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Aspects of Asymmetric Nucleophilic Amine Catalysis:Organocatalyst Design and Implementation
MacMillan Group MeetingIan Storer
February 28, 2005
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Asymmetric Nucleophilic CatalysisOutline
! Introduction to
N-centred nucleophilic catalysts
! Design, development and application of asymmetric nucleophilic catalysts
!concepts and definitions
!origins and requirements
!Natural alkaloid catalysts - Precejus, Wynberg
!Biomimetic histidine containing peptide catalysts - Miller
!
Synthetic alkaloid analogues - Lectka, Hatekeyama, Deng
Useful Reviews:
!
Fance, S.; Guerin, D. J.; Miller, S. J.; Leckta, T., Nucleophilic Chiral Amines as Catalysts inAsymmetric Synthesis. Chem Rev.2003, 103, 2985-3012.
!Fu, G. C. Asymmetric Catalysis with "Planar-Chiral" Derivatives of DMAP. Acc. Chem. Res.2004,37, 542-547.
!Asymmetric DMAP equivalents - Fuji / Fu
!Miller, S. J. In Search of Peptide-Based Catalysts for Asymmetric Organic Synthesis. Acc. Chem.Res. 2004, 37, 601-610.
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Definitions
! Nucleophilic Catalysis
Catalysis by a Lewis base, involving formation of a Lewis adduct as a reaction intermediate. For example,the esterification of anhydrides catalysed by DMAP:
O
OR R
O
O R
O
Lewis base
Lewis base complex
N
Lewis base
! Lewis base
OH
R1 R3
R2N
NMe Me
N
NMe Me
O RO R
O
R3
R1
R2
IUPAC Compendium of ChemicalTerminology
A molecular entity (and the corresponding chemical species) able to provide a pair of electrons and thuscapable of coordination to a Lewis acid, thereby producing a Lewis adduct.
The catalyst has to be a very effective nucleophile and a good leaving group .
! Implication on Choice of catalyst
N
MeMe
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Useful Nucleophilic Catalysts
! Commonly applied 'everyday' nucleophilic catalysts
N
NMe Me
! Common applications
N
N
N N
HN
Nucleophilic Aromatic Amines nucleophilic teriary amines
! Ineffective bases: Nucleophilicity highly sensitive to steric and electronic factors
N
DABCOImidazolePyridineDMAP
good Bronsted bases, poor nucleophilic catalysts
Me N Me N MeMe Me
Me
picoline lutidine collidine
!O-acylation - electrophile activation (pyridine, DMAP)!O-silylation - electrophile activation (imidazole, DMAP)!Baylis-Hilman reaction - nucleophile activation (DABCO, DMAP)
N
N
PPY
N
N
Me
NMI
N
Et
EtEt
TEA
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Cinchona Alkaloids: Earliest Successful Nucleophilic Asymmetric Catalysts
!First used for a resolution of a racemate in 1853 by Pasteur.
N
R1
HOH
H
N
H
Cinchonidine (CD)Quinine (QN)
R1= H
R1= OMe
pseudoenantiomers
N
R1
HHO
N
H
Cinchonine (CN)Quinidine (QD)
R1= H
R1= OMe
H
!Asymmetric Bronsted bases!Asymmetric phase transfer reagents (as salts)!Asymmetric bifunctional catalysts (acid / base)!Asymmetric nucleophilic catalysts
!Several modes of application
Moncure, R. MacMillan Group Meeting, 2003, web. contains a more fully discussion of cinchona alkaloids
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QuinidinePracejus (1964)Wynberg (1983)Simpkins (2001)
site of quaternary saltformation, nucleophilicaddition or basicity
site of modification
site of modification:ether/ ester formation
site of inversion ofconfiguration (epi alkaloids)-pseudoenantiomers
Alkaloids and Derivatives as Nucleophilic Catalysts
! Natural alkaloids
N
OMe
H
N
OH H
O O
O O
N OMe
N
Et
H
N
Et
NMeO
(DHQD)2AQNDeng
N
Me
O
N
OH
Hatakeyama
N
OMe
N
O H
benzoylquinineLectka (2000)
O
! Synthetically modified analogues
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Seminal Findings: Pracejus Methanolysis of Ketenes
!Pracejus proposed a mechanism involving QN activation of methanol.
N
OMe
H
N
OH H
QuinidineMe Ph
O12 mol % quinidine
MeOH, 110 C
up to 76% ee
Precejus, H.; Mtje, H. J. Prakt. Chem. 4. Reihe. 1964, 24, 195.Precejus, H.; Santleben, R. J. Prakt. Chem. 1972, 314, 157.
O
OMePh
Me
NHR3
O
OMePh
Me
NMeO
H
N
HO
Hselective
protonationH
OMe
+MeOH
H-bond activation
!Simpkins proposes alternative nucleophilic mechanism
Me3Si Bn
O
10 mol % quinidine
benzene, 78 C 79-93% ee
O
SPhBn
SiMe3
NMeO
H
N
HO
H
PhSH
O
NR3Bn
SiMe3
selectiveprotonation
Blake, A. J.; Friend, C. L.; Outram, R. J.; Simpkins, N. S.; Whitehead, A. J. Tetrahedron Lett. 2001, 42, 2877.
SPh
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Development of Functionalised Alkaloid Analogues:Catalytic Asymmetric Cycloadditions
!!-lactone synthesis: Romo's expansion of Wynberg's method
N
OMe
HN
O H
Acyl-quinidine
H
O
CCl2R2 O
O
R
2
Cl2C
R1= H, alkyl, arylR2= Cl, alkyl
O
Me
R
1
O
ClR1
O
NR3
R1Base: iPr2NEt
PhMe, 25 C
>90% ee
!The use of pre-acylated catalyst stops unwanted acylation of the catalyst during the reaction.
!Applies a stoichiometric, non-nucleophilic base to turn over the catalyst.
!In situ ketene generation
!Solubility of the Hunigs salt may be crucial to catalyst turnover.
Tennyson, R.; Romo, D. J. Org. Chem. 2000, 65, 7248.
2 mol% cat.
R3Ncat.
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Development of Functionalised Alkaloid Analogues:Catalytic Asymmetric Cycloadditions
N
OMe
H
N
O H
Benzoyl-quinidine
O
!
!-lactam synthesis: Lectka
NO
EtO2C R1
O
ClR1
O
NR3
R
1
N
CO2EtH
Ts
N
CO2EtH
Ts
O
NR3
R
1
EtO2C
NTs
R3Ncat.
10 mol% cat.PhMe, 78 C
Base: proton sponge or K2CO3or NaH
Ts 45-65% yield
95-99% ee25-99:1 dr
Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J.; Lectka, T. J.. J. Am. Chem. Soc. 2000, 122, 7831.Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J.. J. Am. Chem. Soc. 2002, 124, 6626.
cat.
!'Shuttle deprotonation' using excess of a thermodynamic, non-nucleophilic base.!Concomitant Lewis acid activation of the imine later provided better yields
!Proposed transition state
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Development of Functionalised Alkaloid Analogues:Catalytic Asymmetric Halogenation
N
OMe
H
N
O H
Benzoyl-quinidine
O
!Halogenation: Lectka
O
ClR1
10 mol% cat.
THF, 78 C
Base: BEMP orK2CO3or NaH
Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Lectka, T. J. J. Am. Chem. Soc. 2001, 123, 1531.Hafez, A. M.; Taggi, A. E.; Wack, H.; Esterbrook, J.; Lectka, T. J. Org. Lett. 2001, 3, 2049.
Taggi, A. E.; Wack, H.; Hafez, A. M.; France, S.; Lectka, T. J. Org. Lett. 2002, 4, 627.
OCl
ClCl
Cl
Cl
Cl
O
BrBr
Br Br
MeN NMeP
NEt2NBut
10 mol% cat.
THF, 78 C
Base: BEMP orK2CO3or NaH
O
ClR1
O
OR1
Br
Br
Br
Br
O
OR1
Cl
Cl
Cl
Cl
Cl
Cl
65-85% yield99% ee
55-80% yield>90% ee
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Deng's Application of bis-quinuclidines
N
MeO
O
H
N
H
Et
N N
Ph
Ph
O
N
OMeH
H
N
Et
catalyst
!Mechanism of asymmetric induction not well understood
!Cyanation
O
OEtR3N
CN NC
R1
R2
OO
OEtR3N
Deng, L. et al. J. Am. Chem. Soc. 2001, 123, 7475.
R1
O
R2 NC
O
OEt
10-35 mol% catalyst
CHCl3, 12 to 24 C0.5 - 7 days
NC
R1R2
O
O
OEt
R1
O
R2
R3Ncat.
O
O
O
R
R
MeOH5-30 mol% catalyst
Et2OOMe
OH
O
O
R
R
( )n( )n
Deng, L. et al. J. Am. Chem. Soc. 2000, 122, 9542.
!Desymmmetrization of meso anhydrides
52-78% yield87-97% ee
70-99% yield90-98% ee
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Designing Asymmetric Variants of Known Nucleophilic Amine Catalysts
! Considerations
! Synthetic chiral analogues of common nucleophilic heterocycles
!Must be nucleophilc, but maintain good leaving group ability!Must have a valid chiral pocket to transfer asymmetry to product.
FeN
NMeMe
Ph
Ph
Ph
Ph
Ph N
N
H H
OH
Synthetic chiral DMAP equivalents
Fu (1998-current)
N
N
BocHNO
O
NH
NH
Me
Me Me
O
Synthetic chiral imidazole equivalents
Miller
O O
O O
N OMe
N
Et
H
N
Et
NMeO
(DHQD)2AQNDeng
N
OMe
H
N
OH H
QuinineWynberg
N
Me
O
N
OH
Hatakeyama
! Alkaloids and analogues
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Biological Role of Nucleophilic Catalysis
Admiraal, S. J.; Herschlag, D.; J. Am. Chem. Soc., 1999, 121, 5837-5845
!Phosphorylation transfer from ATP is ubiquitous in biological chemistry.!
Histidine often serves as in vivoacceptors of the !-phosphate of ATP.!Proposed mechanism of ATPases and nucleoside diphosphate kinase (NDPK).
O
OH OH
AOPO
O
O
P
O
O
OP
O
O
OO
OH OH
AOPO
O
O
P
O
O
OP
O
O
E
NH
N
O
E
NH
N
ATP
! Mechanism of some kinases - role of histidine
ADP
NDP3 E
NH
N
NTP4fast
!First in vitro example of imidazole participating in phosphoryl transfer from ATP analogues.!N-nucleophiles found to react 30-100 fold faster than O-nucleophiles at physiological temperatures.!Carried out in vitro experiments on ATP.!Supports proposed enzymatic mechanism.
OP
O
O
O P
O
O
NH
N
O
NH
NH2O
NH
N
HOPO32
fast
NO2 O NO2
! In vitro phosphorylation of imidazole
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Miller N-Methyl Imidazole-Containing Tripeptide
! Synthesis of a nucleophilic tripeptide
Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.
N
N
BocHNO
O
NH
NH
Me
Me Me
O
N
N
H2N
OH
O
N
N
BocHNO
O
NH
NH
Me
Me Me
O
MeO
Ac2O
OAc
acyl imidazolium
!Peptide-substrate interactions are crucial for the fidelity by which an enzyme imparts its selectivity.
!Incorporating an amino acid residue as an analogue of known nucleophilic catalyst N-methyl imidazolium (NMI).
!Work focused on peptides that had propensity to form stable secondary structures (!-turn) in solution.
! Modularity of peptide-based systems allows for the rapid synthesis and screening of many analogues.
!Initial designs drew heavily from the peptide design literature in order to generate a relatively rigid !-turn structure
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Miller Chiral Imidazole Tripeptide:Kinetic Resolution of Alcohols
! Kinetic resolution of amino-alcoholscatalyst
anti, racemic
10 equiv
O
Me O Me
O
5 mol% catalyst0 C
Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.
NHAc
OH
NHAc
OH
NHAc
O Me
O1.0 equiv CH3CN = 12% eeCH2Cl2 = 40% eePhMe = 84% ee (S = 12.6)
!Amide in amino-alcohols necessary for good levels of stereoinduction
!Non-polar solvents which favour H-bonding work best
!Replacement of the amide with an ester provides only poor selectivity
N
N
BocHNO
O
NH
NH
Me
Me Me
O
! Kinetic resolution of mono-acylated diols
anti, racemic
10 equiv
O
Me O Me
O
5 mol% catalyst0 C
OAc
OH
OAc
OH
OAc
O Me
O1.0 equivPhMe = 14% ee
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Probing Origins of Selectivity
! Diastereomeric catalysts display enantiodivergence
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 4306.
Harris, R. F.; Nation, A. J.; Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2000, 122, 11270.
NN
BocHNO
O
NH
NH
Bn
O
OMe
Me Me
O
!Changing a single stereocentre in the catalyst causes a change in secondary structure.
!
Changing a single stereocentre in the catalyst causes a complete switch in enantioselectivity.
! What is the mechanism of binding and role of the peptide backbone structure?
H
Me
N
O
O
NH
NH
Bn
O
OMe
Me Me
OH
HN
N
Me
Boc
S = kSS/ kRR= 3.1 S = kRR/ kSS= 28
L-Pro D-Pro
anti, racemic10 equiv
O
Me O Me
O
5 mol% catalyst0 C
NHAc
OH
NHAc
OH
NHAc
O Me
O1.0 equiv
! Test System: Kinetic resolution
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Miller: Development of a Fluorescence Assay
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc.. 1999, 121, 4306.Harris, R. F.; Nation, A. J.; Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc.. 2000, 122, 11270.
! Development of a fluorescence probe for rapid reaction conversion analysis
N
O
OMe
H
OAc
N
O
OMe
Non-Fluorescent Fluorescent
!Fluorescence intensity is a function of acetic acid concentration
!Assisted rapid catalyst discovery.
AcOH
! Kinetic resolution of amino-alcohols
O
Me O Me
O
catalyst
NHAc
OH
NHAc
OH
NHAc
O Me
O1.0 equivAcOH
reaction byproduct
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Fuji Chiral DMAP Equivalent:Kinetic Resolution of Alcohols
! Kinetic Resolution of Alcohols catalyst
syn, racemic
O
Bui O iBu
O
5 mol% catalysttoluene, rt, 2-5 h
Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169-3170.
! Induced-fit Mechanism
N
N
H
H
OH
OCOR
OH
OCOR
OH
OCOR
O iBu
O0.7 equiv81->94% ee
68-72% conv.
N N
H H
HO
H
H
open conformation
NN
H H
reactive, closed conformation
OH
O
H
Me
Me
Nu
!
First non-enzymatic chiral resolution of alcohols
!
Take advantage of charged Lewis adduct!Cation-p interaction holds transition state rigid
O
Bui O iBu
O
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Fu - Planar Chirality: Kinetic Resolution of Alcohols
! Kinetic Resolution of Alcohols
FeN
NMeMe
Ph
Ph
Ph
Ph
Ph
catalyst
OH
R1 R2
racemic
O
Me O Me
O
2 mol% catalystEt3N,t-amyl alcohol
OH
R1 R2
O
R1 R2
O
Me
Me
OH
tBu
OH OHCl
Me
OH
F
Me
OH
Me
OH
Me
OH
Me
99% ee55% conv.
99% ee55% conv.
99% ee55% conv.
99% ee55% conv.
99% ee55% conv.
99% ee55% conv.
99% ee55% conv.
Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492-1493.Ruble, J. C.;Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794-2795.
! Very high enantioselectivities for Aryl and Cinnamyl alcohols
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Fu Chiral DMAP: Origins of Enantioselectivity
!Acetyl rotamer consistent with minimization of sterics between the methyl Rgroup and ferrocene.
!Selectivity increases as the size of the alkyl group Rincreases.
!Nucleophile approaches from the top face of the DMAP catalyst.
! Geometry of acyl rotamers
FeN
NMeMe
Ph
Ph
Ph
Ph
PhO
Me
FeN
NMeMe
Ph
Ph
Ph
Ph
PhMe
O
HH
Favoured rotamer Disfavoured rotamer
! Crystal Structure of Acyl salt
FeN
NMeMe
Ph
Ph
Ph
Ph
PhO
Me
Nu
Nu
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! The substrate amine is nucleophilic enough to add directly to most acylating agents careful selection of acylating reagent proved necessary to render no background reaction
Kinetic Resolution of Amines
!First non-enzymatic acylation catalyst for kinetic resolution of amines
FeN
Ph
Ph
Ph
Ph
Ph
catalyst
NH2
Ar Me
racemicCHCl3, 50 C
NH2
Ar Me
HN
Ar Me
O
Me
Me
NH2
Me
NH2
s=12 s=27
Arai, S.; Laponnaz-Bellemin, S.; Fu, G. C. Angew. Chem. Int. Ed., 2001, 40, 234-236.
! Very high enantioselectivities for Aryl and Cinnamyl alcohols
NO
OMeO
N
O
!-naph
But
Me
NH2
s=22
MeO
NH2
s=16
Me
10 mol% catalyst
reacts faster with catalystthan substrate amine
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Rearrangement of O-Acylated Azalactones
!First non-enzymatic acylation catalyst for kinetic resolution of amines
FeN
Ph
Ph
Ph
Ph
Ph
catalyst
0 C, t-amyl alcohol2-6 h
Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc., 1998, 120, 11532-11533.
! Direct synthesis of dipeptides
NO
XO
N
O
R2
R1
10 mol% catalyst O
!
N
O
R2
R1
O
X
X = OMe, OBnR1= Me, Et, Bn
R
2
= Me, Ph, PMP
54-90% ee
0 C, t-amyl alcohol2-6 h
O
OBnO
N
OMe 10 mol% catalyst
O
N
OMe
O
BnO
0 C, t-amyl alcohol
2-6 h
10 mol% catalyst
OMe OMe
91% ee91% yield
Me NH
NH
O Me
OMe
O
O
BnO
O
OMe
95% yielddipeptide
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Chiral Planar DMAP Analogues: Rearrangements
!Intramolecular rearrangement of O-acylated oxindoles and benzofurans
FeN
Ph
Ph
Ph
Ph
Ph
catalyst
CH2Cl2, 35 C
Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed., 2003, 42, 3921-3924.
! A crystal structure was obtained
N
5 mol% catalyst
X = NMe, OR1= alkyl, aryl
72-95% yield88-99% ee
X
R1
O
OR2O
X
O
O
OR2R1
FeN
N
PhPh
Ph
PhPhO
O
R2
OPh
O
endo (cation-!)
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Chiral Planar DMAP Analogues: Rearrangements
!Intermolecular C-acylation of silyl ketene acetals
FeN
Ph
PhPh
Ph
Ph
catalyst
Et2O, CH2Cl2, 23 C
Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc., 2003, 125, 4050-4051.
N
5 mol% catalyst
R1= aryl
R2= H, Me
73-92% yield80-99% eeO
R2
R2
OTMS
R1O
R2
R2
O
R1Me
O
O
OMe Me
O
!Currently limited to !-aryl substrates
O
NR3Me O Me
O
O
R2
R2
OTMS
R1
O
NR3Me
O
R2
R2
O
R1
cat.cat.
TMSOAc
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Chiral Planar DMAP Analogues: Reactions with Ketenes
!!-lactam Staudinger synthesis
NO
R1
O
NR3
R1
N
R2H
Ts
N
CO2EtH
Ts
O
NR3
R1
EtO2C
NTs
R3Ncat.
10 mol% cat.
PhMe, 78 C
Ts
45-65% yield95-99% ee8:1-15:1 dr
Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579.
cat.
!Reaction successful for both symmetrical and unsymmetrical ketenes
FeN
Me
Me
Me
Me
Me
catalyst
N
Ph R1
O
Ph
zwitterion A zwitterion B
R1 = alkyl, R2= alkyl, aryl
PhR2
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Summary and Conclusions
! Miller's combinatorial approach has successfully obtained catalysts that show high selectivity
! Natural and synthetic alkaloids continue to have success across a variety of reaction types, although definitive stereochemical rationale is not always possible
! Fu has developed the first truly general synthetic DMAP analogue catalyst system. Led the way in showing that nucleophilic catalysis is a general and useful concept.
! Chiral amines have become functional nucleophilic catalysts, having been larglyoverlooked until recently.