Advances in Peptide Coupling

activation

PHN

OH
R

coupling

PHN

X
R

Lead References:
K. Devries, Evans group Friday seminar, 4/9/91
L. Carpino Methods in Enzymology 1997, 289, 104

Evans Group Seminar

Jeff Katz
12/15/98

Overview

1. The role of DMAP

2. Amide formations
i. Carbodiimides
ii. Mixed anhydrides of carbon
iii. Acyl azides & cyanides
iv. Mixed anhydrides of phosphorus
v. Pentafluorophenyl esters
vi. Phosphonium & aminium reagents
vii. Acid fluorides
viii. Obscurities
3. The coupling of hindered amino acids
4. Complex peptide synthesis:
i. Didemnin
ii. Microcystin LA

PHN

NHR'
R

Pentafluorophenyl Esters

Preactivation method:

DCC/PFPOH
or

O
H
N

R"O
O

OH

PFP-Trifluoroacetate
pyr.

H
N

R"O
O

H2NR'
O

H
N

R"O
O

Stable, isolable active ester

Green Tet. Lett. 1990, 31, 5851

Pentaflurorophenyl Esters

NHZ
O

H
N

OPFP
O

i-Bu

N
H

NHZ

H
N

1. HCl, dioxane, 20 C
O

Me
O

2. NaHCO3/CHCl3 room temp

NHBoc

72%, 2 steps

Me

O
N
H

i-Bu
O

OH

OH

OH
OH

1. PFPOH, EDC, DMAP, 97%

i-Pr
O

BocHN

HN
O

OH

ZHN

NHR'

F
F

2. Pd black, -terpinene, 4-PPY

dioxane/t-BuOH, reflux, 49%

O
i-Pr
O

BocHN

O
NH

HN

i-Bu

i-Bu

Joullie Tet. Lett. 1998, 39, 7211

Schmidt Chem. Commun. 1994, 1003

4-PPY

Pentafluorophenyl Esters
Ph2

O
P

F
F

FDPP

O
R

FDPP, DIEA, H2NR'

DMF, room temp.

OH

NHR'

Xu Tet. Lett. 1991, 32, 6711

O
O
O

H
N

2:1

H
N

HO2C

H
N
O

1. PFPOH, DCC, DMAP

H
N

NHZ

NH

2. 4-PPY, Pd/C, 90 C, 5h
30% yield, 2:1 ratio of epimers

OMe
OMe

OMe
OMe

MeO
MeO
triazine
Cl

HO
H
N
HO2C

H
N

Cl

HO
H
N

NHBoc
O

NH2
BnO

triazine

Br

FDPP, i-Pr2NEt, DMF, 25 C

Br

H
N

NHBoc
O

NH

12h, 52% yield, no epimers

OMe
OMe

BnO
OMe
OMe

MeO
MeO

K. C. Nicolaou Chem. Commun. 1997, 1899

K. C. Nicolaou Angew. Chem. Int. Ed. 1998, 37, 2708

Pentafluorophenyl Esters

Ar
O

HN
Bn
O

Coupling agent % Yield

HN

O
HO2C

OH

16

EDC/HOBt

Coupling agent

NH

NHAc
N

DPPA

DEPC

12

PFP ester

8
57

FDPP*

NH2
*

Shioiri Tet. Lett. 1996, 37, 2261

O
i-Bu

i-Bu
Me
N

O
NH2

FDPP, i-Pr2NEt, DMF, r.t. 14h

HO2C

Bn
O

Coupling agent

N
H

Coupling agent

% Yield

DPPA

low

FDPP

60

HATU

50
85

PFP ester*

i-Bu
*

Ulrich Schmidt Chem. Commun. 1994, 2381

CHCl3-NaHCO3, room temp. 5h

Pentafluorophenyl Esters

The "first" In situ activation method:

PF6- O
N

PFP

PF6- O
Me

Me

N
Me

Me

PfPyU

PFP

PfTU

CO2t-Bu
t-BuO

C(O)NHTrt
O
H
N

O
H
N

FmocHN
O

N
H

O
N
H

OSugar

H
N
O

i-Pr
H
N

N
H

CO2H

Me

CO2t-Bu

Synthesized in 13 steps on solid phase (tentagel) in an overall yield of 76% (98%/step):

(Hunig's base, collidine, PfPyU, NMP)

Habermann J. Prakt. Chem. 1998, 340, 233

Phosphonium Reagents

X
N
N

PF6

(NMe2)3

X = C: BOP
X = N: AOP

3
PF6-

X = C: PyBOP
X = N: PyAOP

Highly active coupling reagents with "built-in" additive:

O
R

reagent
OH

DIEA

OBt

OP+(NR2)3

O
R

N
O

N
X

active species
HOAt derivatives invariably preform better than the corresponding HOBt derivatives
Pyrollidine derivatives generally preform better than the corresponding dimethylamino derivatives

Castro Tet. Lett. 1975, 1219; Tet. Lett. 1990, 31, 205
Carpino Chem. Commun. 1994, 201

X
N
N

PF6-

Aminium Reagents

(NMe2)2

X = C: HBTU
X = N: HATU

X = C: HBPyU
X = N: HAPyU

O
R

PF6-

OH

Aminium reagent
R

amine base

OXt

fast

OC+(NR2)3

N
O

N
X

Higher reactivity than carbodiimide reagents

H2NR'

Added base is necessary

HOAt derivatives invariably preform better than the corresponding HOBt derivatives
Pyrollidine derivatives generally preform better than the corresponding dimethylamino derivatives
O
R

Knorr Tet. Lett. 1989, 1927

Carpino J. Am. Chem. Soc. 1993, 115, 4397

Aminium Salt Couplings Effects of the Amine Base

Aminium Salt DIEA

HBPyU

10.7

HATU

NMM Pyridine collidine

5.7

7.7

2.7
1.7

lutidine DMAP

0.6
0.1

HAPyU

2.3

6.2

HBPyU

26.6

13.7

HATU

6.5

1.7

HAPyU

6.3

5.9

0.1

0.1

Aminium Salt Additive

0.6

10.4

% Racemization for
2+1 segment coupling of
Z-Phe-Val-Ala-OMe in DMF
% Racemization for
2+1 segment coupling of

2.3

NMM (2 equiv)

Z-Phe-Val-Pro-Ot-Bu in DMF

HAPyU

none

12.2

% Racemization for
2+1 segment coupling of

HAPyU

HOAt

3.3

Z-Phe-Val-Pro-NH2 in DMF

Added HOAt/HOBt is shown to have a deliterious effect for solid phase coupling reactions

Carpino J. Org. Chem. 1994, 59, 695

Carpino J. Org. Chem. 1996, 61, 2460

NHR'

Amino Acid Fluorides

H2N

PHN

CO2Me

H
N

DIEA
PHN

DMF

R'
O

CO2Me

R'

Acid Fluoride Formation:

F
N

CH2Cl2, pyridine

R
F

OH

PHN

PHN

or

DAST, CH2Cl2
Bench stable compounds for most Fmoc-protected amino acids
Do not form oxazolone intermediates in the presence of tertiary amines
Relatively unreactive to neutral oxygen nucleophiles
React readily with anionic oxygen nucleophiles and neutral amines
Sillicon protecting groups are problematic

Carpino Acc. Chem. Res. 1996, 29, 268

Me2N
Me2N

PF6-

PF6-

Amino Acid Fluorides In Situ Generation

TFFH

BTFFH

R
H2N

OH

PHN

TFFH/DIEA
or
BTFHH/DIEA

CO2Me
R'

R
H
N

PHN

CO2Me

R'

Bn

For segment condensations, HOAt is needed to suppress racemization:

1:1
O
Bn

Bn

Bn
OH

N
H

TFFH/DIEA

Bn

"segment-like"

H
N

Ala-OMe

Bn

N
H

CO2Me
Me

only isolable product

% Racemization:

Z-Phe-Val-OH
H-Ala-OMe

Coupling agent
Base, DMF

Z-Phe-Val-Ala-OMe

TFFH
TFFH/HOAt

Carpino J. Am. Chem. Soc. 1995, 117, 540

Carpino Chem. Lett. 1998, 671

i-Pr2NEt

NMM

collidine

25
2

23

6
<0.1

Amino Acid Fluorides

R
H2N

PHN

H
N

DIEA

CO2Me

PHN

R'

X
F

CO2Me
R'

equiv of DIEA % Conversion

0

100*

100

Cl

50

Cl

100

Reaction rate is only slightly retarded

No-base approach has been shown to be general for both solid- and solution-phase couplings
No epimerization is observed

Carpino Chem. Commun. 1995, 669

Acid Fluorides Racemizaton

CO2R

Ph
F

ZHN

Ph

Solvent, base

HN

ZHN
O

CO2R

preformed

base

% epimer

DMF

DIEA

19.0

DMF

collidine

11.6

CH2Cl2

collidine

<0.1

Solvent

Highly racemization-prone amino acids still require carefully controlled conditions

Wenschuh, Carpino J. Org. Chem. 1995, 60, 405

Segment Couplings

Z-Phe-Val-Pro-NH2 via 2+1 segment coupling in DMF

Reagent

Base (equiv) % Yield % epimer

Reagent

Base (equiv) % Yield % epimer

EDC/HOAt

85

4.7

HATU/HOAt

DIEA (2)

76

10.9

EDC/HOBt

87

18.9

HATU/HOAt

DIEA (3)

88

15.8

EDC/HODhbt

89
89

7.3
5.3

HATU/HOAt

EDCHCl/HOAt TMP (1)

HATU/HOAt

TMP (2)
TMP (3)

72
87

2.4
4.5

HAPyU
HAPyU/HOAt

TMP (2)
TMP (2)

87
76

3.5
1.6

HAPyU/HOAt

TMP (3)

89

2.3

HAPyU/HOAt

DIEA (2)

77

3.2

HAPyU/HOAt

DIEA (3)

90

12.1

EDCHCl/HOBt TMP (1)

87

19.9

HATU

TMP (2)

83

5.3

HATU
HBTU

DIEA (2)
TMP (2)

86
81

13.9
14.2

BOP

TMP (2)

81

13.9

Carpino J. Org. Chem. 1995, 60, 3561

Obscurities Couplings with kinetic resolution

Me

Me

Cl

Cl

collidine
N

THF
Cl

OH

Cl

Cl

O
OH
R

i-Pr

i-Pr

ZHN

H2N

OMe

O
H
N

1, conditions?
PHN

R'

one residue is racemic

Coupling partners (substrate ratio)

% Yield

ee or de

Z-Gly-OH + D,L-Ala-OEt (1:2)

87

93 (L)

Z-D,L-Ala-OH + Gly-OEt (2:1)

86

100 (L)

Z-D,L-Ala-OH + L-Leu-OMe (2:1)

72

100 (L,L)

Z-D,L-Ala-OH + L-Phe-OEt (2:1)

75

100 (L,L)

OMe
R'

%ee measured by rotation only

Kaminski Synthetic Communications 1998, 28, 2689

Obscurities Polymer-bound coupling reagents

Resin

P-Xxx-OH

PPh2

I2
P-Xxx-Yyy-OR

H-Yyy-OR
imidazole, CH2Cl2
25 C, 2 hr, 90-99%

Xxx

Yyy

% Yield

Fmoc

Ala

Leu

Allyl

99

Cbz

Met

Ala

Me

98

Boc

Leu

Phe

t-Bu

95

Fmoc

Val

Val

Allyl

99

Me

95

Me

94

Fmoc

Cys(Trt) Cys(Trt)

Boc

Trp

Leu

Authors propose an acyl iodide as the active species

Caputo et. al. Synthesis 1995, 141

PF6Br

PF6-

Secondary Amine Coupling

(NMe2)2

Br

BroP

PyBroP

More Powerful activation is needed for Secondary Amines:

R
P

R'
OH

N
H
O

Me

N
H

Coupling agent

CO2Me

Me
N

N
H
O

CO2Me
R'

% Yield (hours)
Sequence

PyBOP PyBroP

Z-MeVal-Val-OMe

90 (1)

85 (1)

Z-Val-MeVal-OMe

11 (1)

70 (1)

Fmoc-Val-MeVal-OMe 30 (24)

84 (3)

Boc-Val-MeVal-OMe

44 (3)

45 (24)

CH2Cl2, DIEA, room temp.

Coste J. Org. Chem. 1994, 59, 2437

Phosphonium Reagents Active Coupling Species

R
P

PyBOP

N
H

slow

N
N

N
R

R'
P

Me

N
H

CO2Me

Me
N

N
H
O

CO2Me
R'

PyBroP

N
H

fast

For PyBroP, The "active ester" is a mixture of species:

R
O

N
H

N
H
O

O
O

R'O

Secondary Amine Coupling: Side-product Pathways

R
H
t-Bu

O
O

slow

R' = H

R
R'

t-BuO

R'
X

N
O

O
O

N-carbonic anhydride

fast

R' = Me
R
Me
t-Bu

O
O

Coste Tet. Lett. 1992, 33, 2815

Secondary Amine Couplings

An electron-poor HOBt additive can increase reactivity:

NO2

N
O
CF3

2
CF3-NO2-PyBOP

% Yield
Sequence

PyBroP

CF3-NO2-PyBOP

Z-Val-Val-OMe

89

98

Z-Val-MeVal-OMe

49

76

Fmoc-Val-MeVal-OMe

57

85

Boc-Val-MeVal-OMe

25

62

Boc-MeLeu-MeLeu-OMe

47

87

Z-MeVal-MeVal-OMe

22

71

CH2Cl2, DIEA, room temp., 1 hr

Bloemhoff Tet. Lett., 1995, 36, 4643

,-Dialkylamino Acids

O
PHN
Me

OH
Me

carbodiimides or

H2N

OR'

inconsistent results, low yields

mixed anhydrides

Aminoisobutyric acid (Aib)

% Yield for Phosphonium-based Aib couplings (CH2Cl2, room temp.)

Sequence

BOP PyBOP BroP PyBroP

Z-Aib-Gly-OEt

92

Z-Aib-Val-OMe

88

87

84

Z-Aib-Pro-Ot-Bu

82

84

95

25
76*

25
77*

Z-Aib-Aib-OMe
Boc-Aib-Aib-OMe

87

89

89
80

86

87

77
*

With added DMAP

Aib-Aib coupling is still sluggish reaction times are 16 to 24 hours

While good yields can be obtained, sluggish and varied reaction conditions make this unsuitable for solid phase

Coste Tetrahedron 1991, 47, 259

DMAP Acylation Catalysis

Me
OH

Acylation Reagent

DMAP

Ac2O

DMAP

AcCl

20

pyridine

Ac2O

1000

1:1 pyridine:NEt3

Ac2O

1000

OAc

Ac2O, base

t 1/2 (min)

Base
Me

CDCl3, 27 C

General Base Acceleration:

N
O
-

N
Me

Me

O
R

Steglich ACIEE 1978, 17, 569

DMAP Equilibrium Concentrations

O
Me

X-

Pyridine

N +
Me

Undetectable in non-polar solvents, but

has been detected in H2O by UV

N
O
Me

XX

DMAP

N +
Me

% Pyridinium in solution

Cl

>95

OAc

5-10

CDCl3, room temperature

,-Dialkylamino Acids

Aminium salts and acid fluorides for solid-phase ,-dialkyl and N-methylamino acid synthesis:

Reagent
H-Tyr-Aib-Aib-Phe-Leu-NH2

sequence purity

HATU

94%

TFFH

92%

HBTU

43%

7 min. activation, 30 min. coupling in DMF

H-D-Ala-MeLeu-MeLeu-MeVal-Phe-Val-OH

Reagent

sequence purity

HATU

85%

HBTU

8%

7 min. activation, 30 min. coupling in DMF

Carpino Chem. Commun. 1994, 201

Peptaibols

Bioactive linear peptide sequences

Sequences are approx. 20 residues and contain unusually high amounts of ,-dialkylamino acids
Aib-Pro linkages are acid-sensitive (cleaved by TFA)

Ac-Aib-Pro-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-Glu-Gln-Pheol
alamethicin F-30
Synthesized on solid phase via Fmoc-amino acid fluorides in 78% purity

Ac-Aib-Ala-Aib-Leu-Aib-Gln-Aib-Aib-Aib-Ala-Aib-Aib-Pro-Leu-Aib-Iva-Gln-Valol
trichotoxin A-50
Synthesized on solid phase via Fmoc-amino acid fluorides in 60% purity

Wenschuh, Carpino J. Org. Chem. 1995, 60, 405

Didemnin

N
i-Bu
O
Me
i-Pr

O
NH
O

Ar

N
Me

O RO

O
Et

O
O

Me
O

N
NH H

Me
N
R'
i-Bu

Me

Didemnin

O
N
i-Pr

i-Bu
O

N
Me

NHZ
CO2H

1. PFPOH, DCC, DMAP

O

OMOM
O
O TIPSO

Me
i-Pr

NHBoc

Et

Me

Ar

N
O

FDPP, BOP and HBTU were unsuccessful

Et

Me

Ar

N
O

i-Pr

FDPP, 30%
or

Me

cyclized product
HBTU, 50%

OMOM
O
O MeO
O

cyclized product

FDPP, room temp. 4h, 68%

N
Me

NH2
CO2H
Me

NHBoc
NH

i-Bu

DPPA, 0 C, 72h, 42%

or

Me

OMOM
O
O TIPSO

i-Pr

72%

N
Me

NH2
CO2H
Me

2. Pd/C, 4-PPY, 95 C

i-Pr

cyclized product

Me

NHBoc
NH

Joullie J. Org. Chem. 1994, 59, 5192

Joullie Bioorg. Med. Chem. Lett. 1996, 6, 2713
Joullie J. Org. Chem. 1996, 61, 1655

Didemnin

HATU/HOAt - Macrolactamizaton

HBTU/HOBt
Stepwise coupling
O

Ar

N
i-Bu

TBTU
stepwise coupling

Me
i-Pr

DIC/DMAP/DMAPCF3COOH
Segment coupling
(DIC/DMAP fails)

i-Bu
O

Me
i-Pr

HN

OR

OR

Me

N
H
NH

O
Et

Me

O
Me
N
i-Bu

BOP/HOBt - Stepwise coupling

HBTU/HOBt - Stepwise coupling

HATU, HOAt

O
O

Me

R = H, R' = H: 76% yield

R = TBS, R' = Boc-(R)-N(Me)-Leu-OH: 28% yield

NHR'
NH

cyclized product, 1 isomer

Me

NH

Ar

CO2H

N
Me

NH
O

DCC/DMAP - Stepwise coupling

O

Et

Giralt J. Org. Chem. 1997, 62, 354

Microcystin LA

HATU/DIEA - stepwise coupling

(DCC/HOBt and BOP fail)
DCC/HOBt - stepwise coupling
CO2H

O
Me
N

HATU/collidine
HN
OMe

Me

NH

Me
O

Ph

NH
Me

Me
H
N

HN
H
N

1. DCC/PFPOH
Me
O H2OC
2. CHCl3-pH 9.5 buffer
macrolactamization
HATU/DIEA (88%)
56%
or
DCC/DMAP (71%)
stepwise coupling

DCC/HOBt - stepwise coupling

i-Bu
O

HATU/collidine - segment coupling

Richard Chamberlin J. Am. Chem. Soc. 1996, 118, 11759

Overview

Stepwise couplings:
Standard amino acids EDC/HOBt. DEPC, or BOP are also good choices
Racemization-prone amino acids If EDC/HOBt is insufficient, try EDC/HOAt or HATU/collidine
Segment couplings:
Phosphonium or aminium salts are good choices, HOAt/pyrollidine derivatives for the difficult cases

Macrolactamizations:
FDPP/PFP esters, DPPA and HAPyU/collidine are good bets

Hidered couplings:
Acid fluorides and HAPyU/collidine are good choices. PyBroP and BOP-Cl work for solution phase.

DMAP Acylation Catalysis

+
N

X-

N +

X-

X-

N +
Me

N +

O
Me

Me

A1 (X=Cl)

B1 (X=Cl)

A2 (X=OAc)

B2 (X=OAc)

O -

Me

B"

B'

X-

B1 and B2 are observable by 1H NMR in CDCl3 or CD2Cl2 at low temperature

N + H
O -

Me

B"
4 distinct resonances

DMAP Acylation Catalysis

Me

Me
OH

Ac2O, base

Base

Acylation Reagent

DMAP

Ac2O

DMAP

AcCl

20

pyridine

Ac2O

1000

1:1 pyridine:NEt3

Ac2O

1000

OAc

CDCl3, 27 C

Rate of pyridinium-acylations is tied to:

Concentration/solubility
Identity of counterion
Tightness of ion pair

t 1/2 (min)

DMAP Acylation Catalysis

A Reactivity Reversal:

Hydrolysis Rate
Cl-

pH 5.5 buffer
2000

N +
Me

H 2O

Cl-

pH 5.5 buffer

N +

H 2O
Me

Rate of pyridinium-acylations is tied to:

Tightness of ion pair
Concentration/solubility
Identity of counterion

Overview

1. The role of DMAP

2. Amide formations
i. Carbodiimides
ii. Mixed anhydrides of carbon
iii. Acyl azides & cyanides
iv. Mixed anhydrides of phosphorus
v. Pentafluorophenyl esters
vi. Phosphonium & aminium reagents
vii. Acid fluorides
viii. Obscurities
3. The coupling of hindered amino acids
4. Complex peptide synthesis:
i. Didemnin
ii. Microcystin LA

Carbodiimide Activation

Et

DIC

DCC

N
Me

EDCHCl

Me

Cl

Gives a water-soluble urea by-product

O
R

Cy

OH

Cy

Cy

N
H

Cy
O
Cy

N
H

O
N
H

Cy
R

NH

H2NR'
R

NHR'

C
N

Cy

Sheehan J. Am. Chem. Soc. 1955, 77, 1067

Rebek J. Am. Chem. Soc. 1973, 95, 4052

Carbodiimides Reaction Pathways

Cy

O-acyl urea
R'O

Cy

NH
O

N
H

NH

Cy

Cy

NHP
O

HOBt

N-acyl urea

R
N

PHN
O

OR'

R
NHP

PHN
O

N
N

symmetrical anhydride
stabilized active ester

oxazolone
increased racemization

R
NHR"

PHN
O

HO

N
N

HOBt

Cy

Racemization Pathways

H
N

R'O

H
N

R'O

active ester

oxazolone
increased risk of racemization

OR'

OR'

Direct deprotonation of active esters does occur, but oxazolone formation is the major racemization pathway
Carbamate-protected amines help supress oxazolone formation and deprotonation
Amide "amino-protection" is the main reason for increased racemization in segment couplings

Modern Advances in Coupling Additives

Higher reactivity
Increased racemization
More side-reactions
Moisture-sensitive

additive

PHN

PHN
O

HO

N
N

Less water sensitive

Lower reactivity
Decreased racemizaton
resistant to side-reactions

HO

Most common coupling additives:

HOBt

OH

N
N

HOAt

HODhbt
Decreased racemization vs. HOBt but more
side-reactions

Z-Phg-Pro-NH2 formation in DMF:

R'HN

Reagent
EDC/HOAt

% Yield % epimer
81

EDC/HOBt

80

25

EDC/HODhbt

82

10

N
O

PHN
O

N
N

NHR'

PHN
N

HOAt has the advantage of internal base acceleration

Konig Chem. Ber. 1970, 103, 2024,2034

Carpino J. Org. Chem. 1995, 60, 3561

Mixed Anhydrides of Carbon

O
R

O
OH

Cl

amine base
R

OR'

O
O

NH2R"
OR'

NHR"

preactivation

Amine

equiv

% Yield

% epimer

NMe3
NMe3

1
2

NEt3

90
<5
82

0
68
8

NEt3
i-Pr2NEt

2
1

59
3

16
0.2

i-Pr2NMe
i-Pr2NMe
NMM

1
2
1

NMM

94
85
92
93

0
3
0
0

Common chloroformates
O
Cl

O
O

Et

Cl

i-Bu

Z-Gly-Phe-Gly-OEt synthesis in THF at -15 C,

12 min activation with i-BuOC(O)Cl

The solvents of choice are ethyl acetate and THF. Acetonitrile, CH2Cl2, NMP and DMF should be avoided.
Side reactions: disproportionation to symetrical anhydride, attack at undesired carbonyl

Anderson J. Am. Chem. Soc. 1967, 89, 5012

Jouin Tetrahedron 1989, 45, 5039

Mixed Anhydrides of Carbon

In situ generation (no preactivation) of mixed anhydrides:

O
R

OH

OR"

OR"

EEDQ:

R" = Et

IIDQ:

R" = i-Bu

O
OR"

Yajima Chem. Commun. 1972, 942

Belleau J. Am. Chem. Soc. 1968, 90, 1651

OR"

No additional base is necessary

DPPA and DEPC

O
(PhO)2

O
N3

(EtO)2

DPPA

CN

DEPC

Tends to be used for macrocylizations

Tends to be used for stepwise couplings

DPPA

OH

O
O

N3-

(OPh)2

N3

active species
Curtius rearrangement is slow relative to coupling
Acyl azide relatively unreactive to non-amine nucleophiles

DEPC
R

OH

CN(OEt)2

CN

active species

Yamada J. Am. Chem. Soc. 1972, 94, 6203

Yamada Tet. Lett. 1973, 1595

DPPA

Me O

Me O
Ph

N
H

N
H

HN
O

NH2
H
N

N
H
O

Ph

Conditions

CO2H

N
H

N
H

HN
O

NH
H
N

N
H
O

CO2Me

Pritchard Tetrahedron 1992, 48, 8471

CO2Me

Method

% Yield

DPPA
BOP
DCC, HOBt

71
49
31

BOP-Cl Activation

O
O

O
N

P
Cl

BOP-Cl

BOP-Cl
DIEA

O
R

OH

CH2Cl2

O
O
O
O

N
O
N

H2NR' (or HOR')

R

Active acylating species

Mixed anhydride intermediate is very reactive and will form both esters and amides
Less prone to side-reactions than chloroformate-based anhyrides
Active enough to couple N-alkyl amino acids, but requires long reaction times

A. Palomo-Coll Synthesis 1980, 547

Daniel Rich J. Am. Chem. Soc. 1985, 107, 4342
Daniel Rich J. Org. Chem. 1986, 51, 3350

BOP-Cl Macrolactamization

Me

Me

Me
Me

MeO
OMe
OMe

MeO

HO2C

Me

MeO

OTBS

OMe OTBS

BOP-Cl, DIEA, 15h

Me

Me

Me

85 C, 85%

NH2

Me

O
OMe

MeO

OMe

Me
NH

OMe

DCC, DEPC, DPPA fail

Baker Chem. Commun. 1989, 378

NHR'

Me
N PF6
Cl
N
Me

PF6-

Me2N

Me2N

PF6

X = C: HBTU
X = N: HATU

2
BTFFH

OR"

CIP

(NMe)2

EEDQ:

R" = Et

IIDQ:

R" = i-Bu

O
P

(PhO)2

HO

DPPA

FDPP

HOBt

N3

F
F

O
P

Ph2

PF6-

OR"

PF6-

TFFH

(EtO)2

CN

DEPC
HO

X = C: HBPyU
X = N: HAPyU

PF6

Me

Me

HOAt

(NMe2)3

Me

PfTU
DCC

OH

X = C: BOP
X = N: AOP

Me

PF6-

N
N

PFP

PFP

PF6- O
N

HODhbt

DIC
PfPyU

O
O

X
O
O
P
N
N
O
Cl

N
N

PF6-

PF6Br

N
N

PF6-

CF3-NO2-PyBOP

CF3

Br

EDCHCl

NO2

(NMe)2

BroP

X = C: PyBOP
X = N: PyAOP

BOP-Cl

Et

+
PyBroP

N
Me

Me

Cl