综述,缩合试剂制备酰胺键物质

Eric Valeur*w and Mark Bradley*

Received 23rd June 2008

First published as an Advance Article on the web 4th December 2008DOI:10.1039/b701677h

Amide bond formation is a fundamentally important reaction in organic synthesis,and is typically mediated by one of a myriad of so-called coupling reagents.This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of ‘‘acronym’’based reagents.It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179references).

Introduction

Amide bonds play a major role in the elaboration and composition of biological systems,representing for example the main chemical bonds that link amino acid building blocks together to give proteins.Amide bonds are not limited to biological systems and are indeed present in a huge array of molecules,including major marketed drugs.For example,Atorvastatin 1,the top selling drug worldwide since 2003,blocks the production of cholesterol and contains an amide bond (Fig.1),1as do Lisinopril 2(inhibitor of angiotensin converting enzyme),2Valsartan 3(blockade of angiotensin-II receptors),3and Diltiazem 4(calcium channel blocker used in the treatment of angina and hypertension).4

Amide bonds are typically synthesised from the union of carboxylic acids and amines;however,the unification of these two functional groups does not occur spontaneously at ambient temperature,with the necessary elimination of water only taking place at high temperatures (e.g.42001C),5conditions typically detrimental to the integrity of the

substrates.For this reason,it is usually necessary to first activate the carboxylic acid,a process that usually takes place by converting the –OH of the acid into a good leaving group prior to treatment with the amine (Scheme 1).Enzymatic catalysis has also been investigated for the mild synthesis of amides and the organic chemist may find some of these methods useful as an alternative to traditional methods.6,7In order to activate carboxylic acids,one can use so-called coupling reagents,which act as stand-alone reagents to generate compounds such as acid chlorides,(mixed)anhydrides,carbonic anhydrides or active esters.The choice of coupling reagent is however critical.For example,in medicinal chemistry library-based synthesis,amides are often generated using broad ranges of substrates with varying reactivities (e.g.anilines,secondary amines,bulky substrates).A coupling reagent needs to be able to cope with this whole portfolio of reactivity.Many reviews on coupling reagents have been published,8–14illustrating their importance in the synthetic armoury of the synthetic chemist,but these reviews have often failed to offer a critical view on the subject making the choice of reagent difficult.An important issue is that many of the coupling reagents reported have not been compared to others,making any real evaluation impossible.As many groups have reported ‘‘new’’reagents as being wonderful and better than others,the chemist looking at the field of coupling reagent for

University of Edinburgh,School of Chemistry,West Mains Road,Edinburgh,UK EH93JJ.E-mail:mark.bradley@ed.ac.uk;Fax:(+44)13165053;Tel:(+44)131650

4820

Eric Valeur

Eric Valeur obtained his Ph.D.under the guidance of Prof.Bradley at the Univer-sity of Edinburgh in 2005,and worked as a Postdoctoral fellow at the Northern Insti-tute for Cancer Research,Newcastle,in Prof.Griffin’s group.He then joined Merck-Serono in France,before moving recently to Novartis,within the medicinal chemistry group of the Expertise Protease

Platform.

Mark Bradley

Professor Bradley’s research interests are focused on the application of the tools and techniques of chemistry to address biological problems and needs,typically with a high-throughput twist.Two themes dominate at this time:the development of non-DNA based microarray platforms for cell and enzymatic based assays and the development of chemistries that enable effi-cient cellular delivery of pro-teins,nucleic acids,sensors and small molecules.

w Present address:Novartis Pharma AG,FAB-16.4.06.6,CH-4002Basel,Switzerland.evaleur@yahoo.fr CRITICAL REVIEW www.rsc.org/csr |Chemical Society Reviews

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Coupling using carbodiimides

1.1Dicyclohexylcarbodiimide

Carbodiimides were thefirst coupling reagents to be synthe-

sised.Dicyclohexylcarbodiimide(DCC,5)has been used for

coupling since1955,21and the mechanism for coupling

carboxylic acids to amines is shown in Scheme2.

Thefirst step involves the reaction of the carboxylic acid

with DCC to form the O-acylurea6.This intermediate can

then yield a number of different products:

The amide via direct coupling with the amine(the

by-product formed,dicyclohexylurea(DCU7),is usually

insoluble in the reaction solvent and can be removed via

filtration).

Formation of an N-acylurea8by-product

Formation of the carboxylic acid anhydride which

subsequently yields the amide by reaction with the amine

(needs2equiv.of acid).

When using DCC,oxazolone formation can take place after

generation of the O-acylurea leading to epimerisation,19

especially important when activating acid groups in the a

position of an amide bond.

In addition to peptide synthesis,carbodiimides(often

with N-hydroxysuccinimide as an additive)have been used

extensively in nanotechnology for the functionalisation of

monolayers on surfaces and nanoparticles.22,23

1.2Use of additives

In order to reduce the epimerisation level when using carbo-

diimides as coupling reagents,Koenig and Geiger introduced

1-hydroxy-1H-benzotriazole(HOBt)9as an additive,24,25

showing that,when using this additive,yields were higher

and epimerisation levels lower.For example,when coupling

Z-Gly-Phe-OH to H-Val-OMe,the epimerisation levels

dropped from35%to1.5%.

HOBt9is believed to work by initially reacting with the

O-acylurea6to give the OBt active ester10,which enhances the

reactivity of the‘‘activated ester’’by encouraging/stabilising

the approach of the amine via hydrogen bonding(Scheme3).

However,HOBt can yield by-products,thus it catalyses the

formation of diazetidine11(Scheme4).26

In1994,Carpino reported a related additive,1-hydroxy-

7-azabenzotriazole(HOAt)12(Fig.2),which was even more

efficient than HOBt9in terms of yield,kinetics and reduced

epimerisation levels.27For example epimerisation during

coupling of Z-Val-OH and H-Val-OMe using DCC5dropped

from41.9%with HOBt9to14.9%with HOAt12,while

during the coupling of Z-PheVal-OH to H-Ala-OMe using

Table1Common epimerisation tests used for coupling reagent evaluation involving amino acids

Entry Author Acid Amine Analysis method

1Young15Z-Leu-OH H-Gly-OEt Optical rotation

2Weinstein16Ac-Phe-OH H-Ala-OMe NMR

3Bodansky17Ac-iso Leu-OH H-Gly-OMe Chiral HPLC

4Anteunis18Z-Gly-Phe-OH H-Val-OMe HPLC or NMR

5Anderson19Z-Gly-Phe-OH H-Gly-OEt Fractional crystallisation

6Izumiya20Z-Gly-Ala-OH H-Leu-OBz Hydrogenation followed by HPLC D

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EDC,it dropped from 4.1%with HOBt 9to under 2%with HOAt 12.27

Much work has been carried out on the benefit of using additives.In particular,Carpino studied various isomers of HOAt concluding that the 7-isomer was the most efficient.28Albericio also showed that copper(II )complexes with HOAt 11or HOBt 9were efficient additives in lowering the epimerisation level.29

However,safety considerations when using benzotriazoles (and variants)need to be carefully considered as these compounds display explosive properties.30,311.3.

Other carbodiimides

Since the application of DCC to amide bond formation,many carbodiimides,including DIC 13(diisopropylcarbodiimide),have been reported and this field has been reviewed.26In particular,attention has focused on so-called water-soluble carbodiimides,as the ureas formed when using DCC 5or the popular diisopropylcarbodiimide DIC 13can sometimes be difficult to remove.Sheehan investigated several derivatives 14–17,and concluded that coupling was more efficient when using tertiary amine carbodiimides rather than quaternary derivatives (e.g.14416).32,33

Carpino compared DIC 13to EDC 20and analogues 18–19,34and also compared DIC 13to some unsymmetrical alkyl/aryl carbodiimides such as phenyl ethyl carbodiimide (PEC 21)and phenyl isopropyl carbodiimide (PIC 22)(Fig.3,Table 2).Overall,when using HOAt as an additive,DIC gave the best results for peptide segment coupling.

Other carbodiimides,BMC 23and BEC 24have been proposed by Izdebski,but these reagents showed no benefit over DIC 13.35Another so-called ‘‘water extractable’’carbodiimide,BDDC 25was synthesised and its efficiency was comparable to DCC 5and EDC 20.36

2.Coupling reagents based on 1H -benzotriazole

Several ‘‘salts’’are often associated with reagents based on 1H -benzotriazoles,including uronium/aminium,phosphonium and immonium salts (Fig.

4).

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2.1Uronium/aminium salts

Many coupling reagents are based on the HOBt/HOAt system and uronium/aminium salts.37Uronium 26and aminium 27isomers of these reagents have been structurally identified and the true forms is probably a mater of debate depending on solvent,isolation method and counter anion etc .(Fig.5).38Coupling reagents based on uronium salts were first reported as the O -isomer (26).However,Carpino showed by X-ray crystallography that HATU 28a and HBTU 28b were in fact the N -isomer (27).38

These reagents react with carboxylic acids to form OAt/OBt active esters,which then react with amines (Scheme 5).

A side-reaction can often take place with the amine reacting with the coupling reagent to form a guanidinium by-product 29(Scheme 6),14thus order of addition and timing are crucial.Comparative studies using HBTU 3928b and TBTU 4030b showed that the counter-anion had no practical influence on the outcome of coupling reactions using these reagents (Fig.6).Carpino showed that the best results were obtained with HOAt,and many coupling reagents started to be based on this additive such as HATU 28a and TATU 30a .27It has been proven that coupling reagents based on HOAt (compared to HOBt)give faster,more efficient couplings with less epimerisation.41Much work has been carried out with variation of the substituents,yielding HAPyU 31(also named BBC by Chen 42)and TAPipU 32with relatively little impact on the outcome of couplings.43Other modifications include

HAPipU 3733a ,HBPipU 4433b ,HAMDU 3734a ,HBMDU 37

34b (also named BOI),and HAMTU 3735.Overall the structural differences between these reagents did not appear to be based on rational considerations and were merely a screening of different substituents.Reagents 33–35gave poor coupling results because the reagents were too reactive and degraded before coupling could take place.

Carpino modified the HOAt ring to form 5,6-benzo (36)and 4,5-benzo (37)derivatives,45which showed no real benefit over classical methods.In fact when used as additives with DIC,the epimerisation was higher than when using HOAt as additive.More recently,derivatives HCTU 40a and TCTU 40b based on 6-chloro-HOBt were developed by Albericio,46but these reagents have not been directly compared to other coupling reagents.

Scientists at Argonaut also reported a 6-chloro-HOBt-based reagent,ACTU 40c ,47which was compared to DIC 13.Some results were very disappointing as a simple,unhindered acid (phenylacetic acid)was only activated to 36%.This result was only improved to 70%when using an excess of acid,demon-strating that ACTU is a fairly poor coupling reagent.

Recently El-Faham developed some new reagents based on ‘‘immonium salts’’.48However,according to the terminology used in coupling reagents,these belong to the aminium/uronium salt-based class.Based on HOAt-/HOBt-rings,HAM 2PyU 41a ,HBM 2PyU 41b ,HAM 2PipU 42a ,HBM 2PipU 42b ,HAE 2PyU 43a ,HBE 2PyU 43b ,HAE 2PipU 44a ,HBE 2PipU 44b ,HATeU 45a and HBTeU 45b were synthe-sised.El-Faham firstly investigated the stability of these new reagents both in solution and in the solid state.Solids and solutions (in DMF)were stable for 3–4weeks when kept under an inert atmosphere.However,like most coupling reagents,the reagents degraded rapidly when left in solution in the presence of a base.Thus,coupling involving hindered or poorly reactive substrates can be expected to be poor as longer reaction time are typically required for these substrates.Efficiency of the reagents was tested by measuring

the

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half-life of the activated esters of Z-Aib-OH in the presence of 4-chloroaniline.HOAt-based reagents HAM 2PyU 41a ,HAM 2PipU 42a ,HAE 2PyU 43a ,HAE 2PipU 44a ,HATeU 45a reacted more quickly than the HOBt-based reagents HBM 2PyU 41b ,HBM 2PipU 42b ,HBE 2PyU 43b ,HBE 2PipU 44b ,HBTeU 45b .However no yields were given,which makes the direct comparison of the reagents impossible.Indeed,the

activated esters might be hydrolysed rather than coupled to the poorly nucleophilic 4-chloroaniline.Epimerisation was low (Anteunis test)when the reagents were used in the presence of collidine but was as high as 11.8%in the presence of DIPEA when using HBTeU 45b .Overall it was not

evident

Table 2Results obtained when coupling Z-Phe-Val-OH to H-Pro-NH 2with various carbodiimides and HOAt as an additive 34Entry Coupling reagent Yield (%)LDL

(%)

1DIC 86 2.12PEC 91 5.63PIC 9.EDC

85 4.75

EDC ÁHCl

81

4.1

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that any of the new reagents reported were beneficial over a reagent like HATU 28a .

Recently,El-Faham reported further development of such coupling reagents.49HDMA 46a ,HDMB 46b ,and 6-HDMCB 47were evaluated and little variation on epimerisation levels was noticed,but HDMA 46a proved to give higher yields for the synthesis of Fmoc-Val-Val-NH 2compared to HATU 28a .Other reagents such as 6-HDMFB 48,4-HDMA 49,HDMTA 50a and HDMTB 50b were also synthesised.50Overall there was hardly any difference between the different reagents.HDMB 46b displayed the best hydrolytic stability while having better solubility than HATU 28a .Morpholino derivatives HDMA 46a and HDMB 46b showed better efficiency than their thio analogues HDMTA 50a and HDMTB 50b .2.2

Phosphonium salts

Another family of coupling reagents based on HOBt/HOAt uses a phosphonium group.Phosphonium salts have the advantage of not yielding guanidinium by-products via reac-tion of the coupling reagent with amines.The first HOBt/HOAt-phosphonium salt introduced was BOP 51b ,51but its use has been limited due to the carcinogenicity and respiratory toxicity associated with HMPA generated when BOP 51b is used in coupling reactions,leading to the development of the pyrrolidino derivative PyBOP 52b .52Carpino prepared AOP 3751a and PyAOP 37,5352a and compared them to BOP 51b and PyBOP 52b ,and showed that the aza-derivatives were more reactive.

For the synthesis of thioamides,Hoeg-Jensen developed phosphonium coupling reagents based on 6-nitro HOBt

(Fig.7).54PyNOP 53,PyFOP 54and NOP 55were used successfully for the formation of thioamides,with good thioamide/amide selectivity but their solubility in organic solvents was poor.Moreover,the results obtained with PyBOP were very similar to PyNOP 53,PyFOP 54and NOP 55.

In a recent patent,PyClock 56was disclosed as a new coupling reagent.55However hydrolysis was shown to be worse than PyBOP 52b in the absence of base after 6h and this was also worse in the presence of a tertiary base as around 88%had been hydrolysed after 1h compared to 81%for PyBOP 52b under these conditions.The efficiency of PyClock 56was evaluated via the solid-phase synthesis of three pentapeptides which incorporated hindered/N -methylated aminoacids (Table 3).2.3Immonium salts

Li designed and synthesised immonium/carbonium type cou-pling reagents,56,57such as BOMI 57,56,58–61BDMP 58,56,60,61BPMP 59,BMMP 60,and AOMP 56,5961(Fig.8).BOMI 57and BDMP 58showed the best results,achieving 490%conversion within 10min during the coupling of Z-Gly-Phe-OH with H-Val-OMe (Anteunis test).In addition,epimerisation was low,BOMI 57displaying 3.1%and BDMP 582.3%of the DL -isomer.However,these reagents were not compared to classic reagents such as HATU 28a or PyBOP 52b .As an application,these reagents were used to carry out the total synthesis of Cyclosporine O,an immunosuppressive agent.62

2.4Other reagents

DepOBt (originally called BDP)62b was reported by Kim (Fig.9).63The reagent appeared to couple aniline to benzoic acid or phenylacetic acid in high yield,and also aminoacids (Phe,Val,Met,Ile)to other amino acids (Gly,Ser,Val)in high yield although N -Methylated substrates were not tested.Epimerisation was evaluated via Young’s test and found to be low.The same group reported DpopOBt 63b but epimeri-sation was high.

Carpino reported DepOAt 62a ,DpopOAt 53a ,DmppOAt ,DtpOAt 65a and DtpOBt 65b .65Again,no real improve-ment was gained compared to HATU 33a .For the synthesis of ACP(65-74),HATU 33a outperformed any of these reagents.An epimerisation study for the coupling of Z-Phe-Val-OH and H-Pro-NH 2showed that DmppOAt (3.6%of LDL isomer)and DtpOAt 65a (2.9%)gave less epimerisation than HATU 28a (5.0%),while DtpOBt 65b was worse (11.4%),but no explanation was given.

HAPyTU 66,a thio-analogue of HAPyU 31,was tested by Klose but proved to be unsuccessful as yields were lower and epimerisation higher than HAPyU 31.66

Another type of reagent based on sulfonates was developed by Itoh.67These reagents 67–70incorporated HOBt or HOCt (6-chloro-HOBt)with different substituents on the sulfonate.The best results were obtained with HCSCP 70,the chlorine group enhancing the reactivity of the reagent.However,the reagents were not compared directly to each other.Compared to DCC 5(without using HOBt),these reagents gave less side-reactions and the by-products were easily removed during aqueous workup.According to the authors,epimerisation

was

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lower than with DCC 5,but this was no surprise as DCC alone give very high levels of epimerisation.2.5

Conclusion on 1H -benzotriazole-based reagents

1-H -benzotriazole-based reagents probably represent the widest class of coupling reagents.Although differences in reactivities have been reported by their authors,there is practically very little difference,as exemplified by Hachman,68and HBTU 28b or TBTU 30b are reagents which usually perform very well.Surprisingly,the potential explosive prop-erties of these reagents is almost always disregarded.30,31

3.Reagents generating acid halides

3.1General reagents used in organic chemistry and triazine-type reagents

Fischer reported the first synthesis of a dipeptide (Gly-Gly)in 1901using acid chlorides for coupling.69The general approach consisted of using reagents such as thionyl chloride or phos-phorus pentachloride to generate the acid chloride which

reacted quickly with amines to form amides.This original method was quite harsh and not compatible with many protecting groups.It has however been adapted by Carpino to synthesise peptides via a Fmoc strategy.70Triphosgene has also been reported to generate amino-acid acid chlorides,71especially useful for hindered substrates.72Similarly,acid cyanides and azides have been used to synthesise amides.73Cyanuric fluoride 71can be used to synthesise acid fluorides,74which couple N -methylated amino-acids very efficiently.A variety of other reagents have been reported for the formation of acid fluorides,and include Deoxo-Fluor 72and DAST 73(Fig.10).75However a side-reaction is observed when using Deoxo-Fluor 72especially with hindered amines (Scheme 7),which limits the applicability of this reagent.In addition,Deoxo-Fluor 72and DAST 73are expensive and hazardous reagents,and purification by chromatography is required after reaction.

Part of this category of reagents is based on triazines (cyanuric fluoride,chloride and derivatives)and has been reviewed in details by Kaminski.76The mechanism of activa-tion involves the generation of an acid halide

moiety

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(Scheme 8).Thus CDMT 74and DCMT 75(2,4-dichloro-6-methoxy-1,3,5-triazine)have been successfully applied in the synthesis of acid anhydrides (Fig.11).77

3.2Halo-uronium and halo-phosphonium type reagents (Fig.12)

TFFH 76a ,78BTFFH 77,78,79and DFIH 7878a have been used to generate acid fluorides with amino acids such as histidine and arginine since the activated form of Fmoc-Arg-OH under-went deactivation via lactam formation when using cyanuric fluoride.78PyFloP 79a did not yield any acid fluoride.78Interestingly,TFFH 76a (100%coupling after 10min)gave better results than the analogues TCFH 76b (86%)and TBFH

76c (79%),for the coupling of Fmoc-Val-OH to H-Ile-PEG-PS,78but overall,BTFFH 77gave the best conversions.79

El-Faham synthesised three acid fluoride generating reagents:DMFFH 80,DEFFH 81and TEFFH 82,48but these were poorly stable to hydrolysis in the presence of a base (most of the reagent hydrolysed within 1h).The reactivity of these reagents was studied by monitoring acid fluoride formation for various hindered and unhindered amino acids,and all three reagents were shown to be less reactive than TFFH 76a or BTFFH 77.

Reagents aimed at generating acid chlorides or bromides under milder conditions than thionyl chloride have been targeted.BroP 83a was first synthesised by Coste,80followed by PyBroP 79b and PyCloP 79c .81These reagents were

shown

Table 3Comparison of pentapeptides yield when using PyClock 56and PyBOP 52b

Yield (%)

Entry Amine

PyClock PyBOP 1H-Tyr-NMeVal-Phe-Leu-NH 21102H-Tyr-Aib-Aib-Phe-Leu-NH 297833

H-Tyr-Arg-Arg-Phe-Leu-NH 2

85

75

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to be more efficient that PyBOP 52b in coupling N -methylamino

acids.PyClU 84,also synthesised by Coste,gave high yields when coupling hindered amino acids,81while DCIH 78b (named CIP originally)gave comparable results to PyBroP 79b and PyCloP 79c .82One of the drawbacks of PyBroP 79b ,PyCloP 79c and DCIH 78b is the established formation oxazolones.CloP 83b was reported by Castro and shown to give low levels of epimerisation via Young’s test.83

PyClopP 85,an analogue of PyCloP 79c ,was reported by Li in an attempt to increase reactivity by replacing a pyrrolidine ring with a phenyl group.The reagent was reported as being efficient for hindered peptide synthesis,but no results were given to illustrate this fact.57

BOP-Cl 86is a reagent that has been widely used in peptide synthesis,84and was in particular reported as being suitable for

coupling hindered substrates,85but it has the major drawback of capping primary amines.86

Other reagents include CDTP 8787and CMMM 8488,but these reagents,like PyBroP 79b and PyCloP 79c ,usually give high epimerisation during coupling.CMMM 88was also compared to other reagents such as FEP 96b ,and gave poor results with coupling times of over 2h and epimerisation of over 30%(Anteunis test).57

DMC ,has been investigated as a coupling reagent.88It proved to be successful in the generation of some amides but questions of functional group compatibility are raised when considering its high reactivity.Recently,El-Faham tested DMFH 90a and DMCH 90b .DMFH 90a was really efficient for coupling the hindered Aib amino acid to a tripeptide Aib-Phe-Leu.The tetrapeptide was synthesised on solid phase in 99%yield compared to 68%for HATU 28a ,50but complete scope of this reagent was not investigated.DMCH 90b on the other hand performed poorly.

3.3Halo-sulfonium,halo-dioxolium and halo-dithiolium coupling reagents

Li synthesised other types of coupling reagents,including CDMS 91,CBDO 92and CPDT 93(Fig.13).57However these reagents were far too reactive and decomposed in solution before activation could take place.

3.4Halo-thiaziolium and halo-pyridinium type reagents Li designed reagents based on thiazolium and 2-halopyridinium salts.Their design was based on the fact that,in halouronium type coupling reagents,the carbocation is well stabilised via the electron pairs on the amine groups.Therefore,the carbocation shares a relatively high electron density and the uronium salt demonstrates relatively low reactivity in the addition of the carboxylic acid.For this reason Li attempted to replace one nitrogen group with other groups without lone pairs or more electronegative groups with lone pairs to enhance the reactivity of the reaction-mediated carbocations.The first attempt to replace nitrogen with sulfur yielded thiazolium reagent,BEMT 9

4.The same type

of

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reagent,BMTB 95,was proposed by Wischnat (Scheme 9).90BMTB 95performed better than HATU 28a in coupling Boc-N (Me)-Ile to N (Me)-Ile-OBn.However BMTB 95was not compared to BEMT 94.

Li reported 2-halopyridinium salts such as BEP 96a ,FEP 96b ,BEPH 97a and FEPH 97b (Fig.14).91Mukaiyama has extensively used 2-chloro-and 2-bromo-pyridinium iodide 98

to synthesise esters,lactones and amides,92but the conditions used were not ideal for peptide synthesis,as reactions had to be performed at reflux in DCM due to the poor solubility of the reagents.For this reason Li used tetrafluoroborate and hexachloroantimonate counter anions to improve solubility,and chose the fluoro-analogues for higher reactivity.The efficiency of these reagents proved to be higher than BTFFH 77,PyBrop 79b ,PyClU 84or BOP-Cl 86.However these reagents might be a bit too reactive as the base used during the coupling had to be added very slowly to avoid the coupling reagents reacting too violently.Thus side-reactions may be expected for some substrates.

4.Other coupling reagents

4.1Reagents generating carbonic anhydrides (Fig.15)EEDQ 99,was originally developed in 1967.93EEDQ 99offers

several advantages over most coupling reagents,as the reaction with an amine cannot yield a guanidinium salt,a typical side reaction observed with uronium type

coupling

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reagents.In addition,the carbonic anhydride is formed slowly but consumed rapidly,which avoids its accumulation and therefore minimises the possibility of side-reactions such as epimerisation,and it can also be used with unprotected hydroxy residues.93EEDQ 99has thus been used for the synthesis of various amide derivatives.94,95Analogues of EEDQ 99have also been successfully investigated such as IIDQ 100,and a number of unsymmetrical reagents.96Not many comparison studies have been published,but IIDQ 100proved,over a few examples,to perform slightly better than EEDQ 99(Table 4).97Interestingly,when compared to other coupling reagents without activation,IIDQ 100outperformed HATU 28a ,PyAOP 52a and BOP-Cl 86.974.2

Triazine-based reagents (not generating acid halides)

DMTMM 101is a triazine derivative,which has the particular

advantage of promoting amide synthesis in alcohols or aqu-eous media,without ester formation and with selectivity comparable to DCC 5and EDC 20.98Recently,a series of reagents based on DMTMM 101was developed by Kaminski (Scheme 10).99N -Triazinylammonium salts were synthesised using different tertiary bases and the derivative incorporating

DABCO proved to give the best yield.However a full study was carried out on the N -methylmorpholine derivative 102,because of its lower production cost.The reagent proved to be particularly efficient with high yields and low epimerisation levels.For the synthesis of the 65–74segment of ACP,each coupling went faster (15min.)than with TBTU 30b (45min)or HATU 28a (30min)and gave better purities (84%)than TBTU 30b (69%).99Sulfonates of N -triazinylammonium salts were also synthesised,but a complete evaluation of these reagents was not reported.100The reagents were further optimised by replacing the methoxy groups by benzyloxy groups (Fig.16).101

Remarkably,reagents such as triazine 103proved to be stable in DMF with only 2.5%decomposition after 48h.Comparison between the parent methoxy compounds (e.g.97)and the benzyloxy derivatives (e.g.103)showed that the later were more efficient for the synthesis of the 65–74segment of ACP.

4.3Pentafluorophenol (HOPfp)-based coupling reagents (Fig.17)

These types of reagents are based on the traditional penta-fluorophenol leaving group and the generation of active esters.They usually require the addition of HOAt as the level of epimerisation is quite high:when coupling Z-Phe-Val-OH to H-Pro-NH 2,33.7%of the LDL isomer was observed in solution phase when using HPyOPfp 104a ,while epimerisation dropped to 1.7%when adding HOAt to the reaction mixture.The use of a thiophenol-analogue,HPySPfp 104b did not change the outcome of the coupling reactions.66Like most reagents based on HOAt/HOBt,these reagents are not ideal for solution-phase chemistry as the use of an additive means that this has to be removed from the reaction mixture after coupling.

Li described a pentafluorophenyl immonium type reagent FOMP 105,56but this reagent was not as efficient as the other immonium type reagents,based on HOBt/HOAt.

A reagent,PFN

B 106,was reported by Pudhom,but Boc-Gly-OH reacted slowly and incompletely and it was necessary to add HOBt to get good conversion.102In order to synthesise thioamides,Hoeg-Jensen synthesised PyPOP 107,but this reagent was not as efficient as PyNOP 53or PyFOP 54.54Other reagents include FDPP 108,which gave lower epimer-isation levels than HBTU 28b ,BOP 51b and DC

C 5.103

Recently,HDMPfp 109was synthesised by El-Faham but the reagent proved to be outperformed by HATU 28a .

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Table 4Comparison of EEDQ and IIDQ Entry Amine Acid IIDQ yield EEDQ yield 14-tert -Butylaniline Phenylacetic acid

96942Benzylamine Phenylacetic acid

91873Morpholine Phenylacetic acid

383244-tert -Butylaniline Benzoic acid 88855Benzylamine Benzoic acid 85666

Morpholine

Benzoic acid 5041Average

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4.4Reagents based on 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HODhbt)

HODhbt was first mentioned in 1970by Koenig who investi-gated over 30N -hydroxy compounds as additives for peptide synthesis.25HOBt gave excellent results but HODhbt proved to be generally superior.However Koenig pointed out that the

potential of HODhbt is limited due to inherent side reactions,in particular the formation of an azido-benzoyl derivative 110(Fig.18).

Knorr proposed the generation of a HODhbt based coupling reagent,synthesising TDBTU 111(Fig.19).40Although TDBTU 111gave little epimerisation,its use was recommended only in critical cases because of the risk of side reactions.Indeed,ring opening of the 3,4-dihydro-4-oxo-1,2,3-benzotriazine ring can occur to form 110,which can then react with amines.Another reagent,HDTU 112b ,where the counter ion of TDBTU 111was replaced by hexafluoro-phosphate had similar efficiency to TBTU 30b .104The disadvantage of HDTU 112b has ever being its poor stability in DMF compared to classic reagents such as HATU 28a as after 5h HDTU 112b had totally decomposed compared to less than 1%for HATU 28a .

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Carpino compared some organophosphorus reagents to commonly used coupling reagents,65and showed that DpopODhbt 113was comparable to HATU 28a in terms of reaction times for the formation of the active ester of Z-Aib-OH (o 2min)but DepODhbt 114(also named DEPBT by Ye 105,106)was not as efficient (7–8min).Similarly DOPBT 115was poorer than DepODhbt 114.107Another reagent,DtpODhbt 116gave more epimerisation (4.3%of LDL isomer)than DepODhbt 114(3.5%)but less than HATU 28a (5.0%)when carrying out the coupling of Z-Phe-Val-OH and H-Pro-NH 2.The synthesis of the ACP decapeptide (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-NH 2)was used to show that DepODhbt 114gave poor results (o 1%yield)compared to HATU 28a (85%).

Li also based immonium type reagents on HODhbt,but DOMP 117showed very poor results for the coupling between Z-Gly-Phe-OH and H-Val-OMe with only 5.6%yield after 2h compared to 95%for BDMP for example.56PyDOP 118a was targeted for the synthesis of thioamides,but proved to be surpassed by PyNOP 53or PyFOP 54.54

More recently,Carpino developed coupling reagents based on aza-analogues of HODhbt,65and successfully synthesised HDATU 112a ,PyDAOP 118b ,HDADU 119,HDAPyU 120a ,and HDPyU 120b .As expected,derivatives of HODAhbt were more reactive than their HODhbt analogue.Thus,HDATU 112a gave better results than HDTU 112b ,but was still less reactive than HATU 28a .Moreover,results were more random for segment coupling as they depended on the system studied.However,in many cases,HDATU 112a proved to be better than HATU 28a for the solid-phase synthesis of ACP.

Itoh developed sulfonate reagents based on HODhbt.67The two reagents synthesised,SMDOP 121and SPDOP 122were however not as efficient as the other sulfonate reagents that this group synthesised,such as HCSCP 70.

Overall,reagents based on 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HODhbt)do not appear to be more efficient that classical reagents like DIC 13.Moreover,a critical issue regarding the safety of these materials has to be addressed due to the presence of the azide moiety.4.5Reagents based on 2-hydroxysuccinimide (HOSu)and 2-(5-norbornene–2,3-dicarboximide)(HONB)(Fig.20)Only a few reagents incorporating the hydroxysuccinimide leaving group have been synthesised.Knorr developed TSTU 123a and its norbornene–dicarboximide analogue TNTU 124,which showed high epimerisation levels without the use of additives.40Gruber reported HSTU (also called SbTMU)123b ,but the reagent was not studied in detail as it was directly used for the preparation of thiol-reactive Cy5derivatives.108

Other examples are SOMP 56125and SOMI 57126developed by Li,and similar other immonium type reagents,but they gave poor results.

Phosphate-based succinimide coupling reagents such as NDPP 109127and SDPP 110128have also been developed.The use of ENDPP 129proved to be a better method than the isobutylchloroformate method because it could be performed

at room temperature,but no other comparison was reported.Similarly,SDPP 128was only reported as being a ‘‘more convenient method’’to use than DCC 5.

El-Faham reported the use of HDMS 130,which was based on a morpholino uronium salt.50The reagent proved to be less efficient than the HOAt/HOBt based analogues HDMA 46a and HDMB 46b .

4.6Phosphorus-type reagents (not based on HOAt,HOBt,–OPfP,–OSu,and –ODhbt)(Fig.21)

PyTOP 131was developed by Hoeg-Jensen for the formation of thioamides but the reagent gave poorer selectivities than PyNOP 53or PyFOP 54.54

The possibility of using DPP-Cl 132was first investigated with success by Jackson,111who claimed that NMR proved that no epimerisation was observed,112although this result is quite surprising,as epimerisation is usually high when acid chlorides are generated.

Other derivatives have also been synthesised and include the azide analogue DPPA 133a ,113and cyano analogue DECP 134,which gave good coupling yields but with many side-reactions via the cyanide.114Dpop-Cl 133b was also tested but poor results were observed without the use of an additive.65Similarly DEPC 115135a and DEPB 116135b typically give side reactions due to the release of the reactive halogen atom.Reagents based on the same principle,Cpt-Cl 117136,MPTA 118137a ,Mpt-Cl 119137b ,MPTO 118138,and BMP-Cl 120139,appeared overall to have similar efficiencies to reagents such as DPP-Cl 132

.

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A wide range of phosphorus-based coupling reagents 141–153were investigated by Mukaiyama.122Using Young’s test as model reaction,it was concluded that the bis(nitrophenyl) phenylphosphonates149and150gave the best results.Further studies,using this time phosphinic esters154–158showed that(5-nitropyridyl)diphenylphosphinate154was an efficient coupling reagent,giving92%of the expected dipeptide in Young’s test,with less than2%epimerisation.123

DEBP124159and DPOOP125160have been proposed as coupling reagents,but for both reagents,examples were limited to a few dipeptides and were not compared to any classical methods.T3P161was claimed to be more efficient than HAPyU31for head-to-tail cyclisation of hindered peptides.126However,the use of T3P may be limited as yields were lower and epimerisation higher than HAPyU when segment coupling studies were carried out.

Other reagents include FDMP162,which gave poor results (2%yield compared to84%yield for BEMT when coupling Z-Gly-Phe-OH to H-Val-OMe),57BIODPP163,which gave amides in good yields but was not compared to any other coupling reagent,127and DEPBO1and DOPBO165,which proved to be not as efficient as DepODhbt114.107PyDPP166 was reported as giving low epimerisation rates,but was not compared to other coupling reagents.128

Kokare reported three new reagents166–169based on phosphate derivatives of1-hydroxy-2-phenylbenzimidazole.129 The reagents gave in most cases similar results and yields over a wide range of substrates(e.g.4-nitrobenzoic acid,cinnamic acid,anisic acid,piperidine,tert-butylamine)were excellent. However,one can wonder at the purity of the isolated products. The synthesis of the three reagents were reported(63–71%yields), but when used for amide bond formation,the reagents were generated in situ through the reaction of2-phenylbenzimidazole with a chlorophosphate or phosphinic chloride.The acid and then amine were added to this mixture,and side-reactions were thus likely to occur.Kokare also used the diethylphosphate derivative170as a coupling reagent for the synthesis of O-alkyl hydroxamic acids(Scheme11).130Yields were excellent for the12amides synthesised but comparison with other coupling reagents was not carried out.

4.7Miscellaneous reagents

CPMA171,a reagent based on a chloroimmonium salt (Fig.22),mediated the esterification of carboxylic acids,131 and in terms of amide bond formation,the reagent performed well(complete conversion)but only two examples were reported.

2-Mercaptopyridone-1-oxide172was used as a starting material to generate a cheaper and new type of uronium coupling reagent TOTT173and HOTT174(Scheme12).132 Both reagents gave better results that DCIH78b or PyBrop 79b and were comparable to HATU28a,and the dipeptide Z-MeVal-Aib-OMe was obtained in80%yield(%for HATU28a).The epimerisation level was evaluated via Young’s test and the use of TOTT173resulted in only3.7% epimerisation compared to BOP51b(20%),PyBOP52b (15%),or HATU28a(20%).TOTT173and HOTT174have also been successfully used to synthesise primary amides from carboxylic acids and ammonium chloride.133

Najera synthesised two analogues of HOTT/TOTT,HODT 175and TODT176(Fig.23).134These two reagents gave higher yields in solid phase peptide synthesis,but associated with more epimerisation.

A reagent similar to the ones based on2-mercaptopyridine oxide was proposed by Knorr but TPTU177(Fig.24),based on2-hydroxypyridine-N-oxide,gave high epimerisation level when used without an additive.40

The possibility of using a2-pyridinone based reagent, DPTC178(Fig.25),for amide synthesis was investigated by Shiina.135Carboxylic acids were activated as2-pyridyl esters using DPTC178and a catalytic amount of DMAP.However, a long pre-activation time was required(over25min)to limit the formation of an isothiocyanate specie(and probably a thiourea)upon addition of an amine.Thus the application of DPTC178is limited although simple amides can be obtained in good yield at room temperature.More hindered substrates imply carrying out the synthesis at higher temperature.

An original coupling reagent based on the rearrangement of carboxylic–sulfonic mixed anhydrides has been reported.Sub-stituted O-hydroxybenzenesulfonyl chlorides179were used as condensation reagents via the mechanism suggested in Scheme13.136Using this method various peptides were obtained in good yields.The epimerisation level was assessed through optical purity,but no comparison was made with any common coupling reagent.Itoh investigated the possibility of using sulfonate-based coupling reagents,and developed 2-methanesulfonyloximino-2-cyanoacetate180(Fig.26), which proved however to be outperformed by HCSCP69.

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A related reagent,also based on a cyanoacetate moiety,TOTU 181was reported by Ko nig.137

Carbonyl-diimidazole (CDI 182)has been used to generate amide bonds.138Interestingly,Sharma showed that CDI

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could be used to couple unprotected amino acids to amines in water.139The strategy however offers limited applicability as only primary amines were successfully coupled,while yields were moderate.

More recently,Saha proposed the use of an analogue,CBMIT 183.140He obtained good yields and low epimerisation but these were not evaluated on standard tests and are therefore difficult to compare to classical reagents.

DPTF 184was reported by Ito as a dehydrating reagent.141Its mechanism of action follows the active ester pathway to generate amides in good yields (Scheme 14).However hindered building blocks were not evaluated.One of the main advantages of DPTF 184is its ability to activate a carboxylic acid in aqueous media.

In order to avoid the use of expensive reagents,Campagne suggested the use of ethyl propiolate 185as coupling reagent,as described in Scheme 15.142Although being original,this route required a long pre-activation time (12h)and the use of an additive (sodium bisulfite)was necessary to give good yields.Moreover,yields were typically lower than standard coupling reagents such as PyBOP 52b .

Recently,diphenyl phosphite (DPP 186),143and tetrakis-(pyridine-2-yloxy)silane 187,144have been used to synthesise amides.DPP 186forms a phosphonic-carboxylic mixed

anhydride,while tetrakis(pyridine-2-yloxy)silane gives silyl esters 188(Scheme 16).These reagents afforded amides in good yields but were not compared to other coupling reagents.Phenylsilane PhSiH 31has been used in amide library formation.145The reagent was tested on seven carboxylic acids and 11amines.Although amides were sometimes obtained in good yield,it was necessary to use reverse phase HPLC to purify the products,making the phenylsilane method unattractive for library generation.In addition,anilines and some secondary amines failed to couple with this reagent resulting in poor scope.

5.Other methods of N -acylation

5.1Mixed anhydrides

The formation of mixed anhydrides is a classic method of amide bond formation.It is important to note that many mixed anhydrides can be generated using some of the coupling reagents reported so far in this review.The mixed anhydride method was first reported by Vaughan,146who tested many acid chloride derivatives and concluded that the success of the amide-bond formation was governed by steric and inductive effects.Isovaleryl chloride proved to give the best results.However,as reported by many research groups,this method has a tendency to generate symmetrical anhydrides by reaction of a second carboxylic acid molecule on the mixed anhydride (Scheme 17).In addition regioselectivity is a major issue,as the amine can potentially react at either carbonyl group although this can be biased by using a bulky acid group.These drawbacks can sometimes be minimised by carrying out the coupling reactions at low temperature.5.2Chloroformates

The use of chloroformates for amide-bond formation was first reported by Vaughan,147and was based on the mixed anhydride method.In the presence of a base,the reaction between a carboxylate and a chloroformate yields a mixed carbonic anhydride,which reacts quickly with amines to form amides.Vaughan’s study highlighted slightly better results when using sec -butylchloroformate compared to isobutylchloro-formate.148The method was ‘‘reinvestigated’’by Anderson,149who tested several different chloroformates,and whose conclusions suggested that isobutylchloroformate was the most efficient

reagent.

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The direct formation of active esters has often attracted a lot of attention due to the stability of many of them,which allows storage.Many example of active esters have therefore been reported and include–O-succinimides,150–OBt and derivatives,24 p-nitrophenol,151–OPfP,152–ODhbt,153and PTOC.154As this review focuses directly on coupling reagents,this useful method of amide-bond formation will not be discussed herein,but the reader is referred to Montalbetti’s review for further details.13

5.4Newer approaches to amide bond formation

Several alternatives to the use of coupling reagents have been reported.These interesting new methods were reviewed by Bode,155and include the so-called native chemical ligation and the Staudinger ligation(Scheme18).Recently,Milstein reported another approach based on the ligation of amines to alcohols using a ruthenium complex as catalyst.156 Molecular hydrogen was formed during the reaction and amides were obtained in high yield.6.Polymer-supported coupling reagents

6.1Immobilised carbodiimides

Only a few polymer-supported coupling reagents are available, probably because coupling reagents are mainly used in peptide synthesis,which is usually carried out on solid phase,the coupling reagent being in solution.Nevertheless,DCC5,157 DIC13,158and EDC15920have been successfully immobilised and applied to the synthesis of amides.160However these carbodiimides maintain the same drawbacks as their solution-phase equivalents,in particular in terms of epimerisation in the absence of an additive.Furthermore,one can wonder at the interest of PS-EDC190(Fig.27)in comparison to PS-DCC191as EDC20was originally designed and synthesised to be water soluble.Having the‘‘extractable’’moiety on a polystyrene support appears to be odd,especially as the ionic part of EDC20in solution-phase has proven to be counterproductive regarding the coupling reaction rate compared to DIC13.34A polyhexamethylene-carbodiimide has also been reported.161

Charette‘‘attached’’carbodiimides to tetraarylphosphonium salts as a means of‘‘tagging’’the reagent.162Reaction was carried out in solution phase,before precipitation of the salt with apolar solvents.Several carbodiimides derivatives 192were synthesised(Fig.28),and the ethyl and isopropyl derivatives based on a hexafluorophosphate salt were the most efficient,both in terms of yields and purities.

6.2Immobilised additives and reagents based on HOBt Some coupling reagents in solution can in rare cases be extracted after reaction(e.g.EDC20).However,the use of an additive is often required to limit epimerisation,and this additive has also to be separated from the reaction mixture. Therefore polymer-supported HOBt has been reported in different guises.163,1PS-HOBt193has also been used as a core for synthesising supported reagents for the preparation of N-hydroxysuccinimide active esters.165

The idea of using PS-HOBt193to form an immobilised HOBt-based coupling reagent wasfirst exploited by Chinchilla, who synthesised polymer-supported TBTU194.166This idea was also applied by Filip for the synthesis of polymer-supported BOP195.167These reagents offer however the

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drawbacks as TBTU 30b and BOP 51b in solution,while the structure of the reagent means that part of it will end up in solution after the coupling,clearly an undesirable occurrence for a supported reagent.6.3

Other immobilised reagents

Triazine-based coupling reagents have been widely used in solution-phase.In 1999,Taddei reported polymer-supported chlorotriazine 196.168Although amides were synthesised in moderate to good yield using this reagent,the 1H NMR of the crude compounds revealed the presence of 5to 10%of by-products.Hioki used another strategy to obtain polymeric triazine-type reagents.169Using a norbornene-derivatised triazine,they synthesised via ROMP an immobilised mono-methoxychlorotriazine,which was tested on anilines and primary amines.Yields were good (nine examples,80–98%),

but no secondary amine was tested while the reagent was not compared to other classical amide bond formation methods.PS-DMC 197,a supported equivalent of DMC ,was reported by Ishikawa.170Yields over five examples were slightly lower for the polymer-supported version of the reagent,and the examples provided did no allow a full display of the scope and limitations of the reagent.

Chinchilla developed some reagents based on polymeric succinimides such as P-TSTU 198and P-HSTU 199,171and 200(Fig.27).172The results were good for classic amino acids but the yields were moderate to low when coupling hindered amino acids.Globally these reagents did not really add any benefit to the range of coupling reagents available,and,like PS-TBTU 194and PS-BOP 195,part of the reagent ended up in solution.

More recently,Convers reported an immobilised Mukaiyama reagent 201.173However,Crosignani investigated this new reagent and concluded that the synthesis was poorly reprodu-cible,and developed another route.174This reagent 202appeared to work very efficiently for the synthesis of esters and amides including hindered substrates,secondary amines and anilines.174,175

Polymer-supported IIDQ 203is an immobilised version of the solution-phase IIDQ 100reagent.97,176It was synthesised in three steps from Merrifield resin and 6-hydroquinoline to provide a high loading reagent (41.68mmol/g).The

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advantages of PS-IIDQ 203are that no base is required during coupling,while the order of addition of amine,carboxylic acid and reagent do not influence the outcome of the reaction (Scheme 19).

This reagent was compared to other classically used and commercially available coupling reagents such as Polymer-supported EDC 190and DCC 191,as well as HATU 28a .Interestingly,PS-IIDQ 203performed better than any of these reagents on a set of three amines and three carboxylic acids,including anilines and bulky substrates (Table 5).Furthermore,PS-IIDQ 203was evaluated on 9amines and 5carboxylic acids and gave an average yield of 73%.Epimerisation was low as Anteuni’s test did not reveal any trace of the diastereo-isomer by NMR.PS-IIDQ 203was stable under standard laboratory storage conditions and it was shown that the reagent could be advantageously recycled after any coupling reaction.Thus PS-IIDQ 203appears to be a very versatile coupling reagent for the parallel synthesis of amides.

Very recently,Kakarla duplicated these studies to make PS-EEDQ 204.177It was obtained using identical conditions for the transformation of PS-Quinoline into PS-EEDQ 204,the only variation being the use of a Wang resin.However the loading of the so-called ‘‘high-loading’’PS-EEDQ 204was erroneous (starting from a 1.7mmol/g Wang resin,the maximum physical loading of PS-EEDQ 204would be 1.19mmol/g assuming total conversion during synthesis,while the authors claimed 1.36mmol/g loading),while a Wang linker was clearly of no use.When looking at the efficiency of EEDQ 99and IIDQ 100(Table 4),97the choice appears evident.

7.Conclusion on available coupling reagents

Although hundreds of coupling reagents have been reported,conclusions on their efficiency are in fact quick and simple.Most of these reagents are simply not efficient for a broad range of amide bond formation.Some reagents do perform well in general,but differences are typically small.Solid-phase peptide chemists may find useful reagents which display fast kinetics for coupling as the synthesis of long peptides has ideally to be rapid.However,for the general organic chemist,simple reagents are often the most appropriate allowing coupling reagents to be used on a large selection of substrates with varying reactivities.

This summary can be illustrated by the comparison of coupling reagents carried out by Hachman.68Very few comparisons of reagents have been published and the work by Hachman displayed the importance of a comparison system.Hachman compared classical reagents such as phosphonium salts,uronium salts,reagents generating acid halides and carbodiimides.During the synthesis of decapeptides,HBTU 28b was the ‘‘fastest’’reagent after 2min while almost none of the expected amide was formed by DIC after this time.However,after 8min,DIC 13was comparable to HBTU 28b .In addition very few side-reactions were observed with DIC 13(in particular deletion)compared to BOP 51b or HATU 28a .This demonstrated that a simple reagent like DIC 13(using HOBt as additive)performs well in many cases,and a compromise of speed/purity/by-products needs to be sought.

An important point is the way new coupling reagents are reported.As stated and demonstrated by Hachman:‘‘the use of only one model sequence for evaluation of synthetic reagents [...]can be misleading.’’As such,unless new reagents are systematically tested against commonly considered ‘‘top coupling reagents’’,such as HATU 28a ,and traditional methods such as DIC/HOBt,it is likely that most new coupling reagents will have an application limited to the original publication by their authors.

Overall,keeping in mind all possible issues (side-reactions),HATU 28a and HBTU 28b offer generally excellent

reactivity.

Table 5Comparison of the yields and purities obtained over three amines (4-tert -butylaniline,benzylamine,H-PhG-OMe)and three carboxylic acids (Boc-Aib-OH,phenylacetic acid,benzoic acid)Entry Coupling reagent Average yield (%)Average purity (%)1PS-IIDQ 721002HATU 55983PS-EDC 419

PS-DCC

26

97

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If quick coupling times are required,HATU 28a probably represents the reagent of choice,providing the substrates are not hindered.Otherwise,the traditional method DCC 5(or DIC 13)/HOBt remains an excellent choice for many sub-strates.One has nevertheless to keep in mind potential hazards when using reagents based on 1H -benzotriazole due to the potential explosive properties of HOBt.30,31

For difficult couplings (e.g.secondary amines),our experi-ence tells us that PyBrop 79b is generally reliable.178Triazines can be an alternative for difficult coupling,although the most reactive reagents tend to give side-products.However,the recent developments by Kaminski are bringing new applica-tions to this class of coupling reagents.

Finally,for library synthesis either the PS-Mukaiyama reagent 202or polymer-supported IIDQ 203are clearly the most suitable reagents,179and their efficiency has been con-firmed by many groups.These reagents have the advantage of simplifying purification as the reagent is separated via simple filtration after reaction.

In conclusion,selecting suitable coupling reagents could be summarised by ‘‘keep it simple’’as most reagents appear to be merely fancy and costly alternatives.Finding a universal coupling reagent remains elusive considering the wide portfolio of potential substrates and it is generally wise to avoid ‘‘exotic’’reagents and not be mislead by ‘‘fast’’coupling reagents.Efficiency is the key,with high conversions,low levels of epimerisation and limited by-products all being essential criteria.

List of abbreviations

General ACP acyl carrier protein decapeptide 65–74DABCO bicyclo[2,2,2]-1,4-diazaoctane DCU dicyclohexylurea

DMAP 4-dimethylaminopyridine DMPU dimethylpropyleneurea HMPA hexamethylphosphoramide

LHRH Luteinising Hormone Releasing Hormone NMM N -methylmorpholine

ROMP

Ring Opening Metathesis Polymerisation

Coupling reagents and additives ACTU (2-(6-chloro-1-H -benzotriazol-1-yl)-1,1,3,3-tetramethylaminium)hexachloroantimonate AOMP 5-(7-azabenzotriazol-1-yloxy)-3,4-dihydro-1-methyl-2H -pyrrolium hexachloroantimonate AOP (7-azabenzotriazol-1-yl)oxytris(dimethyl-amino)phosphonium hexafluorophosphate BBC benzotriazoloxy-bis(pyrrolidino)carbonium hexafluorophosphate

BDDC bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl]-carbodiimide

BDMP 5-(1H -benzotriazol-1-yloxy)-3,4-dihydro-1-methyl-2H -pyrrolium hexachloroantimonate BDP benzotriazol-1-yl diethylphosphate BEC

N -tert -butyl-N 0-ethylcarbodiimide

BEMT

2-bromo-3-ethyl-4-methylthiazolium tetrafluoroborate

BEP 2-bromo-1-ethylpyridinium tetrafluoroborate BEPH 2-bromo-1-ethylpyridinium hexachloroanti-monate

4,5-B(HATU)N -[(dimethylamino)(3H -1,2,3-triazolo[4,5-c ]-isoquinolin-3-yloxy)-N -methylmethanaminium hexafluorophosphate

5,6-B(HATU)1-[bis(dimethylamino)methylene]-1H -1,2,3-triazolo[4,5-b ]quinolinium hexafluorophosphate-3-oxide

BIODPP diphenyl benzo[d ]isoxazol-3-ylphosphonate BMC N -tert -butyl-N 0-methylcarbodiimide BMMP 1-(1-(1H -benzo[d ][1,2,3]triazol-1-yloxy)ethyl-idene)pyrrolidinium hexachloroantimonate BMP-Cl N,N 0-bismorpholinophosphonic chloride BMTB 2-bromo-3-methyl-4-methylthiazolium

bromide

BOI 2-(benzotriazol-1-yl)oxy-1,3-dimethylimid-azolidinium hexafluorophosphate BOMI benzotriazol-1-yloxy-N ,N -dimethylmethan-iminium hexachloroantimonate BOP benzotriazolyl-N -oxytrisdimethylaminophos-phonium hexafluorophosphate BOP-Cl N ,N 0-bis(2-oxo-3-oxazolidinyl)phosphinic

chloride

BPMP 1-(1H -benzotriazol-1-yloxy)phenylmethylene

pyrrolidinium hexachloroantimonate

BroP bromotris(dimethylamino)phosphonium

hexafluorophosphate

BTFFH bis(tetramethylene)fluoroformamidinium

hexafluorophosphate

CBDO 2-chlorobenzo[d ][1,3]dioxol-1-ium hexachloro-antimonate CBMIT 1,10-carbonylbis(3-methylimidazolium)triflate CDI carbonyldiimidazole CDMS chlorodimethylsulfonium hexachloroantimonate CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine CDTP 2-chloro-1,3-dimethyl-3,4,5,6-tetrahydro-pyrimidin-1-ium perchlorate CIP 2-chloro-1,3-dimethylimidazolidinium

hexafluorophosphate

CloP chlorotris(dimethylamino)phosphonium

hexafluorophosphate

CMMM chloro(4-morpholino)methylene

morpholinium hexafluorophosphate

CPMA (chlorophenylthiomethylene)dimethyl-ammonium chloride CPDT 2-chloro-5-phenyl-1,3-dithiol-1-ium

hexachloroantimonate

Cpt-Cl 1-oxo-chlorophospholane DAST diethylaminosulfur trifluoride DCC dicyclohexylcarbodiimide DCIH 1,3-dimethyl-2-chloro-4,5-dihydro-1H -imidazolium hexafluorophosphate DCMT 2,4-dichloro-6-methoxy-1,3,5-triazine DEBP diethyl-2-(3-oxo-2,3-dihydro-1,2-benziso-sulfonazolyl)phosphonate

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DEFFH 1,2-diethyl-3,3-tetramethylenefluoroform-amidinium hexafluorophosphate DECP diethylcyanophosphonate DEPC diethyl phosphorochloridate DEPB diethyl phosphorobromidate

DEPBO N -diethoxyphosphorylbenzoxazolone

DEPBT 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H )-one

DepOAt 3H -[1,2,3]triazolo[4,5-b ]pyridin-3-yldiethyl phosphate

DepOBt diethoxyphosphinyloxybenzotriazole

DepODhbt

diethyl 4-oxobenzo[d ][1,2,3]triazin-3(4H )-yl phosphate

DFIH 1,3-dimethyl-2-fluoro-4,5-dihydro-1H -imid-azolium hexafluorophosphate DIC diisopropylcarbodiimide

DMC 2-chloro-1,3-dimethylimidazolinium chloride DMCH N -(chloro(morpholino)methylene)-N -methyl-methanaminium hexafluorophosphate

DMFFH 1,2-dimethyl-3,3-tetramethylenefluoroform-amidinium hexafluorophosphate

DMFH N -(fluoro(morpholino)methylene)-N -methyl-methanaminium hexafluorophosphate DmppOAt 1-(2,8-dimethylphenoxaphosphinyloxy)-7-azabenzotriazole

DMTMM 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride

DOMP

5-(30,40-dihydro-40-oxo-10,20,30-benzotriazin-30-yloxy)-3,4-dihydro-1-methyl 2H -pyrrolium hexachloroantimonate

DOPBO N -(2-oxo-1,2,3-dioxaphosphorinanyl)benz-oxazolone

DOPBT 3-[O -(2-oxo-1,2,3-dioxaphosphorinanyl)oxy]-1,2,3-benzotriazin-4(3H )-one

DPOOP diphenyl-2-oxo-3-oxazolinylphosphonate Dpop-Cl diphenyl phosphorochloridate

DpopOAt 1-(diphenoxyphosphoryloxy)-7-azabenzo-triazole

DpopOBt 1-(diphenoxyphosphoryloxy)benzotriazole DpopODhbt 3-(diphenoxyphosphinyloxy)-3,4-dihydro-4-oxo-1,2,3-benzotriazene DPP diphenylphosphite

DPPA diphenylphosphoryl azide Dpp-Cl diphenylphosphinic chloride DPTC O ,O 0-di(2-pyridyl)thiocarbonate

DPTF 2,2-dichloro-5-(2-phenylethyl)-4-(trimethylsilyl)-3-furanone

DtpOAt 1-[di(O -tolyl)phosphinyloxy]-7-azabenzotriazole DtpOBt 1-[di(O -tolyl)phosphinyloxy]benzotriazole DtpODhbt 3-di(O -tolyl)phosphinyloxy]-3,4-dihydro-4-oxo-1,2,3-benzotriazine

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide

EEDQ N -ethoxycarbonyl-2-ethoxy-1,2-dihydro-quinoline

ENDPP phosphoric acid 3,5-dioxo-10-oxa-4-azatri-cyclo[5.2.1.02,6]dec-8-en-4-yl ester diphenyl ester FDMP

3,5-bis(trifluoromethyl)phenyl diphenylphosphinate

FDPP

pentafluorophenyl diphenyl phosphinate FEP 2-fluoro-1-ethylpyridinium tetrafluoroborate FEPH 2-fluoro-1-ethylpyridinium hexachloroanti-monate

FOMP 5-(pentafluorophenyloxy)-3,4-dihydro-1-methyl-2H -pyrrolium hexachloroantimonate HAE 2PipU

O -(1H -1,2,3-triazolo[4,5-b ]pyridin-1-yl)-1,1-diethyl-3,3-pentamethyleneuronium hexafluorophosphate

HAE 2PyU

O -(1H -1,2,3-triazolo[4,5-b ]pyridin-1-yl)-1,1-diethyl-3,3-tetramethyleneuronium hexafluoro-phosphate

HAMDU O -(7-azabenzotriazol-1-yl)-1,3-dimethyl-1,3-dimethyleneuronium hexafluorophosphate HAM 2PipU

O -(1H -1,2,3-triazolo[4,5-b ]pyridin-1-yl)-1,1-dimethyl-3,3-pentamethyleneuronium hexafluorophosphate

HAM 2PyU

O -(1H -1,2,3-triazolo[4,5-b ]pyridin-1-yl)-1,1-dimethyl-3,3-tetramethyleneuronium hexafluorophosphate

HAMTU O -(7-azabenzotriazol-1-yl)-1,1,3,3-bis(penta-methylene)uronium hexafluorophosphate HAPipU O -(7-azabenzotriazol-1-yl)-1,1,3,3-bis(penta-methylene)uronium hexafluorophosphate HAPyTU S -(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetra-methylene)thiouronium hexafluorophosphate HAPyU

1-(1-pyrrolidinyl-1H -1,2,3-triazolo[4,5-b ]pyridin-1-ylmethylene)pyrrolidinium hexafluorophos-phate N -oxide

HATeU

O -(1H -1,2,3-triazolo[4,5-b ]pyridin-1-yl)-1,1,3,3-tetraethyluronium hexafluorophosphate

HATU O -(7-azabenzotriazol-1-yl)-1,1,3,3-tetra-methyluronium hexafluorophosphate

HBE 2PipU

O -(1H -benzotriazol-1-yl)-1,1-diethyl-3,3-penta-methyleneuronium hexafluorophosphate

HBE 2PyU O -(1H -benzotriazol-1-yl)-1,1-diethyl-3,3-tetra-methyleneuronium hexafluorophosphate HBMDU O -(benzotriazol-l-yl)-l,3-dimethyl-l,3-di-methyleneuronium hexafluorophosphate HBMP

1H -benzo[d ][1,2,3]triazol-1-ylmethanesulfonate HBM 2PipU O -(1H -benzotriazol-1-yl)-1,1-dimethyl-3,3-pentamethyleneuronium hexafluorophosphate HBM 2PyU O -(1H -benzotriazol-1-yl)-1,1-dimethyl-3,3-tetramethyleneuronium hexafluorophosphate HBPipU O -(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)-uronium hexafluorophosphate

HBSP 1H -benzo[d ][1,2,3]triazol-1-ylbenzenesulfonate HBTeU O -(1H -benzotriazol-1-yl)-1,1,3,3-tetraethyl-uronium hexafluorophosphate

HBTU O -(benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate

HCTU (2-(6-chloro-1-H -benzotriazol-1-yl)-1,1,3,3-tetramethylaminium)hexafluorophosphate HCSCP 6-chloro-1H -benzo[d ][1,2,3]triazol-1-yl-4-chlorobenzenesulfonate

HCSP

6-chloro-1H -benzo[d ][1,2,3]triazol-1-ylbenzene-sulfonate

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HDATU

(bis(dimethylamino)methyl)(4-oxopyrido[3,2-d ]-[1,2,3]triazin-3(4H )-yl)oxonium hexafluorophosphate

HDADU

(bis(dimethylamino)methyl)(4-oxopyrido[3,2-d ]-pyrimidin-3(4H )-yl)oxonium hexafluorophosphate

HDAPyU

1-((4-oxopyrido[3,2-d ][1,2,3]triazin-3(4H )-yloxy)-(pyrrolidin-1-yl)methylene)pyrrolidinium hexafluorophosphate

HDMA

1-((dimethylamino)(morpholino)methylene)-1H -[1,2,3]triazolo[4,5-b ]pyridinium hexafluoro-phosphate 3-oxide

4-HDMA

3-((dimethylamino)(morpholino)methylene)-1H -[1,2,3]triazolo[4,5-b ]pyridinium hexafluoro-phosphate 1-oxide

HDMB

1-((dimethylamino)(morpholino)methylene)-1H -benzotriazolium hexafluorophosphate 3-oxide

HDMCB

6-chloro-1-((dimethylamino)(morpholino)-methylene)-1H -benzotriazolium hexafluorophosphate 3-oxide

HDMFB

6-trifluoromethyl-1-((dimethylamino)-(morpholino)methylene)-1H -benzotriazolium hexafluorophosphate 3-oxide

HDMPfp

1-((dimethyamino)(morpholino))oxypenta-fluorophenyl metheniminium hexafluoro-phosphate

HDMS 1-((dimethyamino)(morpholino))oxypyrrolidine-2,5-dione methanaminium hexafluorophosphate HDPyU

1-((4-oxobenzo[d ][1,2,3]triazin-3(4H )-yloxy)-(pyrrolidin-1-yl)methylene)pyrrolidinium hexafluorophosphate

HDTMA

1-((dimethylamino)(thiomorpholino)methylene)-1H -[1,2,3]triazolo[4,5-b ]pyridinium hexafluoro-phosphate 3-oxide

HDTMB

1-((dimethylamino)(thiomorpholino)methylene)-1H -benzotriazolium hexafluorophosphate 3-oxide

HDTU O -(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOAt 1-hydroxy-7-azabenzotriazole HOBt 1-hydroxy-1H -benzotriazole

HODhat 3-hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazine

HODhbt 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine HODT S -(1-oxido-2-pyridinyl)-1,3-dimethyl-1,3-tri-methylenethiouronium

HONB 2-(5-norbornene-2,3-dicarboximide)HOPfp pentafluorophenol

HPyOPfp N ,N ,N 0,N 0-bis(tetramethylene)-O -pentafluoro-phenyluronium hexafluorophosphate

HPySPfp 1-((perfluorophenylthio)(pyrrolidin-1-yl)-methylene)pyrrolidinium hexafluorophosphate HOSu N -hydroxysuccinimide

HOTT S -(1-oxido-2-pyridinyl)-1,1,3,3-tetra-methylthiouronium hexafluorophosphate

HSTU

O -(N -succimidyl)-N,N,N 0,N 0-bis(tetramethylene)-uronium hexafluorophosphate

IDDQ N -isobutoxycarbonyl-2-isobutoxy-1,2-dihydro-quinoline

MPTA dimethylphosphinothioyl azide MPT-Cl dimethylphosphinothioyl chloride

MPTO 3-dimethylphosphinothioyl-2(3H )-oxazolone NDPP norborn-5-ene-2,3-dicarboximidodiphenyl-phosphate

NOP [(6-nitrobenzotriazol-1-yl)oxy]tris(dimethyl-aminop)phosphonium hexafluorophosphate PEC phenylethylcarbodiimide

PFNB perfluorophenyl 4-nitrobenzenesulfonate PIC phenylisopropylcarbodiimide PTOC pyridine-2-thione-N -oxycarbonyl

PyAOP [(7-azabenzotriazol-1-yl)oxy]tris(pyrrolidino)-phosphonium hexafluorophosphate PyBOP benzotriazol-1-yloxytri(pyrrolidino)-phosphonium hexafluorophosphate PyBroP bromotri(pyrrolidino)phosphonium hexafluorophosphate

PyClock

6-chloro-1-hydroxybenzotriazol-1-yl-N -oxy-tris(pyrrolidino)phosphonium hexafluorophosphate

PyCloP chlorotri(pyrrolidino)phosphonium hexafluoro-phosphate

PyClopP chlorobispyrrolidinophenylphosphonium hexachloroantimonate

PyFloP fluorotri(pyrrolidino)phosphonium hexafluorophosphate

PyClU chlorodipyrrolidinocarbenium hexafluorophosphate

PyDAOP

(4-oxopyrido[3,2-d ][1,2,3]triazin-3(4H )-yloxy)-tripyrrolidin-1-ylphosphonium hexafluorophosphate

PyDOP

[(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-oxy]tris(pyrrolidino)phosphonium hexafluorophosphate

PyDPP diphenyl 2-oxopyridin-1(2H )-ylphosphonate PyFOP [[6-(trifluoromethyl)benzotriazol-1-yl]oxy]tris-(pyrrolidino)phosphonium hexafluorophosphate PyNOP [(6-nitrobenzotriazol-1-yl)oxy]tris(pyrrolidino)-phosphonium hexafluorophosphate

PyPOP (perfluorophenoxy)tripyrrolidin-1-ylphosphonium PyTOP (pyridyl-2-thio)tris(pyrrolidino)-phosphonium hexafluorophosphate

SbTMU O -(N -succimidyl)-N ,N ,N 0,N 0-bis-(tetramethylene)-uronium hexafluorophosphate

SDPP 2,5-dioxopyrrolidin-1-yl diphenyl phosphate SMDOP 4-oxobenzo[d ][1,2,3]triazin-3(4H )-yl methanesulfonate

SPDOP 4-oxobenzo[d ][1,2,3]triazin-3(4H )-yl benzenesulfonate

SOMI 5-(succinimidyloxy)-N ,N -dimethylmethaniminium hexachloroantimonate

SOMP 5-(succinimidyloxy)-3,4-dihydro-1-methyl-2H -pyrrolium hexachloroantimonate T3P 2-propanephosphonic acid anhydride TATU

O -(7-azabenzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate

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TAPipU

1-(1-pyrrolidinyl-1H -1,2,3-triazolo[4,5-b ]pyridin-1-ylmethylene)pyrrolidinium tetrafluoroborate N -oxide

TBFH N ,N ,N 0,N 0-tetramethylbromoformamidinium hexafluorophosphate

TBTU O -benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate

TCFH N ,N ,N 0,N 0-tetramethylchloroformamidinium hexafluorophosphate

TCTU (2-(6-chloro-1-H -benzotriazol-1-yl)-1,1,3,3-tetramethylaminium)tetrafluoroborate

TDBTU

2-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate TEFFH tetraethylfluoroformamidinium hexafluorophosphate

TFMS-DEP diethylphenyl(trifluoromethylsulfonyl)-phosphoramidate

TFFH tetramethylfluoroformamidinium hexafluorophosphate

TNTU 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate TOTT S -(1-oxido-2-pyridinyl)-1,1,3,3-tetra-methylthiouronium tetrafluoroborate

TODT S -(1-oxido-2-pyridinyl)-1,3-dimethyl-1,3-tri-methylenethiouronium tetrafluoroborate TOTU O -(cyano(ethoxycarbonyl)methylenamino)-1,1,3,3-tetramethyluronium tetrafluoroborate TPTU 1-((dimethylamino)(dimethyliminio)methoxy)-2-hydroxypyridinium tetrafluoroborate TSTU

2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate

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