1. Additions to carbonyl compounds
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

4. Addition to Cram Karabatsos
Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.

5. Addition to R S M L Nu d.e.% H Me Et Ph MeMgI EtMgBr PhMgBr EtMgI
PhMgI 33 43 50
>60 66 75 83
Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.

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

8. Nucleophile Approach
Anh, Bürgi-Dunitz

9. Chelation Control
J Amer Chem Soc 1990, 112, 6130.

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

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
Tetrah Lett 1991, 32, 2919

13. 1,3-Oxathianes

14. Transition state model

15. Auxiliary attached to nucleophile
J C S Perkin I 1981, 1278

16. Organometallic: Chiral ligand
Tetrah Lett 1986, 27, 5711

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

18. Chiral boron reagents

19. Examples (1) R anti:syn e.e. % n-C9H19 > 99:1 88
TBSOCH2CH2 > 97:3 85
tBu :5 73
n-C7H15CH=CH > 99:1 74

20. Examples (2) R anti:syn e.e. % n-C9H19 3:97 86 TBSOCH2CH2 > 3:97 72
tBu > 1:
n-C7H15CH=CH 3:

21. Examples (3) R e.e. % n-C4H9 95 Ph 90 tBu 98 C6H11 99
Chen, Eur J Org Chem 2005,

22. Transition state

23. Selectivity: E → anti

24. Double asymmetric synthesis

25. Iterative Asymmetric Synthesis
J Amer Chem Soc 1990, 112, 6348

26. Diisopinocampheylborane

27. Addition to aldehydes R e.e. % Yield % Me 93 74 Et 86 71 iPr 90 86
nBu
tBu Ph

28. Other allylic boranes High diastereoselectivity and enantioselectivity
Reagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivity
Consistent and predictable
Also with -chiral aldehydes
Diamine-based ligands

29. Allylsilanes and Allylstannanes
Promoted by Lewis acids
High diastereoselectivity
‘Cram controlled’
“Chelation controlled’

30. Chiral Catalysts
Organozinc catalysts
Chiral amplification

31. 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.

32. Dialkylzinc addition to aldehydes
R Nu e.e., %
Ph Me
Ph Et
Ph Bu
p-Cl-Ph Et
p-MeO-Ph Et
2-Furyl C5H >95
(E)-C6H5-CH=CH Et
(E)-Bu3SnCH=CH C5H
PhCH2CH2 Et
J Amer Chem Soc 1986, 108, 6071

33. Transition state model

34. Aminothiocyanate derivatives
R Yield, % e.e., % Ph
p-Cl-Ph
o-MeO-Ph
p-MeO-Ph
2-Naphthyl
C6H
Tetrahedron Letters 2005, 46(15),

35. Transition state?
Tetrahedron Letters 2005, 46,

36. Chiral amplification High catalyst optical purity is not needed!
J Amer Chem Soc 1989, 111, 4028

37. Why amplification?
(50%)
(50%)

38. Summary
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’

39. Questions ?