ASYMMETRIC SYNTHESIS # Additions to carbonyl compounds # CHELATION CONTROL # ALLYLIC NUCLEOPHILES # DOUBLE ASYMMETRIC SYNTHESIS # ITERATIVE ASYMMETRIC SYNTHESIS # ADDITION TO ALDEHYDES # CHIRAL LIGAND AS CATALYST # AMINOTHIOCYANATE DERIVATIVES #

1. ASYMMETRIC SYNTHESIS
Additions to carbonyl
compounds

2. OUTLINE
• Addition of non-chiral nucleophiles to chiral
aldehydes or ketones
• Cram’s rule
• Felkin-Anh model
• Chelation control
• Chiral auxiliaries
• Chiral acetals
• Chiral reagents
• Chiral catalysts
• ‘Chiral amplification’

3. ACHIRAL NU + PROCHIRAL C=O
A
R
O
B
C
Nu A
R
B
OH
C
Nu
A
R
B
Nu
C
HO
A
B
OH
C
R
Z
R1
R2
A
B
OH
C
R
Z
R2
R1
A
B
R
C
HO
Z
R1
R2
A
B
R
C
HO
Z
R2
R1
R1
R2 Z

4. ADDITION TO
O
R
Nu L
S M
O
R
L
S
M
O
R
S
M
L
Nu
Cram Karabatsos

5. ADDITION TO
R S M L Nu d.e.%
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
Me
Et
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeMgI
MeMgI
EtMgBr
PhMgBr
MeMgI
EtMgI
PhMgI
33
43
50
>60
66
75
83
O
R
L
S
M
O
R
S
M
L
Nu

6. FAULTY ASSUMPTIONS
• Ground state and reactive conformation are
wrong.
• Ground state and reactive conformation (TS)
cannot be assumed to be the same.
• The directing influence of substituents does not
only derive from their steric effects. Electronic
interactions are crucial.
• The C=O group assumes pyramidal state early,
therefore Cram model is unfavourable.

7. FELKIN-ANH MODEL
O
R
S
L
M
O
R
L
M
S
Nu
R
O
L
M
S
Nu
R
S
L
M
Nu
HO

8. NUCLEOPHILE APPROACH
Anh, Bürgi-Dunitz
C
O
103o
-109o
Nu

9. CHELATION CONTROL

10. EXAMPLES
R S L Y: Nu(solvent) d.e.%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C7H15
H
OH
OH
OH
OH
OMe
OMe
OMe
OH
OMe
OMEM
OH
MeLi(Et2O)
Me2Mg(Et2O)
MeMgBr(Et2O)
MeMgBr(THF
MeLi(Et2O)
MeMgBr(Et2O)
MeMgBr(THF)
Ph2Mg(Et2O)
Ph2Mg(THF)
C4H9MgBr(THF)
PhLi(Et2O)
84
66
50
80
34
34
84
74
86
100
46
O
R
L
Y
S
Nu
M

11. CHIRAL AUXILIARIES
• Attached to the carbonyl compound
• Attached to the nucleophile
• Chiral acetals and a-ketoaldehydes
• Sulfoxides
• Organometallics
• Allylboranes, -silanes, -stannanes

12. AUXILIARY ATTACHED TO CARBONYL
MeO
O
PhN
N
H
H
R1
O
PhN
N
H
H
R1
OH
PhN
N
H
H
R1
MgBr R2
MgBr
R
2
d.e. 60-98%
Ph
O
PhN
N
H
H
Ph
OH
PhN
N
H
H
R
RTi(iPrO)3
d.e. > 97%
Ph
R
PhN
N
H
H
HO
RLi
d.e. ~ 60%
R
1
CHO
R2
OH

13. 1,3-OXATHIANES
O
O
S
1. BnSH, NaOH
2. Na/NH3
3. (CH2O)n, TsOH
1. BuLi
2. EtCHO
3. DMSO, TFAA, Et3N
O
S
Et
O
O
S
Et
nPrMgBr
HO
nPr
d.e. > 92%
N-CSI, AgNO3
Et
OHC
nPr
HO
O
S
O
+
O
S
Me
O
O
S
Me
HO
d.e. > 92%
MgCl2;
CH2=CHMgBr
O O
OH
Me
(R)-mevalolactone

14. TRANSITION STATE MODEL
PhN
N
H
R
1
O
H
Nu
MLn
O
S
Et
O
LnM
Nu

15. AUXILIARY ATTACHED TO NUCLEOPHILE
S
Tol O
Pri
Me
O
S
Tol
O
Me
S
Tol
O
CF3
OH
Ph
MeMgBr
1. LDA
2. PhCOCF3
d.e. ~ 50%
S
Tol
O
STol
S
Tol
O
STol
R OH
H
CHO
R OMe
H
BuLi;
RCHO
R = Ph, e.e. 70%
H
O
S
O
Li
Tol
H
STol
Ph

16. ORGANOMETALLIC: CHIRAL LIGAND
Ph OH
Me NH
SO2Tol
N
Ti
O Me
OiPr
SO2Tol
Ph
Me
Me
OH NO2
e.e. 90%
1. TiMe4
2. iPrOH
o-NO2C6H4CHO
OH
OH
O
O
Ti
OiPr
OiPr
Ph C10H7
OH
Ti(OiPr)3Cl 1. PhMgBr
2. C10H7CHO
e.e. > 98%

17. ALLYLIC NUCLEOPHILES
• Alternative route to aldol-type products
• Two new chiral centres introduced
• Complication: reaction at C-1
• Achiral reactants: syn and anti racemates
• Chiral reactants: in principle one major stereoisomer
R
1
CHO R2
MLn
+ R
1
OH
R
2
O3
Me2S
R
1
OH
CHO
R
2

18. CHIRAL BORON REAGENTS
MgBr
B
OiPr
OiPr
B
O
O
HO
OH
CO2iPr
CO2iPr
CO2iPr
CO2iPr
(iPrO)3B;
H3O+
B
O
O
CO2iPr
CO2iPr
K
BuLi,
tBuOK
K
BuLi,
tBuOK B
O
O
CO2iPr
CO2iPr
RCHO
R
OH
R'

19. EXAMPLES (1)
R H
O
B
O
O
R
CO2IPr
OH
CO2iPr
anti
+
R anti:syn e.e. %
n-C9H19 > 99:1 88
TBSOCH2CH2 > 97:3 85
tBu 95:5 73
n-C7H15CH=CH > 99:1 74

20. EXAMPLES (2)
R H
O
B
O
O
R
CO2IPr
OH
CO2iPr
+
syn
R anti:syn e.e. %
n-C9H19 3:97 86
TBSOCH2CH2 > 3:97 72
tBu > 1:99 70
n-C7H15CH=CH 3:97 62

21. EXAMPLES (3)
R H
O
B
O
O
R
CONHBn
OH
CONHBn
+
R e.e. %
n-C4H9 95
Ph 90
tBu 98
C6H11 99

22. TRANSITION STATE
B
O
O
CO2iPr
CO2iPr
O
B
O
O
CO2iPr
CO2iPr
H
R
RCHO
R
OH
Favoured
B
O
O
Pri
O2C
Pri
O2C
B
O
O
O
Pri
O2C
O
Pri
O
H
R
R
OH
RCHO
Disfavoured

23. SELECTIVITY: E → ANTI
B
O
O
R
CO2IPr OH
CO2iPr
anti
O
B
O
O
CO2IPr
CO2IPr
H
R
RCHO

24. DOUBLE ASYMMETRIC SYNTHESIS
B
O
O
CO2IPr
CO2iPr B
O
O
CO2IPr
CO2iPr
(R,R) (S,S)
OR
RO
CHO
(R,R): matched pair: 92 : 8
(S,S): mismatched pair: 13 : 87
RO RO
OH OH
+

25. ITERATIVE ASYMMETRIC SYNTHESIS
R1
CHO + R2
MLn
R
1
OH
R2
R
1
OP
R2
R
1
OP
CHO
R
2
+
R3
MLn
R
1
OP
R
2
OH
R
3
OSitBuPh2
CHO
Me
24
OMe
OMe
OMe
Me
O
Me
OAc
Me Me
O
Me Me
24
A B
C
D
Order of bond formation: A, B, C, D
Each with >90% stereoselectivity

26. DI ISO PINOCAM PHEYLBORANE
Me
Me
Me
Me
Me
Me
B
2
(-)-a-Pinene
Me
Me
Me
H3B-SMe2
Me
Me
Me
BH
2
MeOH
Me
Me
Me
BOMe
2
H2C=CHCH2MgBr
Me
Me
Me
B
2
(+)-a-Pinene (-)-Ipc2BH

27. ADDITION TO ALDEHYDES
Ipc2B
(-)-
RCHO
R
OH
R e.e. % Yield %
Me 93 74
Et 86 71
iPr 90 86
nBu 87 72
tBu 83 88
Ph 96 81

28. OTHER ALLYLIC BORANES
• High diastereoselectivity and enantioselectivity
• Reagent enantioselectivity overrides intrinsic chiral
aldehyde facial selectivity
• Consistent and predictable
• Also with a-chiral aldehydes
• Diamine-based ligands

29. ALLYLSILANES AND ALLYLSTANNANES
• Promoted by Lewis acids
• High diastereoselectivity
• ‘Cram controlled’
• “Chelation controlled’
CHIRAL CATALYSTS
• Organozinc catalysts
• Chiral amplification

30. CHIRAL LIGAND AS CATALYST
• Organometallic reagent must be relatively unreactive
towards C=O unless combined with the catalyst –
ligand acceleration.
• Catalyst must have suitable 3D structure to provide
high e.e.

31. DIALKYLZINC ADDITION TO ALDEHYDES
R CHO + Nu2Zn + (-)-DAIB (~2 mol%)
R Nu
OH
NMe2
Me
Me
Me
OH
(-)-3-exo-(dimethylamino)isoborneol (-)- DAIB
R Nu e.e., %
Ph Me
91
Ph Et
99
Ph Bu
98
p-Cl-Ph Et 93
p-MeO-Ph Et 93
2-Furyl C5H11 >95
(E)-C6H5-CH=CH Et 96
(E)-Bu3SnCH=CH C5H11 85
PhCH2CH2 Et 90

32. TRANSITION STATE MODEL
N
Me
Me
Me
O ZnA
Me
Me O
Nu
R
ZnB
Nu
Nu
H

33. AMINOTHIOCYANATE DERIVATIVES
RCHO + Et2Zn
R Et
H OH
L* (5 mol%)
RT
R2N SCN
Me Ph
L*
(R)
R Yield, % e.e., %
Ph 98
96
p-Cl-Ph 97 95
o-MeO-Ph 96 90
p-MeO-Ph 95 91
2-Naphthyl 95 93
C6H13 82 75

34. TRANSITION STATE?
Me
Ph
N
S
Zn
R
R
Et
Et
NC
O
H
R

35. CHIRAL AMPLIFICATION
• High catalyst optical
purity is not needed!

36. WHY AMPLIFICATION?
(-)-DAIB + (+)-DAIB
(75%) (25%)
(-)-DAIB/(-)-DAIB) (+)-DAIB/(+)-DAIB (-)-DAIB/(+)-DAIB
dimer dimer meso-dimer
Et2Zn
+
(50%) (50%)