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Non-Linear Effects inAsymmetric Catalysis: A
Useful Tool in UnderstandingReaction Mechanisms
Group MeetingAaron Bailey12 May 2009
What is a Non-Linear Effect?In asymmetric catalysis, the ee (er) of theproduct can be predicted based on theenantiopurity of the chiral substrate (auxiliaryor ligand)
eemax= eeproduct/eeauxiliary
By using this equation a linear correlation isobtained (line a)
However, this equation cannot hold true for all reactions as aggregation of ligands occursfrequently to form homochiral and heterochiral (meso) complexes
When products are obtained in higher enantiopurity than predicted a (+)-NLE is observed(curve d & c)Likewise, if a lower enantiopurity is obtained that what is predicted a (–)-NLE is observed(curve e & b).
Kagan, H. B. et al. Angew. Chem. Int. Ed., 2009, 48, 456-494.Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357.
First Observed Reports
Asymmetric sulfideoxidation displayed(–)-NLE effectsdependent on purity andconcentration ligand
Curve A= stoichiometricamounts of reagents
Curve B= Sub-stoichiometric amounts(0.5 eq Ti)
Me
SMe
Me
SMe
O
Ti(Oi-Pr)4
DET, H2O, t-BuOOH
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357
First Observed Reports
Asymmetric epoxidationdisplayed(+)-NLE effects
Ti(Oi-Pr)4
DET, H2O, t-BuOOH
O
OH
OH
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357
Revision of Asymmetric ModelML*2 Model (Differences in Reactivity)
Metal complexes can (if enantioenriched) form homochiral systems(MLRR & MLSS) as well as heterochiral (meso) dimers (MLRS).
Revision of mathematical modeleemax≠ eeproduct/eeauxiliary must apply correction factor eeproduct=eemaxeeauxiliaryƒ
Ƒ=(1+β)/(1 + gβ) if fast equilibrium occurs between complexes
then β=
Where β is the relative amount of meso- to chiral-type complexes in solutionAnd g is the relative reactivity of the meso-type complex with respect to the chiral complex
Kagan, H. B. et al. J. Am. Chem. Soc. 1994, 116, 9430-9439.
Reservoir Model
eeeff= eeaux-αeeres/(1- α)
Note: Both models can operate independently but manyreactions display both such NLE’se.g. if a dimeric (meso) complex is completely inactive and anenergy sink ML2 equation simplifies toeeprod= ee0eeaux(1+β)
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357
Higher Order Systems-ML3, ML4ML3 ML4
At least 4 possible structuresMLRRR MLRSR MLRSS MLSSSAll will be chiral
Homochiral complexgive greaterselectivity thatheterochiral complex
Heterochiralcomplex giveshigher selectivityand is morereactive
Five possible structure:MLRRRR, MLRRRS, MLRRSS, MLRSSS, MLSSSS
Assumes statistical distribution between ligands
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357
Asymmetric Sulfide Oxidation
Me
SMe
Me
SMe
O
Ti(Oi-Pr)4
DET, H2O, t-BuOOH
From experiment Calculated data overlay with experimental
Observing NLE’s and using derived equations a mechanistic hypothesis can be proposed:Data consistent with ML4 system
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357
Asymmetric EpoxidationTi(Oi-Pr)4
DET, H2O, t-BuOOH
O
OH
OH
Active catalyst in solution
Ligand “reservoir” or inactive dimer
Ti
O
Ti
O
O
CO2Et
CO2Et
O
OR
RO
OROR
CO2Et
CO2Et
meso
Ti
O
Ti
O
O
CO2Et
CO2Et
O
OR
RO
OROR
CO2Et
CO2Et
Homochiral dimer
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357Sharpless, K. B., et al. J. Am. Chem. Soc. 1991, 113, 106-113.Sharpless, K. B., et al. J. Am. Chem. Soc. 1991, 113, 113-126.
Proposing Mechanisms using NLEs
A large (+)-NLE was observed using catalyticamount of DAIB ligand
A 1:1 ligand:Zn results in no alkylationOptimal reaction conditions used 1:2stoichiometry
Propose a mechanism that accounts for theobserved NLE.
Which model does it fit? MLn? Reservoir? Orboth?
O
H ZnEt2
NMe2
OH
Et
OH
toluene, 0 º, 6 h
97 %,
99:1 er
*
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357.Noyori, R. et. al. J. Am. Chem. Soc. 1989, 111, 4028-4036.Noyori, R. et. al. J. Am. Chem. Soc. 1986, 108, 6071-6072.
Mechanistic Proposal I
Based on early kinetic, NMR, and stoichiometric studies the mechanism above was proposedThis does not necessarily account for the dramatic NLE observedNoyori, R. et. al. J. Am. Chem. Soc. 1989, 111, 4028-4036.
Reservoir Effect in ZnEt2 Additions
Homochiral and Heterochiral dimers forming in solutionExperimental observations sugges KDHomo=3x10–2
KDMeso=1x10–5
MO calculations predict meso complex energetically favored by 3.1 kcal/mol
Noyori, R. et. al. J. Am. Chem. Soc. 1995, 117, 6327-6335.
Absence of NLE in ZnEt2 AdditionsStudy wanted to examine stereochemical controlling elements offerrocene ligands.
Proposed TS
Due to linear correlation between ee ofligand and product, authors could ruleout possibility of inactive aggregates(MLn) or reservoir effect
Bolm, C. et al. J. Org. Chem. 1998, 63, 7860-7867.
Other NLE in Organometallic Rxns
H
OOMe
TMSO
OH
N
HO
Me
CO2H
MeO
1. L1/A1/Ti(OiPr)4
2. TFAO
O
Ph
L1
A1
O
BnOH
OTMS
StBu
N
ON
N
O
Cu
2+
2 SbF6–
CH2Cl2
BnO
OH O
StBu
Ph Ph
Both examples show significant (+)-NLE’s
Elucidation of the mechanisms was achieved by observing NLE
Both are thought to proceed via the reservoir model- meso-Dimer favored by 2.9 kcal/mol
Ding, K. et al. Chem. Eur. J. 2002, 8, 5033-5042.
Evans, D. A. et al. J. Am. Chem. Soc. 1999, 121, 669-685.
NLE in Organocatalytic Reactions
H
O
Me
O
N
H
Me
Me
Me
Me
O
H
O
Three possible roles of catalystsJørgensen, K. A. et al. J. Org. Chem. 2003, 68, 4151-4157.
(–)-NLE Provides Mech. InsightsPresence of (–)-NLE indicates more thanone molecule of chiral amine present instereodefining step
Eq 5 is proposed mechanism with iminiumintermediate and enamine formation occurring
Matched-Mismatched case proposed to beresponsible for lower selectivity
N
Me
Jørgensen, K. A. et al. J. Org. Chem. 2003, 68, 4151-4157.
Juliá-Colonna EpoxidationO
H2O2, NaOH
poly-L-leucine
OO
Originally proposed catalytic pocket shownKelly, D. R. et al. Chem. Comm. 2004, 2021-2022.Kelly, D. R. et al. Chem. Comm. 2004, 2018-2020.
(+)-NLE Observed for PLLBased on ML2 system described previously, assuming statistical mixture of monomer and dimeramino acid residues as well as the heterodimer chains are not-reactive the following equationcan be deduced
Kelly, D. R. et al. Chem. Comm. 2004, 2021-2022.Kelly, D. R. et al. Chem. Comm. 2004, 2018-2020.
Revision of Mechanism
5 Leucine residues matched theamount of asymmetric amplificationobserved as well as the rate (amount ofactive catalyst)
Stereocontrolling element
H-bonding assists epoxide formation
Kelly, D. R. et al. Chem. Comm. 2004, 2021-2022.Kelly, D. R. et al. Chem. Comm. 2004, 2018-2020.
Asymmetric Allylations
Kinetic data coupled with NLE led to conclusion that twophosphoramide ligands present in stereodetermining step
Mechanistic experiments utilizing bisphosphoramideligands further supported hypothesis of two ligandspresent in stereodefining step
Denmark, S. E. et al. J. Am. Chem. Soc. 2000, 122, 12021-12022.Denmark, S. E. et al. J. Org. Chem. 2006, 71, 1513-1522.
Asymmetric Openings of meso-Epoxides
Observation of (–)-NLE along with kinetic datasuggests two phosphoramides present inmechanismWas able to rule out reservoir effect and productinhibition
Bisphosphoramide catalysts did not improveselectivities
Rate=–dprod/dt=K[HMPA]2[epoxide]
Denmark, S. E. et al. Adv. Syn. Cat. 2007, 349, 567-582.
Proposed Mechanism
Denmark, S. E. et al. Adv. Syn. Cat. 2007, 349, 567-582.
False Positives in NLE Systems
Initial studies by Kaganled to the conclusionthat a (–)-NLE waspresent
Recent studies have concluded the absenceof a NLE
Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357List, B. et al. J. Am. Chem. Soc. 2003, 125, 16-17.List. B. et al. J. Am. Chem. Soc. 2003, 125, 2475-2479.
Solubility Differences
Homochiral dimers less stabilized by H-bonding compared to HeterochiralBut how does this explain observed (–)-NLE?
Hayashi, Y. et al. Angew. Chem. Int. Ed. 2006, 45, 4593-4597.
Method of Amino Acid AdditionIn experiments, L-Proline and D-Proline were added separately causing the solids to have aconglomerate equilibrium in the solvent
Blackmond, D. G. et al. Angew. Chem. Int. Ed. 2006, 45, 7989-7992Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353-2357
Autoinduction/AutocatalysisA + B
A + B
Cat. P
Cat.-P P
OEt
OEtH
O O
Et
L (5 %)
ZnEt2 (10 %)
MS, toluene
O
EtOEt
EtO
OH
Trost, B. M. et al. J. Am. Chem. Soc. 2004, 126, 2660-2661.
L=
NLE and Autocatalysis- A BriefIntroduction
N
N
H
O
Zn
N
N
OH
N
N
OH
(0.0005 % ee)
99 % ee
Based on kinetic data observed adimeric complex is believed to bethe mechanism; however, thishypothesis is speculative anddebate is ongoing
Soai, K. et al. Tet. Asymmetry, 2001, 12, 1965-1969Soai, K. et al. Nature, 1995, 378, 767-768Soai, K. et al. Chirality, 2002, 14, 548-554.
Conclusions• The observation of NLE’s can have significant mechanistic
implications
• Careful analysis of the effect coupled with kinetic data,theoretical calculations, and isolation of intermediates can helpelucidate mechanisms
• The fundamental theory behind NLE’s has contributed to muchof the debate centered around asymmetricamplification/autocatalysis and the evolution of chirality theories
