1. Applications of Atropisomerism: the Use and the Versatility of Enantioenriched BINOL Reagent in Organic Chemistry
Literature Meeting, January 13th 2009
By Sebastien F.Vanier

2. Optically Active Metal Complex in Asymmetric Reaction: more then useful

3. Chiral 1,1’-Binaphthyl-2,2’-diol in Organic Reactions: Few Examples…

4. Chiral 1,1’-Binaphthyl-2,2’-diol in Organic Reactions: Few Examples…

5. Presentation Overview
Introduction: BINOL’s synthesis and chirality
Enantiomeric resolution strategies: Metal complex catalyst
Reduction and epoxidation reactions: Chiral reagent
C-C Bond formation: Chiral Lewis Acid
BINOL as a Chiral auxiliary
Conclusion

6. Introduction: Easy Access to BINOL
First racemic synthesis in 1873 by von Richter1
Then the preparation of racemic BINOL has been widely studied… here few methods
Oxidative coupling of 2-naphthol using FeCl3, K3Fe(CN)6 Mn(acac)3, Cu-amine complexes or
TiCl4 are commonly used with yields up to 90% (Brunel, J. M., Chem. Rev., 2005, 105, 857)

7. Introduction: Easy Access to BINOL
Mechanistic example with FeCl31
1Iwata, S. et al. J. Org. Chem., 1989, 54, 3007; Wu, S. H. et al. Chin. J. Chem., 1996, 14, 561
See also Matsuura, T. et al. Tetrahedron, 1996, 52, 1005

8. Introduction: Easy Access to BINOL
Asymmetric synthesis…
Most commonly, a chiral amine is used for the oxidative dimerization…
(8 equiv. needed / 2 equiv. Metal)
Usually, the chirality is not induced by the oxidative
dimerization but by the stereoselective crystallization
of the complex (partial racemization), but…3
Enzymatic procedure can be used too on a multigram scale using
Bovine Pancreatic active3,4 component but…
Radical species directed by complexation with chiral amine!1

9. Introduction: Easy Access to BINOL
Resolution methods (all based on diastereoselective isolation with a chiral auxiliary)
Jacques and coworkers were the first but… (90% ee and 26% yield for (S)-BINOL)
But attempts with (L)-Menthol derivatives are the best4,5

10. Introduction: Easy Access to BINOL
Resolution methods
Simplest and very
efficient technique

11. Atropisomerism: Introduction
Racemization kinetics of optically active 1,1’-binaphthyl
was studied by Cooke and Harris in 19631
Substituants introduced into the 2,2’-positions
stabilize drastically the chiral configuration
Ex.: (S)-1,1’-binaphthyl-2,2’-dicarboxylic acid could not be
racemized at 175°C in DMF2

12. Atropisomerism: Introduction
Absolute configurations of chiral binaphthyl compounds
were originally proposed by Mislow1 (optical analysis)
(R)-BINOL
1Mislow, K. et al. Angew. Chem., 1958, 70, 683
2Mason, S. F. et al. J. Chem. Soc., Perkin Trans. 2, 1981, 167
3Curtin, D.Y. et al. J. Am. Chem. Soc., 1980, 102, 7709; Pu, L. Chem. Rev., 1998, 98, 2405

13. BINOL in Chemical Reactions
Few attractions in BINOL’s antecedents
First applied as a chiral phase transfert by Cram in 19781
Its potential as chiral ligand for metal-mediated catalysis was first recognized by Noyori in 19792
Since 1990, enantioenriched BINOL have become among the most widely used ligands for both stoichiometric and catalytic asymmetric reactions3
1Cram, D. et al. J. M. Acc. Chem. Res., 1978, 11, 8
2Noyori, R. J. Am. Chem. Soc., 1979, 101, 3129 for reduction of aromatic ketones and aldehydes
3Brunel, J. M. Chem. Rev., 2005, 105, 857; Yudin, A. K. et al. Chem. Rev., 2003, 103, 3155
Pu, L. Chem. Rev., 1998, 98, 2405; Salvadori, P. et al. Synthesis (Rev.), 1991, 503

14. BINOL in Kinetic Resolution Strategies
Yamamoto reported for the first time the use of chiral binaphthyl organoaluminum
reagent (1988)1
Then, there is several examples of Natural alkaloids in kinetic resolution3,4,5
Via
Matched / Mismatched
aluminocomplexation
Via
Steric complementary (matched chirality)
and specific intermolecular forces

15. BINOL in Kinetic Resolution Strategies
In 2006, Berkessel’s group claimed a highly selective chemoenzymatic DKR of secondary alcohols using Nguyen’s works in the field…
The BINOL-Al catalyst acts as a Racemizative Reagent
in this Meerwein–Ponndorf–Verley / Oppenauer reaction
(1-phenylvinyl acetate as the acylating agent gives acetophenone as the
by-product, which acts as a hydrogen acceptor…)
1Harris, W. W. et al. Tetrahedron Lett., 1996, 37, 7623 – 7626; Nguyen, S. T. et al. Angew. Chem. Int. Ed., 2002, 41, 1020

16. BINOL in Kinetic Resolution Strategies
Here, (R)-BINOL is used
but rac-BINOL has also
been tested
As the acylating agent has
the same core than the s.m.,
Acylation can directly be done…
1Kurti L. and Czako B. Strategic Application of Named Reaction in Organic Synthesis, Elsevier Academic Press, 2005
2Jackman, L. M. and J. A. Mills. Mechanism of the Meerwein–Ponndorf Reduction, Nature, 164, 1949,
3Nguyen, S. T. et al. J. Am. Chem. Soc., 2006, 128,

17. Reduction reaction: BINOL as a chiral reagent
Prochiral carbonyl reduction is one of the most studied transformation1:
Metal complex as hydride reagent are use widely
Easily prepared from (R)-BINOL
First introduce by Noyori in 19792,3
But first attempts were disappointing (2% ee)…
(the two Hydrogen were homotopic)
1Deloux, L.; Srebnik, M. et al. Chem. Rev., 1993, 93, 763
2Noyori, R. et al. J. Am. Chem. Soc., 1979, 101, 5843; Noyori, R.; Takaya, H. et al. Chem. Scr., 1985, 25, 83
3Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, ; Noyori, R. Chem. Soc. Rev., 1989, 18, 187

18. Reduction reaction: BINOL as a chiral reagent
Modifications were taken by adding an alcohol on the reagent
Now the chiral information can be efficiently transferred to the hydride3
High Enantioselectivities were obtained
for several carbonyl compounds
1Noyori, R. et al. J. Am. Chem. Soc., 1979, 101, 5843; Noyori, R.; Takaya, H. et al. Chem. Scr., 1985, 25, 83
2Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, ; Noyori, R. Chem. Soc. Rev., 1989, 18, 187
3Suter, M. et al. J. Organomet. Chem., 2001, 621, 231

19. Reduction reaction: BINOL as a chiral reagent
Only unsaturated and aromatic
Compound are used…
1Brunel, J. M. Chem. Rev., 2005, 105, 857
2Noyori, R. et al. J. Am. Chem. Soc., 1984, 106,
3Noyori, R. Chem. Soc. Rev., 1989, 18, 187

20. Reduction reaction: BINOL as a chiral reagent
Reductive ‘phospholidine-borane’ system developed by Tang and coworkers1
1Tang, C. et al. Tetrahedron: Asymmetry, 1999, 10, 3259

21. Reduction reaction: BINOL as a chiral reagent
Reductive Ti-BINOL system developed by Nakai and coworkers1
1Emma, H.; Mori, M.; Nakai, T. Synlett, 1996, 1229

22. Reduction reaction: BINOL as a chiral reagent
But further examination of the reaction showed some enantioselective autoinduction1
1Emma, H.; Mori, M.; Nakai, T. Synlett, 1996, 1229

23. Reduction reaction: BINOL as a chiral reagent
In 2006, Nguyen’s group reported an efficient asymmetric Imine reduction1
(Enantioselective Meerwein-Schmidt-Ponndorf-Werley reduction)
Ligand-accelerated
reaction
(increasing Al L.A.)
1Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett., 2006, 8, 1229

24. Nonlinear Effect (NLE) with BINOL
Mikami and Nakai reported a remarkable level of positive NLE in Ene reaction2,3:
Kagan’s
pioneering work
on asymmetric
Amplification1
(sulfide oxidation
and epoxidation)
Positive NLE
Direct. Prop. effect
Negative NLE
Only 35-40% ee is good enough to
provide the same level of enantiomeric
excess as enantiopure BINOL!
Positive NLE: Optical purity of the products of a given reaction can exceed
the optical purity of the catalysts (or chiral auxiliaries)
Chiral Ti complex derived
from a 100% ee BINOL reacts
35 times faster! (dimers stabilisation)2,3
1Kagan, H. B. J. Am. Chem. Soc., 1986, 108, 2353; Kagan, H. B. J. Am. Chem. Soc., 1994, 116, 9430
2Mikami, K. and Nakai, T. J. Chem. Soc., Chem. Commun., 1990, 1623
3Mikami, K.; Terada, M. et al. Tetrahedron, 1992, 48, 5671

25. Nonlinear Effect (NLE) with BINOL
Mikami and Nakai’s explanation of the diastereoisomers stabilisation1,2
3D Representations
Of Titanium complex1
(R,R)-BINOL-Ti
dimer
(S,R)-BINOL-Ti
dimer
More Stable from 1.08 kcal/mol
Less prone to reacts!
DIMER / MONOMER EQUILIBRIUM
1Mikami, K.; Nakai, T. et al. J. Chem. Soc., Chem. Commun., 1994, 833
2Matsumoto, Y. and Mikami, K. Chem. Commun., 1997, 281
3Kagan, H. B. Angew. Chem. Int. Ed., 1998, 37,
See also
Mikami, K. et al. J. Chem. Soc. Chem. Commun., 1990, 1623
Mikami, K. et al. Synlett., 1992, 255; Mikami, K. Tetrahedron, 1992, 48, 5671
Mikami, K. et la. Adv. Asymmetric Synth., 1995, 1

26. Enantioselective epoxidation reactions
In 1997, Shibasaki’s group claimed a Lanthanum-BINOL catalytic system1,2
(In attempts to develop new heterometallic chiral catalysts)
Since Ln complexes are
useful in Michael addition3
Also, they observed
some Asymmetric
amplification in the reaction!
1Shibasaki, M. et al. J. Am. Chem. Soc., 1997, 119, 2329
2Shibasaki, M. et al. Angew. Chem., Int. Ed., 2004, 43, 317
3Shibasaki, M. et al. J. Am. Chem. Soc., 1995, 117, 6194

27. Enantioselective epoxidation reactions
In attempt to find a mechanism, Shibasaki’s group studied some additives1,2,3
- Increasing the L.A. of the complex
Directing the epoxidation by attraction
with the peroxide reagent
Generating a more appropriate
chiral environment
And with a single recrystallization,
ee were increase to >99%
1Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett., 1998, 39, 7353
2Shibasaki, M. et al. Tetrahedron Lett., 2000, 41,

28. Enantioselective epoxidation reactions
Optimization of the last attempts with Shibasaki’s new methodology1
Based on X-Ray
Of the La-complex
1Yamaguchi, K.; Shibasaki, M. et al. J. Am. Chem. Soc., 2001, 123, 2725

29. C-C Bond Formation: Aldol reaction
Utilisation of BINOL-Ti complex in C-C bond reaction are frequent

30. C-C Bond Formation: Aldol reaction
In 1990, Mukaiyama reported the use of BINOL-Ti complex in Aldol Reaction1
Usually, an acyclic antiperiplanar
transition state is proposed
1Mukaiyama, T.; Inubushi, A.; Suda, S.; Hara, R.; Kobayashi, S. Chem. Lett., 1990, 1015

31. C-C Bond Formation: Aldol reaction
Then Mikami optimized the reaction by changing the BINOL-Ti complex1
When –SR1 is to much bulky, Zimmerman-Traxler model can be applied1
1Mikami, K. and Matsukawa, S. J. Am. Chem. Soc., 1994, 116, 4077

32. C-C Bond Formation: Ene reaction
Nakai and Mikami expand their system in the Mukaiyama Aldol Reaction1…
1Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M. Angew. Chem. Int. Ed. Engl., 1997, 36, 2768

33. C-C Bond Formation: Ene reaction
Z and syn selectivity
directed by allylic strain
and steric repulsion with
the carbonyl/Ti complex
BINOL chirality
directs the Re face
attack2
1Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M. Angew. Chem. Int. Ed. Engl., 1997, 36, 2768
2Yudin, A. K. et al. Chem. Rev., 2003, 103, 3155

34. C-C Bond Formation: Ene reaction
The Greatest contribution in the field done by Nakai and Mikami1,2
1Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc., 1989, 111, 1940
2Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc., 1990, 112, 3949

35. BINOL in Friedel-Crafts Reaction
In the development of their aldol reaction, Mikami obtained surprising results2
One of the most fundamental C-C bond formation reaction1
1Mikami, K. et al. Tetrahedron Lett., 1997, 38, ; Meyer, C. et al. Tetrahedron Lett., 1996, 37,
2Mikami, K. et al. Org. Lett., 1999, 1, 2013

36. BINOL in Friedel-Crafts Reaction
Binaphthol is newly introduced by Mikami and coworkers1
Steric silyl group is needed (inter. attack)
Aromatic group stabilize the charge
1Mikami, K. et al. Org. Lett., 1999, 1, 2013

37. BINOL in Friedel-Crafts Reaction
Few years later, the same group optimized a real Friedel-Crafts reaction1
Need of a stronger Lewis Acid2
1Mikami, K. et al. J. Org. Chem., 2000, 65,
2Yudin, A. K. et al. Chem. Rev., 2003, 103, 3155

38. Chemistry of BINOL as a Chiral Auxiliary
Introduced as a leaving group in limonene synthesis1,2:
Main goal: mimic the biogenetic pathway
Proceed via a
metal-anchimeric assistance
1Maruoka, K. and Yamamoto, H. J. Am. Chem. Soc., 1983, 105, 6154
2Maruoka, K. and Yamamoto, H. Tetrahedron, 1986, 42, 2193

39. Chemistry of BINOL as a Chiral Auxiliary
This part blocks
The front face
Recuperation of the chiral
auxiliary is also possible
Since these experiments,
BINOL has been consider
as C.A. in Terpene synthesis,
affording acceptable e.e 1,3
1Maruoka, K. and Yamamoto, H. J. Am. Chem. Soc., 1983, 105, 6154
2Maruoka, K. and Yamamoto, H. Tetrahedron, 1986, 42, 2193
3Cho, J. H. et al. Bull. Korean Chem. Soc., 1989, 10, 323

40. Chemistry of BINOL as a Chiral Auxiliary
In 1989, Hosoi and coworkers introduced BINOL in Aldol reactions1,2:
Conclusion:
Kinetic Control
from the Naphthyl core
and the directing hydroxyl group
Here, a substituted phenyl
group is used: other
functions are also possible
with high ee
vinyl, crotyl,etc.)
1Hosoi, D.; Fuji, K. et al. Tetrahedron Lett., 1989, 30, 2825
2Fuji, K. J. Am. Chem. Soc., 1995, 117, 12159
3Ireland, R. E. et al. J. Am. Chem. Soc., 1976, 98, 2868

41. Chemistry of BINOL as a Chiral Auxiliary
In 1996, Fuji’s group upgraded their methodology in amino acids synthesis1,2,3:
1Fuji, K. et al. Tetrahedron: Asymmetry, 1996, 7, 1771
2Fuji, K. et al. Tetrahedron: Asymmetry, 1990, 31, 6553
3Fuji, K. et al. Tetrahedron: Asymmetry, 1991, 32, 7281

42. Chemistry of BINOL as a Chiral Auxiliary
Optically active ß-substituted carboxylic acid can be obtained1,2:
(via Michael addition)
Less cuprate reagent decrease both yield and ee
IDEM with lower temperature
(ketene formation disfavoured)
1Hosoi, D.; Fuji, K. et al. Tetrahedron Lett., 1989, 30, 2825
2Fuji, K. J. Am. Chem. Soc., 1995, 117, 12159

43. Chemistry of BINOL as a Chiral Auxiliary
Chemical Mechanistic proposed for the Gilman reagent addition:
1Hosoi, D.; Fuji, K. et al. Tetrahedron Lett., 1989, 30, 2825
2Fuji, K. J. Am. Chem. Soc., 1995, 117, 12159

44. Chemistry of BINOL as a Chiral Auxiliary
With the same starting reagents, the other isomer is accessible!1,2
1Fuji, K. J. Am. Chem. Soc., 1995, 117, 12159
2Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett., 1989, 30, 2825

45. Future Literature Meeting Works…
Substituted BINOLs are also possible for new or improved asymmetric reactions
Good precursor to other chiral ligand like BINAP: opening to new applications
Sky’s the limit with this excellent chirality generator

46. Conclusion
Easily accessible, BINOL can be buy and/or synthesized in an asymmetric manner or by resolution of the racemic mixture with high recovery yields of the chiral reagents
Versatile reagent that can be use in many reactions with good to excellent yields and enantiomeric excess
BINOL shows also great selectivity in many other reactions like hydrogenation reactions and crown ethers- phase transfert reactions

47. Thank you Do not ask what BINOL can do for you
But what you can do with some BINOL