Research areas

Research areas

Natural product isolation and total synthesis.

Chemistry and biology of free radicals

Dr. Andrew ClarkAssociate Professor in Synthetic Chemistry

Development of synthetic methodology using copper, iron and ruthenium

Functional Genomics / Chemical Genetics / Interactomics

Use of plants in renewable plastics manufacture

Dr. Andrew ClarkChemistry Department, University of Warwick

Coventry, UK+44 24 76523242

[email protected]

Atom Transfer Radical Cyclisation

OO

ClCl Cl

OO

ClCl30mol% CuCl

MeCN, 140oC Cl

OO

ClCl

CuCl2

CuCl

OO

ClCl

CuCl2

CuCl

H. Nagashima et al, Tetrahedron Lett., 1983, 24, 2395A. J. Clark, Chem. Soc. Rev., 2002, 31, 1

NN

BipyOO

Cl ClCl

30 mol% CuClLigand 1, 110 C, MeCN, 18 hrs, 98%

O

ClCl Cl

O

Ligand 1

NN

R

R

H. Nagashima et al, J. Org. Chem., 1993, 58, 464

NN

R

R

NN

NN

RR N

CHOR H2N R

NN

1 mol % CuCl

CH2Cl2, RT

NN

NTs

ClClCl

O NTs

ClCl

O

Cl

99%, 6 hrs

A. J. Clark, D. Duncalf, R. P. Filik, D. M. Haddleton, G. H. Thomas, H. Wongtap, Tet. Letts, 1999, 40, 3807

NTs

BrMeMe

O NTs

MeMe

O

BrCH2Cl2, RT

30 mol % CuBr

95%, 6 hrs

NTs

BrMeH

O NTs

MeH

O

Br30 mol % CuBr

CH2Cl2, 40 ºC

92%, 30 hrs, de 64%

05

101520253035404550

Ligand A Ligand B Ligand C Ligand D

de = 2% de = 34%

de = 44%

de = 54%

NN

NN

NN

NN

Ligand A Ligand B Ligand C Ligand D

NTs

Me Cl

O

Cl

NTs

Me Cl

O

Cl30 mol% CuCl30 mol% Ligand

0.12M in substrteNTs

Cl

O

Me

Cl

Steric Effect of N-Substituent

012345678

0.5 eq 1.0 eq 2.0 eq 3.0 eq

NTs

Me Cl

O

Cl

NTs

Me Cl

O

Cl30 mol% CuCl30 mol% Ligand

0.12M in substrteNTs

Cl

O

Me

Cl

Relative rate versus ligand equivalence

Toluene

CH2Cl2

NN

A. J. Clark, F. De Campo, R. J. Deeth, R. P. Filik, S. Gatard, N. A. Hunt, D. Lastecoueres, G. H. Thomas, J-B. Verlhac, H. Wongtap, J. Chem. Soc., Perkin 1, 2000, 671

N

N

CuN

N

D. M. Haddleton, A. J. Clark, D. J. Duncalf, A. M. Heming, D. Kukulj, A. J. Shooter , J. Chem.Soc., Dalton Trans, 1998, 381

D. M. Haddleton, D. J. Duncalf, D. Kukulj, M. C. Crossman, S. G. Jackson, S. A. F. Bon, A. J. Clark, A. J. Shooter, Eur. J. Inorg. Chem. 1998, 1799

NTs

BrMeMe

O NTs

MeMe

O

Br

Me2NN

NMe2

Me2N

CH2Cl2, RT

30 mol %

NN

95%, 6 hrs92%, <30 mins

NTs

BrMeH

O NTs

MeH

O

Br30 mol %

CH2Cl2, RT94%, 12 hrs, 66% d.e.

92%, 30 hrs, 40ºC, de 64%

A. J. Clark, F. De Campo, R. J. Deeth, R. P. Filik, S. Gatard, N. A. Hunt, D. Lastecoueres, G. H. Thomas, J-B. Verlhac, H. Wongtap, J. Chem. Soc., Perkin 1, 2000, 671

N CHO NN

Si NNreflux, 24 hrs

SiCu

CuX

XMeCN

MeCN

ICP = 4.3% Cu

NH2

9 % functionalised

Si

NTs

BrH

O NTs

H

O

Br30 mol %

ClCH2CH2Cl,reflux

48 hours 72%

NTs

H

O

Br

A. J. Clark, J. V. Geden, and S. Thom. J. Org. Chem., 2006, 71, 1471

Ligand Acceleration

NN N

N

NN

N

NN

NN

N

N

NNR

NN

Tren-Me6 PMDETA TMEDA

TPA NPMI BiPy

Solid Supported Catalysts for ATRC

NN

NMe2

NMe2

N

N *

N *

N*

Me

Me

MeCuX

Me

CuX

PS-Me6-tren.CuX PS(CL)-Me6-tren.CuX

OO

O

N

Et2NNEt2

NN

NMe2

JJ

JJ-TEDETA.CuX1

CuX

Me

Me

PS-PMDETA.CuX

CuX

X=Cl, Br

A. J. Clark et al, J. Org. Chem., 1999, 64, 8954

0

0.5

1

1.5

2

2.5

3

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5

Run 2

Run 3

Run 4

Run 5

Run 6

Run 7

Time (hrs)

Kinetics to 80% Conversion (PS-PMDETA.CuCl)L

n([

Ao

]/[A

])

NTs

ClClCl

O NTs

ClCl

O

ClDCE, reflux

30 mol %

A. J. Clark, J. V. Geden, and S. Thom. J. Org. Chem., 2006, 71, 1471

N

Cl Cl

O

Bn

N

Cl Cl

O

Bn

N

Cl

Cl

O

Bn

N

Cl

Cl

O

Bn

CuCl, Ligand

RT, CH2Cl2

NN

?

F. Ghelfi et al, Tetrahedron., 1997, 41, 1403

N

Cl

O

Bn

N

Cl

O

BnN

Cl

O

Bn

Cl

N

MeCl Cl

OBoc

30 mol% Cu(A)Cl

N

Me

OBoc

ClCl

RT, CH2Cl250%

N

MeCl

OBoc

N

MeCl

OBoc

Cu(I)

N

MeCl

OBoc

ClCu(II)

AgNO3, THF:H2O

N

Me

OBoc

CHO

77%

N

Me

OBoc

ClCu(I)

NN

N

Me

OBoc

Cl

Cu(II)

A. J. Clark, G. M. Battle, A. Bridge, Tet. Letts., 2001, 42, 1999.

4-exo vs 5-endo

NBn

BrMe

Me

O

NBnO

Br

4-exo

NBn

OBr

5-endo

NBn

O NBn

ONBn

O

Br 30 mol% CuBr, 30 mol% ligand

CH2Cl2, 20 mins, RTn n n

n = 1 39% 43%n = 2 52% 10%n = 3 21% 60%n = 7 15% 40%

NN N

N

4-exo

NBn

MeMe

O 4

5

5-endo

NBn

MeMe

O

A. J. Clark, C. P. Dell, J. M. Ellard, N. A. Hunt, J. P. McDonagh, Tet. Letts., 1999, 40, 8619

Cu(I)

NBn

O n NBn

O n

NO Bn

4-exo

5-endo

A. J. Clark, C. P. Dell, J. M. Ellard, N. A. Hunt, J. P. McDonagh, Tet. Letts., 1999, 40, 8619

NBn

O NBn

ONBn

O

Br 30 mol% CuBr, 30 mol% ligand

CH2Cl2, 20 mins, RTn n n

Cu(II)

NBn

O n

H

H

N

OH

OMe

OMe

OMe

ERYTHRINITOL

N

Br

O

MeOOMe

NO

NO84% 1:1

ArAr

NO

MeOOMe

N

OMe

OMe

O30 mol% CuBr,

30 mol% tren-Me6CH2Cl2, 20 mins, RT

'Friedel-Crafts'N

OMe

OMe

O

-H

H2N

Br

O

OMe

OMe

O

Br, base

1)

2)

NO

Ph

Br

NO

Ph

toluene, 110ºC, 2 hrs

30 mol% CuBr, TPA

72%N

N

N

N

TPA

NO

Ph

Br30 mol% CuBr, TPA

NO

Ph

Me

1,2 DCE, 110 ºC, 2 hrs

42%

A. J. Clark, C. P. Dell, J. P. McDonagh, C. R. Acad. Sci. Ser IIc: Chim, 2001, 4, 575

NPMB

O

BrHH

H

NN

N

N

TPA

NPMB

OH

H H

CuBr, TPAtoluene, reflux2 hr, 69%

NPMB

OH

H H

CuBr, TPA1,2-DCE, reflux2 hr, 79%

Application to natural product synthesis

NH

O

HHO

O

H

Eremophilne lactam, Petasites hybridus.

Sesquiterpenic lactone, Ligularia species.

O

Br

NPMB

O

O

Br

NPMB

(a) CuBr.TPA, toluene,

110oC, 2h

(b) CAN, MeCN, H2O

89%

NH

O

R

Mn+

Mn+1

X R

Traditional Radical Polar Crossover Reaction

N

O

R

N

O

R

Br

Mn+1

Mn

RN

O

R

OMe

O

Cl

ClOMe

O

O

MeO

OMe

O

2 eq CuCl, DMSO

R

Mn+

Mn+1

X R

Radical CarbeneCrossover Reaction

Mn

Mn+1

R

N

ClCl

Cl

O

R

N

Cl

Cl

O

R O

R

30 mol%CuBrTPA

NOR O

Br

NOR O

OMe OMe

toluene reflux

R = Boc, yield 54%R = PMB, yield 83%

A. J. Clark, J. V. Geden, S. Thom, J. Org. Chem., 2006, in preparation

Cl

NPMB

O

OMe

O

Cl

Cl

CuCl/TPA

NPMB

O

O

PMBN

O

O

toluene, reflux5 h, 35%

Ar

Ar

NH

O

HN

O

HO

OH

N

O

MeN

O

Me

Trikendiol

Indigoid

Cl

NPMB

Ar

O

O

Cl

ClCu(I) NPMB

Ar

O

O

Cl

ClNPMB

Ar

O

O

Cl

Cl

R XMn+

Mn+1

RMn+

Mn+1

X R

NPMB

Ar

O

O

Cl

ClCu(II)

Mn+

Mn+1

Mn+1

Mn

R R-H

-H

NPMB

Ar

O

O

Cl

Cl

Cu(I)NPMB

Ar

O

O

Cl

Mn+

Mn+1

Mn+

Mn+1

R

Cu(I)NPMB

Ar

O

O

Mn+

Mn+1

Mn+

Mn+1

R

observed dimer

Formal radical/polar/carbene triple crossover reaction

NR

O

Br

30 mol% CuBr30 mol% TPACH2Cl2, RT 1hr N

O

Br

R

R Yield (%) Time (hr)

Bn 96 1

PMB 98 1

i-Bu 98 2

t-Bu 0 24

A. J. Clark, G.M. Battle, A. Bridge, Tetrahedron Letts., 2001, 42, 4409

NBn

O

Br

30 mol% CuBr30 mol% TPAtoluene, reflux24hrs, 82%

NO Bn

3:1

NO R

DBU, CH2Cl2,

12 hrs

R

NR

O

Br

R

5-endo

4

5 R

NR

O

Br

?

R

NR

O

Br

?

R 55

44

NO

Br30 mol% CuBr/TPA,

DCM, RT, 20 mins, 98%

4-exo vs 5-exo

4

5

NO

Br

PMB

30 mol% CuBr / TPAtoluene, reflux, 1 hr

NO PMB

Br

60%

NO

Cl

ClCl

PMB

30 mol% CuCl / TPAtoluene, reflux, 18 hrs

NO PMB

Cl

NO PMB

CHO

23% 12%

NO

4.25

Br

NO

Br

: 1

NPMB

O

30 mol% CuCl / TPA

toluenereflux, 5 h

BrN

O PMB

26%

NPMB

O

30 mol% CuCl / TPA

toluenereflux, 6 DAYS

ClCl

H

NO PMB

Cl

NPMB

OClCl

H

10%2%

N

O

Br

PMB30 mol% CuCl / TPA

toluenereflux, 3 h

5-exo5-endo

N

Br

O

PMB N

Br

O

PMB

52% 20%

N

OCl

ClCl

PMB30 mol% CuCl / TPA

toluenereflux, 3 h

N

Cl

ClCl O

PMB N

Cl

ClCl O

PMB

13% 7%

N

ClCl O

PMB

5%

N

OCl PMB

N

OCl PMB

Cl

29% 21%

6-endo

30 mol%CuCl(TPA)

DCM

NN

N

N

TPA

NO

Cl

Pmb

ClCl

NO

Cl

Pmb

NO

Cl

Pmb

NucNO

Cl

Pmb

Nuc

30 mol%CuCl(TPA)

DCMNO

Cl

Pmb

ClCl

NO

Cl

PmbMeOH

OMe

67%

NHOR

OO

N

OX

PGCu

NHOH

O

OO

NHOMe

OO

OH

L-755,807Bradykinin inhibitor

Microsphaeropsis sp. MF6057

PI-091Platelet aggregation inhibitor

Paecilomyces sp. F-3430

NHOH

O

OO

MeO2C

EpolactaeneNeuritogenic agent

Penicillium sp. BM1689-P

NHN

OO

HOMe

Quinolactacin Tumor necrosis factor inhibitor

Penicillium sp. EPF-6

O

X

I

O

Bu3Sn OEt

Pd(0)

Bu3SnCO2Et

1) DIBAL-H2) TPAP3) BuLi, (EtO)2P(O)CH2CO2Et

40%

Bu3SnCO2Et

NHOH

O

OO

O

X

NO

OY

PGPG

NHOMe

OO

OH

O

OPGX

I

Bu3SnCO2Et

PdCl2(MeCN)2DMF, RT, 53%

O

MeOEt

H

H H

5.4%

3.7%

Me

CO2Et

H

2.4%

O

OEt

23

21

24

C21 C23 C24

29.5 19.4 20.5

O

OEt 30.3 19.0 21.3

NHOH

O

OO

30.4 19.2 21.4

NH

O

O

MeOCl

Cl

NH

O

O

MeO

OHCuCl, ligand

H2O

NHOH

O

OO

NO

O

OMe

PMB

4 eq CAN, MeOH, RT

20 mins 67% NO

MeO2C

PMB

OMe

NO

4 eq CAN, MeCN

wet20 mins 94%

O

OMe

PMB

NO

MeO2C

PMB

OH

A. J. Clark, C. P. Dell, J. M. McDonagh, J. Geden, P. Mawdsley, Org. Letts., 2003, 5, 2063

Stuart RookeJoanne PeacockAwh WongtapRobert FilikJohn EllardNicola HuntGary BattleJohn McDonaghJoanne GeddenNicholas MurphyLina YahyahTracey ThompsonTracey Li

EPSRCEPSRC Thailand GovernmentKnoll PharmaceuticalUniversity of WarwickEPSRC Project StudentshipAventis (Industrial CASE)Lilly Research CentreAstraZeneca (Industrial CASE)EPSRCSelf fundedAstraZenecaSelf funded

Triethyl Borane Initiated Radical ReactionsNitrogen Centered RadicalsAmidyl Radicals, Macrocyclisations ATRCLigand Testings for ATRCSynthesis of L-755,807 via ATRCAsymmetric ATRCBeta Lctam Synthesis via ATRC5-Endo cyclisation ATRC ReactionsSolid Supported and Dienamide ATRCCopper Mediated Rearrangements6-Exo ReactionsATRC5-Endo ATRCATRC in Ionic Liquids

RADICAL CHEMISTRY

POLYMER CHEMISTRYDr. Tom StrawDr. L. MwaikamboDr. David DuncalfDr. John Sherringham

OTHER PROJECTSDr. Suzanne DillyIsmail KasujeeKaren WorsfoldDivya PatelYasair Al-Faiyz

BBSRC GENOMICSUniversity of WarwickEPSRC/DTI/ HypersilRoche PharmaceuticalsSaudi Government

cDNA Viral Display, Ligand ImmobilisationEnantioselective AllyzirconationChiral FLASH Colum ChromatographyHydroxamic Acid ChemistryHydroxamic Acid Chemistry

EPSRC polymer initiativeDEFRAEPSRCHome Grown Cereals Authority

Dendrimer SynthesisPolymers from Renewable ResourcesCopper Mediated ATRPPolymers from Renewable Rsources

Cyclisation in ionic liquids

N

Br

TsO

N

NPF6

30 mol% CuBr30 mol% tren-Me6

NTs

O

Br

Run 1 20min 99%

Run 2 1hr 99%

Run 3 2hr 99%

Run 4 6hr 90%

Run 5 12hr 14%

Run 6 36hr No reaction

Work-up add toluene decant off ionic liquid

Further Application of Solid Supported Catalysts

PMBN

O

Cl

ClCl

N O

ClCl

PMB

Toluene, 0.12 M

30 mol% Cu (I) catalyst

Catalyst Time (hrs) Yield (%)

30 mol% TPA, CuCl 3 71

JJ-NPMI.CuCl 1 61

JJ-TEDETA.CuCl 2 60

PS-Me6-tren.CuCl 5 62

PS(CL)-Me6-tren.CuCl 4 64

Si-NPMI.CuCl 9 63

PS-PMDETA.CuCl 23 33

0 2000 4000 6000 8000

0.0

0.5

1.0

1.5

2.0

2.5

0 2000 4000 6000 8000

0.0

0.5

1.0

1.5

2.0

2.5

ln[M

]o/[M

]

2,6-Di-tert-butyl-4-methylphenol4-Methoxyphenol 2,6-Diisopropylphenol Phenol Control

time/seconds

Polymerisation of MMAin presence of various phenols

Control

Ortho substitutedhindered phenol

Unhindered phenols

N

N

CuO

O

Br

CuN

NBr

A. J. Clark, M. C. Crossman, D.Duncalf, D. M. Haddleton,S. R. Morsley, A. J.Shooter, J. Chem.Soc., Chem Commun., 1997, 1734

a

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

a + eb c

df

g

hWater

t = 0

t = 10h

N N CH2 CH2 CH3

a

b

c d

e

f g h

Catalyst complex in water 25°C (Cu : ligand = 1 : 3)

N N1

2

3 4

5

6

7 8

Catalyst Complex in water at 50°C

NHOH

O

OO

NHOMe

OO

OH

L-755,807Bradykinin inhibitor

Microsphaeropsis sp. MF6057

PI-091Platelet aggregation inhibitor

Paecilomyces sp. F-3430

NHOH

O

OO

MeO2CEpolactaene

Neuritogenic agentPenicillium sp. BM1689-P

NHN

OO

HOMe

J. Antibiotics, 2000, 1247

NH

O

Me

OMe

O

H

Phytochemistry 1999, 1507

NH

O

O OMe

H

H

J. Org. Chem., 2000, 6412

N

O

Cl

ClCl

PMBO

i) PMBNH2, ZnCl2,

Benzene, Dean-Stark, 4 hrs

ii) Cl3CCOCl, DCM, 0oC, DEA, 31%

5-Exo Cyclisation

N O

Cl

PMB

Cl N O

PMB

ClCl

N O

PMB

ClCl

Cl

Cu(I)Cl

5-exo Cu(II)Cl

-HCl

N O

ClCl

PMB

71%

CuCl, TPA (30 mol%)

Toluene, 0.12 M, 3 hrs

NPMBCl

O

NPMBCl

O

Cl

NPMB

OClCl

Cl

NPMB

OClCl

Cl

NPMB

OClCl

+

A (29%) B (21%)

+

C (13%) D (7%)

++

E (5%)

• Five cyclisation products isolated; 6-endo (A and B) and 5-exo (C, D and E)

• Ratio A : B : C : D : E = 6.5 : 4.5 : 4.5 : 1.8 : 1.0 : (crude 1H NMR)

• NMR experiments have confirmed relative stereochemistry of C and D

• Ratio 6-endo : 5-exo = 1.5 : 1 (crude 1H NMR) = 2 : 1 (isolated)

NPMB

O

Cl

Cl

Cl CuCl, TPA (30 mol%)

Toluene, 0.12 M, 5 hrs

6-Endo Cyclisation

NPMBCl

O

Cl

NPMB

O

ClCl

NPMB

O

ClCl

NPMB

O

ClCl

Cl

NPMB

O

ClCl

NPMB

O

ClNPMB

Cl

O

NPMB

O

Cl

ClNPMB

Cl

O

NPMB

O

Cl

Cl

Cl

A

B

6-endo Cu(II)Cl -HCl

Cu(I)Cl

Cu(II)Cl

-HCl

H -HCl

Cu(II)Cl

H

NPMB

O

Br

NPMB

O

Br

52% 20%

+

de=44%

NPMB

O

Br

CuBr, TPA (30 mol%)

Toluene, 0.12 M, 2.5 hrs

NPMB

O

Cl

ClCuCl, TPA (30 mol%)

Toluene, 0.12 M, 5 hrs

NPMB

O

Br

CuBr, TPA (30 mol%)

Toluene, 0.12 M, 3 hrs

NPMB

O

NPMB

O

Br

NPMB

O

Br

45% 22%

+ +

7%de=34%

NPMB

O

Cl

Cl

NPMB

O

Cl

Cl

27% 2%

+

de=86%

NRO

Ph

PhO

OMe2 eq CAN, MeOH

NRO

Ph

PhO

OMeOMe

NRO

OO

Ph

Ph

NRO

Ph

PhO

OMe

NRO

Ph

PhO

OMe

NRO

Ph

PhO

OMe

A. D'Annibale et al, Tetrahedron Letts., 1997, 38, 1829

NRO

Ph

PhO

OMe

NRO

Ph

PhO

OMe

CAN

NHOH

OO

NO

MeO2C

PMB

OH CAN or TFA

N-Deprotection

NH

O

MeO2C

86-95%

NO

MeO2COH

NHOMe

OO

4 eq CAN MeCN

5-exo verses 5-endo

20 min, 75%NO

MeO2C

NO

4 eq CAN, MeOH, RT

65% NO

MeO2C

5-Endo cyclisation

O

OMe

PMB PMBOMe

NPMB

O

MeO2C

CAN

CAN

NPMB

O

MeO2C

NPMB

O

MeO2C

MeOH

NO

MeO2C

PMBNO

MeO2C

PMB

NO

MeO2C

PMB

CAN

CAN

NH

O

Me

OMe

O

H

NO

4 eq CAN, MeOH, RT

65% NO

MeO2C

5-Endo cyclisation

O

OMe

PMB PMBOMe

NH

O

Me

OMe

O

H

6-Endo Cyclisation

NPMBCl

O

Cl

NPMB

O

ClCl

NPMB

O

ClCl

NPMB

O

ClCl

Cl

NPMB

O

ClCl

NPMB

O

ClNPMB

Cl

O

NPMB

O

Cl

ClNPMB

Cl

O

NPMB

O

Cl

Cl

Cl

A

B

6-endo Cu(II)Cl -HCl

Cu(I)Cl

Cu(II)Cl

-HCl

H -HCl

Cu(II)Cl

H

NHOH

O

OO

O

X

NO

OY

PGPG

O

X

I

O

Bu3Sn OEt

Pd(0)

Bu3SnCO2Et

1) DIBAL-H2) TPAP3) BuLi, (EtO)2P(O)CH2CO2Et

40%

Bu3SnCO2Et

N

OOH

1) LDA, 4:1 THF:HMPA-78 C 5 hrs, RT 24 hrs

I

2) 10% HCl, reflux3) CH2N24) LiAlH4,

OH

9:1 mixture of diastereomers

34%

TPAPCHO

OPEtO

EtO CO2Et

Me NaH, THF

Me

CO2Et

CO2Et

Me

PhSSPh

1) DIBAl2) TPAP3) CrCl2, CHI3

I

I

I

I

Bu3SnCO2Et

PdCl2(MeCN)2DMF, RT, 53%

O

MeOEt

H

H H

5.4%

3.7%

Me

CO2Et

H

2.4%

NO

MeO2C

PMB

OH 2 eq MeMgBr

37%

NHOMe

OO

HO

NO

MeO2C

PMB

O

HN

HH

CO2Me

O

NO

MeO2C

PMB

OH H2, Pd/C, EtOAc

NO

MeO2C

97%PMB

OH

NHOH

OO

NOH

O

MeO

O

PMB

NO

MeO2COH4 eq CAN MeCN

20 min, 75%NO

MeO2C

Cyclisation in ionic liquids

N

Br

TsO

N

NPF6

30 mol% CuBr30 mol% tren-Me6

NTs

O

Br

Run 1 20min 99%

Run 2 1hr 99%

Run 3 2hr 99%

Run 4 6hr 90%

Run 5 12hr 14%

Run 6 36hr No reaction

Work-up add toluene decant off ionic liquid

N

N

CuO

O

Br

CuN

NBr

A. J. Clark, M. C. Crossman, D.Duncalf, D. M. Haddleton,S. R. Morsley, A. J.Shooter, J. Chem.Soc., Chem Commun., 1997, 1734

a

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

a + eb c

df

g

hWater

t = 0

t = 10h

N N CH2 CH2 CH3

a

b

c d

e

f g h

Catalyst complex in water 25°C (Cu : ligand = 1 : 3)

N N1

2

3 4

5

6

7 8

Catalyst Complex in water at 50°C

NHOH

OO

NO

MeO2C

PMB

OH CAN or TFA

N-Deprotection

NH

O

MeO2C

86-95%