Syntheses of Azetidines and Azetidin-2-ones

Literature Seminar on Apr.18th (Sat.) Gang Lu (D3)

NN

O

NO

azetidines azetidin-3-ones azetidin-2-ones

(β-lactams)

huge literature coveragelower attention

key role in anti-baterial activitystrained nature and difficulty of formation

1. Azetidines synthesis

1) Cyclization by nucleophilic substitution of amine nucleophiles

2) Cyclization by C-C bond formation

3) Cycloaddition

4) Reduction of β-lactams

5) other methods

2. Important azetidine compounds

1) Natural products

2) Azetidine ligands and auxiliaries for asymmetric reactions

3. Azetidine-3-ones synthesis

Contents (based on a recent review: Brandi A. et al. Chem. Rev. 2008, 108, 3988.)

1. Azetidines synthesis

1) Cyclization by nucleophilic substitution of amine nucleophiles

LG NHR

R1

R2

R3

N

R3 R2

R1R

i) To Use Halides, Sulfonic esters, triflates, etc. as Leaving groups

LG= X, OMs, OTf, OTs

R= alkyl, Ar, OBn

MeO2C NHTs

CO2Me

I N

MeO2C

Ts

MeO2CNaOMe, MeOH

quant.

eg 1. CL 1988, 1065.

eg 2. NH2

ClCl+K2CO3, H2O

MW 80-100W, 120 °C, 20 min

N

54%

JOC 2006, 71, 135.

12

3

X, OMs, OTf, OTs as leaving group

ring opening: epoxide, aziridine, Br+, etc

Carbanion mediated

Radical cyclization

eg 3.

HO OH

HO

OH

1) Tf2O, DIPEA, -20 °C

2) Ph2CHNH2, DIPEA, 70 °CN N

Ph

Ph Ph

Ph

35%

JOC 2006, 71, 7885

eg 4.

OBC 2007, 5, 3510

eg 5.

PhPh

Ph

N N3PhHN

Ph Ph

Ph

4N HBr/HOAc, rt, overnight, 94%

or 1M HCl, EtOH, reflux, 2 h, 92%HX• ARKIVOC 2005, xiii, 8

eg 6.

CO2Me

NHPf

OMs

MsONPf

CO2Me

OMs

NPf

MsO CO2Me

+

DMF, Et3N, 80 °C

4 1

CO2Me

NHPf

OMs

MsO

NPf

CO2Me

OMs

NPf

MsO CO2Me

+

DMF, Et3N, 110 °C

0 100

Ph

Pf=

H

NHPfMeO2C

OMs

OMs

H

H

NHPfMeO2C

OMs

MsO

H

cis-TSanti-TS

unfavored favoredJOC 2002, 67, 3637

eg 7.

71%

73%

R

N

H R

N

H

Br

FN

F

R1.1eq NBS2.2 eq Et3N• 3HF NaBH4, MeOH

61-70%

JOC 2006, 71, 7100

pentaerythritol4

7 8

65

9a

9b

syn-azetidine anti-azetidine

syn-azetidine

anti-azetidine

1011

R2

N

Cl

Cl

R1

R2

NR1

OMs

Cl ClR3 R2

HNR1

OMs

Cl ClR3

R2Cl Cl

R3

NNC H

R1

R2Cl Cl

R3

NH H

R1

1) ArCHO, LDA2) MsCl, Py

NaCNBH3HOAc

71-88%

KCN, MeOH K2CO3, DMSO 63-78%54-84%R1= iPr, Et

R2= H, Cl

R3= H, Me

JOC 1998, 63, 6

eg 9. OH

I

NBn2

NBn2

BF4−

HO

AgBF4

62%

O

Cl

NBn2 OEt

OLi

+CO2Et

NBn2

HO

Cl

NBn2

HO CO2EtAgBF4

BF4−

NBn

HO CO2Et

87%

Pd/HCO2HJOC 1997, 62, 8902

OL 2002, 4, 1299

eg 10.

N3

BnO

BnOH

H

OH(+)-DET

NH

BnO

OBn

1) MsCl

2) Raney Ni

86%

N

BnO

OBn

NH2

N

HO

OH

N

NH

XR

O

1) i-amyl-NO2

2) LiAlH4

83%

R=H, X=O Me O H NH2

BMCL 1994, 4, 2083

eg 11.

OAcO

HON3 O

O

OAcO

TsON3 O

O

OAcO

NH

O

O95%

H2, Pd/C

EtOAc, 60 °C

65%

T 2003, 59, 1333

1213

1514

eg 8.

16a 17

16b 18 19 20

21

22 23

24 25

26 27

eg 12.

OTsO

BnOOBn

OBn

OTs

O

BnOOBn

OBn

BuN

tBuNH2

76%

Carb. Res. 1997, 299, 253

eg 13. Br Br

NH2

Br NH2

Br

NH2

N

Nu-R

N

Nu

R

NaOH, 80 °C

BuLi

NCS, 0 °C

ACIE. 1969, 80, 70

SC. 1998, 28, 3949

JOC. 1995, 60, 4943

eg 14.

HO R1

R2

HNPMP

Im Im

O

N

R2 R1

PMP

JOC. 2006, 71, 4147

iii) Opening of Aziridines

eg 17.

NR2 R1

H H

SO2R3

S

O

+

R2 R1

NS

O

SO2R3

R2 R1

N

18-77%

Synlett 2008, 108

OL 2007, 9, 4399

NR1

R1

SO2R3

eg 18.

HN

CO2R2

Ph

Ph

N

PhPh

CO2R2

NHTs

R1

R1Et3N, MeCN

70 °C, 20 h

44-80%

28 29

3031

32 33

ii) Opening of Epoxides

ClO

+R

SiMe3

NH2

Cl

OH

NH

SiMe3

R

IPA

reflux

eg 15.

NHHO

R

SiMe3

ClNHO

R

SiMe3NaOH R=SiMe3, Et, Pr, Cy

Synlett 1998, 510

eg 16. ClO

+ R NH2RHN

O• HCl

EtOH

rt

Et3N, MeCN NHO

Rreflux

SC. 2003, 33, 4297

34 35

36

34 3738

39 40

41 42

SO2R3

N

NO2

NO

N

PhCl

S SR31a 31b

(CDI)

iv) Opening of Bromonium, Iodonium or Seleniranium Intermediates

eg 19. Ph NHTs Br+(collidine)2PF6−

95%N

Br Ph

Ts

EJOC 2000, 3007

eg 20.HN

TMS

Ph

Ph

OH

1) NIS

75%N

Ph

H

Br

TMS

Ph

OH

EJOC 2007, 4517

eg 21.OH

BnOBnO

NAcBn

OBn

OBn OBn

OBnOH

N

OAc

Bn

H

NBS

2) NaHCO3, H2O

41%

Carb. Res. 2002, 337, 273

eg 22.

NHBn

R2 R1

PhSeX, MeCN

Na2CO3, rt, 16 hN

BnR1

R2

SePh

+N

R1

R2

SePh

Bn15-32%

6-38%

EJOC 2002, 995

LDA (2 eq)

2) Cyclization by C-C bond formation

i) Carbanion-mediated cyclization

eg 23.Cl

N CO2H

Boc rtN

CO2H

Boc45%

CC. 1994, 879

eg 24.

Me

Ph Cl

N

R

CN

LiHMDS (2 eq)

-78 °C then -30 °CN

CN

R

Ph

Me

R= Me (78%) Bn (84%)

TA 2003, 14, 2407

eg 25.

Cl

N CO2Bn

Ph

LiHMDS

N

CO2H

Ph

N

CO2H

N

CO2H

Ph

N

CO2H

+

H2, Pd/C

32% 29%

JOC. 2005, 70, 9028

43 44

45 46

4748

4950

51 52

53 54

55

56a 56b

Me

Ph Cl

N P(OEt)2

eg 26.

OLiHMDS

N

P(OEt)2Ph

Me

O

30% 82%

TMSBrN

P(OH)2Ph

Me

O

eg 27.

Me N

Bn

CN

CO2Et

LiHMDS

74% N

CN

BnMe

EtO2C

NH

CO2H

Me

HO2C1) 6N HCl

2) H2, Pd/C

TL 2002, 43, 4633

OBC 2005, 3, 3926

ii) Radical cyclization involving C=O group

N

Ar

R1

CO2R2

eg 28. 1) e−, Pt catode

TMSCl, Et3N

2) BzCl, Et3N NAr R1

Bz

OMeTMSO

34-60%

eg 29.

Ph

O

OTDS

NCH3Cbz

Ph

OH

OTDS

NCH3Cbz

•

•N

Cbz

OTDSHOPh

NH

CO2HMeOPh

71%54%

hν

eg 30.N NR

O

Ph

O

hνN NR

O

H OHPh

+ N NR

O

H PhHO

exo endo51%

OL 2006, 8, 1323

JACS 2003, 125, 11591

Helv. Chim. Acta 1998, 81, 1803

CEJ 2002, 8, 2464

3) Cycloaddition

N

N

N

O NMe

O

Oeg 31. hν

85%

N

N

N

O NMe

O

O EJOC 2000, 743

eg 32.N

Ac

hν

52%

NNAc

Ac

+

N

NAc

Ac

eg 33. O

Ph

Ph

NAc

+110 °C

O Ph

PhN

Ac91%

toluene

TL 1998, 39, 5481

TL 1999, 40, 443

57 58 59

60 61 62

63 64

65 66 67 68

69

70 71

72 73

74 75a 75b

76 77 78

SiTDS:

eg 34.

OR1N

SO2Ar

R2+

MeCN, 80 °CN

R2 SO2Ar

OR1

cis/trans >1/145-97%

eg 35.N

NH

N

Ac

NH

NHAcNHPh

PhNH2

91%

CC 2002, 444

ACIE 2006, 45, 5176

4) Reduction of Azetidin-2-ones

LiAlH4 alane/etherdiborane DIBAL-H AlH2Cl

eg 36.N

PhO Ph

O

NO

Ph

Me

OH

N

PhO Ph

N

Ph

Me

OH

AlH2Cl, ether

85%

JACS.1983, 105, 6339

JOC.1991, 56, 5263

eg 37.

N

BnO

O

AlH2Cl, ether

89%N

BnOJOC.1998, 63, 6786

N

CHO

O PMP

eg 38.AlH2Cl, ether

45% N

CH2OH

PMP

eg 39.

N

BnO

O

N

O N

BnO N

OAlH2Cl, ether

100%

JOC.1994, 59, 7994

EJOC.2005, 1680

eg 40.

NO PMP

O

O

NO PMP

O

O

AlH2Cl, ether

74%

NO PMP

O

O

NO

O

PMP

AlEt2Cl, CH2Cl2

86%

JOC.1994, 59, 7994

JOC.1999, 64, 9596

79 80 81

82

74

83 84

8586

87 88

89 90

91 92

93

95 96

94

iii) Cyclization of ββββ-amino allene

eg 46.R1 C

NHArO2S

Pd(0) (10 mol%)RI, K2CO3

DMF, 70 °C NSO2Ar

R

R1

C

NHMts

eg 47.H

BrN

Mts

NMts

84 16:

+

70%

JOC. 2001, 66, 4904

JACS. 2002, 124, 15255NaH, DMF

NaOR1

ii) Ring Rearrangement

eg 44. NOR

X

Cl

NR

CO2R1

X41-88%

TL 1991, 32, 4795

eg 45. O N R1

O

R2

O

N

O

R1

R2

N O R1

O

R2TfOMe

PhNO2

150 °C42-75%

T 2002, 58, 7049

eg 41.

NO R

R1OX

n

NR

R1OX

nAlH2Cl, ether

57-95%N

R1O

Rn

X

N

Br

R1O

R

92-98%N

R1O Nu

R44-52%

n=0n=1R= Bn, allyl, tBu, Cy

R1= Me, Bn

X= Cl, Br

n= 0, 1

Nu= Cl, BrOH, CN, N3

OL.2006, 8, 1105

eg 42.

NO

OTBS

OSO2Gly

F

F N

OTBS

OSO2Gly

F

F

AlH2Cl, ether

94%

cholesterol absorption inhibitorOL.2005, 7, 1145

i) Eletrophilic Attack on C=C

eg 43.N

Ar

R

O +TIPS

N

Ar

R

OLA

N

TIPS

Ar

O

R

CL 1995, 789

TiCl4 or BF3

9798

99

100101

5) Other methods

102

103

104105

106

107 108

109 110

111 112

113 114a 114b

53-98%

eg 49.

N

O

Ph

SCSOEt

O

F

+

N

O

Ph

SCSOEtAr

O

lauroyl peroxideDCE, 50%

trans/cis=2.6/1TL.2000, 41, 9815

eg 50.

Ar1 Ar2

O

Ar3HN P(OEt)2

Ο+

1) NaH

2) [bmim]XN

Ar1

Ar3

Ar2

X Synlett 2008, 583

(X = PhS−, NCS−)76-89%

2. Important azetidine compounds

1) Natural products

iv) Pd-Catalyzed Decarboxylation

N O

O

Ts

R1

R2

R

eg 48.N

R1

R2

Ts

R

Pd(PPh3)4 (5 mol%)

CH2Cl2, rt

JOC.1994, 59, 1465

60-93%

115

116

v) Others

117118 119

120 121122

phytosiderophoresiron-chelating amino acidspromote uptake and transport of iron for chlorophyl biosynthesis

actomyosin ATPase-activating activity

protein Kinase C inhibitory activity

potent inhibitors of chitin synthetase

NBoc

NHBoc

PMP PMPeg 51.

TrocO NBoc

NHBoc

CO2H CO2H

TrocO

OHCNBoc

NHBoc

CO2tBu CO2tBu

NBoc

NHBoc

CO2tBu CO2tBu

N

CO2tBu

NH

NH2

CO2H CO2H

N

CO2H

1) RuCl3, NaIO4 EtOAc, NeCN, H2O

2) O-tBu-N,N'-diisopropyl- isourea, tBuOH, CH2Cl2

1) Zn, HOAc, THF (97%)2) Swern Oxi. (94%)

NH• HOAc

CO2tBu

NaBH3CN

THF, MeOH

eg 52.

T 1994, 50, 9457

OOTBS

5

OTBS

5

OMs

OTBS

TsHN

TBSO

JCSPT 1997, 2, 971) NaH (88%)

2) deprotection

2) Ligands for Metal-Catalyzed Reactions

eg 53.

Ph H

O Et2Zn (2.2 eq), L (3 mol %)

toluene, 0°C to rt, 48 h Ph

OH

97% y., 98% ee

Ar1 H

OEt2Zn (3 eq.), L (10 mol %)

toluene, rt, 48 h Ar1 Ar2

OH

up to 99% y., 96% ee

Ar2B(OH)2 (1 eq.)

eg 54.

Synlett 2006, 3443

J Organomet Chem 2005, 690, 2306

123124

125

126 127

(nicotianamine)

128129

130

actomyosin ATPase-activating activity

for Suzuki reaction:

1−0.1 mol % cat., 77-87% y.

L

35% (2 steps)

93%

deprotection

3. Azetidine-3-ones synthesis mainly by NH insertion in diazo compounds

eg 55.

JOC 1985, 50, 5223

eg 56.

OH

OHN

R

PG

eg 57.

JCSPT 1999, 1, 2277

eg 58.

TL 2004, 45, 3355J Organomet Chem 2005, 690, 5636

eg 59.

EJOC 2006, 2440

eg 60.

TL 2001, 42, 2373

131 132

133134

135 136

137 138

143

139140 141

142

144 145