Aspects of Asymmetric Nucleophilic Amine Catalysis: Organocatalyst Design and Implementation

MacMillan Group Meeting Ian Storer February 28, 2005 Asymmetric Nucleophilic Catalysis Outline

! Introduction to N-centred nucleophilic catalysts

! concepts and definitions ! origins and requirements

! Design, development and application of asymmetric nucleophilic catalysts

! Natural alkaloid catalysts - Precejus, Wynberg ! Synthetic alkaloid analogues - Lectka, Hatekeyama, Deng ! Biomimetic histidine containing peptide catalysts - Miller ! Asymmetric DMAP equivalents - Fuji / Fu

Useful Reviews:

! Fance, S.; Guerin, D. J.; Miller, S. J.; Leckta, T., Nucleophilic Chiral Amines as Catalysts in Asymmetric Synthesis. Chem Rev. 2003, 103, 2985-3012.

! Miller, S. J. In Search of Peptide-Based Catalysts for Asymmetric Organic Synthesis. Acc. Chem. Res. 2004, 37, 601-610.

! Fu, G. C. Asymmetric Catalysis with "Planar-Chiral" Derivatives of DMAP. Acc. Chem. Res. 2004, 37, 542-547. Definitions ! Lewis base A molecular entity (and the corresponding chemical species) able to provide a pair of electrons and thus capable of coordination to a Lewis acid, thereby producing a Lewis adduct.

! 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: IUPAC Compendium of Chemical Terminology

Me Me Me Me N N OH

R1 R3 1 O O O 2 R O N N R R2 R O R Lewis base O R R3 O R O R Lewis base complex Me Me N

N Lewis base

! Implication on Choice of catalyst The catalyst has to be a very effective nucleophile and a good leaving group . Useful Nucleophilic Catalysts

! Commonly applied 'everyday' nucleophilic catalysts

Me Me N N Me H N N N

N N N N N N PPY DMAP Pyridine Imidazole NMI DABCO Nucleophilic Aromatic Amines nucleophilic teriary amines

! Common applications

! O-acylation - electrophile activation (pyridine, DMAP) ! O-silylation - electrophile activation (imidazole, DMAP) ! Baylis-Hilman reaction - nucleophile activation (DABCO, DMAP) ! Ineffective bases: Nucleophilicity highly sensitive to steric and electronic factors Me

Et N N Me Me N Me Me N Me Et Et picoline lutidine collidine TEA good Bronsted bases, poor nucleophilic catalysts Cinchona Alkaloids: Earliest Successful Nucleophilic Asymmetric Catalysts

! First used for a resolution of a racemate in 1853 by Pasteur.

H H

H H HO N N HO pseudoenantiomers H H R R1 1

N N

1 Cinchonidine (CD) R1 = H Cinchonine (CN) R = H 1 Quinine (QN) R1 = OMe Quinidine (QD) R = OMe

! Several modes of application

! Asymmetric Bronsted bases ! Asymmetric phase transfer reagents (as salts) ! Asymmetric bifunctional catalysts (acid / base) ! Asymmetric nucleophilic catalysts

Moncure, R. MacMillan Group Meeting, 2003, web. – contains a more fully discussion of cinchona alkaloids Alkaloids and Derivatives as Nucleophilic Catalysts

! Natural alkaloids

site of modification: ether/ ester formation OMe site of inversion of site of modification configuration (epi alkaloids) OH H -pseudoenantiomers

N N H site of quaternary salt Quinidine formation, nucleophilic Pracejus (1964) addition or basicity Wynberg (1983) Simpkins (2001)

! Synthetically modified analogues

Me

OMe OH Et Et O O O O O H N O O N N N N N H

benzoylquinine Hatakeyama MeO N N OMe Lectka (2000)

(DHQD)2AQN Deng OMe Seminal Findings: Pracejus Methanolysis of Ketenes H ! Pracejus proposed a mechanism involving QN activation of methanol. OH

O O N 1–2 mol % quinidine N Ph H MeOH, –110 °C OMe Quinidine Me Ph Me H selective OMe up to 76% ee protonation N H

H O HO +MeOH NHR3 Ph H-bond activation OMe Me MeO N Precejus, H.; Mätje, H. J. Prakt. Chem. 4. Reihe. 1964, 24, 195. Precejus, H.; Santleben, R. J. Prakt. Chem. 1972, 314, 157.

! Simpkins proposes alternative nucleophilic mechanism

O PhSH O 10 mol % quinidine Bn benzene, –78 °C SPh 79-93% ee Me3Si Bn SiMe H 3

N

H HO O SPh selective Bn protonation NR3 MeO N SiMe3

Blake, A. J.; Friend, C. L.; Outram, R. J.; Simpkins, N. S.; Whitehead, A. J. Tetrahedron Lett. 2001, 42, 2877. Catalytic Asymmetric Cycloadditions: Synthesis of !"Lactones OMe

H ! An early example of asymmetric nucleophilic catalysis using an alkaloid. OH

O O N O 2.5 mol % Amine O N H 1 2 Toluene, –50 °C, 1 h Quinidine R CCl2R 1 R 2 H H CCl2R R1 = H, alkyl, aryl R2 = Cl, alkyl up to 95 % yield 45-98 % ee catalyst O (nucleophile) H O 1 2 R CCl2R

H NR3 zwitterionic intermediate ! Unprotected quinidine also catalyses its own acylation at OH ! Wynberg's proposed this stereoselectivity model

O Me O CCl3 O O H H CCl3 CH O Me 2 H O Me OR N O H HC Me H H Cl C Me H 3 MeO CCl3 ! In the left TS, the ketene oxygen faces the methylene of the catalyst ring .The chloral approaches the catalyst with the trichloromethyl group facing away from the methyl group of the catalyst to avoid steric strain.

! In the bottom TS, the ring is the dominant form of stereocontrol, and the CCl3 orients itself away from the ring methylene protons.

Wynberg, H. J. Am. Chem. Soc. 1982, 104, 166. Wynberg, H. J. Org. Chem. 1985, 50, 1977. Development of Functionalised Alkaloid Analogues: Catalytic Asymmetric Cycloadditions

! !-lactone synthesis: Romo's expansion of Wynberg's method

O OMe Me O O O O 2 mol% cat. 2 H CCl2R O H R1 >90% ee O Cl NR3 PhMe, –25 ˚C 2 1 R1 R Cl2C R N i R N N Base: Pr2NEt 3 R1 = H, alkyl, aryl cat. H R2 = Cl, alkyl Acyl-quinidine

! 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. Development of Functionalised Alkaloid Analogues: Catalytic Asymmetric Cycloadditions ! !-lactam synthesis: Lectka Ts O Ts 45-65% yield N O N 10 mol% cat. 95-99% ee R1 25-99:1 dr 1 Cl H CO2Et PhMe, –78 ˚C EtO2C R Base: proton sponge OMe cat. or K2CO3 or NaH O Ts N O H Ts O N O R N H CO2Et 3 N cat. N NR3 EtO2C NR3 H R1 R1 Benzoyl-quinidine

! 'Shuttle deprotonation' using excess of a thermodynamic, non-nucleophilic base. ! Concomitant Lewis acid activation of the imine later provided better yields

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.

! Proposed transition state Development of Functionalised Alkaloid Analogues: Catalytic Asymmetric Halogenation

! Halogenation: Lectka Cl O Cl Cl O Cl 10 mol% cat. O Cl 1 R1 Cl THF, –78 ˚C R Cl O Cl Cl Cl Base: BEMP or Cl Cl K2CO3 or NaH Cl OMe 65-85% yield O t 99% ee Bu N NEt2 O H P MeN NMe N N H O Benzoyl-quinidine Br Br Br Br O 10 mol% cat. O R1 R1 Cl THF, –78 ˚C O Br Br Base: BEMP or Br Br K2CO3 or NaH 55-80% yield >90% ee

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. Development of Functionalised Alkaloid Analogues: Catalytic Asymmetric Baylis-Hillman Reaction ! Natural alkaloid - poor enantioselectivity

O OH O OMe O 15 mol% catalyst 2 R R1 R2 up to OH H R1 H 45% ee THF, 30 ˚C, 34 h N cat. N O H O O O O quinidine R1 H R2 R2 R1 R2

R3N NR3 R3N

Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015. ! Synthetic analogue - better results Me

O CF3 OH O CF3 OH O 15 mol% catalyst 31-58% yield 1 O O CF3 R O CF3 91-99% ee R1 H THF, 30 ˚C, 34 h N

Me N

quinidine analogue O N O CF3

O CF3 ! Mechanism of asymmetric induction not well understood N H ! Hatekayama proposes a 13-membered ring transistion state O Ph H ! Limited substrate scope O Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatekeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. Et Et N N Ph H H O O H Deng's Application of bis-quinuclidines H MeO N N OMe

Ph N N catalyst

! Cyanation O O O 10-35 mol% catalyst O OEt 52-78% yield NC 87-97% ee R1 R2 NC OEt CHCl3, –12 to –24 °C R2 0.5 - 7 days R1 cat. R3N

O ! Mechanism of asymmetric induction CN O O NC O not well understood R1 R2 1 R3N OEt R R3N OEt R2

Deng, L. et al. J. Am. Chem. Soc. 2001, 123, 7475. ! Desymmmetrization of meso anhydrides O O R R 5-30 mol% catalyst OH 70-99% yield O MeOH ( ) OMe 90-98% ee ( )n n R Et2O R O O

Deng, L. et al. J. Am. Chem. Soc. 2000, 122, 9542. Designing Asymmetric Variants of Known Nucleophilic Amine Catalysts

! Considerations ! Must be nucleophilc, but maintain good leaving group ability ! Must have a valid chiral pocket to transfer asymmetry to product.

! Alkaloids and analogues Me

OMe OH Et Et O O O OH H N O O N N N N N H H

Quinine Hatakeyama MeO N N OMe Wynberg

(DHQD)2AQN Deng

! Synthetic chiral analogues of common nucleophilic heterocycles

O Me OH Me Me Me N H N O N H H Fe N Ph Ph N BocHN H O Me Ph Ph N Ph N Fu (1998-current) N Miller Synthetic chiral imidazole equivalents Synthetic chiral DMAP equivalents Biological Role of Nucleophilic Catalysis

! Mechanism of some kinases - role of histidine ATP ADP

O O O O O O E N O P O P O P O A O P O O P O P O A 3– O O NDP O O O E N O O NH fast E N NH NTP4– OH OH OH OH NH ! Phosphorylation transfer from ATP is ubiquitous in biological chemistry. ! Histidine often serves as in vivo acceptors of the !-phosphate of ATP. ! Proposed mechanism of ATPases and nucleoside diphosphate kinase (NDPK).

! In vitro phosphorylation of imidazole

O O N O P O NO2 O P O O NO2 H2O O N NH fast N 2– NH HOPO3

NH ! 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.

Admiraal, S. J.; Herschlag, D.; J. Am. Chem. Soc., 1999, 121, 5837-5845 Miller N-Methyl Imidazole-Containing Tripeptide

! Synthesis of a nucleophilic tripeptide

! 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.

O O Me Me Me Me

N O N O OH H H N N H2N BocHN H Ac2O BocHN H O O Me O Me

N N N

N N N OAc O Me acyl imidazolium

! 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

Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630. O Me Me

N O H N Miller Chiral Imidazole Tripeptide: BocHN H Kinetic Resolution of Alcohols O Me

N

! Kinetic resolution of amino-alcohols N catalyst O O

NHAc NHAc NHAc Me O Me O 1.0 equiv CH3CN = 12% ee CH Cl = 40% ee OH 5 mol% catalyst OH O Me 2 2 anti, racemic 0 ˚C PhMe = 84% ee (S = 12.6) 10 equiv

! Kinetic resolution of mono-acylated diols O O

OAc OAc OAc Me O Me 1.0 equiv O PhMe = 14% ee OH 5 mol% catalyst OH O Me anti, racemic 0 ˚C 10 equiv

! 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

Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630. Probing Origins of Selectivity ! Test System: Kinetic resolution

O O

NHAc NHAc NHAc Me O Me 1.0 equiv O OH 5 mol% catalyst OH O Me anti, racemic 0 ˚C 10 equiv ! Diastereomeric catalysts display enantiodivergence

! 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.

L-Pro D-Pro O O Me Me Me Me

N O N O H H Me H H N N N BocHN H H O Bn O Bn O N N O Boc H N OMe OMe N Me

S = kSS / kRR = 3.1 S = kRR / kSS = 28

! What is the mechanism of binding and role of the peptide backbone structure?

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. Miller "Biomimetic" Strategy

! Kinetic resolution of amino-alcohols

O O

NHAc NHAc NHAc Me O Me 1.0 equiv O OH 5 mol% catalyst OH O Me 0 ˚C

! Mechanistic postulate

H H Me N N Me OH O OH O O O Me Me Me N Me Me Me N N H Me H O H O Me N H Me Me N H N N N N H N H O O O H Ph O H Ph H N N N O N N Boc H O OMe Ph Boc H O OMe H N H O H krel = 28 O krel = 1 OMe OtBu

Larger rate acceleration than using DMAP - NMI is usually less activating?

Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem. Int. Ed. 2001, 40, 2824-2827. Miller: Development of a Fluorescence Assay

! Kinetic resolution of amino-alcohols

O O

NHAc NHAc NHAc Me O Me O 1.0 equiv AcOH OH catalyst OH O Me reaction byproduct

! Development of a fluorescence probe for rapid reaction conversion analysis

AcOH

N N H O O –OAc

OMe OMe Non-Fluorescent Fluorescent

! Fluorescence intensity is a function of acetic acid concentration

! Assisted rapid catalyst discovery.

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. Miller Histidine-Containing Peptide Catalysts

! Catalyst for the kinetic resolution of tertiary alcohols

H-bonding O

N O OH OH Me N H H NHAc NHAc N Me Me N H O H N N Boc H O NH

nucleophilic Me

krel = >50 krel = 40

OMe

! Kinetic resolution acetylation of unfunctionalised alcohols

Me N N OH t Me Me Ph BuO Me OH O O O O Me H H H H Ph N N N N BocHN N N N OMe H H H O O O O Me Me Me Me NTrt Me N Me krel = >50 krel = >50 The conformation / contribution of the peptide backbone is not known

Jarvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J. J. Org. Chem. 2001, 66, 5522. Miller: Development of a Desymmetrising Phosphorylation

! Asymmetric phosphorylation of meso triols

O O OBn OBn O OBn O OBn P P HO OH PhO Cl HO O P OPh HO OH PhO Cl PhO P O OH PhO PhO OPh PhO

BnO OBn Et3N, PhMe BnO OBn BnO OBn Et3N, PhMe BnO OBn OH 2 mol% catalyst OH OH 2 mol% catalyst OH >98% ee >98% ee Ph Ph Ph NH O

O N O H Me N H N N Me N N H Ph O N O N H O HN O OBu N N Boc H O NH N O N Boc H O O t Bu O NH Ph OMe O Me OMe

! Two very different peptides give very highly enantioselective phosphorylation in opposite enantioseries

Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc.. 2001, 123, 10125. Designing Asymmetric Variants of Known Nucleophilic Amine Catalysts

! Considerations ! Must be nucleophilc, but maintain good leaving group ability ! Must have a valid chiral pocket to transfer asymmetry to product.

! Alkaloids and analogues Me

OMe OH Et Et O O O OH H N O O N N N N N H H

Quinine Hatakeyama MeO N N OMe Wynberg

(DHQD)2AQN Deng

! Synthetic chiral analogues of common nucleophilic heterocycles

O Me OH Me Me Me N H N O N H H Fe N Ph Ph N BocHN H O Me Ph Ph N Ph N Fu (1998-current) N Miller Synthetic chiral imidazole equivalents Synthetic chiral DMAP equivalents Early Attempts to Make Chiral DMAP Equivalents ! Vedejs pioneering contribution: kinetic resolution O Me Me O O N OH OH O Me Me O Me S = 11-53 t R1 R2 R1 R2 R1 R2 Bu 100 mol% base complex Me N – racemic Me Cl OMe Cl C O O ! This DMAP equivalent is not nucleophilic enough to permit catalytic turnover 3 ! A variety of substrates gave good levels of enantioselectivity Lewis Base Complex

Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584. ! Spivey: C symmetric DMAP 2 O

O O N OH OH O Me OBn OBn Me O Me Me Me Me S = 1.8

2 mol% catalyst N Et3N, THF, –78 ˚C Catalyst Spivey, A. C et. al.. J. C. S. Perkin 1 2000, 14, 3460.

! Spivey: axially chiral symmetric DMAP O

O O OH OH O Pr cat. a MeN NEt2 S = 7.6 Pr O Pr Me Me Me cat. b 2 mol% catalyst S = 29 N N Et3N, THF, –78 ˚C Spivey, A. C et. al.. J. Org. Chem. 2000, 65, 3154. Spivey, A. C et. al.. J. C. S. Perkin 1 2001, 15, 1785. Catalyst a Catalyst b Fuji Chiral DMAP Equivalent: OH Kinetic Resolution of Alcohols H H N ! First non-enzymatic chiral resolution of alcohols

N

! Kinetic Resolution of Alcohols catalyst O O

OCOR OCOR OCOR Bui O iBu 81->94% ee 0.7 equiv O 68-72% conv. OH 5 mol% catalyst OH O iBu syn, racemic toluene, rt, 2-5 h

! Induced-fit Mechanism

OH

O O H H N O Bui O iBu HO N Me H H H Me H H N N Nu open conformation reactive, closed conformation

! Take advantage of charged Lewis adduct ! Cation-p interaction holds transition state rigid

Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169-3170. Fu Planar Chirality: Designing an Alternative Chiral DMAP

! Fu built a variety of Sandwich complex derived chiral nucleophilic amines

Me Me N N

N N N Fe Fe Fe Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me pyridine analogues

Me Me N N OSiR3 N N N Fe Fe Fe Me Me Ph Ph Ph Ph Me Me Ph Ph Ph Ph Me Ph Ph pyrroles DMAP PPY analogues analogues analogues

! In general best results were obtained with DMAP and PPY derivatives

France, F.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985-3012. Fu, Gregory C. Acc. Chem. Res. 2004, 37, 542-547. Fu - Planar Chirality: Kinetic Resolution of Alcohols

! Kinetic Resolution of Alcohols Me Me N O O O N Fe OH OH O Me Ph Ph Me O Me 1 2 1 2 1 2 Ph Ph R R 2 mol% catalyst R R R R racemic Et N, t-amyl alcohol Ph 3 catalyst

! Very high enantioselectivities for Aryl and Cinnamyl alcohols

OH OH OH Cl Me tBu

99% ee 99% ee 99% ee 55% conv. 55% conv. 55% conv.

OH OH OH OH

Me Me Me Me Me F 99% ee 99% ee 99% ee 99% ee 55% conv. 55% conv. 55% conv. 55% 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. Fu Chiral DMAP: Origins of Enantioselectivity ! Geometry of acyl rotamers

Me Me Me N Me N

N N Fe H Fe H Ph O Ph Ph Me Ph PhMe Ph PhO Ph Ph Ph Favoured rotamer Disfavoured rotamer

! Crystal Structure of Acyl salt

Me Me Nu N N Fe Ph O Ph PhMe Ph

Nu Ph

! Acetyl rotamer consistent with minimization of sterics between the methyl R group and ferrocene.

! Selectivity increases as the size of the alkyl group R increases.

! Nucleophile approaches from the top face of the DMAP catalyst. Kinetic Resolution of Amines

! First non-enzymatic acylation catalyst for kinetic resolution of amines N O O N Fe NH2 O OMe 10 mol% catalyst NH2 HN Me Ph Ph But Ph Ph Ar Me O CHCl , –50 ˚C Ar Me Ar Me 3 Ph racemic N catalyst !-naph

! The substrate amine is nucleophilic enough to add directly reacts faster with catalyst to most acylating agents – careful selection of acylating reagent than substrate amine proved necessary to render no background reaction

! Very high enantioselectivities for Aryl and Cinnamyl alcohols

NH2 NH2 NH2 NH2 MeO Me Me Me Me

s=12 s=27 s=22 s=16

Arai, S.; Laponnaz-Bellemin, S.; Fu, G. C. Angew. Chem. Int. Ed., 2001, 40, 234-236. Rearrangement of O-Acylated Azalactones

! First non-enzymatic acylation catalyst for kinetic resolution of amines N O N O Fe O X 10 mol% catalyst O Ph Ph R1 X 54-90% ee Ph Ph O 0 ˚C, t-amyl alcohol R1 ! O Ph N 2-6 h N catalyst R2 R2 X = OMe, OBn R1 = Me, Et, Bn R2 = Me, Ph, PMP

! Direct synthesis of dipeptides O

O OBn O O O O Me OMe Me BnO BnO N O 10 mol% catalyst Me O 10 mol% catalyst H Me NH N N O 0 ˚C, t-amyl alcohol 0 ˚C, t-amyl alcohol O 2-6 h 2-6 h 91% ee 95% yield 91% yield dipeptide OMe OMe OMe

Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc., 1998, 120, 11532-11533. Chiral Planar DMAP Analogues: Rearrangements

! Intramolecular rearrangement of O-acylated oxindoles and benzofurans N O 1 1 N R O R Fe Ph Ph OR2 5 mol% catalyst OR2 72-95% yield O O 88-99% ee Ph Ph CH Cl , 35 ˚C X 2 2 X Ph X = NMe, O catalyst R1 = alkyl, aryl

! A crystal structure was obtained

Ph O O N

N Fe Ph O Ph PhO Ph 2 R Ph endo (cation-!)

Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed., 2003, 42, 3921-3924. N Chiral Planar DMAP Analogues: Rearrangements N Fe Ph Ph Ph Ph ! Intermolecular C-acylation of silyl ketene acetals Ph catalyst

OTMS O O O O 5 mol% catalyst R1 73-92% yield O Me O 80-99% ee 1 Me O Me Et2O, CH2Cl2, 23 ˚C R R2 R2 R2 R1 = aryl R2 R2 = H, Me cat. cat. OTMS

R1 O O

R2 R1 O O O O R2 2 Me NR3 O Me Me NR3 R R2 TMSOAc

! Currently limited to !-aryl substrates

Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc., 2003, 125, 4050-4051. Chiral Planar DMAP Analogues: Reactions with Ketenes

! !-lactam Staudinger synthesis

O Ts Ts O N N 10 mol% cat. N 45-65% yield 95-99% ee N H R2 Ph Fe 1 PhMe, –78 ˚C 1 Ph R 2 R 8:1-15:1 dr Me Me R1 = alkyl, R2 = alkyl, aryl R Me Me cat. Me Ts N catalyst Ts O N O R N H CO2Et 3 Ph cat. NR3 EtO2C NR3 R1 R1 zwitterion A zwitterion B

! Reaction successful for both symmetrical and unsymmetrical ketenes

Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579. Summary and Conclusions

! Chiral amines have become functional nucleophilic catalysts, having been largly overlooked until recently.

! Natural and synthetic alkaloids continue to have success across a variety of reaction types, although definitive stereochemical rationale is not always possible

! Miller's combinatorial approach has successfully obtained catalysts that show high selectivity

! 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.