Account 886 Utilization of N,N,N¢,N¢-Tetramethylfluoroformamidinium Hexafluoro- phosphate (tffh) in Peptide and Organic Synthesis

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ACCOUNT

886

Utilization of N,N,N¢,N¢-Tetramethylfluoroformamidinium Hexafluoro-

phosphate (TFFH) in Peptide and Organic Synthesis

TFFH in Peptide and Organic Synthesis

Ayman El-Faham,*

a,b

Sherine N. Khattab*

Faculty of Science, Chemistry Department, Alexandria University, P.O. Box 426, Ibrahemia, 21321 Alexandria, Egypt

E-mail: Aymanel_faham@hotmail.com; E-mail: ShKh2@Link.net

College of Science, King Saud University, P.O. Box 2455, Riyadh, Saudi Arabia

Received 20 August 2008

SYNLETT 2009, No. 6, pp 0886–0904

xx.xx.2009

Advanced online publication: 16.03.2009

DOI: 10.1055/s-0028-1088211; Art ID: A51208ST

phosphate (TFFH) has been shown to be an excellent peptide-cou-

pling reagent. It is an easily handled, crystalline compound, it has a

long shelf life, and it reacts rapidly with carboxylic acids to give the

corresponding acid fluorides or mixed anhydrides depending on the

reaction conditions. TFFH has been shown to be useful as a peptide-

coupling reagent and for the preparation of various carboxylic acid

derivatives. Both aspects will be surveyed in this Account.

Introduction

Formation of Carboxylic Acid Halides

General Method for the Synthesis of Fluoroformamidinium

Salts

Solution and Solid-Phase Peptide Coupling Using TFFH

Synthesis of Small Phosphotyrosine-Containing Peptides

and Peptide Mimetics Incorporating a-Methylated Amino

Acids

Synthesis of Lysine Analogues

Synthesis of Proline Conformation in Tripeptide Fragments

of Bovine Pancreatic Ribonuclease A Containing the Non-

natural Proline Analogue 5,5-Dimethylproline

Synthesis of Different Types of Dipeptide Building Units

Containing N- or C-Terminal Arginine for the Assembly of

Backbone Cyclic Peptides

Synthesis of Peptidyl Methylcoumarin Esters as Substrates

and Active-Site Titrants for Prohormone Processing

Synthesis of Boc-(N-All)Xaa-(N-All)Xaa-OMe

Synthesis of Alamethicin F30 and Analogues Using TFFH

11.1

C-Terminal Alamethicin F30–Fullerene C

and C

Conju-

gates

11.2

N-Terminal Alamethicin F30–Fullerene C

Conjugate

12 Miscellaneous

Examples

12.1

Synthesis of Isothiocyanates and Hydrazides

12.2

Conversion of Carboxylic Acids into Anilides and Azides

12.3

Acylation of Alcohols, Thiols, and Dithiocarbamates

12.4

Conversion of Carboxylic Acids into Alcohols and Hydrox-

amic Acids Using TFFH/PTF

12.5 Preparation of 2-Aminobenzimidazole, 2-Aminobenz-

oxazole, and 2-Aminobenzothiazole Derivatives

12.6

Formation of Interchain Carboxylic Anhydrides on Self-

Assembled Monolayers

12.7 Synthesis of the A

B(A)C Fragment of Everninomicin

13,384-1

12.8

Synthesis of Chiral Polyionic Dendrimers with Comple-

mentary Charges

13 Conclusion

Key words: TFFH, amino acid fluorides, solution-phase peptide

synthesis , solid-phase peptide synthesis, carboxylic acid deriva-

tives, heterocycles

1 Introduction

Recently, the use of new coupling reagents for peptide

synthesis has been reviewed.

The present Account con-

centrates on the fluoroformamidinium salts which show

some advantages over other commonly used coupling re-

agents.

2

Formation of Carboxylic Acid Halides

The most obvious method for activating the carboxyl

group of an amino acid for amide bond formation at room

temperature or below would appear to be via a simple acid

chloride.

The acid chloride method was first introduced

into peptide chemistry by Fischer in 1903.

Since then,

chlorination of amino acids has been carried out with

various chlorinating reagents, such as pivaloyl chloride,

phthaloyl dichloride,

thionyl chloride,

and oxalyl chlo-

ride.

Thionyl chloride in pyridine was applied to the cou-

pling reactions for this purpose.

Other useful acid

halogenating reagents are cyanuric chloride

(1) and 2-

chloro-4,6-dimethoxy-1,3,5-triazine

(CDMT, 2) (Figure 1).

Gilon has reported the use of bis(trichloromethyl) carbon-

ate (BTC, 3) as a chlorinating reagent in solid-phase pep-

tide synthesis.

There is some question as to the nature of

the exact intermediates involved in the Gilon process.

10b

Coupling reactions mediated by BTC gave good results

for Fmoc-amino acids containing acid-labile side chains.

In some solvents, such as N-methyl-2-pyrrolidinone, reac-

tion with BTC gives the chloroiminium ion. Since this

leads to racemization, inert solvents such as tetrahydro-

furan or dioxane are used in the Gilon reaction. For many

Figure 1

Structures of chlorinating reagents

N

N

cyanuric chloride, 1

OMe

MeO

CDMT, 2

BTC, 3

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ACCOUNT

TFFH in Peptide and Organic Synthesis

887

Synlett 2009, No. 6, 886–904

years acid chlorides were rarely used and, among peptide

practitioners, they long ago gained the reputation of being

‘overactivated’ and therefore prone to numerous side

reactions including loss of configuration.

However, be-

cause of the stability of the 9-fluorenylmethoxycarbonyl

(Fmoc) group to the conditions of preparation, Fmoc-

amino acid chlorides were shown to be very useful in pep-

tide coupling. Under appropriate conditions such acid

chlorides can be used without loss of configuration. Be-

cause of their high reactivity, they can be used for highly

hindered substrates. One deficiency of these systems is

that acid-sensitive side chains, such as those derived from

tert-butyl residues, cannot be accommodated.

Acid fluo-

rides, on the other hand, are known to be more stable to

hydrolysis than acid chlorides and, in addition, are not

subject to the limitation mentioned with regard to tert-

butyl-based side-chain protection. Thus, Fmoc-based

solid-phase peptide synthesis can be easily carried out via

Fmoc-amino acid fluorides.

12,13

Cyanuric fluoride (4)

(Figure 2) is the most commonly used reagent for the con-

version of amino acids into the corresponding acid fluo-

rides.

13

Other reagents which can be used are (diethylamino)sul-

fur trifluoride (DAST),

and the pyridinium salts FEP (2-

fluoro-1-ethylpyridinium tetrafluoroborate, 5) and FEPH

(2-fluoro-1-ethylpyridinium hexachloroantimonate, 6)

(Scheme 1), Mukaiyama reagents modified by substitu-

tion of the simple halide counterion for the more solubi-

lizing BF

–

or SbCl

–

counterion.

15,16

The conversion of acids into acid fluorides with all of

these reagents follows a similar process. For example,

with cyanuric fluoride (4) the intermediate 7 is involved

Ayman El-Faham received

his BSc degree in chemistry

in 1980 and his MSc degree

in physical organic chemis-

try in 1985, from the Faculty

of Science, Alexandria Uni-

versity, Egypt. In 1991 he

received his PhD in organic

chemistry in a joint project

between Alexandria Uni-

versity and the University of

Massachusetts, Amherst,

U.S.A., under the supervi-

sion of Professor L. A. Car-

pino, in which he worked on

the synthesis of new protect-

ing groups for both solution

and solid-phase peptide syn-

thesis. In addition, he was

involved in the development

of new coupling reagents

based on 1-hydroxy-7-aza-

benzotriazole. He continued

working on these new cou-

pling reagents during his

postdoctoral work (1992–

1999) in Professor Carpi-

no’s laboratory at the Uni-

versity of Massachusetts.

He holds many patents in

this field. He received the

Alexandria University

Award in Chemistry in

1999. He joined the Barce-

lona Science Park during the

summers of 2006 and 2007,

working with Professor

Fernando Albericio on the

development of a new fami-

ly of immonium-type cou-

pling reagents. His research

interests include the syn-

thesis of peptides under

solution and solid-phase

conditions, natural prod-

ucts, heterocyclic synthesis,

and biologically active syn-

thetic targets. He acted as

Head of the Chemistry De-

partment, Beirut Arab Uni-

versity, Lebanon (2000–

2004), and as Professor of

Organic Chemistry, Faculty

of Science, and the Direct

Manager of both the NMR

Laboratory and the Central

Laboratory at the Faculty of

Science, Alexandria Uni-

versity, Egypt (2004–2008).

Currently, he is Professor of

Organic Chemistry at the

College of Science, King

Saud University, Riyadh,

Saudi Arabia.

Sherine N. Khattab re-

ceived her BSc degree in

chemistry in 1987 from the

Faculty of Science, Alexan-

dria University, Egypt. In

1990 she received her Di-

ploma in Organic Chemistry

from the University of Zur-

ich-Irchel, Switzerland. In

2000 she received her PhD

in organic chemistry from

the Faculty of Science, Al-

exandria University, Egypt.

The title of her thesis was

‘Synthesis of Some Biode-

gradable Peptides for Possi-

ble Use as Sequestering

Agents’. She received the

Alexandria University

Award in Chemistry in

2008. Her research interests

include the synthesis of pep-

tides under solution and

solid-phase conditions, de-

velopment of new coupling

reagents, heterocyclic syn-

thesis, and biologically ac-

tive synthetic targets.

Currently, she is Associate

Professor of Organic Chem-

istry at the Faculty of

Science, Alexandria Uni-

versity, Egypt.

Biographical Sketches

Figure 2

cyanuric fluoride, 4

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A. El-Faham, S. N. Khattab

ACCOUNT

Synlett 2009, No. 6, 886–904

(Scheme 2). The presence of a base was found to be essen-

tial for formation of the carboxylic acid fluorides. IR and

UV spectroscopic measurements confirm this course of

the reaction.

16–18

Standard methods for the preparation of carboxylic acid

fluorides often involve noxious reagents such as various

metal fluorides.

A notable advance was the development

of fluoroformamidinium salts. Carpino and El-Faham re-

ported that the air-stable, non-hygroscopic solid

N,N,N¢,N¢-tetramethylfluoroformamidinium hexafluoro-

phosphate (TFFH, 8) acts as a convenient in situ reagent

for the formation of amino acid fluorides during peptide

synthesis (Scheme 3).

TFFH is especially useful for the

two amino acids histidine and arginine since the corre-

sponding amino acid fluorides are themselves not stable

toward isolation or storage.

Infrared examination shows that, in the presence of N,N-

diisopropylethylamine (DIPEA), Fmoc-amino acids are

converted into the acid fluorides using TFFH.

In dichlo-

romethane solution at room temperature, an IR absorption

characteristic of the carbonyl fluoride moiety (1842 cm

–1

)

appears after about 3 minutes, with complete conversion

into the acid fluoride occurring after 8–15 minutes. For

hindered amino acids [e.g., a-aminoisobutyric acid

(Aib)], complete conversion may require 1–2 hours.

20,21

desired, the acid fluorides may be isolated and purified,

making TFFH a benign substitute for the corrosive cyanu-

ric fluoride.

Other analogous reagents have also been synthesized

(Figure 3). Bis(tetramethylene)fluoroformamidinium hexa-

fluorophosphate (BTFFH, 9) has the advantage over

TFFH in that, upon workup, the reaction mixture does not

generate toxic byproducts.

21,22

Fluorinating reagents 9, 11, 12, and 13 behave in a similar

way to 8 in their ability to provide a route to amino acid

fluorides for both solution and solid-phase reactions,

20,21

whereas 10, being more reactive but more sensitive to

moisture, never gives complete conversion into the acid

fluoride. Except for 10, all of these reagents can be han-

dled in air in the same way as common onium reagents,

such as N-[(dimethylamino)(1H-1,2,3-triazolo[4,5-b]py-

ridin-1-yl)methylene]-N-methylmethanaminium hexa-

fluorophosphate N-oxide (N-HATU, 14)

and N-[(1H-

benzotriazol-1-yl)(dimethylamino)methylene]-N-methyl-

Scheme 1

OBF

SbCl

FEP, 5

FEPH, 6

3

OSbCl

6

Scheme 2

Synthesis of amino acid fluorides using cyanuric fluoride

Y-NH-CH-C-OH

N-protected amino acid

N

H

NHY

Y-NH-CH-C-F

N-protected amino acid fluoride

O

4

R

Scheme 3

Synthesis of amino acid fluorides using TFFH

N

Me

TFFH, 8

base

–

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ACCOUNT

TFFH in Peptide and Organic Synthesis

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Synlett 2009, No. 6, 886–904

methanaminium hexafluorophosphate N-oxide (N-HBTU,

15)

(Figure 4).

For some amino acids, e.g. Fmoc-Aib-OH, it was found

that the use of TFFH alone gave results that were less sat-

isfactory than those obtained with isolated amino acid fluo-

rides. The deficiency was traced to inefficient conversion

into the acid fluoride which, under the conditions used

(DIPEA, 2 equiv), was accompanied by the corresponding

symmetric anhydride and oxazolone.

21,26

On the other

hand, it has now been shown that if a fluoride additive

such as benzyltriphenylphosphonium dihydrogen trifluo-

ride (PTF, 16) or hydrogen fluoride–pyridine (17)

(Figure 5) is present during the activation step, the latter

two products can be avoided and a maximum yield of acid

fluoride is obtained. Assembly of the difficult pentapep-

tide Tyr-Aib-Aib-Phe-Leu-NH

via TFFH coupling in the

presence of PTF (16) gave a product of similar quality to

that obtained via the isolated acid fluorides.

Figure 5

More interestingly, conversion of the acid into the acid

fluoride was also observed upon treatment with N,N¢-di-

cyclohexylcarbodiimide (DCC, 18), diisopropylcarbodi-

imide (DIC, 19) (Figure 6), N-HATU (14), or N-HBTU

(15) in the presence of the additive PTF (16).

27,28

Figure 6

Because the fluoride additive binds excess hydrogen fluo-

ride as part of the complex dihydrogen trifluoride anion,

an accompanying acidic buffering effect might prove to

be of value in the case of coupling reactions where loss of

configuration at the activated carboxylic acid residue

might be important. Such a protective effect was in fact

observed in the case of the sensitive histidine derivative

Fmoc-His(Trt)-OH upon reaction with proline amide,

which with TFFH/DIPEA under ordinary conditions gave

the desired dipeptide in good yield with 7.4% stereomuta-

tion; in the presence of additive 16, stereomutation

dropped to 1.8%.

Generation of the amino acid fluoride using TFFH (8) is

more efficient if PTF (16) is present, as shown by model

solid-phase syntheses.

Presumably, this technique can

also be used to improve conversion into the isolable acid

fluorides.

28

3

General Method for the Synthesis of Fluoro-

formamidinium Salts

Following is a typical procedure for the preparation of

fluoroformamidinium salts;

namely, TFFH (8)

(Scheme 4):

In a two-liter, three-necked round flask equipped with a

mechanical stirrer, an addition funnel, and a reflux con-

denser, oxalyl chloride (70 mL, 0.80 mol) was added in

one portion to a solution of 1,1,3,3-tetramethylurea (69.7

g, 0.60 mol) in toluene (1 L) with vigorous stirring. The

mixture was heated at 60 °C for two hours and then cooled

to room temperature. The addition funnel was replaced

with a fritted adapter and the supernatant liquid was ex-

pelled using a positive pressure of nitrogen. The precipi-

tate was collected and washed with toluene and then with

anhydrous diethyl ether. The dichloro salt was collected

and dissolved quickly in dichloromethane (1 L) and treat-

ed with a saturated solution of potassium hexafluorophos-

phate (0.6 mol) in water. The reaction mixture was stirred

vigorously at room temperature for 10–15 minutes and

then the dichloromethane phase was collected and dried

(MgSO

). The solvent was removed under reduced pres-

sure to give the chloro salt, TCFH (20). To a solution of

20 (0.5 mol) in anhydrous acetonitrile (300 mL) was add-

ed oven-dried anhydrous potassium fluoride (1.5 mol) and

the mixture was stirred at room temperature for three

hours (monitoring by

H NMR spectroscopy). Longer

times are required for large-scale preparations. Following

the removal of potassium chloride by filtration, the filtrate

was concentrated and the residue was recrystallized

(MeCN–Et

O) to give TFFH (8) as non-hygroscopic,

white crystals in 92% yield.

Figure 3

Structures of fluorinating reagents

N

N

BTFFH, 9

FIP, 10

TEFFH, 11

6

PF

DMFFH, 12

DEFFH, 13

6

Figure 4

N

N

N-HATU, 14

N

N

N-HBTU, 15

(HF)

PTF, 16

(Ph)

PBn

DCC, 18

DIC, 19

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890

A. El-Faham, S. N. Khattab

ACCOUNT

Synlett 2009, No. 6, 886–904

The above method has been modified for a one-pot prep-

aration,

as follows:

In a one-liter, three-necked flask equipped with a mechan-

ical stirrer, an addition funnel, and a reflux condenser, ox-

alyl chloride was added over a period of 10 minutes to a

solution of 1,1,3,3-tetramethylurea in anhydrous dichlo-

romethane with vigorous stirring. The reaction mixture

was refluxed for three hours and the solvent was removed

under reduced pressure. The residue was washed twice

with anhydrous diethyl ether and dissolved in anhydrous

acetonitrile. Then, a predried mixture of potassium fluo-

ride (3 equiv) and potassium hexafluorophosphate (1

equiv) was added. The resulting mixture was heated at

60 °C for three hours, then the reaction mixture was

cooled to room temperature, filtered, and washed with

acetonitrile. The combined filtrate was concentrated, the

resulting oily residue was taken up in hot dichlo-

romethane, and the cloudy solution was filtered while hot

and concentrated under reduced pressure to approximate-

ly half the volume. Anhydrous diethyl ether was added

with vigorous stirring to promote precipitation of the salt

as a white solid, in a yield of 91%.

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