
O
O
O N
TiCl4, (iPr)2NEt
Bn
CHO
O
O
O
N
Bn
Bn
O
O
CHO
+
Sn(OTf)2
OH
OH
Sn
O Ph
H
O
N
Acyclic T.S.
Mukaiyama aldol : acid catalyzed aldol
Silyl enol ether + lewis acids + carbonyl (or acetal)
OTMS
O
CHO
OH
TiCl 4
+
92%
MeO
Ph
OTMS
Ph
OMe
+
OH
TiCl 4
91%
OTMS
O
O
+
Ph
Ph
Ph O
TiCl 4
Ph
95%
Mukaiyama aldol : acid catalyzed aldol
Silyl enol ether + lewis acids + carbonyl (or acetal)
i)
Usually acyclic transition state
ii) Catalytic aldol condensation !!!
O
Cp2Ti(OTf)2
OTMS
+
Ph
CHO
0.5mol%
OH
Ph
O
OTMS
+
PhCHO
Ph
Yb(OTf)3
OH
10mol%
91%
O
OTMS
+
PhCHO
Ph
InCl3(20mol%)
OH
H2O
78%
Anti – selective aldol condensation
Selective formation of E- enolate
O
BOTf
O
BR2
O
RCHO
OH
R
2
(iPr)2NEt
85:15
With 9-BBN-- >97:3 -- syn selective
Lewis acid catalyzed aldol
O
O
O
i) MgCl2(10mol%),
Et3N, TMSCl
N
Bn
PhCHO
O
O
O
OH
Ph
N
32 : 1
Bn
ii) TFA/ MeOH
JACS, 2002, 124, 392
Evans Chiral Aldol condensation
O
O
N
O
LDA
O
R
Bn
O
M
O
N
R2BOTf; R3N
R'
CHO
R
O
OH
O
O
R'
N
Bn
Bn
R
TiCl4; R3N
O
O
O
N
Bn
O
i) LDA
R
ii) ClTi(Oi-Pr)3
O
M
O
N
Bn
R'
R
CHO
O
OH
O
O
R'
N
Bn
R
Evans Chiral Aldol condensation
O
O
N
O
LDA
O
O
R
R2BOTf; R3N
Bn
M
O
N
R'
CHO
R
O
TiCl4; R3N
O
O
O
Bn
M
O
N
Bn
R'
CHO
R'
N
Bn
Bn
N
O
R
H
M
O
H
O
R'
R
OH
O
O
R
Evans Chiral Aldol condensation
O
O
O
N
Bn
O
i) LDA
R
M
O
ii) ClTi(Oi-Pr)3
O
N
R'
R
O
H
R'
O
N
Ti(OiPr)3
O
O
R
O
R'
N
Bn
Bn
Bn
CHO
OH
O
O
R
Evans Chiral Aldol condensation
O
O
O
N
MgCl2; R3N
R
M
O
O
O
N
Bn
S
O
R'
CHO
R
O
O
N
Bn
MgCl2; R3N
R
O M
S
O
R'
N
Bn
Bn
N
Bn
R
R'
CHO
R
OH
O
S
O
OH
O
O
R'
N
Bn
R
Evans Chiral Aldol condensation
O
O
O
N
O
MgCl2; R3N
O
R
Bn
M
O
N
R'
CHO
R
O
Mg
O
O
O
Bn
O
R'
R'
R
N
H
O
N
O
MgCl2
H
O
Bn
R'
N
Bn
Bn
R
H
O
Boat-like T.S.
OH
O
O
R
Evans Chiral Aldol condensation
S
S
O
N
MgCl2; R3N
R
Bn
S
S
M
O
N
R'
CHO
R
R'
N
S
Bn
Bn
S
Bn
O
MgCl2
S
R'
R
N
S
S
O
Bn
H
MgCl2
R'
H
N
O
R
H
Boat-like T.S.
OH
O
S
O
R
Enantio-selective aldol condensation
i)
ii)
iii)
iv)
v)
Chiral center in enolate
Chiral center in aldehyde
Chiral auxiliary
Chiral metal
Chiral Lewis acid
Enantio-selective aldol condensation
i)
Chiral center in enolate
O
O
i) Et2BOTf
O
OH
OH
+
ii) C2H5CHO
O
i) LDA
65
:
O
OH
TL 21, 4678(1980)
35
O
+
Ph
TMSO
ii) PhCHO
TMSO
9
:
OH
Ph
TMSO
1
Through extra chelation
O
O
Ph
H
Li
O
TMS
Enantio-selective aldol condensation
ii) Chiral center in aldehyde
R
CHO
R'
+
O
-
OH O
R
OH O
R
+
R'
10
:
R'
1
Anti aldol products are very minor
** Chiral centers in both aldehyde and enolate **
R
CHO
OH O
O-
R
+
OTMS
OTMS
85%
• Kinetic resolution or
• Double stereodifferentiation
JOC 46, 2290 (1981)
Mutual kinetic resolution
Matched v.s. Mismatched
O
OH
O
OH
Ph
O+ OHC
Ph
OTMS
9
TMSO
Ph
1
TMSO
O
OH
O
OH
Ph
O+ OHC
Ph
OTMS
1.3
TMSO
Ph
TMSO
1
Mutual kinetic resolution
O-
RCHO
OH O
+
OH O
+
R
80
OH O
OTMS
OTMS
10
-
:
1
OH O
OH O
O
+
+
R
OTMS
O-
R
OTMS
OTMS
20
R
R
+
OTMS
RCHO
1
R
+
CHO
:
OH O
OR
R
:
1
Product ratio??
CHO +
OTMS
B
O
O
O
+
B
PhCHO
O
OH
O
Ph
+
Ph
(n-Bu)2BOTf
97 : 3
9-BBNOTf
97
: 3
(2-BCO)2BOTf
3
: 97
B OTf
9-BBNOTf
B OTf
(2-BCO)2BOTf
OH
Enantio-selective aldol condensation
iii) Chiral auxiliary
O
O
O
TiCl4, (iPr)2NEt
N
Bn
Cl 3
Ti
O
O
O N
O
O
CHO
N
O
Bn
Bn
D.A. Evans
i) Et2BOTf
N
N
SO2O
ii) RCHO
SO2O
R
OH
W. Oppolzer
• Reliable, can predict stereochemistry
• stoichiometric, not economic
OH
vi) Chiral Metal
Ph
+
O
Ph
ArO2S N B N SO2Ar
Br
i) (iPr)2NEt
R
ii) RCHO
O
OH
95% e.e.
1 eq.
E.J. Corey, JACS 5493(1989)
O
Ph
t-Bu +
O
Ph
ArO2S N B N SO2Ar
Br
i) Et3N
t-Bu
ii) RCHO
R
O
O
OH
94% e.e.
S
O
Ph
Ph
+
Ph
ArO2S N B N SO2Ar
Br
i) EtN(i-Pr)2
ii) RCHO
Ph
R
S
O
OH
97% e.e.
E.J. Corey, JACS 4977(1990)
v) Chiral Lewis acid
OTMS
OEt
+ C3H7CHO
Catalyst!!
OH O
catalyst
OEt
NH
> 98% e.e.
O
S. Masamune
E.J. Corey
O
ArO2S N B
C4H9
OTMS
OEt
TMSO
catalyst(2mol%)
+ RCHO
R
t-Bu
N
Ti O
OO O
O
OEt
94-97% e.e.
Br
O
t-Bu
t-Bu
M. Shibasaki
E. Carreira
Intramolecular Aldol condensation
Scheme 2.9
OBn
OBn
Na 2CO 3
O
CHO
CHO
O
O
O
O
10N HCl
O
COOMe
Dieckman condensation
EtOOC
COOEt
NaOEt/EtOH
COOEt
O
Robinson annulation
O
-
O
O
+
Too reactive
Enolate control needed
O
-
O
O
O
-
O
HO
Robinson annulation
Stable Vinylketone
O
O
O
OSi(CH3)3
Si(CH3)3
Si(CH3)3
Enamines for annulation
O
N
+
O
O
O
+
O
NaOEt
Robinson annulation
O
O
+
O
Steroids
O
O
Wieland-Miescher ketone
Asymmetric synthesis
O
O
+
O
N
H
O
COOH
O
O
O
O
O
O
O
proline
N H O
O
N
O
COOH
O
O
Proline
Proline catalyzed Asymmetric aldol reaction
Boc
Boc
N
OHC
N
proline
Cocaine
CHO
OH
CHO
O
OHC
+
OH
N
H
COOH
O
OL, 3305 (2004)
OH
OH
> 99% e.e.
JACS, 123, 5260(2001)
O
OHC
+
N
H
COOH
O
OH
85% e.e.
Proline catalyzed Asymmetric aldol reaction
Boc
Boc
N
OHC
N
proline
Cocaine
CHO
OH
CHO
O
N
H
OHC
+
COOH
O
OL, 3305 (2004)
OH
OH
OH
JACS, 123, 5260(2001)
> 99% e.e.
O
H
+
OHC
N
H
COOH
O
OH
H
JACS, 124, 6798(2002)
97% e.e.
anti:syn=3:1
Application to organic synthesis : “biogenetic type synthesis”
Science, 305, 1754(2004)
N
H
O
H
COOH
O
OH
(10mol%)
anti:syn=4:1
OTIPS
H
OTIPS
OTIPS
95% e.e.
O
OH
OTIPS
H
OTMS
+
OAc
OTIPS
MgBr2
OH OH
OHC
Et2O
O
TIPSO
OTIPS
TIPSO
OH
OAc
OAc OTIPS
OH
glucose
O
OH
OTIPS
H
OTMS
+
OAc
OTIPS
MgBr2
CH2Cl2
OH OH
OHC
O
TIPSO
OTIPS
TIPSO
OH
OAc
OAc OTIPS
OH
mannose
O
OH
OTIPS
H
OTIPS
+
OTMS
OAc
TiCl4
CH2Cl2
OH OH
OHC
TIPSO
OTIPS
OAc OTIPS
O
TIPSO
OH
OAc
OH
allose
Modificaiton of the reaction
Electrophile : C NR
<
C O
<
C NR 2
< C OH
reactivity
Mannich reaction
R2
1
R
N
+ HCHO
HN
+
R2
1
O
R
O
HCHO
HN
+
N
2
R
1
R
O
1
R
Eschenmoser's salt
2
R
OH
Mannich Reaction
O
O
+ HCHO + CH3NH2
EtOOC
COOEt
N
COOEt
OH N
OH
H
N
+
EtOOC
EtOOC
EtOOC
COOEt
O
EtOOC
NH
COOEt
O
HCHO
EtOOC
COOEt
N
COOEt
Synthesis of tropinone : biogenetic type synthesis Sir. Robinson
N
CHO
CHO
+ CH3NH2
+ OOC
COO O
H2O
O
Tropinone
HN
+
-
COO-
OOC
Decarboxylation
O
CHO
HN
CHO
COOO
COO-
COO-
COON
O
COO-
N
O
COO-
Tropinone
COOH
CHO
+
H2NMe +
Roboinson
O “Mannich reaction”
N
O
Aqua
CHO
COOH
Willstatter
H2N
O
NMe 2
i) NH 2OH
i) MeI(xs.)
i) Br 2
ii) Na/EtOH
ii) Ag 2O
ii) Me 2NH
i) MeI(xs.)
ii) Ag 2O
iii) Br 2 quinoline
N
O
i) 130oC
ii) HBr
iii) H 2SO4
iv) CrO 3
NMe 2
N
i) Br 2
ii) heat
iii) NaOH
i) HBr
ii) Me 2NH
iii) Na/EtOH
Synthesis of tropinone : biogenetic type synthesis Sir. Robinson
N
CHO
CHO
+ CH3NH2
+ OOC
COO O
H2O
O
Tropinone
N
CHO
CHO
+ CH3NH2
+ -OOC
COOMe
COOMe
O
H2O
O
N
COOMe
OBz
Cocaine
Amine catalyzed reaction
Knoevenagel reaction
catalytic BuNH2
Ar-CHO
+
CH3NO2
Ar-CHO
+
NO2
Ar
BuNH2
Ar
N
H
Bn
H2C NO2
NO2
Ar
NO2
Ar
Bn
N
H2
NO2
Ar
N
H
Bn
Knoevenagel reaction
O
CHO
O
piperidine
COOEt
+
COOEt
81%
O2N
O
CHO
+ HO
pyridine
COOH
O2N
COOH
80%
OHC
OHC
TMSO
Bn2NH.TFA
OHC
O
O
TMSO
OBn
OBn
Amine catalyzed reaction
Baylis-Hillman reaction
Org. Rxn. 51, 201 (1997)
Chem. Rev. 103, 811 (2003)
OH
catalytic DABCO
COOEt
+ CH3CHO
COOEt
N
N
76%
N
N
+
CH3CHO
N
N
COOEt
N
N
O-
O
OEt
OEt
-
N
N
O
O
+
N
N
OEt
HO
O
OEt
HO
The Baylis-Hillman Reaction
N
O
O
R
H
OH O
N
+
OR
R
O
OH O
R
OR
N
OR
OR
N
O
OR
O
R
H
O
N
OR
N
RDS
N
N
RCHO
Rate is slow, reaction limited to reactive substrates
Asymmetric Baylis Hillman Reactions: Chiral Auxiliary
O
O
DABCO
RCHO
+
N
CH2Cl2, 0 oC
S O
O
O
R
O
R
Yield: 33-98%
ee: >99%
R = Alkyl
HO
N
O
MeOH, CSA
N
H
S O R
O
OH O
OMe
Leahy, JACS. 1997, 119, 4317
~85% yield
Asymmetric Baylis Hillman Reactions: Chiral Catalyst
OH
O
N
O
O
OH O
N
+
R
CF3
O
H
-ICD
CF3
R
CF3
O
R
DMF, -55 oC
HFIPA
CF3
Yield: 31-58%
ee: R (>91%)
>91% ee
R = Alkyl, Aryl
Hatakeyama : JACS 1999, 121, 10219
OH
PPh2
N
Ar
Ts
O
NHTsO
H
+
10 mol%
Ar
o
THF, -30 C, or MS 4A
Yield: 82-96%
ee: (S) 79-92%
Shi : Chem. Commun. 2003, 1310
Application of the Baylis-Hillman reaction
Bu3P
COOEt
EtOOC
COOEt
87%
H. Tae, Ph.D.Thesis, KAIST
O
O
COOEt
OBn
COOEt
OBn
Bu3P
OBn
OBn
OBn
OBn
71%
M. Krische, JACS, 2003, 124, 2404
Claisen condensation
O
OH
O
+
O
O
-
O
O
OMe
Michael addition
O
-
OH
O
+
O
Ph
COOMe
Ph
OMe
Acylation
-
O
R
O X
W
R
R'
+
X
R'
W
O-
Forming the enolate
Drives equilibrium.
O
W
R
R'
W
R
R'
Electrophile
O
R
X
X = OR
Cl
OCOR
Imidazol
O-acylation competes
Mg enolate prevents O-acylation
Acylation
O
R
N
OMe
O-
+
O
R
OEt
Weinreb amide
MgCl2, NaI, Et3N
O
O
then CO2
O
O
*
O
O
COOH
O
O
O
Mg
2
O
HOOC
O
DMF, 110oC
O
Stile’s reagent
O
COOEt
Homework
Chapter 2 : 1, 2, 13, 15
Due : April, 27