1

Applications of Atropisomerism: the Use and the Versatility of Enantioenriched BINOL Reagent in Organic Chemistry

Literature Meeting, January 13th 2009By Sebastien F.Vanier

2

Optically Active Metal Complex in Asymmetric Reaction: more then useful

OMe

O O

OMe

OH OH2

RuCl2(L)(DMF)2

100% yield, 99% ee Ph2P

Ph2PL =

Mohr, J.T. et al. J. Org. Chem., 1997, 62, 7092-7093

BO

O

OHO

H

Na2CO3 (20 mol%), PhMe, -78°C

99% yield, 95% ee

Hall, D. G. et al. J.Am.Chem.Soc., 2008 ,130, 8481-8490

Ph L-SnCl4 (5 mol%) Ph

OHHO

L =

Ar Me

OH

Ar Me

OH O

NH

Ru

TsN

(S,S)

L =

Ar Me

O

Ar Me

OH OH

R

H2

L, DMF

Noyori, R. et al. Angew. Chem. Int. Ed., 1998, 37, 1703-1707

50% yield, 92% ee after 36h

OO

H83% yield, 99% ee

cat. 123b

cat. 123b =

C6H6, Ar atm

Schrock, R. R. et al. Organometallics, 2002, 409-417

3

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

OH

OH

(S)-(-)-BINOL

OO

O

O

N

N

Crown Ether1

O

OLa O

Lewis Acid

Ex.: Nitroaldol reaction2, ketone reduction3

O

OAl X

POPh2

POPh2

Lewis Acid / Lewis Base

Ex.: ketone reduction4, Dield-Alder reaction5

O

OH

R

Chiral Auxiliary10,11

O

OTi

X

X

Lewis Acid

Ex.:Aldol reactions8, Allylation reaction9

O

OZr

O

O Lewis Acid

Ex.: Baylis-Hillman Reaction6, Aldol reaction7

1Cram, D. J. et al. J. Org. Chem., 1977, 42, 41732Shibasaki, M. et al. Angew. Chem. Int. Ed., 2002, 41, 36363Shibasaki, M. et al. J. Am. Chem. Soc., 114, 1992, 44194Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, 6709

5Wulff, W. D. et al. J. Am. Chem. Soc., 1993,115, 38146Kobayashi, S. et al. J. Am. Chem. Soc., 2000, 122, 8180-81867Wang, J. et al. Org. Lett., 2003, 5, 15278Keck, G. E. et al. J. Am. Chem. Soc., 1995, 117, 2363

9Keck, G. E. et al. J. Am. Chem. Soc., 1993, 115, 8467-846810Yamamoto, H. et al. J. Am. Chem. Soc., 1983, 105, 615411Yamamoto, H. et al. Tetrahedron, 1986, 42, 2203

4

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

OH

OH

(S)-(-)-BINOL

OO

O

O

N

N

Crown Ether1

O

OLa O

Lewis Acid

Ex.: Nitroaldol reaction2, ketone reduction3

O

OAl X

POPh2

POPh2

Lewis Acid / Lewis Base

Ex.: ketone reduction4, Dield-Alder reaction5

O

OH

R

Chiral Auxiliary10,11

O

OTi

X

X

Lewis Acid

Ex.:Aldol reactions8, Allylation reaction9

O

OZr

O

O Lewis Acid

Ex.: Baylis-Hillman Reaction6, Aldol reaction7

1Cram, D. J. et al. J. Org. Chem., 1977, 42, 41732Shibasaki, M. et al. Angew. Chem. Int. Ed., 2002, 41, 36363Shibasaki, M. et al. J. Am. Chem. Soc., 114, 1992, 44194Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, 6709

5Wulff, W. D. et al. J. Am. Chem. Soc., 1993,115, 38146Kobayashi, S. et al. J. Am. Chem. Soc., 2000, 122, 8180-81867Wang, J. et al. Org. Lett., 2003, 5, 15278Keck, G. E. et al. J. Am. Chem. Soc., 1995, 117, 2363

9Keck, G. E. et al. J. Am. Chem. Soc., 1993, 115, 8467-846810Yamamoto, H. et al. J. Am. Chem. Soc., 1983, 105, 615411Yamamoto, H. et al. Tetrahedron, 1986, 42, 2203

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 BINOLFirst 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)

OH

OH

Specific rotation: +/- 35.5° (THF, c = 1,0) mp: 205-211 °C5

1von Richter, V. et al. Chem. Ber., 1873, 6, 12522Zavada, J. et al. Tetrahedron, 1992, 48, 95033Pac, C. et al. J. Org. Chem., 1997, 62, 31944Bills, R. A. et al. Synth. Commun., 2002, 32, 20675Havlas, Z. et al. J. Org. Chem., 2003, 68, 5677

OH

CuCl(OH)-TMEDA (1 mol%)

O2, DCM, r.t., 1h, 92%2

CuSO4 / Al2O3 (20 mol%)

O2, DCM, r.t., 1h, 93%3

FeCl3. 6 H2O (2 mol%)

Microwaves, 40W, 20s, 95%4

or

or2-naphthol

rac BINOL

Neat! Open Pyrex tube!

7

Introduction: Easy Access to BINOLMechanistic example with FeCl31

1Iwata, S. et al. J. Org. Chem., 1989, 54, 3007; Wu, S. H. et al. Chin. J. Chem., 1996, 14, 561See also Matsuura, T. et al. Tetrahedron, 1996, 52, 1005

OH

H+

Fe3+Fe2+

O

O

Resonanceand coupling

OH H

O2OH

OH

rac BINOL

Oxydationand H+

Release

2-naphthol

8

Introduction: Easy Access to BINOLAsymmetric synthesis…

Most commonly, a chiral amine is used for the oxidative dimerization…(8 equiv. needed / 2 equiv. Metal)

Enzymatic procedure can be used too on a multigram scale usingBovine Pancreatic active3,4 component but…

OH

OH

1Bobbitt, J. M. et al. J. Chem. Soc., Chem. Commun., 1994, 25352Kazlauskas, R. J. et al. J. Am. Chem. Soc., 1989, 111, 49533Ikekawa, N. et al. J. Chem. Soc., Chem. Commun., 1985, 1333

OH

TEMPO modified GF

Charge passed / C = 5132(-)-sparteine 1 equiv., MeCN

r.t., 1h1,22-naphthol

(S)-BINOL94%, 99%ee

GF = Grafite felt

Usually, the chirality is not induced by the oxidativedimerization but by the stereoselective crystallizationof the complex (partial racemization), but…3

Radical species directed by complexation with chiral amine!1

9

Introduction: Easy Access to BINOLResolution 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)

OH

OH

rac BINOL

1Miyano, S. et al. Synthesis, 1990, 222

2Hu, B. F. et al. J. Org. Chem., 1995, 60, 73643De Lucchi, O. et al. J. Org. Chem., 1995, 60, 65994Buono, G. et al. J. Org. Chem., 1993, 58, 73135Tang, C. C. et al. Chin. J. Chem., 2002, 13, 617

1- POCl3

2- H2O, reflux

O

O

rac-1

P

O

OH

Phosphoric acid

THF, reflux +

separation of the salts(cristallisation), then hydrolysis

(R)-2-aminobutanol

OHH2N

O

O

(R)-1

P

O

OH

O

O

(S)-1

P

O

OH

LiAlH4

30% 3 steps100% ee

LiAlH4

15% 3 steps100% ee

(R)-BINOL (S)-BINOL

Later, it has been clamed that amine like optically active phenethylamines can increased yields up to 70%2,3

But attempts with (L)-Menthol derivatives are the best4,5

10

Introduction: Easy Access to BINOL

OH

OH

rac BINOL

1 Mak, T. C. W. et al. Chem. Lett., 1984, 20852Tanaka, K. J. et al. Org. Chem., 1988, 53, 3607

3Gilheany, D. G. et al. Tetrahedron: Asymmetry, 2003, 14, 27634Ding, K. et al. Tetrahedron Lett., 2002, 43, 52735Kumar, N. S. et al. Tetrahedron: Asymmetry, 1999, 10, 23076Ding, K. et al. Tetrahedron, 2000, 56, 4447; Kazlauskas, R. J. et al. Organic Syntheses, 9, 77

Chiral m-tolyl methyl sulfoxide1, chiral tartaric acid derivatives2, (1R,2R)-diaminocyclohexane3, (S)-proline derivatives4

and, more recently, (R)-R-methylbenzylamine5 can be used.

Chiral auxiliary*

Solvant

r.t. or heatprecipitate filtrate (in solution)

(S)- or (R)-BINOL>99%ee, good yields

(S)- or (R)-BINOL>99%ee, good yields

Chiral auxiliarycleavage

Resolution methodsChiral N-benzylcinchonidinium chloride6

The best one with >95% yield and >99%eefor each isomers

N

ClN

OH

Simplest and veryefficient technique

11

Atropisomerism: Introduction

1Cooke, A. S.; Harris, M. M. J. Chem. Soc., 1963, 23652Turner, E. E. et al. J. Chem. Soc., 1955, 1242

G = 23.5 kcal mol-1

t1/2 = 14,5 min., 50°C1

Racemization kinetics of optically active 1,1’-binaphthylwas studied by Cooke and Harris in 19631

Substituants introduced into the 2,2’-positionsstabilize drastically the chiral configuration

Ex.: (S)-1,1’-binaphthyl-2,2’-dicarboxylic acid could not be racemized at 175°C in DMF2

G Isomer BIsomer A

12

Atropisomerism: Introduction

OHAr

Ar

OH

12

3

4

(S)-isomerC2-symmetry = 180° for the other isomer

(R)-BINOL

Absolute configurations of chiral binaphthyl compoundswere originally proposed by Mislow1 (optical analysis)

1Mislow, K. et al. Angew. Chem., 1958, 70, 6832Mason, S. F. et al. J. Chem. Soc., Perkin Trans. 2, 1981, 1673Curtin, D.Y. et al. J. Am. Chem. Soc., 1980, 102, 7709; Pu, L. Chem. Rev., 1998, 98, 2405

13

BINOL in Chemical Reactions

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, 82Noyori, R. J. Am. Chem. Soc., 1979, 101, 3129 for reduction of aromatic ketones and aldehydes3Brunel, 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

Few attractions in BINOL’s antecedents

14

BINOL in Kinetic Resolution Strategies

O

O

O

O

H

OO

1Yamamoto, H. et al. Tetrahedron Lett., 1988, 29, 14172Yamamoto, H. et al. Tetrahedron, 1988, 44, 4747

(S)-BINOL 0.5 equiv.EtOH, 43%, 100% ee1

AlOt-Bu

Cl

Yamamoto reported for the first time the use of chiral binaphthyl organoaluminum reagent (1988)1

ViaMatched / Mismatchedaluminocomplexation

Then, there is several examples of Natural alkaloids in kinetic resolution3,4,5

ViaSteric complementary (matched chirality)

and specific intermolecular forcesOHOH

1Gao, L.-X. et al. Tetrahedron: Asymmetry, 2005, 16, 21412Zhou, Q. L. et al. Org. Lett., 2004, 6, 2381–23833Zhu, J. et al. Chem. Eur. J., 2003, 9, 2611–2615

N N

Ph

(R)-BINOL 0.5 equiv.EtOH, 43%, 100% ee1

rac 1-benzylisoanabasine

N N

Ph

15

In 2006, Berkessel’s group claimed a highly selective chemoenzymatic DKR of secondary alcohols using Nguyen’s works in the field…

Me

OH

OH

Me

or

Me

O

O

Me

or

1Harris, W. W. et al. Tetrahedron Lett., 1996, 37, 7623 – 76262Berkessel, A. et al. Angew. Chem., Int. Ed., 2006, 45, 6567

(R)-BINOL 10 mol%AlMe3 10 mol%

Novozym 435acylating agent (1.2 equiv.)

EtOH, 43%, 100% ee2

93% yield95% ee

98% yield99% ee

Me

O

Me

O

The BINOL-Al catalyst acts as a Racemizative Reagentin 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…)

R

OH

R

enzyme1

R

O

R R

OH

R

Me

O

????

1Harris, W. W. et al. Tetrahedron Lett., 1996, 37, 7623 – 7626; Nguyen, S. T. et al. Angew. Chem. Int. Ed., 2002, 41, 1020

BINOL in Kinetic Resolution Strategies

16

O O

Al

(S)Me

OH(S) Me

OH

Isomer thatdid not react

with the enzyme

O

Me

Side productof 1-phenylvinyl acetate

O O

Al

Me

O

H

O

Me

Me

O

Me

O

O O

Al

Me

O

Me

O

O O

Al

(R) Me

OH

Enzyme pathway

Asymmetric reduction

(acetone can be also use)

1Kurti L. and Czako B. Strategic Application of Named Reaction in Organic Synthesis, Elsevier Academic Press, 20052Jackman, L. M. and J. A. Mills. Mechanism of the Meerwein–Ponndorf Reduction, Nature, 164, 1949, 789-7903Nguyen, S. T. et al. J. Am. Chem. Soc., 2006, 128, 12596-12597

Here, (R)-BINOL is usedbut rac-BINOL has alsobeen tested

As the acylating agent hasthe same core than the s.m.,Acylation can directly be done…

O

AlO

H

O

O

R

R

R

R

BINOL in Kinetic Resolution Strategies

17

Reduction reaction: BINOL as a chiral reagent

O

OAl

H

H

Li

Known as (R)-BINAL-H

(1,1’-binaphthyl-2,2’-dioxy)hydridoaluminate

Prochiral carbonyl reduction is one of the most studied transformation1:

1Deloux, L.; Srebnik, M. et al. Chem. Rev., 1993, 93, 7632Noyori, R. et al. J. Am. Chem. Soc., 1979, 101, 5843; Noyori, R.; Takaya, H. et al. Chem. Scr., 1985, 25, 833Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, 6709-6717; Noyori, R. Chem. Soc. Rev., 1989, 18, 187

Metal complex as hydride reagent are use widely

First introduce by Noyori in 19792,3

O

OAl

H

H

LiOH

OHLiAlH4

1:1

THF

Easily prepared from (R)-BINOL

But first attempts were disappointing (2% ee)…(the two Hydrogen were homotopic)

18

Reduction reaction: BINOL as a chiral reagentModifications were taken by adding an alcohol on the reagent

1Noyori, R. et al. J. Am. Chem. Soc., 1979, 101, 5843; Noyori, R.; Takaya, H. et al. Chem. Scr., 1985, 25, 832Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, 6709-6717; Noyori, R. Chem. Soc. Rev., 1989, 18, 1873Suter, M. et al. J. Organomet. Chem., 2001, 621, 231

O

OAl

Hb

Ha

LiO

OAl

Hb

OEt

Li

EtOH 1 equiv.

(R)-(+)-BINAL-OEt

Now the chiral information can be efficiently transferred to the hydride3

High Enantioselectivities were obtainedfor several carbonyl compounds

19

Reduction reaction: BINOL as a chiral reagent

1Brunel, J. M. Chem. Rev., 2005, 105, 8572Noyori, R. et al. J. Am. Chem. Soc., 1984, 106, 6709-67173Noyori, R. Chem. Soc. Rev., 1989, 18, 187

Absolute configuration greatly influenced by:1,2,3

- steric effects

- various electronic factors including LUMO level and electron density at the carbonyl carbon

- flexibility of the molecule (liberty level), etc.

Al

OLi

O

CH

(Zimmerman-Traxler TS)

R

R

Et

O

O

(S)-BINAL-OEt

O

LiO

Al

HC

R

R

Et

O

O

VS

Al

OLi

O

CH R

EtO

O

O

(S)-BINAL-OEt

R

For unsaturatedcarbonyl

Disfavored TS: electronic repulsion effects

Only unsaturated and aromaticCompound are used…

20

Reduction reaction: BINOL as a chiral reagent

OH

OH

(S)-Binaphthol

P(NEt2)3

PhMe

O

O

BF3, THF

DCM

95% yield /2 steps>99% ee

P(NEt2)O

OP

NEt2

BF3

catalyst A

Reductive ‘phospholidine-borane’ system developed by Tang and coworkers1

1Tang, C. et al. Tetrahedron: Asymmetry, 1999, 10, 3259

Ph Me

O

BF3 THFcatalyst A (6 mol%)

toluene94%, 99% ee Ph Me

OH

21

Reduction reaction: BINOL as a chiral reagent

O

OTi

Cl

Cl

OH

OHTi(OiPr)2Cl2

1:1

4Å Mol. sieves

Et2O

2

catalyst B (dimer)Et2O

O

OTi

OiPr

OiPr

2

catalyst C (dimer)

(R)-BINOL

1Emma, H.; Mori, M.; Nakai, T. Synlett, 1996, 1229

Reductive Ti-BINOL system developed by Nakai and coworkers1

R Me

O

HSi(OEt)3catalyst C 10 mol%

Et2O, 50°C, 5h R Me

OH

Entry yield (%)ee (%)

abs. config.12

34

5678

9

>98>98

>98>98

>98847751

86

55 (R)52 (R)

53 (R)54 (R)

49 (R)45 (R)31 (R)

R

Php-MeOPh

p-ClPhnaphthyl

H

n-C6H13

p-NO2Ph

c-C6H13

I88 (S)

76 (S)

22

Reduction reaction: BINOL as a chiral reagentBut further examination of the reaction showed some enantioselective autoinduction1

1Emma, H.; Mori, M.; Nakai, T. Synlett, 1996, 1229

23

Entry yield (%)ee (%)

abs. config.123456

857980858480

96 (R)96 (R)98 (R)93 (R)94 (R)94 (R)

R1 R2

PhPhMeEtMe

Mei-Pr

1-naphthyl

Me(CH2)4

c-Hexyl

Ph

Me

N(Ph)2P

O

Reduction reaction: BINOL as a chiral reagent

OHOH

(S)-BINOL 1.2 equiv.

R1 R2

N(Ph)2P

Me Me

OH

O

R1 R2

NH(Ph)2P

Me Me

O

O

4 equiv.

AlMe3 1.2 equiv.PhMe, 60°C

In 2006, Nguyen’s group reported an efficient asymmetric Imine reduction1

(Enantioselective Meerwein-Schmidt-Ponndorf-Werley reduction)

1Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett., 2006, 8, 1229

Ligand-acceleratedreaction

(increasing Al L.A.)

24

Nonlinear Effect (NLE) with BINOL

Ge n

erat

ed e

e %

Chiral aux. or catalyst ee %

Positive NLE: Optical purity of the products of a given reaction can exceed the optical purity of the catalysts (or chiral auxiliaries)

Direct. Prop. effect

Kagan’spioneering workon asymmetricAmplification1

(sulfide oxidationand epoxidation)

1Kagan, H. B. J. Am. Chem. Soc., 1986, 108, 2353; Kagan, H. B. J. Am. Chem. Soc., 1994, 116, 94302Mikami, K. and Nakai, T. J. Chem. Soc., Chem. Commun., 1990, 16233Mikami, K.; Terada, M. et al. Tetrahedron, 1992, 48, 5671

Negative NLE

Positive NLE

Mikami and Nakai reported a remarkable level of positive NLE in Ene reaction2,3:

Ph CO2MeH

O (R)-BINOL (X% ee), TiBr2(iOPr)21:1 (1 mol %)

DCM, r.t.92% average yield

Ph CO2Me

OH

up to 91% ee

Only 35-40% ee is good enough toprovide the same level of enantiomericexcess as enantiopure BINOL!

Chiral Ti complex derivedfrom a 100% ee BINOL reacts 35 times faster! (dimers stabilisation)2,3

25

Nonlinear Effect (NLE) with BINOLMikami and Nakai’s explanation of the diastereoisomers stabilisation1,2

1Mikami, K.; Nakai, T. et al. J. Chem. Soc., Chem. Commun., 1994, 8332Matsumoto, Y. and Mikami, K. Chem. Commun., 1997, 2813Kagan, H. B. Angew. Chem. Int. Ed., 1998, 37, 2922-2959

3D RepresentationsOf Titanium complex1

(R,R)-BINOL-Tidimer

(S,R)-BINOL-Tidimer

More Stable from 1.08 kcal/molLess prone to reacts!

DIMER / MONOMER EQUILIBRIUM

O

OTi

iOPr

iOPr

O

OTiPrOi

PrOi

O

OTi

iOPr

iOPr

O

OTiPrOi

PrOi

(R,R)-BINOL-Tidimer

(S,R)-BINOL-Tidimer

For a 40% ee mixture(70% R, 30% S)

Inactive30%

Active once separated20%

O

OTi

iOPr

iOPr

O

OTiPrOi

PrOi

(S,S)-BINOL-Tidimer

0%

See alsoMikami, K. et al. J. Chem. Soc. Chem. Commun., 1990, 1623 Mikami, K. et al. Synlett., 1992, 255; Mikami, K. Tetrahedron, 1992, 48, 5671Mikami, K. et la. Adv. Asymmetric Synth., 1995, 1

26

R1 R2

O (R)-La catalyst 5 mol%TBHP

4Å Mol. sievesTHF, r.t.

R1 R2

OO

Entry yield (%) ee (%)

123

939383

838688

R1 R2

PhPh

Me

Phi-Pr

Ph

In 1997, Shibasaki’s group claimed a Lanthanum-BINOL catalytic system1,2

(In attempts to develop new heterometallic chiral catalysts)

1Shibasaki, M. et al. J. Am. Chem. Soc., 1997, 119, 23292Shibasaki, M. et al. Angew. Chem., Int. Ed., 2004, 43, 3173Shibasaki, M. et al. J. Am. Chem. Soc., 1995, 117, 6194

Enantioselective epoxidation reactions

O

OLa

OH

OHLa(OiPr)3

1:1

4Å Mol. sieves

THF, r.t.

active Catalyst Ln(still under investigation)

(R)-BINOL

OiPr

n

Since Ln complexes areuseful in Michael addition3

Also, they observedsome Asymmetricamplification in the reaction!

27

In attempt to find a mechanism, Shibasaki’s group studied some additives1,2,3

1Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett., 1998, 39, 73532Shibasaki, M. et al. Tetrahedron Lett., 2000, 41, 9569-9574

Enantioselective epoxidation reactions

- 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%

Me

O (R)-BINOL catalyst 25 mol%TBHP 2 equiv.

4Å Mol. sievesTHF, r.t.

Entry catalyst (1:1) yield (%) ee (%)

1234567

88289889559492

83209791759694

Yb–(R)-BINOLLa–(R)-BINOLLa–(R)-BINOLLa–(R)-BINOLLa–(R)-BINOLLa–(R)-BINOLYb–(R)-BINOL

Time

15252.54

252

48

additive (mol %)

--

O=PPh3 (100)O=PPh3 (25)

O=AsPh3 (100)O=AsPh3 (25)

water

MOMO

Me

O

MOMO

O

1:1 ration is neededfor La-BINOL-As complex

28

R1 R2

O (R)-La catalyst 10 mol%O=AsPh3 10 mol %

TBHP 2 equiv.4Å Mol. sieves

THF, r.t.

R1 R2

OO

Entry yield (%) ee (%)

123

999594

969498

R1 R2

PhPh

t-Bu

Phi-PrPh

45

9289

9995

MePh

Me C5H11

Optimization of the last attempts with Shibasaki’s new methodology1

1Yamaguchi, K.; Shibasaki, M. et al. J. Am. Chem. Soc., 2001, 123, 2725

Enantioselective epoxidation reactions

Based on X-RayOf the La-complex

29

C-C Bond Formation: Aldol reactionUtilisation of BINOL-Ti complex in C-C bond reaction are frequent

O

OTi

R

R

30

C-C Bond Formation: Aldol reaction

O

OTi O

H

O

R

20 mol %

-78oC, PhMe*t-BuO

OSit-BuMe2

Proposed catalyst; Prepared with (R)-BINOL,Ti(i-OPr)2O and benzene...

OH

Rt-BuO

O

*

Entry yield (%) ee (%)

1

2

3

4

91

91

98

98

60

44

80

85

R

Ph

p-ClPh

B-naphthyl

(E)-PhCH=CH

*PhMe is important whileDCM did not afford any ee

1Mukaiyama, T.; Inubushi, A.; Suda, S.; Hara, R.; Kobayashi, S. Chem. Lett., 1990, 1015

In 1990, Mukaiyama reported the use of BINOL-Ti complex in Aldol Reaction1

Usually, an acyclic antiperiplanar transition state is proposed

31

O

OTi

Cl

H

O

R

5 mol %

0oC, PhMeEtS

OSiMe3 OH

REtS

O

Entry yield (%) ee (%)

1

2

3

4

81

60

61

84

94

91

85

95

R

BnOCH2

n-C8H17

i-Pr

n-BuO2C

ClPrepared with 1:1 mixtureof (R)-BINOL and Ti(i-OPr)2Cl2O

OTi

Cl

H

O

R

5 mol %

0oC, PhMeEtS

OSiMe3 OH

REtS

O

Entry yield ee (%)

1

2

3

85

60

72

90

98

90

R

BnOCH2

n-BuO2C

ClPrepared with 1:1 mixtureof (R)-BINOL and Ti(i-OPr)2Cl2

Me

Me

t-BuS

OSiMe3

Me

BnOCH2

syn / anti

72:28

92:8

8:92

C-C Bond Formation: Aldol reaction

1Mikami, K. and Matsukawa, S. J. Am. Chem. Soc., 1994, 116, 4077

Then Mikami optimized the reaction by changing the BINOL-Ti complex1

O

O

R3Si

SR1

Me

H

H

RTiCl2

O

O

O

O

R3Si

SR1

Me

H

H

RCl2Ti

O

O

E/Z formation: syn product

TS Z-eq

O

R1S OSiR3

Me

R H

Cl2Ti

O

O

Silatropic ene transitionstates

E formation: syn product Z formation: anti product

TS E-eq

When –SR1 is to much bulky, Zimmerman-Traxler model can be applied1

32

O

OTi

Cl

Cl

H

O

CO2Me

5 mol %

4Å Mol. sieves0oC, DCM

OSiMe3

CO2Me

OH

Entry yield ee (% of E)

1

2

3

99

99

77

silyl ether E/Z

4>99

98:2

R1

OSiMe3

R2

R2

R1

5

Me

OSiMe3

Me

Me

OSiMe3

Me

Me

OSiMe2 t-Bu

Me

Me

OSiMe2 t-Bu

Me

Et

OSiMe3

>99

syn/anti

58

54

73

71

67

94:6

96:4

84:16

95:5

98:2

73:27

- -

-

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

C-C Bond Formation: Ene reaction

33

O

H

OSiR3

R2

H

H

CO2R4 R1

Cl2Ti

O

OO

H

OSiR3

R2

H

H

CO2R4

R1

TiCl2

O

O

Z formation

H H

O

H

OSiR3

R2

HH

CO2R4 R1

Cl2Ti

O

O*

O

H

OSiR3

R2

H

H

CO2R4

R1

Cl2Ti

O

OH

H

E formation

TS Z-ax TS Z-eq

TS E-ax

Z, antiZ, syn

TS E-eq

C-C Bond Formation: Ene reaction

1Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M. Angew. Chem. Int. Ed. Engl., 1997, 36, 27682Yudin, A. K. et al. Chem. Rev., 2003, 103, 3155

Z and syn selectivitydirected by allylic strainand steric repulsion withthe carbonyl/Ti complex

BINOL chiralitydirects the Re faceattack2

34

O

OTi

Cl

Cl

olefinH

O

CO2Me

x mol %

4Å Mol. sievesDCM, r.t.

R CO2Me

OH

Entry yield (%) ee (%)

1

2

3

97

72

68 (9:1)

97

95

75

olefin cat. mol%

482 83

Ph Me

Me Me

Et Et

10

1

10

Several studies have been donewith many catalytic system butBINOL-Ti system was the best

The Greatest contribution in the field done by Nakai and Mikami1,2

C-C Bond Formation: Ene reaction

O

OTi

Cl

Cl

OH

OHTi(OiPr)2Cl2

1:1

4Å Mol. sieves

Et2O

2

BINOL-Ti catalyst(R)-BINOL

1Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc., 1989, 111, 19402Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc., 1990, 112, 3949

35

In the development of their aldol reaction, Mikami obtained surprising results2

BINOL in Friedel-Crafts Reaction

H

O

R2

R3

OSiR3

OH

R2R3

O

R1

*R1

Cat.*

Mukaiyama-aldol reaction

1Mikami, K. et al. Tetrahedron Lett., 1997, 38, 7021-7024; Meyer, C. et al. Tetrahedron Lett., 1996, 37, 375-3782Mikami, K. et al. Org. Lett., 1999, 1, 2013

One of the most fundamental C-C bond formation reaction1

H

O

R2

R3

OSiR3

OH

R2R3

O

R1

*R1

Cat.*

Mukaiyama-aldol reaction

OH

R2R3

OSiR3

R1

*Friedel-Crafts reaction

[H+]

[E+]

OH

R2R3

O

R1

*E

*

*syn

36

BINOL in Friedel-Crafts Reaction

H

O

CF3

R1

OSit-BuMe2

R2

OH

CF3R1

Me2t-BuSiO

R2H

O

OTi

Cl

Cl

20 mol %

4Å Mol. sieves0oC, DCM

Entry yieldee

(% of Z)

1

2

3

98

94

95

silyl ether E/Z

4

Ph

OSit-BuMe2

p-MePh

OSit-BuMe2

Me

p-MeOPh

OSit-BuMe2

Me

67

77

68

1:5

1:6

1:5

yield ofB

OH

CF3R1

O

R2

B

67

10

22

p-MeSPh

OSit-BuMe2

Me 95721:6 18

Binaphthol is newly introduced by Mikami and coworkers1

1Mikami, K. et al. Org. Lett., 1999, 1, 2013

OH

CF3Ph

Me2t-BuSiO

MeTBAF

THF / H2O, r.t.

MCPBA

MeOH, r.t.

OH

CF3Ph

O

Me

60%, >95 de

OH

OH

CF3Ph

O

Me

quant., 92 de

Steric silyl group is needed (inter. attack)Aromatic group stabilize the charge

37

O

OTi

Cl

Cl

20 mol %

0oC, DCMMeO H

O

CF3MeO

CF3

HO H

Entry yield A / B

1

2

3

4:1

4:1

4:1

ligand cat.

82

11

94

30

5

5

ee(% of B)

73

22

84

(mol%)

(R)-H8-BINOL

(R)-BINOL

(R)-6,6'-Br2-BINOL

R

R

MeO

CF3

HO

H

A B

BINOL in Friedel-Crafts Reaction

OR1

TiCl2

O

R2H

O O*

Ortho position ifthis transition stateis generated(via 6 m-r.)

Few years later, the same group optimized a real Friedel-Crafts reaction1

1Mikami, K. et al. J. Org. Chem., 2000, 65, 1597-15992Yudin, A. K. et al. Chem. Rev., 2003, 103, 3155

Need of a stronger Lewis Acid2

38

Chemistry of BINOL as a Chiral AuxiliaryIntroduced as a leaving group in limonene synthesis1,2:

1Maruoka, K. and Yamamoto, H. J. Am. Chem. Soc., 1983, 105, 61542Maruoka, K. and Yamamoto, H. Tetrahedron, 1986, 42, 2193

antiperiplanardeparture

O

*M

O

* Generated fromthe chiral auxiliary

Main goal: mimic the biogenetic pathway

Proceed via ametal-anchimeric assistance

39

OH

OH

(R)-(+)-Binaphthol

O

HO

1- TMSCl 1.1 equiv., TEA, THF, 3h

2- Neryl bromide 1.1 equiv., NaHTHF/HMPA, 1d; acid work-up

45-50% yield over 2 steps

D-limonene

77% ee

Ali-BuOTf

Enantiofacialdifferentiationenhanced(Than DIBAL for ex.)

CF2Cl2

54%

1Maruoka, K. and Yamamoto, H. J. Am. Chem. Soc., 1983, 105, 61542Maruoka, K. and Yamamoto, H. Tetrahedron, 1986, 42, 21933Cho, J. H. et al. Bull. Korean Chem. Soc., 1989, 10, 323

Recuperation of the chiralauxiliary is also possible Since these experiments,

BINOL has been consideras C.A. in Terpene synthesis,affording acceptable e.e 1,3

This part blocksThe front face

Chemistry of BINOL as a Chiral Auxiliary

40

1Hosoi, D.; Fuji, K. et al. Tetrahedron Lett., 1989, 30, 28252Fuji, K. J. Am. Chem. Soc., 1995, 117, 121593Ireland, R. E. et al. J. Am. Chem. Soc., 1976, 98, 2868

In 1989, Hosoi and coworkers introduced BINOL in Aldol reactions1,2:

OH

OH

(R)-BINOL

O

OH

CO2H

X OX

1- LDA, HMPT, THF-78°C, 30 min.

2- RX, -78°C, 4h.

O

OH

O

X

R

O

X

R

HO

H2SO4 conc. Unsubstituted aryl

R = Me: 93% yield, 72% de (without HMPA, 8h) Me: 85% yield, 54% de (with HMPA, 30 min.) n-Bu: 90% yield, 56% de

allyl: 84% yield, 64% de

i-Pr: 95% yield, 86% de

80-100% yield

ViaZ-enolate also for steric reasons...3

de higher without HMPA...

EWG or EDG had noremarkable effect on de

Poor selectivity withsmall alkylating reagent

76-97% yield

ee's up to 97%

Conclusion: Kinetic Control

from the Naphthyl coreand the directing hydroxyl group

Here, a substituted phenylgroup is used: otherfunctions are also possiblewith high ee vinyl, crotyl,etc.)

O

O

LiO

Ph

Li

Li

O H

Ph

O

LiO

E-enolateZ-enolate

H

O

O

LiO

H

Li

Li

O Ph

H

O

LiO

Ph

Favored Unfavored

O

Ph

H O

O

Favoredwithout HMPA

Better de but lower yield1...

Pi staking?!

Li Li

Li

OH

Ph

O

OLi

With HMPA,less or no chelation

Chemistry of BINOL as a Chiral Auxiliary

41

1Fuji, K. et al. Tetrahedron: Asymmetry, 1996, 7, 17712Fuji, K. et al. Tetrahedron: Asymmetry, 1990, 31, 65533Fuji, K. et al. Tetrahedron: Asymmetry, 1991, 32, 7281

In 1996, Fuji’s group upgraded their methodology in amino acids synthesis1,2,3:

O

OH

O

1- LDA, HMPT, THF-78°C, 30 min.

2- RX, -78°C, 4h.

O

OH

O

RNHBz

O

R

HO

O

OH

O

N

Ph

Ph

R

N Ph

Ph

NHBz

1- HCl aq., THF

2- BzCl, DIPEA, DCM

R = Me: 62% yield, 82% de

allyl: 66% yield, 72% de

acetate: 71% yield, 86% de

CN: 77% yield, 80% de

(R)-amino acid

3 steps from (R)-BINOL

(R)-BINOL0.5N NaOH

MeOH / H2O

O

O

LiO

N

Ph

PhLi Li

O H

NPh

Ph

O

Si -face approach

Z-enolate formation

LiOH

Chemistry of BINOL as a Chiral Auxiliary

421Hosoi, D.; Fuji, K. et al. Tetrahedron Lett., 1989, 30, 28252Fuji, K. J. Am. Chem. Soc., 1995, 117, 12159

Optically active ß-substituted carboxylic acid can be obtained1,2: (via Michael addition)

O

OH

O

R1

HO

O

R1

O

OH

O

R1

R'

HO

O

R1

R'M

O

OH

O

Me2CuLi, THF

-78°C, 30 min.

O

OH

O

Ph Ph

Me

OMe2CuLi, THF

-78°C, 30 min.

O

OH

O

Ph

Ph

Me

1,4-addition followed by 1,2-additionfor a new one-pot synthesis ofchiral bêta-substituted ketone

OMe2CuLi 10 equiv., Et2O/PhMe0°C, 60 min.

84% yield, 87% ee

O

OH

O

Ph

Ph

Me

1,4-addition followed by 1,2-additionfor a new one-pot synthesis ofchiral bêta-substituted ketone

Via Keteneformation

Less cuprate reagent decrease both yield and eeIDEM with lower temperature (ketene formation disfavoured)

Chemistry of BINOL as a Chiral Auxiliary

431Hosoi, D.; Fuji, K. et al. Tetrahedron Lett., 1989, 30, 28252Fuji, K. J. Am. Chem. Soc., 1995, 117, 12159

Chemical Mechanistic proposed for the Gilman reagent addition:

O

O

O

Li

Li

Cu

Me Me

Intramolecular deliveryfrom the reagent captured bythe phenolic hydroxyl group claimed

O

O

HO

OLi

Ph

Ph

Me

Me

O

Ph

MeAddition ofanother

Gilman reagentthen quench

Based on:

-Masking or hiding the hydroxy group (lower ee)

-X-ray analysis of the naphthyl ester

- Polar solvant decreasing ee

Best overlap of the HOMOof the cuprate: Si-face approach

H

Chemistry of BINOL as a Chiral Auxiliary

441Fuji, K. J. Am. Chem. Soc., 1995, 117, 121592Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett., 1989, 30, 2825

With the same starting reagents, the other isomer is accessible!1,2

OMeMgBr-CuI 10 equiv., Et2O/THF

0°C, 30 min.73% yield, 48% ee

O

OH

O

Ph

Ph

Me

O

O

O

Mg

Re-face approach

Mg

Me

MeX

X

CuMe

Me

Mg

Me

Me

Chemistry of BINOL as a Chiral Auxiliary

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 youBut what you can do with some BINOL