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