Construction of Enantiopure Pyrrolidine Ring System via

Asymmetric[3+2]-Cycloaddition of

Azomethine YlidesDu Yu-liu2014.5.5

1. Introduction

1,3-Dipolar cycloaddition reactions are fundamental in organic chemistry, and their asymmetric version offers a powerful and reliable synthetic methodology to access five-membered heterocyclic rings in regio- and stereocontrolled fashion.

The reaction of azomethine ylides (AMY) with alkenes is a powerful method for the syntheses of substituted and stereoisomerically pure pyrrolidines.

I wish to present an exhaustive survey, spanning over the past two decades , for accomplishing asymmetric 1,3-dipolar cycloaddition reactions of the azomethine ylides.

NR'

R

R'' N

R

R' R''

N

R

R''

R'

NR'

R

R''

W-Shaped ylide U-Shaped ylide S-Shaped ylide

N

R

R' R''

EWG

N

R

R' R''

EWG

Extensive studies have been performed in the area of asymmetric [3+2]-cycloaddition of azomethine ylides employing three possible combinations (a) chiral dipoles-achiral dipolarophiles, (b)achiral dipole-chiral dipolarophiles, and (c) chiral catalysis.

The stereochemical outcome of the cycloaddition of AMY is dependent on the geometries of the dipoles as well as the dipolarophiles.

The important methods of their in situ generation can be summarized schematically as follows: (a) Nonstabilized azomethine ylides, (b) Stabilized nonmetalated azomethine ylides (c) Stabilized N-metalated azomethine ylides

2. Asymmetric 1,3-Dipolar Cycloaddition Using Nonstabilized AMY

2.1 Chiral Nonstabilized AMY and Achiral Dipolarophiles

N TMSNC

Ph CH2RH

Ag(I)F

NCH2

Ph CH2RH

PhCHON

Ph CH2RH

OPh

ArNO2

N

Ph CH2RH

Ar NO2

N

Ph CH2RH

Ar NO2

+

1:1

a R=Hb R=OCH3c R=OCH2CH3

a 3:2b 4:1c 4:1

Padwa, A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W. Tetrahedron 1985, 41, 3529.

N

R'

O

LDAN

R'

R1

R2

N

R'

R1 R2

+

N

N

R'

R'

R1=R2=Ph

R*=

OH

H

OH

H H

PhOH

Negron, G.; Roussi, G.; Zhang, J. Heterocycles 1992, 34, 293

Fe R

N C60

PhCH3

NFe R

> 95% de

Mamane, V.; Riant, O. Tetrahedron 2001, 57, 2555.

NRO TMS

ArMeH

CF3COOH N

ArMeH

OO

OO

N

H H

ArMeH

OO

N

H H

ArMeH

+

1:1

Cottrell, I. F.; Hands, D.; Kennedy, D. J.; Paul, K. J.; Wright, S. H. B.; Hoogsteen, K. J. Chem. Soc., Perkin. Trans I 1991, 1091.

2.2. Achiral Nonstabilized AMY and Chiral Dipolarophiles

N

Bn

N

O O

Bn

HHTBSO

O

O

OTBS

OO OEt

OTBSN

Bn

OO

OTBS

OEtHH

OOCO2Me

N

Bn

CO2MeOO

OO

CO2Me

N

Bn

CH2O2MeOO

+

8.5:1.5

N

Bn

CO2MeOO

N

Bn

CH2O2MeOO

+

2:1

TFA

TMS N OMe

Bn

Wee, A. G. H. J. Chem. Soc., Perkin. Trans. I 1989, 1363.

N

Bn+ CbzN

O

HH

Ph

Ph

CbzNO

Ph

Ph

NPh

HN

H3N CO2

S-(-)-Cucurbitine

98% ee

Williams, R. M.; Fegley, G. J. Tetrahedron Lett. 1992, 33, 6755.

HN

NBn

O

Br

NMM

CH3CNN N

O

Bn

i)

ii) NaBH4, EtOH

NS

OO O

HN N

O

BnOH

O

OO

N

O

N H

OH

OH

H

OH

N

(-)-Lemonomycin

94% eeNMM= N-Me-morpholine

N

N

OMe

H Me

OOH

O

(-)-Quinocarcin

a) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 15000b) Kevin M. Allan and Brian M. Stoltz, J. Am. Chem. Soc. 2008, 130, 17270

3. Asymmetric 1,3-Dipolar Cycloaddition Using Stabilized Nonmetalated AMY

3.1. Acyclic Chiral Azomethine Ylides

Rouden, J.; Royer, J.; Husson, H.-P. Tetrahedron Lett. 1989, 30, 5133.

NO

X

Ph TMSOTfCH2Cl2

iPr2NEt

-78℃

NOTMS

X

Ph NO O

Ph

NH

N

OTMS

OO

HH

X

Ph

NH

N

OTMS

OO

H

X

Ph

H

X=CNX=COOCH3

NH

N

OTMS

OO

HH

X

Ph

NH

N

OTMS

OO

HH

X

Ph

a) Garner, P.; Dogan, Ö . J. Org. Chem. 1994, 59, 4.b) Garner, P.; Dogan, Ö .; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.; Zaniewski, R. Tetrahedron 2001, 57, 71

N

O

N

HR

SO O

CO2Me

CO2Me

N

Bn

MeO2C CO2Me

COX*

N

N

Bn

H H

COX*

O O

PhN

N

Bn

COX*

O O

Ph

HH

CO2Me N

Bn

CO2Me

COX* N

Bn

COX*

MeO2C2:1

1.8:1

N

O

N

H SO O

H

Ph

H

3.2. Cyclic Chiral Stabilized AMY

N

N

O O

ArHO

hvelectronicycilicring-opening

N

NMeO

Ar

OH

O

CHO

1,3-dipolarcycloaddtion

endo-re

N

MeN

O

O CHOAr

OHCOOH

endo-si

N

MeN

O

OAr

OHCOOH

N

MeN

COOH

O

MeO

N

MeN

O

HOOH

N O

OMeO

Me

quinocarcin naphthyridinomycin

a) Garner, P.; Ho, W. B. J. Org. Chem. 1990, 55, 3973.b) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1993, 115, 10742

HN

O

O

Ph

Ph

MeOMeMe

OHC

mol. sieves, tol.

NH

EtO2C

O

N

O

O

Ph

Ph

Me

MeMeO

HN

CO2EtO

N

O

O

Ph

Ph

HN

MeMeOMe

H

CO2Et

O

1,3-dipolarcycloaddtion82%

N

N

O

HN

O

OMe

Me

spirotryprotation B

a) Williams, R. M.; Zhai, W.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1992, 57, 6527.b) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666.c) Sebahar, P. R.; Hiroyuki, O.; Usui, T.; Williams, R. M. Tetrahedron 2002, 58, 6311.

O NH

OH

TMS

O

TFA

toluene0℃

O NH

O

HN

O

Ph

Ph

O

CHO

Me

MeMeO

MS 3A, toluene-15-0℃

N

O

Ph

Ph

O

HNMe

Me

MeOO

OMe

H

44%

N

N

O

HN

Me

Me

O

OMe

H

O

spirotryprostatin A

Onishi, T.; Sebahar, P. R.; Williams, R. M. Org. Lett. 2003, 5, 3135.

HN

O

Ph

Ph

O

+O

O

O

MeMe

+N

O

Boc

-H2O N

OPh

Ph

O

OO

MeMe

NO Boc

N

OPh

Ph

OBocN

OO

O

H

H

Me Me

D A

N

BocN

OD

A

H

OCO2Me

E

NO

NH

HF

A BC

D

E

Nakadomarin A

Ahrendt, K. A.; Williams, R. M. Org. Lett. 2004, 6, 4539.

N

N

OMe

H

(HCHO)n

tol. heat

N

N

OMe

NN

N

OMe H O

O

Ph NN

N

OMe H O

O

Ph+

N

N

OMe H

CO2Me

CO2Me

N

N

OMe H

CO2Me

CO2Me

+

80:20up to 60% de

up to 20% de60:40

Peyronel, J.-F.; Grisoni, S.; Carboni, B.; Courgeon, T.; Carrie, R. Tetrahedron 1994, 50, 189.

NH

O

O +NH

COOHNH

N

O

N

H

NH

RO2C

O

CO2R

HN O

N

MeMe

MeH

H

OO

80-82% de77-85% yield

R=(1R, 2S, 5R)- menthyl

Coulter, T.; Grigg, R.; Malone, J. F.; Shridharan, V. Tetrahedron Lett. 1991, 32, 5417

4. Asymmetric 1,3-Dipolar Cycloaddition Using Stabilized N-Metalated Azomethine Ylides

4.1. Chiral N-Metalated Azomethine Ylides and Achiral Dipolarophiles

NO

N

Ar

OMe Ph

AgOTf, Et3N, CH2Cl2

N-methylmaleimide NO

N

Ar

Ph

Ag

MeO

MeN

O

O NO

OMe Ph

HNNMe

O

O

H

H

Ar

(single isomer)Husinec, S.; Savic, V. J. Serb. Chem. Soc. 1998, 63, 921

N

H H X

PMPO

R1Dienophile

AgOAc/Et3N

R1=Vinyl

N

H H

PMPO

R2 N

HHR3 R4

R2

CO2MeH

H N

H H

PMPO

R N

R3

R4HH

CO2MeR2

HH

+

X=NCH(R2)CO2MeR2=H R3=CO2Me R4=H

95:5

Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem. Commun. 2000, 485.Alcaide, B.; Almendros, P, Redondo M. C., Ruiz M. P. , J. Org. Chem. 2005, 70, 8890.

4.2. Achiral N-Metalated AMY and Chiral Dipolarophiles

Kanemasa, S.; Yamamoto, H. Tetrahedron Lett. 1990, 31, 3633.Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido, K. Bull. Chem. Soc. Jpn. 1990, 63, 2857.

R1 N

H R2

O

OR3

M

M=Li or Mg

M=Li

N

H

R3O2C R1

O

NBn +

N

H

R3O2C R1

O

NBn

CO2Me CO2Me

N

H

R3O2C R1

N

N CO2Me

Ph

75:25

Kanemasa, S.; Hayashi, T.; Tanaka, J.; Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56, 4473

R1 N

H R2

O

OR3

M

+N NR R

CO2Me

Ph Ph

(-)- or (+)-

N NR R

Ph Ph

N

R3O2C CO2Me

R1H

N NR R

Ph Ph

N

R3O2C CO2Me

R1H

+

a: R1=Ph, R2=H, R3=Me

b: R1=Ph, R2=H, R3=t-Bu

A

R=Ph 96:4

R=Me 4:96

M=Li

Ayerbe, M.; Arrieta, A.; Cossío, F. P. J. Org. Chem. 1998, 63, 1795.

Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.; Carrascal, T.; Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-Vanaclocha, F.; Cossio, F. P. Angew. Chem., Int. Ed. 2005, 44, 2903.

R1 N

H R2

O

OR3

M

+

R1=Ph, R2=H, R3=Me

A

OBn

NO2N

OBnNO2

R3O2C R1

H

N

OBnNO2

R1

H

+R3O2C

M=Ag 71:29M=Li 95:5

M

O2NXc

R3 N CO2CH3

R4

AgOAc+

NEt3

OHAc+

NEt3

R3 N

R4

O

OMe

AgLn

NR4

O

OMe

AgLn

R3

O

HNO H

Xc

*

*

NR4

O

OMe

AgLn

R3

NOH

Xc*

O

H

HNEt3 + OAc

NEt3 + AgOAc

NH

O2N

R3 CO2Me

Xc

R4

*

Mechanism

O2NR1

CH3

O

R2

+ R3 N CO2CH3

R4

N

H

R3 CO2H

O2N

R4

O

CH3

R1

R2

N

H

R3

O2N

R4

O

CH3

R1

R2

O

HN CO2H

Inhibitors of41-Integrin-MediatedHepatic Melanoma Metastasis

R1 N

H R2

O

OR3

M

+R4

O

NH

R3O2C R1

COMeR4

+NH

R3O2C R1

COMe

R4

95:5

M=Ag

R4= OO OO OBnNBn2

Bn

NBn2

Galley, G.; Liebscher, J.; Pätzel, M. J. Org. Chem. 1995, 60, 5005.

O

O

CO2Me+ R1 N CO2R3

R2 AgOAc (10 mol%)

KOH (10 mol%)toluene, r.t., 1d N

HR1

CO2R3

O

OMeO2C

R2

yield up to 98%de up to 99%

Carmen N. ,M. de Gracia R., José M. S. , Abel d. C., Fernando P. C., Eur. J. Org. Chem. 2007, 5038.

5. Intramolecular Asymmetric Cycloaddition of AMY

ON

R1

O

H

R2

+ HN COOH

Me

ON

R1

N

H

R2

Me

ON

R1

H Me

R2

NTsN

H

R1

R2

R3

Pedrosa, R.; Andrés, C.; Heras, L. de las; Nieto, J. Org. Lett. 2002, 4, 2513

R1 R2

O

ON

Bn

n OBnb),n=0heat

R1=R2=H

HOBn

OO

H H

NBn N O

Bn O

H

H

OBna), n=1

heat

O

R1R2

H

OBn

N

OHBn

N O

Bn O

H

H

OBn

R1

R1=

R1= H

N

HN

O

MeO2C

NBoc

CO2Me

CO2Me

R1=R2=H

N

H OH

R1= H

R1=

OMe

OMe

N

MeHO

OMe

MeON

H

COOH

R1=

R1= H

OPMP

(a) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am. Chem. Soc. 1987, 109, 5523.(b) (1) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1988, 1204.

(2) Takano, S.; Tomita, S.; Iwabuchi, Y.; Ogasawara, K. Heterocycles 1989, 29, 1473.(c) Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett. 1990, 1239.

(d) Hashimura, K.; Tomita, S.; Hiroya, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1995, 2291.

Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41, 1778

NTMS

HO

Et

OEt

Tf2O

F

N

HOTf

Et

OEt

N

HO

EtS

OTf

H

OR N O

N2

O

OMe

CO2Bn

Rh2(OAc)4 (3 mol%)

TFA NEt3 (1 equiv)xylenes, reflux

N

O

CO2Bn

MeO2C

OR

RhIIylide

formation

N

O

CO2Me

CO2Bn

OR

H

first formedU-shaped ylide

N

O

CO2Me

OR

H

S-shaped ylide

BnO2C

1,3-dipolarcycloaddtion

R=TBDPS

N

O

CO2Bn

MeO2C

OR

N

O

CO2Bn

MeO2C

desired

N

O

CO2Bn

MeO2C

OR

N

O

CO2Bn

MeO2C

OR

75% with TFA NEt340% without TFA NEt3

not observed

MeO2CH

O

CO2Bn

ORH

MeO2CH

O

ORH

0% with TFA NEt326% without TFA NEt3not observed

Chao F., Charles S. S., Daniel H. P., Stephen F. M. Angew. Chem. Int. Ed. 2012, 51, 10596.

6. Asymmetric 1,3-Dipolar Cycloaddition of AMY Using Chiral Catalyst

(a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817.(b) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475.

R1 N

H R2

O

OM

+ CO2MeLigand*

25 ℃ N

MeO2C

R1R2

CO2MeH

M

MnBr2, 1eq.CoCl2, 1eq.CoCl2, 1eq.CoCl2, 1eq.

L*

a (4 eq.)a (2 eq.)b (4 eq.)c (4 eq.)

ee(%)

608096 (need large excess of dipolarophile)96

Ph Me

HO NRR'

a: R=R'= Meb: R=R'= -(CH2)4-c: R=Me, R'= Pr

NOH

Co

O

O

N

Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.

R1 N CO2R3AgOAc / Ligands

i-Pr2NEt, solvent, rt R1 N

H R2

OR3

OM

CO2Me

CO2Me

NH

MeO2C CO2Me

R1 CO2R3

+

NH

MeO2C CO2Me

R1 CO2R3

endo exo

up 97%

NH HNO O

Fe FePAr2Ar2P

Ar= 3,5-dimethyl phenyl

Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 4236

Ar N CO2Me +CO2R2

R1

Ligand

Zn(OTf)2, base, -20℃ NH

R2O2C R1

Ar CO2Me

N N

OO

t-Bu t-BuZnII

yield up to 93%ee up to 94%

Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174.

N

HAr

O OMe

+O

OtBu

i-Pr2NEtAgOAc (3 mol%)

(S)-QUINAP

THF, -45 ℃,20h NH

tBuO2C

CO2MeAr

Ar=4-cyanophenylyield up to 95%ee up to 96%

N

PPh2

(S)-QUINAP

Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043.

NArCO2Me

+ NO O

PhLigand

Cu(OTf)2, NEt3

CH2Cl2, -40℃N

HN

O O

Ph

Ar CO2Me

N

HN

O O

Ph

Ar CO2Me

+

exo endo

O

O PPh2

O

O

PPh2

(R)-SEGPHOS

yield up to 95%ee up to 93%

Ph

N

OMeCuX

OPPh

Ph

PPh

Ph

NO

O

Ph

N

OMeCuX

OPPh

Ph

PPh

Ph

N

O

O

NPh

CO2RCO2R

Ph Zn(II)cat.

OZnL2

O

OR

N

RO

Ph

Ph

Me

OMe

[3+2]

[4+2]

PhCO2R

CO2RPh

OMeMe

N

CO2R

CO2R

H

H

Ph

83%d.r.=6:1

76%d.r.=1.3:1

Ph PhZnCl Cl

20 mol%

Pohlhaus, P. D.; Bowman, R. K.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 2294

R

N

H

CO2Et

+OtBu

O

3 mol% L*3 mol% AgOAc

Hunig base

THF, -40℃36h R

NH

tBuO2C

CO2EtH

R= CN (L1=94% yield, 95% ee) (L2=96% ee%)

R= OMe (L1=88% yield, 92% ee)

(L2=95% ee%)N

N

O Ph

Me

PPh2

L1=Pinap

N

PPh2

L2=quinap

T. F. Knöpfel, P. Aschwanden, T. Ichikawa, T. Watanabe, E. M. Carreira, Angew. Chem., Int. Ed., 2004, 43, 5971

Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241.

Ar N CO2Me

CO2R2

R1

+

Ligand (5.5 mol%)

Cu(I) (5 mol%), THFbase(10 mol%), -25 ℃

Fe

NH

R2O2C R1

Ar CO2Me+

NH

R2O2C R1

Ar CO2Me

exo endo

exo/endo: up to 98/2ee of exo: up to 98%

PAr2

O

N t-Bu

Ar N

R1

CO2Me

R2+ NR

O

O

Fesulphos (0.5-3mol %)Cu(CH3CN)4ClO4 (0.5-3 mol %)

Et3N(cat)CH2Cl2 or THF

-10℃ or r.t.NH

N

Ar CO2Me

R

OO

Fe

S-tBu

PPh2

47-97% yield69->99% ee

S. Cabrera, R. Gómez Arrayás and J. C. Carretero, J. Am. Chem. Soc., 2005, 127, 16394

N

R H

CO2Me

+

CO2Me

CO2Me

AgOAc/ L*

Et2O, -25℃ NH

MeO2C CO2Me

R CO2Me

up to 98% ee

Fe P(4-CH3C6H4)2

N

O

Bn

W. Zeng, Y.-G. Zhou, Org. Lett., 2005, 7, 5055

Ar N CO2Me +X Y

Zn(OTf)2L*, Et3N

DCM, -20℃

HNAr CO2Me

X Y

* ** *

63-94% yieldup to 95% ee

N

OH

Ph

Me

H

Fe

O. Dogan, H. Koyuncu, P. Garner, A. Bulut, W. J. Youngs, M. Panzner, Org. Lett., 2006, 8, 4687

R1 N CO2R2 +

CO2Me

CO2Me

AgOAc/ L*

Et2O, -25℃ NH

MeO2C CO2Me

R1 CO2R2

Fe

PAr2

R

R=NH2: 3, up to 92% ee

R=NMe2: ent-3, up to 92% ee

Hydrogen bonding changed the transition state

W. Zeng, G.-Y. Chen, Y.-G. Zhou and Y.-X. Li, J. Am. Chem. Soc., 2007, 129, 750

Ph

R2

N

O

OR1

H R3

+

R4

R5

R6

O

R7

Ph

R2

N

O

OR1

O R7

R6

H

up to quantmajor/minor= up to 91/9

up to 99% ee(major)

NH

R7

OR4

R5

R3R2

Ph

OR1

O

up to quantmajor/minor= up to 98/2

up to 99% ee(major)

LigandCa(Oi-Pr)2

-30℃, THF, 12hMS 4

R4=R5=HLigand

Ca(Oi-Pr)2

-30℃, THF, 12hMS 4

R6=R7=HPh

O

N N

O

H H

Ph

R2

N

O

OR1 NCa

N

OR

*

Ph

R2

N

O

OR1

NCa

N

*

O

OR3

Ph

R2

N

O

OR1

NCa

N

*

O OR3

ROH

Ph

R2

N

O

OR1

O OR3

Protonation

HNPh

R2

R3O2C

OR1

O

Intramolecular cyclization

Mechanism:

S. Saito, T. Tsubogo, S. Kobayashi, J. Am. Chem. Soc., 2007, 129, 5364

Ar N CO2Me+

R1

NO O

[(S)-binap]AgClO4(5 mol%)

Et3N (5 mol%), toluener.t., 16h

N

N OO

ArCO2Me

R1

up to >98:2 endo:exoup to >99% eeendo

P

P

PhPh

PhPh

Ag+ClO4-

C. Nájera, M. de Gracia Retamosa, J. M. Sansano, Org. Lett., 2007, 9, 4025

Ar N CO2R1

R2cat. (5 mol%)

+ CO2tBu

Et3N or DABCO (5 mol%)toluene, -20℃

NH

R2tBuO2C

Ar CO2R1

endoup to e.r >99:1

O

ON

Ph

Ph

+ AgClO4

cat.

C. Nájera, M. de Gracia Retamosa, J. M. Sansano, Angew. Chem., Int. Ed., 2008, 47, 6055

N

O

OMe

(1 equiv)

+

R

R

OtBu

O

CuI /L

AgI /L

NH

R

tBuO2C

CO2Me

R R

R

NH

R

tBuO2C

CH2O2Me

R R

R

NOH

O

HO

H

NH

O

H

OMe

OMe

H

up to 96% ee

up to 96% ee

NO

O

O

H

NH

O

H

OMe

OMe

H

CuHO

BuOt

NPh

OOMe

NO

O

HO

H

NH

O

H

OMe

OMe

H

Ag

H O

BuOt

O

MeON Ph

N-L

Transition State Cu Transition State Ag

H. Y. Kim, H.-Y. Shih, W. E. Knabe, K. Oh, Angew. Chem., Int. Ed., 2009, 48, 7420

N CO2Me

R1

+ N

O

O

R2

Ni(ClO4)2 6H2O (5 mol%)Ligand (5.5 mol%), MS 4A

iPr2NEt(10 mol%), CH2Cl2, 15℃NH

NO O

R2

CO2Me

R1

endo

up to 95% ee

N

N N

N

J.-W. Shi, M.-X. Zhao, Z.-Y. Lei, M. Shi, J. Org. Chem., 2008, 73, 305

R2 NO2 + R1 N CO2Me

LigandNi(OAc)2 (10 mol%)

NH

O2N

CO2Me

R2

R1

exo'up to 99% ee

N N

N

Ph

PhPh

Ts OH

Br

Br

T. Arai, N. Yokoyama, A. Mishiro and H. Sato, Angew. Chem., Int. Ed., 2010, 49, 7895.

NH

R

O +

OMeO

N

Ar

Cu(CH3CN)4PF6 (1-3 mol%)Ligand (2-6 mol%)

Et3N (20 mol%)THF, rt

Fe

N

P

Fe

NH2

PPh2

PhPhCu

H

N

O

OMe

ArO R

HN

Ligand

Transition State

NH

NH

ArO

MeO2C

R

R Ar yield(%) ee(%)

p-OMePhiBu

CO2Me

Ph

p-BrPhp-BrPhp-BrPhp-CH3Ph

80509795

96908594

A. P. Antonchick, C. Gerding-Reimers, M. Catarinella, M. Schürmann, H. Preut, S. Ziegler, D. Rauh, H. Waldmann, Nat. Chem., 2010, 2, 735.

N

R CO2Me

Ar

C60

[M]/ Ligandtoluene, -15℃

R=H, Me

HN Ar

R

MeO2C

+

HNAr

CO2Me

R

Cu(OAc)2/(R)-Fesulphos

AgOAc/BPE

cis:trans=95->99%65-93% ee

cis:trans=80->99%70-90% ee

Fe

S-tBu

PPh2

(R)-Fesulphos

P

Ph

Ph

P

Ph

Ph

BPE

S. Filippone, E. E. Maroto, A. Martı′n-Domenech, M. Suarez, N. Martín, Nat. Chem., 2009, 1, 578

R1 N CO2Et

CO2Et

+ R2 H

O

NH

Ph

OH

Ph

NH

OHC R2

R1CO2EtCO2Et(20 mol%)

DMF

high yield%85%->99% ee

NPh

OH

Ph

R2

NH

Ph

OH

Ph

O

R2

H2O

EWG NH

EWG

R1

EWG N

EWG

R1EWG=CO2Et

N

Ph

O

Ph

R2

H

EWGNH

EWG

R1H

N

Ph

OPh

NH

R2

R1EWG

EWG

H2OOHC

NH

R2

R1EWG

EWG

Mechanism:

Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168

R1CHO +H2N CO2R2

CO2R2

+

CO2Me

CO2Me

Chiral PA (10 mol%)

CH2Cl2, RT, 24h NHR1

MeO2CCO2Me

CO2R2

CO2R2

up to 97% yield, 99% ee

O

OOP

HOO

OO

PO

OH

R1

N

R2

H

CO2R3

H

OO

P*RO OR*

N

R2

H

CO2R3

H

OO

P*RO OR*

R1

EWG

R4

NH

R4EWG

R3O2C

R2

R1

Control of Stereochemirtry with Chiral BH-Bonded Dipole

Chen. X. H. , Zhang. W. Q., Gong. L. Z., J. Am. Chem. Soc. 2008, 130, 565.

N

R2

R1 O

Ac

+ R3CHO + H2N

CO2Et

CO2Et

10 mol% cat.

3A MSDCM, 25℃ N

R1 O

Ac

NHR2

R3

CO2EtCO2Et

2-naphthyl

2-naphthyl

O

OP

O

OH

N

H

R1 CH2O2R6

R5

OP

*RO

OH

OR*

NR1 CO2R6

R5

O

P*RO

OOR*

HH

O

POR*

O

*RO

H

O

H HN

R1

R6O2C R5N

R2

R1

R3

OP

OR*O

OR*

H

HN

R4

R5

CO2R6

ON

R2

R1

R3

O

P*RO

OOR*

H

NR1 O

R3

NHR2

R3

CO2R6

R5

N

R2

R1 O

R3

OP

OR*O

OR*

H

HN

CO2R6

ON

R2

R1

R3

R4

R5

O

P*RO

OOR*

H

NR1 O

R3

NHR2

R5 CO2R6

R4

minor

major

R4

N CO2R6

R5

H

O

P*RO

OOR*

H

Chen. X. H., Wei Q., Luo S. W., Xiao H., Gong L. Z., J. Am. Chem. Soc. 2009, 131, 13819.

NR1

R2

O

OMe + OMe

OAgHMDS/Ligand

(5 mol%)

Et2O, 0℃ NH

MeO2C

R1 R2

CO2Me

O

O

O

O

PAr2

PAr2

Ar=3,5-tBu-4-MeOC6H2(R)-DTBM-segphos

exoup to 99% ee

Y. Yamashita, T. Imaizumi, S. Kobayashi, Angew. Chem. Int. Ed. 2011, 50, 4893.

T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki,H. Sato, J. Am. Chem. Soc. 2010, 132, 5338.

R1 N CO2Me +

PyBidine-Cu(OTf)2 (5 mol%)

CsCO3, dioxane, r.t.NH

R4

O2N

R1 CO2Me

R3

endoendo:exo up to 99:1endo up to 99% ee

R2

R3 NO2

R4R2

N N

HNNH

N

Ph

Ph

Bn

Ph

Ph

Bn

PyBidine

N

Br

N

H

PhOH

Ph

R1 N CO2R2 +R4O2C CO2R4

R3

Ligand (11 mol%)Cu(OTf)2

base, MS 4A, DCMNH

R4O2CR4O2C

R1 CO2R2

R3

up to 99% yield up to 99% ee

N

Br

N

R

PhOH

Ph

Cu(OAc)2

N

Br

N

R

PhO

Ph

CuOAc

OAc

tBuOK

tBuOH+KOAc

N

Br

N

R

PhO

Ph

Cu OAcN

Br

N

R

PhO

Ph

CuOAc

Ph NO

ON

Br

N

R

PhO

Ph

CuOAc

O

O

N

H

OAc

EtO2C CO2Et

Ph

HOAc

N

Br

N

R

PhO

Ph

CuOAc

O

O

N

EtO2C CO2Et

HOAc

NH

EtO2CEtO2C

Ph CO2Me

Ph

M. Wang, Z. Wang, Y.H. Shi, X. X. Shi, J. S. Fossey, W. P. Deng, Angew. Chem. Int. Ed. 2011, 50, 4897 –4900

+N

EtOOC

O

Me

cat. (5-15 mol%)

DCM, r.t.

NO

Me

d.r.> 20:1up to >99% ee

NH

N

S

NH

H

S

O

X

HN

S

COX

CO2Et

X= NO

O

N

S

NN

HH H

O

NR2

OH

N O

O

N

S

R

N

S

NN

HH H

O

NRN

S

NO

O

O

Y.M. Cao, X. X. Jiang, L. P. Liu, F. F. Shen, F. T. Zhang, R. Wang, Angew. Chem. Int. Ed. 2011, 50, 9124.

7. Conclusion

Studies concerning the cycloaddition of chiral nonstabilized azomethine ylides have generally given poor diastereoselectivity. Reaction employing achiral nonstabilized AMY and chiral dipolarophiles has given poor to excellent diastereofacialselectivity. Asymmetric cycloaddition of AMY using chiral Lewis acid catalysts, has shown interesting results, producing good to excellent enantioselectivity.

Syntheses of highly substituted pyrrolidines in optically pure form via asymmetric [3+2]-cycloaddition of azomethine ylides, which allows simultaneous construction of up to four stereocenters, is increasingly becoming an important strategy.

Since the first examples reported in 2002, the catalytic symmetric 1,3-dipolar cycloaddition of azomethine ylides has emerged as one of the most powerful methodologies for the enantioselective preparation of substituted pyrrolidines.

Further progress in this area would include the discovery of more reactive catalyst systems, allowing the use of lower catalyst loadings and the cycloaddition of even more challenging substrates such as non-activated alkenes or highly substituted dipolarophiles and azomethine precursors, as well as the development of applications in the synthesis of natural product and bioactive compounds.

Thank You