asymmetric synthesis additions to carbonyl compounds
TRANSCRIPT
Asymmetric SynthesisAsymmetric Synthesis
Additions to carbonyl Additions to carbonyl compoundscompounds
Outline
Addition of non-chiral nucleophiles to chiral Addition of non-chiral nucleophiles to chiral aldehydes or ketonesaldehydes or ketones• Cram’s ruleCram’s rule• Felkin-Anh modelFelkin-Anh model• Chelation controlChelation control
Chiral auxiliariesChiral auxiliaries• Chiral acetalsChiral acetals• Chiral reagentsChiral reagents
Chiral catalystsChiral catalysts• ‘‘Chiral amplification’Chiral amplification’
Achiral Nu + prochiral C=OAchiral Nu + prochiral C=O
AR
O
BC
Nu AR
B
OH
C
Nu
AR
B
Nu
C
HO
A
B
OH
C
R
Z
R1R2
A
B
OH
C
R
Z
R2R1
A
B
R
C
HO
Z
R1R2
A
B
R
C
HO
Z
R2R1
R1
R2 Z
Addition toAddition to O
R
L
S
M
Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.
O
R
S
M
LNu
Cram Karabatsos
O
RNu L
S M
Addition toAddition to
RR SS MM LL NuNu d.e.%d.e.%HH
HH
HH
HH
MeMe
MeMe
MeMe
HH
HH
HH
HH
HH
HH
HH
MeMe
EtEt
MeMe
MeMe
MeMe
MeMe
MeMe
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
MeMgIMeMgI
MeMgIMeMgI
EtMgBrEtMgBr
PhMgBrPhMgBr
MeMgIMeMgI
EtMgIEtMgI
PhMgIPhMgI
3333
4343
5050
>60>60
6666
7575
8383
O
R
L
S
M
Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.
O
R
S
M
LNu
Faulty AssumptionsFaulty Assumptions
Ground state and reactive conformation are Ground state and reactive conformation are wrong.wrong.
Ground state and reactive conformation (TS) Ground state and reactive conformation (TS) cannot be assumed to be the same.cannot be assumed to be the same.
The directing influence of substituents does not The directing influence of substituents does not only derive from their steric effects. Electronic only derive from their steric effects. Electronic interactions are crucial.interactions are crucial.
The C=O group assumes pyramidal state early, The C=O group assumes pyramidal state early, therefore Cram model is unfavourable.therefore Cram model is unfavourable.
Felkin-Anh ModelFelkin-Anh ModelO
RS
L
M
O
R
L
M
SNu
R
O
L
M
S
Nu
RS
L
M
NuHO
Nucleophile ApproachNucleophile Approach
Anh, Bürgi-Dunitz
CO
103o-109o
Nu
Chelation ControlChelation Control
OH
MeO
HMe
Ph
EtH2OO
O
HEt
Ph
Ti
Me
Et
+O
OEt
HEt
Ph
Ti
Cl
Cl Me
ClO
OEt
HEt
Ph
Ti
Cl
Cl Cl
Meo
-45 C
MeTiCl3
Et
OO
HMe
Ph
J Amer Chem Soc 1990, 112, 6130.
ExamplesExamples
RR SS LL Y:Y: Nu(solvent)Nu(solvent) d.e.%d.e.%PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
MeMe
MeMe
MeMe
HH
MeMe
MeMe
MeMe
MeMe
MeMe
MeMe
MeMe
MeMe
MeMe
HH
MeMe
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
PhPh
CC77HH1515
HH
OHOH
OHOH
OHOH
OHOH
OMeOMe
OMeOMe
OMeOMe
OHOH
OMeOMe
OMEMOMEM
OHOH
MeLi(EtMeLi(Et22O)O)
MeMe22Mg(EtMg(Et22O)O)
MeMgBr(EtMeMgBr(Et22O)O)
MeMgBr(THFMeMgBr(THF
MeLi(EtMeLi(Et22O)O)
MeMgBr(EtMeMgBr(Et22O)O)
MeMgBr(THF)MeMgBr(THF)
PhPh22Mg(EtMg(Et22O)O)
PhPh22Mg(THF)Mg(THF)
CC44HH99MgBr(THF)MgBr(THF)
PhLi(EtPhLi(Et22O)O)
8484
6666
5050
8080
3434
3434
8484
7474
8686
100100
4646
O
R
L
Y
SNu
M
Chiral auxiliariesChiral auxiliaries
Attached to the carbonyl compoundAttached to the carbonyl compound Attached to the nucleophileAttached to the nucleophile
Chiral acetals and Chiral acetals and -ketoaldehydes-ketoaldehydes SulfoxidesSulfoxides OrganometallicsOrganometallics Allylboranes, -silanes, -stannanesAllylboranes, -silanes, -stannanes
Auxiliary attached to carbonylAuxiliary attached to carbonyl
MeO
O
PhN
N
H
H
R1
O
PhN
N
H
H
R1
OH
PhN
N
H
HR1MgBr R2MgBr
R2
d.e. 60-98%
Ph
R
PhN
N
H
HHORLi
d.e. ~ 60%
R1 CHO
R2 OH
Tetrah Lett 1991, 32, 2919
Ph
O
PhN
N
H
H
Ph
OH
PhN
N
H
HR
RTi(iPrO)3
d.e. > 97%
1,3-Oxathianes1,3-Oxathianes
O
O
S1. BnSH, NaOH2. Na/NH33. (CH2O)n, TsOH
1. BuLi2. EtCHO3. DMSO, TFAA, Et3N
O
S
Et
O
O
S
Et
nPrMgBr
HOnPr
d.e. > 92%
N-CSI, AgNO3EtOHC
nPrHOO
S
O
+
O
S
Me
OO
S
Me
HO
d.e. > 92%
MgCl2;CH2=CHMgBr
O O
OHMe
(R)-mevalolactone
Transition state modelTransition state model
PhN
N
H
R1
O
H
Nu
MLn
O
SEt
OLnM
Nu
Auxiliary attached to nucleophileAuxiliary attached to nucleophile
STol O
PriMe
O
STol
O
MeS
Tol
O
CF3
OHPh
MeMgBr 1. LDA2. PhCOCF3
d.e. ~ 50%
STol
O
STol
STol
O
STol
R OHH
CHO
R OMeH
BuLi;RCHO
R = Ph, e.e. 70%
H
O
S
OLi
Tol
H
STol
Ph
J C S Perkin I 1981, 1278
Organometallic: Chiral ligandOrganometallic: Chiral ligand
Ph OH
Me NH
SO2Tol
N
Ti
O Me
OiPr
SO2Tol
Ph
Me
Me
OH NO2
e.e. 90%
1. TiMe42. iPrOH
o-NO2C6H4CHO
OH
OH
O
O
Ti
OiPr
OiPrPh C10H7
OHTi(OiPr)3Cl 1. PhMgBr
2. C10H7CHO
e.e. > 98%
Tetrah Lett 1986, 27, 5711
Allylic nucleophilesAllylic nucleophiles
Alternative route to aldol-type productsAlternative route to aldol-type products Two new chiral centres introducedTwo new chiral centres introduced Complication: reaction at C-1Complication: reaction at C-1 Achiral reactants: Achiral reactants: synsyn and and antianti racemates racemates Chiral reactants: in principle one major Chiral reactants: in principle one major
stereoisomerstereoisomer
R1CHO R2 MLn+ R1
OH
R2
O3Me2S
R1
OH
CHO
R2
Chiral boron reagentsChiral boron reagents
MgBrB
OiPr
OiPr
BO
O
HO
OH
CO2iPr
CO2iPr
CO2iPr
CO2iPr
(iPrO)3B; H3O+
BO
O
CO2iPr
CO2iPrK
BuLi,tBuOK
K
BuLi,tBuOK B
O
O
CO2iPr
CO2iPr
RCHOR
OH
R'
Examples (1)Examples (1)
R H
O
BO
O
R
CO2IPr
OH
CO2iPr
anti
+
RR antianti::synsyn e.e. %e.e. %
nn-C-C99HH1919 > 99:1> 99:1 8888
TBSOCHTBSOCH22CHCH22 > 97:3> 97:3 8585ttBuBu 95:5 95:5 7373
nn-C-C77HH1515CH=CHCH=CH > 99:1> 99:1 7474
Examples (2)Examples (2)
R H
O
BO
O
R
CO2IPr
OH
CO2iPr+
syn
RR antianti::synsyn e.e. %e.e. %
nn-C-C99HH1919 3:97 3:97 8686
TBSOCHTBSOCH22CHCH22 > 3:97> 3:97 7272ttBuBu > 1:99> 1:99 7070
nn-C-C77HH1515CH=CHCH=CH 3:97 3:97 6262
Examples (3)Examples (3)
R H
O
BO
O
R
CONHBn
OH
CONHBn+
RR e.e. %e.e. %
nn-C-C44HH99 9595PhPh 9090ttBuBu 9898
CC66HH1111 9999
Chen, Eur J Org Chem 2005, 1665-1668
Transition stateTransition state
BO
O
CO2iPr
CO2iPrO
BO
O
CO2iPr
CO2iPrH
R
RCHO
R
OH
Favoured
BO
O
PriO2C
PriO2CB
O
O
O
PriO2C
O
PriO
H
R
R
OHRCHO
Disfavoured
Selectivity: Selectivity: EE → → antianti
BO
O
R
CO2IPr OH
CO2iPr
anti
O
BO
O
CO2IPr
CO2IPrH
R
RCHO
Double asymmetric synthesisDouble asymmetric synthesis
BO
O
CO2IPr
CO2iPr BO
O
CO2IPr
CO2iPr
(R,R) (S,S)
OR
ROCHO
(R,R): matched pair: 92 : 8
(S,S): mismatched pair: 13 : 87
RO RO
OH OH
+
Iterative Asymmetric SynthesisIterative Asymmetric Synthesis
R1CHO + R2 MLnR1
OH
R2
R1
OP
R2
R1
OP
CHO
R2
+R3 MLnR1
OP
R2
OH
R3
OSitBuPh2
CHO
Me
24
OMe
OMeOMe
Me
O
Me
OAc
Me Me
O
Me Me
24
A BCD
Order of bond formation: A, B, C, DEach with >90% stereoselectivityJ Amer Chem Soc 1990, 112, 6348
DiisopinocampheylboraneDiisopinocampheylborane
Me
Me
Me
Me
Me
Me
B
2
(-)--Pinene
Me
Me
Me
H3B-SMe2
Me
Me
Me
BH
2
MeOH
Me
Me
Me
BOMe
2
H2C=CHCH2MgBr
Me
Me
Me
B
2
(+)--Pinene (-)-Ipc2BH
Addition to aldehydesAddition to aldehydes
Ipc2B(-)- RCHO
R
OH
RR e.e. % e.e. % Yield %Yield %MeMe 9393 7474EtEt 8686 7171iiPrPr 9090 8686nnBuBu 8787 7272ttBuBu 8383 8888PhPh 9696 8181
Other allylic boranesOther allylic boranes
High diastereoselectivity and High diastereoselectivity and enantioselectivityenantioselectivity• Reagent enantioselectivity overrides Reagent enantioselectivity overrides
intrinsic chiral aldehyde facial selectivityintrinsic chiral aldehyde facial selectivity Consistent and predictableConsistent and predictable Also with Also with -chiral aldehydes-chiral aldehydes
Diamine-based ligandsDiamine-based ligands
Allylsilanes and AllylstannanesAllylsilanes and Allylstannanes
Promoted by Lewis acidsPromoted by Lewis acids High diastereoselectivityHigh diastereoselectivity
• ‘‘Cram controlled’Cram controlled’• ““Chelation controlled’Chelation controlled’
Chiral CatalystsChiral Catalysts
Organozinc catalystsOrganozinc catalysts Chiral amplificationChiral amplification
Chiral ligand as catalystChiral ligand as catalyst
Organometallic reagent must be Organometallic reagent must be relatively unreactive towards C=O relatively unreactive towards C=O unless combined with the catalyst – unless combined with the catalyst – ligand accelerationligand acceleration..
Catalyst must have suitable 3D Catalyst must have suitable 3D structure to provide high e.e.structure to provide high e.e.
Dialkylzinc addition to aldehydesDialkylzinc addition to aldehydes
R CHO + Nu2Zn + (-)-DAIB (~2 mol%)
R Nu
OH
RR NuNu e.e., % e.e., %PhPh MeMe 91 91PhPh EtEt 99 99PhPh BuBu 98 98pp-Cl-Ph-Cl-Ph EtEt 93 93pp-MeO-Ph-MeO-Ph EtEt 93 93
2-Furyl2-Furyl CC55HH1111 >95 >95
(E)-C(E)-C66HH55-CH=CH-CH=CH EtEt 96 96
(E)-Bu(E)-Bu33SnCH=CHSnCH=CH CC55HH1111 85 85
PhCHPhCH22CHCH22 EtEt 90 90
J Amer Chem Soc 1986, 108, 6071
NMe2
Me
MeMe
OH
(-)-3-exo-(dimethylamino)isoborneol (-)- DAIB
Transition state modelTransition state model
N
Me
MeMe
O ZnA
Me
Me O
Nu
R
ZnB
Nu
Nu
H
Aminothiocyanate derivativesAminothiocyanate derivatives
RCHO + Et2Zn
R Et
H OHL* (5 mol%)
RTR2N SCN
Me Ph
L*
(R)
RR Yield, % Yield, % e.e., % e.e., %PhPh 9898 9696pp-Cl-Ph-Cl-Ph 9797 9595oo-MeO-Ph-MeO-Ph 9696 9090pp-MeO-Ph-MeO-Ph 9595 91912-Naphthyl2-Naphthyl 9595 9393
CC66HH1313 8282 7575
Tetrahedron Letters 2005, 46(15), 2695-2696
Transition state?Transition state?
Tetrahedron Letters 2005, 46, 2695-2696
Me
Ph
N
S
Zn
R
REt
Et
NC
O
HR
Chiral amplificationChiral amplification High catalyst High catalyst
optical purity is not optical purity is not needed!needed!
J Amer Chem Soc 1989, 111, 4028
Why amplification?Why amplification?
(-)-DAIB + (+)-DAIB (75%) (25%)
(-)-DAIB/(-)-DAIB) (+)-DAIB/(+)-DAIB (-)-DAIB/(+)-DAIB dimer dimer meso-dimer
Et2Zn
+
(50%) (50%)
Summary
Addition of non-chiral nucleophiles to chiral Addition of non-chiral nucleophiles to chiral aldehydes or ketonesaldehydes or ketones• Cram’s ruleCram’s rule• Felkin-Anh modelFelkin-Anh model• Chelation controlChelation control
Chiral auxiliariesChiral auxiliaries• Chiral acetalsChiral acetals• Chiral reagentsChiral reagents
Chiral catalystsChiral catalysts• ‘‘Chiral amplification’Chiral amplification’
Questions ?