Tetrahedron Report Number 489

TETRAHEDRON Pergamon Tetrahedron 55 (I 999) 4855--4946
Tetrahedron report number 489
Linkers for Solid Phase Organic Synthesis

Ian W. James Chiton TechnologiesPty. Ltd. 11 Duerdin St., Clayton, 3168, Australia. Ph.+61395651111 Fax.+61395651199 lan_Jamesc~ec.chiron.com
Received 8 February 1999
Contents I.
2. 3.
4.
5. 6. 7.
Introduction Linker Design Types of Linker 3.1 Acid labile 3.2 Base labile 3.3 Photolabile 3.4 Traceless linkers 3.5 Cyclative cleavage 3.6 Safety catch linkers Attachment Methods Scavengers Wang and Rink Linkers 6.1 Wang linker 6.2 Rink linker Functional Groups Achieved by Cleavage from a Linker 7.1 Alcohol 7.2 Aldehyde 7.3 Alkene 7.4 Allyl 7.5 Allyl bromide 7.6 Amide 7.7 Amidine 7.8 Amine 7.9 Aminosulfonylurea 7.10 Aniline 7.11 Aromatic group 7.12 Atyl bromide 7.13 Aryl iodide 7.14 Carbamate 7.15 Carboxylic acid
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0040-4020/99/$ - see front matter 1999 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(99)00125-8
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7.16 Carboxylic ester 7.17 Diol 7.18 Furan 7.19 Guanidine 7.20 Hydroxamic acid 7.21 Iodide 7.22 Isoquinoline 7.23 Ketone 7.24 Phenol 7.25 Phosphonate 7.26 Phthalhydrazide 7.27 Purine 7.28 Pyrimidine 7.29 Saccharide 7.30 Silanol 7.31 Sulfonamide 7.32 Tetrazole 7.33 Thioacid 7.34 Thiol 7.35 Urea 8. Traceless Linkers 8.1 Aromatic 8.2 Alkyl 8.3 Allyl 8.4 Alkene 8.5 Benzyl 8.6 Furan 8.7 Active methylene groups 9. Cyclative Cleavage 9.1 Cyclization onto esters 9.2 Cyclization onto amides 9.3 Cyclization onto thioesters 9.4 Displacement of sulfonates 9.5 Other cyclizations 10. Safety Catch Linkers 10.1 DKP formation 10.2 Cyclic urea formation 10.3 Dehydration 10.4 Dithioacetal protection of ketone 10.5 Oxidation of thioether 10.6 Oxidation of hydrazide 10.7 Reduction of sulfoxide 10.8 Kenner's safety catch linker 1 I. Conclusion
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1. INTRODUCTION Solid phase chemistry has been used for the synthesis of molecules for over 30 years, first for peptide, l, 2 and then nucleotide3 synthesis. In the seventies, the synthesis of small organic molecules on the solid phase was investigated by a number of groups. 4,5 However, the wide range of chemical reactions that needed to be
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optimized on the solid phase greatly reduced any advantage gained using this approach for the synthesis of the small number of molecules required. The advent of combinatorial techniques, first for peptides and nucleotides 6,7 then for small molecules,S, 9 has brought about a major revival in the study of solid phase organic synthesis. Large numbers of reactions have been translated from solution phase to solid phase 1'12 and more continue to be developed. Critical to this process is the attachment of the molecule to the solid phase. This is achieved through a cleavable linker. 13,14 A linker has been described as a bifunctional protecting group (Figure 1) - it is attached to the molecule being synthesized through a bond labile to the cleavage conditions (e.g. silyl ethers, esters, carbamates, etc.) and is attached to the solid phase polymer through a more stable bond (alkyl ethers, amides, or alkanes). This definition gives a clear picture for many of the linkers used, and is readily visualized by synthetic chemists familiar with protecting group methods used in standard synthetic approaches. Indeed, linkers perform similar functions to protecting groups and many of the linkers developed in recent years are based on protecting groups frequently used in solution phase synthesis. There are, however, many linkers that are not based on common protecting group methods, such as the increasing range of traceless linkers, and those that rely on 13cleavage or cyclization These fall into the broader definition of a linker as a connection between the molecule being synthesized and the solid phase polymer that is cleaved to release the desired molecule. This cleavage may involve a range of techniques and give a range of functional groups. The functional group obtained may be dependent not only on the linker, but also on the method of cleavage.
Protecting Group-I--Functional Group--Molecule Polymer-Spacer--Linker-I--FunctiGroup--Molecule onal Deprotection 1Cleavage

Functional Group'-Molecule Functional Group'-Molecule
Figure 1. Linkers can perform a similar function to traditional protecting groups.
The ideal linker would fulfill a number of important criteria. It would be cheap and readily available. The attachment of starting material would be readily achieved in high yield. The linker would be stable to the chemistry used in the synthesis. Cleavage would be efficient under conditions that do not damage the final product(s). Given that linkers are often applied to the synthesis of large libraries of compounds, a further important criterion for the ideal linker is: The cleavage method should be easily worked up in large numbers and should not introduce impurities that are difficult to remove. Many linkers do not achieve all of these criteria. The attachment process may be problematic, although attachment via solution phase (Section 4) may be a valid approach. All linkers must survive the synthesis, although the choice of synthetic route may determine the choice of linker, and vice versa. Cleavage conditions are often harsh, for example TFA, and not all molecules will survive these conditions. It is important to assess this when planning a library synthesis.
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The last point is probably open to the greatest contention. Many work up procedures add to the number of post-cleavage manipulations. Most cleavage methods use excess reagents to ensure complete cleavage. Many use reagents that are volatile, and excess reagent is removed by evaporation. Other methods use reagents that may be removed by iyopholization, for example, NThOH. A number of cleavage methods, though, use reagents that are not readily removed by these simple methods, for example cleavage using lithium aluminum hydride. Until recently, there were very few methods suitable for purifying the cleaved products in high numbers. However, new techniques of high throughput purification, 15 the use of disposable short columns16 and solid phase reagents to remove impurities 17-19 may make the introduction of impurities in the cleavage step less problematic than it was only a few years ago. It is important to consider how these extra manipulations may be performed in the numbers required for a library. The use of solid phase reagents to remove impurities is limited to cases where solid phase reagents suitable for the purification step are available. However, the process is easily performed in large numbers, requiring only a filtration step to separate the solid phase purification reagent from the purified product. Other methods, such as the use of short Solid Phase Extraction columns and high throughput HPLC are useful for small to medium numbers of compounds, but can be very time consuming if large numbers are being prepared. Aqueous work up can be automated with modem robotics, though these can typically handle up to only a few hundred compounds at a time. With these factors in mind, the selection of linker and cleavage method is not only based on the compounds being prepared but also on the size of library. It is not surprising that a wide range of linkers have been reported in recent years given the range of reactions that a linker may have to survive during the synthesis of a molecule, the different types of molecules and functional groups that may have to survive the cleavage conditions, and the wide range of functional groups through which a substrate may be attached to the solid phase. This review covers papers published up to August 1998. It will focus on the use of linkers for the synthesis of small organic molecules. Linkers that were initially developed for peptide synthesis and later used for the small molecule synthesis are also described. After a brief discussion on the general design and use of linkers, the emphasis of this review is on the functional group obtained after cleavage. 2. LINKER DESIGN The choice of base polymer, spacer (any atoms between the polymer and the linker) and linker requires careful consideration when planning a reaction sequence on the solid phase. Polymer considerations are outside the realm of this review, but include such issues as solvation (poor solvation may hinder the release of the product molecule) and the presence of functional groups that may interfere with the chemistry. Similarly, spacers are not emphasized in this review, but the presence of problematic functional groups within the spacer has been reported. The method of attachment of the linker to the solid phase may also present problems to the subsequent synthesis on the solid phase. For example, the amide bond used to attach a photolabile carboxylic acid linker lb was believed to interfere with subsequent chemistry. 2 Replacement of the amide with an ester bond la resulted in successful synthesis. Unnecessary heteroatoms were removed from the spacer of linker 2 so as to improve the overall performance when using a ianthanide catalyst. 21 Although preparation of the new spacer/linker combination required some synthetic effort, the workers were rewarded with significant improvements in the yields.
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To cover this area in depth would require a separate review. However, it is important to consider the polymer, spacer and linker, as they may affect the outcome of a synthesis. Me. O..I~R
O2N~ ' O O ~'~ "OMe
(a) X = O avoids the acidic amide proton present when Co)X = NH
Gives superior yields for Sc(OTf)3 chemistry than Wang or chlommethylpelystyrene derived linker
3. TYPES OF L I N K E R In this section a brief description is given for each of the most commonly used types of linkers, which are categorized according to the method of cleavage. Linkers that rely on less common types of cleavage methods, such as oxidation and reduction, are discussed in Section 7. 3.1. Acid Labile Strong acid is one of the most common cleavage conditions used in solid phase synthesis. Volatile acids, such as I-IF or much more commonly TFA, allow easy removal of excess cleavage reagent by evaporation, The lability of an acid labile linker is dependent on the relative stability of the protonated linker versus the cation formed upon cleavage. Therefore within a series of linkers, the more stable the cation formed, the more labile the linker is to acid. This is best illustrated using ester linkers. The stability of the illustrated cations increases from left to right as the number of electron donating groups increases, hence it is not surprising that the same trend is observed when comparing the ester linker 3, derived from hydroxymethylpolystyrene linker (frequently call the Merrifield linker), which requires HF for cleavage, the Wang linker 4, 50% TFA/DCM, and the Sasrin linker 5, 1-3% TFA/DCM (Figure 2). G ~ 0 "Me
< e.o
0 0
e.o
0 "Me 0
4 Figure 2
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Similar trends are observed for arnide linkers, with the Pink linker 6 (TFA cleavage) being significantly more acid labile than the benzhydryl linker 7 (I-IT cleavage).
Me- O
Rink Linker
Benzhydryl linker
As is mentioned below, linkers based on ester bonds, such as 3, 4, and 5, may also be cleaved by nucleophilic attack, e.g. with NaOMe to give the methyl ester. Hence, the acid labile linkers for carboxylic acids may also be cleaved, by these nucleophilic conditions. This is more of a problem with the Wang linker than it is for the Sasrin linker, primarily because of steric factors. Lability towards nucleophiles can be reduced by using sterically congested linkers. For example, both the trityl linker 8 and the hindered handle 9 are significantly hindered such that cleavage by even reactive and unhindered nucleophiles is limited.
9 8
Hindered handle Trityl linker
3.2. Base Labile
Although the term 'base labile' is used, two types of cleavage are included under this heading. The more common type actually involves nucleophilic addition/elimination, usually on an ester, whereas the less common type involves a base catalyzed reaction, such as elimination or cyclization. The nucleophilic labile linker is typified by the ester linker derived from hydroxymethylpolystyrene 3, already discussed above as an HF labile linker. Treatment with NaOH solution leads to the cleavage as the salt of the carboxylic acid (Scheme 1). Cleavage may also be achieved using NaOMe in MeOH to give the methyl carboxylic ester, or by an unhindered amine such as methylamine to give the amide. All of these cleavage reagents are bases, although the reactivity is determined primarily by their nucleophilicity. The true base labile linker is demonstrated by the tertiary amine linker 10 (Scheme 2). Cleavage occurs by Hofmann elimination of the ammonium salt and hence reactivity is determined by the basicity of the cleavage reagent.22-25
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~.NaO~.~
Na + "O~o R
H Me" N,.,IF.R 0
I I
MeNH2
~
3
O..~R
NaOMe ~
Me..O...II..R
0
Scheme 1
O II
R1
p-elimination
. RI
10 r AB
Scheme 2
3.3. Photolabile
Y 0 hv
Me"OxF'~L"x-'~R
'~"0~ II NC~
X=O, NH Y=H, Me
0 X=O, NH Y=H, Me
O HX.~.R +
X--O, NH
HOY
0
F
Me"O"~
OA~/~'-. N O
Y.,
13aY= H bY=Me
Scheme 3
~"O"~2 N O X--O,N H
Y=H, Me
Photolabile linkers are not as commonly used as either the acid labile or base labile linkers. The most common type is based on the nltrobenzyl moiety.26,27 On irradiation of 11, a 1,5-hydrogen abstraction occurs (Scheme 3). Further rearrangement leads to the formation of the acetal 12, which then undergoes elimination releasing the product) s Generally, it has been found that, for the example illustrated, having an alpha-methyl group, which leads to formation of a ketone 13b rather than an aldehyde 13a, gives superior yields. This is due to two factors: the ketone is a superior chromophore than the aldehdye; and the product, once cleaved, can re,attach to the solid phase through the aldehyde group. Electron donating alkoxy substitutions on the aryl group also generally improve yields. 29 Photolytic reactions take significantly longer for polymer hound substrates than they do for compounds in solution, because of shadowing by the polymer present. This prolonged treatment may be damaging to some compounds. One of the key challenges in this field is to improve cleavage rates and yields
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whilst ensuring that cleavage does not occur inadvertently under ambient laboratory lighting. With the potential of developing a linker that will be stable to a large range of chemistries, then cleave under relatively neutral conditions, there continues to be significant research into photolabile linkers, and further improvements should be expected over the next few years. 3.4. Tracdess Linkers Most linkers leave a residue attached to the cleaved molecule; that is the functional group (or a derivative thereof) used to attach the molecule to the linker, i.e, a carboxylic acid, an amide or an alcohol. This is not always desirable for a library. For this reason, a number of groups have investigated linkers that leave no obvious residue on the cleaved molecule, traceless linkers. For the purpose of this review, a traceless linker is defined as one where a new carbon-hydrogen or carbon-carbon bond is formed at the linkage site of the cleaved molecule. This definition includes rearrangements such as retrocycloadditions. By far the most common form are the aryl silyl linkers that are used to attach aromatic molecules and cleave forming a new carbon-hydrogen bond (e.g. Scheme 4).30, 31 These are discussed in detail below (Section 8.1), but they usually rely on cleavage by strong acid such as HF, or TFA. Other strong electrophiles may be used for cleavage, such as I +, but that application does not fall into the above definition of a traceless linker.
-~NHBoc
"
Rn
Rn
R R Scheme 4
'~ R
R'
IP'
Md "Me
3.5. Cydative Cleavage If the bond being broken in an intramolecular reaction is involved in attaching the molecule to the solid phase (i.e. part of the linker) then it is possible to achieve both cyclization and cleavage in the one step, i.e. cyclative cleavage. This is best illustrated by attack of a nucleophile, such as an amine, onto an ester derived linker (Scheme 5) to release a lactam. Rates of cyclization are dependant on the side-chains present on the cycle being formed, and hence vary from compound to compound. This can lead to variable yields. o ~_~ cyclization No~ withcleavage H NH2
lid
~O
Scheme 5
One of the ideals of solid phase chemistry, especially when used for preparing libraries, is to obtain products in high purity on cleavage from the solid phase, avoiding the need for purification. Using cyclative cleavage, only molecules containing the nuclenphile will undergo cleavage, hence even if the synthetic step(s) which introduced the nuclephile into the molecule went in poor conversion, mainly the desired product will he obtained a~er cleavage. This method results in high purity, but at the cost of potentially reduced yields. For example, treatment of an amino acid attached to hydroxymethylpolystyrene 14 with an isocyanate gives the urea
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15 (Scheme 6 ) ) 2 Treatment of 15 with base leads to nucleophilic attack on the ester and cleavage of the product as the hydantoin 16. Only the urea 15 will undergo cleavage under these conditions, any unreacted amino acid 14 will remain on the solid phase. The yields can vary widely, although the purity is generally high.
R' NH
0 OCNR" A..'~
~ -O
15
R' N
R" O DIEA O
R' 16 R
R HN.R.
No reaction
Scheme
DIEA
6
3.6. Safety Catch Linkers Safety catch linkers are those that rely on a two step cleavage process.33 The first step involves activation of the linker, the second step involves the actual cleavage. This is illustrated using two examples. Kenner's safety
catch linker 1734.37 is stable to both acidic and basic conditions until the nitrogen is alkylated either with diazomethane or iodoacetonitrile (Scheme 7). Once activated by alkylation, cleavage proceeds u n d e r nucleophilic conditions. A second example is the pyrimidyl linker 18 (Scheme 8)) s The thiol linkage is stable to a range of conditions, but once activated by oxidization, cleavage is achieved by aromatic nucleophilic substitution with an amine. The view is held by many that these linkers are advantageous as they are stable to a range of conditions, cleavage occurs under mild conditions. In contrast, the conditions for the activation steps are often harsh. The main advantage of these linkers is that if there is a need to use conditions similar to the cleavage conditions during the synthesis, this can be accommodated as the linker is stable until activated. However, the product being cleaved must be stable to both the activation and the cleavage conditions. For example, using Kenner's safety catch linker, the target molecule must be stable to the strong alkylation conditions, as well as the basic conditions of cleavage. Similarly, for the pyridyl linker, the target molecule must be stable to both the oxidation conditions, as well as the nucleophilic conditions. These stability issues must be considered when planning the application of these linkers.
--
~-~-~~~--~ " ~ R 17
activation
"
~~--~S'N"JJ~R
HO"
~,,
cleavage R' = Me, CH2CN
HO
Scheme 7
activation ~ ~ - ~ _ _ O . _ ~ - ~
18
Scheme 8
cleavage
H, N
4864
4. ATTACHMENT METHODS Usually, the starting compound is attached to the support-bound linker. This method is acceptable when the attachment process is achievable in good yield. However, for some linkers, this attachment of the starting material is problematic. This may be for a number of reasons. It may be that the reaction is disfavoured on steric or electronic grounds, leading to low loading on the solid phase. It is possible that an unstable intermediate is formed on the solid phase that leads to unwanted by-products, which are released on cleavage and contaminate the final product. Either way, this will lead to unsatisfactory results. One way of circumventing this problem is to attach the starting material to the linker in solution (Figure 3). The combined linker-starting substrate conjugate can be purified using conventional techniques, then attached to the solid phase using an efficient method, such as amide bond formation. Throughout the review, this method is called attachment via solution phase. It has the advantage that high loading of pure material can be achieved, however, the disadvantage is that the solution phase syntheses may require multiple steps and may not be amenable to high throughput. If only a limited variety of starting materials is used, this is acceptable, but if significant diversity is planned at the stage of the starting materials, then production of the library may be greatly retarded using this method.
SpacermLinker Polymer--Spacer--Linker Substrate PolymermSpacer Linker~Substrate
Substrate
Spacer--Linker --Substrate
J Polymer
purified by I traditional techniques]
Polymer--Spacer --Ltnker--Substrate
Normal Attachment Process
Relies on effective formation of bond between linker and substrate
Attachment via Solution Phase Robust bond formation can be used for attachment to polymer Figure 3
5. SCAVENGERS
During acidic cleavage, a carbocation is typically formed on the solid phase. This carbocation may react with nucleophilic species. If the nucleophilic species is part of the product molecule being cleaved, then the molecule may reattach to the solid phase by a non-cleavable bond, resulting in lower yields of cleaved product. This has erroneously been interpreted as failure to cleave, when in fact it is due to successful cleavage followed by undesired reattachment. Adopting harsher cleavage conditions would not markedly improve the yield, instead, it is necessary to quench the cation prior to its reaction with the cleaved product. This is achieved by scavengers. 39 The selection of scavengers is based on a number of factors:
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The type of linker. The type of molecule being cleaved. The presence of nudeophilic sites in the template or side-chains needs to be noted. The scavenger itself may interfere with the template or side-chains of the cleaved molecule. In many cases, no scavenger is required, and a large number of cases quoted below use a TFA/DCM mixture for cleavage. By far the most common scavenger reagent used for solid phase organic synthesis is water. It is frequently used at 5-10% and is suitable for a wide range of molecules, however, if more reactive moieties such thiols, thioethers, and electron rich aromatic systems, are present in the cleaved molecule, then more effective scavengers may be required. Possible scavengers include dimethylsulfide, 40 ethanedithiol (EDT),41, 42 anisole, 43,44 thioanisole,45, 46 and p-cresol. 47 Triethylsilane (TES) and triisopropylsilane (TIPS) 48 have also been found to be effective scavenger agents. There are disadvantages to each of the scavengers. Water, apart from not being sufficient for all systems, may hydrolyze the desired product, for example hydroxamic acids to carboxylic acids. Anisole and thioanisole are not volatile and need extractive removal from the cleaved product. For peptides, this is usually done by trituation from the precipitated peptide with ether/petrol. This is not suitable for many non-polar organic molecules, hence alternative purification methods would need to be used. EDT is very effective, but requires extractive work up and it does have the problem of stench. TES is attractive in that it does not have the stench problem and is volatile, however, it does partake in a number of side reactions, including addition to indoles and reduction of double bonds. TIPS is similar to TES but side reactions are less problematic because of its bulk. The selection of scavenger agents is often based on experience. Many groups use a cleavage mixture out of habit, only varying it when problems occur. As is seen by looking through the references, scavengers are often not used, however, investigation into which scavenger mixture is best for a specific system may result in significantly improved yields and allow for the preparation of more diverse libraries. 6. WANG AND RINK LINKERS Two of the most widely used linkers in solid phase organic synthesis are the Wang and Rink linkers. They were designed for use in peptide synthesis giving carboxylic acids and primary amides respectively. Their scope has been greatly broadened in recent years such that they are now used to attach a broad range of functionalities.
6.1. Wang Linker
O DIC/DIVIA~o~O/~" R 50%TFA/DCM O =" HO~,~R
Scheme 9
The monoalkoxy benzyl, or Wang linker49 was developed for the attachment of carboxylic acids (Scheme 9). Attachment to 19 can be achieved using a range of coupling methods, but the most common is DIC/DMAP. Cleavage can be achieved using 50% TFA/DCM. As discussed above, it is more stable than the dialkoxy benzyl
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linker that requires only 1% TFA/DCM for cleavage, 5 but less stable then the hydroxymethylpolystyrene derived linker that requires HF. 51,52 The acid is attached through an ester bond, which is susceptible to nucleophilic attack, hence the linker may also be considered base labile. For example 4 can be cleaved with NaOMe 53 or TEA/MeOH/KCN54 to give the methyl ester. The electron rich benzylic position is also susceptible to oxidative cleavage.55, 56 DDQ has been used cleave the ether of the Wang linker 20 (Scheme 10). 57,58 It has been reported that mCPBA may have caused some cleavage of the Wang linker. 59 In this example the linker was used to attach amines, via the carbamate, but the cleavage would probably also occur if it was being used to attach acids. It is unlikely that the cleavage is due to the acidity of mCPBA or its reduced form, as the solution was buffered with NaHC03.
DDQ
- HO-R
Scheme 10
.0 ~ ' ~ O H
19
halogenation (0 R'NH2
~ ~
"
Mitsunobu reaction ~ ~o e n CI3CCN, DBUBF3.OEt2 " hr ROH,
R,,P = ~"~N'S'RR' " (ii)CISO2R

IF"O v21 Cleavage: 95% TFAJDCM
eO
X = Cl, Br, I (i) R'NI-12/
NaOR i O
R'NH2 ICOR 20 Cleavage: 20-50% TFA/DCM O
R
22
(ii)OCt//
0 ..~"-~/~N.~N. R
23
Cleavage: 95% TFN'FES

Scheme 11
Cleavage: 95% TFNDCM
The Wang linker has been used to attach a range of functionalities (Scheme 11). It can be converted to the chloride,6, 61 hromide,61, 62 iodide, 62 or trichloroacetimidate, 63 any of which can be further derivatized with a range ofnucleophiles. For example, displacement with an amine, then sulfonylation gives a solfonamide linker 21 that is cleaved with 95% TFA, 62 whereas acylation of the amine gives an amide linker 22 that cleaves under similar conditions. Acid labile urea linkers 23 also have been developed from Wang amines. 64 The ether 20 can be cleaved using 20% TFA/DCM, 57 although the TFA ester was observed as a major by-product (20-30%).
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Phenols have been attached using Mitsunobu chemistry 6~ The Mitsunobu attachment, though, can be problematic and use of the trichloroacetimidate 63 or attachment via solution phase has been used to avoid this.66, 67 The Wang phenol linker is cleaved using 50% TFA/DCM. Amines attached directly to the Wang linker are not readily cleaved with TFA, although, as has already been mentioned, the amides, sulfonamides, and ureas derived from them are cleaved. To use the Wang linker for amines, the amine is attached in the form of the carbamate 24 (Scheme 12). 68.70 Treatment with 50% TFA/IX~M cleaves the linker to give the amine after m situ decarboxylation. The carbamate can be cleaved by reduction with LiAIH4 to give the methyl amine. 71 Application of the carbonate of Wang, as a potential alcohol linker, failed because of poor stability. 72
"OH
19
,~-,,,..j~O~Jt, y RNH2
/,. ~
24
R50%TFNDCM
Y = p'NO2-C'H4"' Im' CI
1LiAIH4 Me H
Scheme 12
1-cO2
;N-R
H2N-R
The usage of the Wang linker has been extended to include aminosuifonylureas, 73 amidines, 74 sugars, 75 and phosphonates. 76 Tertiary amides have been achieved by treatment of the Wang ester linker with a secondary amine and AICi3 or ZrCI+.77 The Wang linker can also be used for cyclative cleavage78, 79 as is discussed in detail in Section 9.1. 6.2. Rink Linker The Rink linkerS0, 81 is widely used in solid phase organic chemistry. The three electron donating alkoxy groups greatly stabilize the cation formed on cleavage Indeed, the solid phase turns a deep red colour on treatment with TFA, because of the stabilized cation The amine nitrogen 25 can be acylated with a range of reagents and cleavage is achieved with typically 20-50% TFA/DCM (Scheme 13).8, 82 The sulfonamide linker 26 can also be prepared, with 20*/0 TFA/DCM being used to achieve cleavage, s3
O,.~NH O.Me
R 6
NH20"Me
2S
O2s.,NHO.Me
R 26
Cleavage: 20-50% TFNDCM

Scheme 13
Cleavage: 20% TFNDCM
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The use of this linker has been expanded by the development of the Rink chloride 27 (Scheme 14). s4 This is prepared from the Kink alcohol 28 using PPh3/CzCi6 or 1% HCI in DcMrITIF. s5 Treatment with a nucleophile then allows the linker to be used to attach a range of functionalities, including primary and secondary amines, anilines, alcohols, phenols, thiols, thiophenols as well as acids. Cleavage is achieved using 5-10% TFA/DCM. s0 An N-substituted hydroxamic acid linker 29 has been prepared from the Kink chloride with cleavage achieved using 90% TFA. 85 It has also been reported that the cation formed by treatment of the Rink linker with TFA may be reacted directly with nucleophiles such as alcohols, amines, anilines and phenols, thereby avoiding the need to prepare the chloride.S, s6
/O~O'Me
OH 28 O'Me Rink alcohol l PPh3, C2CIs
R. x
OM -~ e
o
zClOM -e
Rink chloride RCO.zH ,
R,.N-RO-Me
R = alkyl, aryl; R' ,, Me, H
X=O, S R = alkyl, awl
R'=H
R"COCI
R.N.O O.~Ij...R,
O.Me
O.~O R
O.Me
O~N- R O'Me R"
29
Scheme 14
The linker has been used to prepare secondary amides, although its bulkiness may lead to problems in some cases. The Kink amine has been reductively alkylated with a range of benzyl aldehydes and ketones to give secondary amines, s7 Amination of the Kink chloride has also been used to prepare secondary amines, s4 Acylation of the secondary amines is typically achieved using the highly reactive acid chlorides s4 or anhydrides s7 and cleavage to give the secondary amide is achieved with 5%TFA in DCM Unlike the Wang linker, which usually involves an ester or carbamate bond, the Kink linker is not higidy susceptible to nucleophile attack, because of both steric hindrance and increased electron density. Therefore, when used to attach carboxylic acids, it is relatively stable to nucleophilic conditions. The highly electron rich benzylic position is prone to oxidation though, as has been observed for electron rich benzylic protecting groups.55, 56 Unpublished work within the laboratories of Chiton Technologies in Australia has shown that treatment with mCPBA or DDQ can cleave the Rink linker.
!. W. James / Tetrahedron 55 (1999) 4855-4946
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From these two examples it can be seen how a linker, developed initially to give a carboxylic acid or an amide, can be expanded for a range of functionalities. Many of the linkers discussed below are based on the same principles as those described above. They are extensions of linkers initially developed for peptide synthesis. These have proved very useful, although it should be recognized that organic chemistry uses a much wider range of reaction conditions than those used in peptide chemistry. This may invalidate a number of peptide derived linkers and provide challenges for the development of new linkers. 7. FUNCTIONAL GROUPS ACHIEVED BY CLEAVAGE FROM A L I N K E R
7.1. Alcohol
7.1.1. A c i d Labile
Trityl: Attachment of the alcohol to trityl chloride 30 on the solid phase may be achieved using pyridine as the solvent (Scheme 15).88 Cleavage can be achieved using <5% TFA/DCM 89 though the use of concentrations as high as 100% TFA88 as well as TFA vapour 9 has been reported. The trifluoroacetate ester is a potential byproduct when using these conditions, although it can be hydrolyzed by treatment of the crude product with sodium carbonate. Alternatively, 0.3M HC1 in dioxane has been used for cleavage. 91-94 Dry I-[Br also gives cleavage, 88,95 though bromination is a potential side reaction. Also used are the 2-chlorotrityl linker 31, which is cleaved with 50% TFA/DCM, 96 and the 4methoxytrityl linker 32, which is cleaved with 1% TFA/DCM. 97 Trityl synthesis examples: perhydro-l,4-diazepine-2,5-diones. 9
50%TFA/DCM ~CRI py CI ROH, ~~--~O-R TFA HO-R 1% DCM TFA/

P
30
-O-R
OMe 32
Scheme 15
DHP Linker: The DHP linker 33 is an example of the development of a new linker based on a common solution phase protecting group. Attachment of an alcohol is catalyzed with PPTS in DCE at 80C or pTsOH at 0C (Scheme 16). 98 Cleavage is achieved with 95% TFA in water. This method has been used a number of times, 99-101 but the loading is dependent on the substrate and has been reported to be poor for highly hindered systems. 102 Phenols have also been attached using this linker. 103 Synthesis examples: pyrrolidines 13 and tropanes. 104
4870
33
PPTS = or TsOH
Scheme 16
D HO-R
Vinvloxv Linker: An acetal linker 34 may be prepared from the vinyloxy linker (Scheme 17). 102 The acetal is formed in solution then attached to the solid phase, i.e. attachment via solution phase. Cleavage is achieved with 30% TFA in DCM. Although less hindered than the DHP linker, use of this linker has not been widely reported.
~O~90"'~'
0 ~' . H o ~ g O ' ~ r ' /

O-R
0 DIC, HOBt= ~ O ~ 9 0 .
34
~
O-R
30%TFA/DCM
HO-R
Scheme 17 Aminals: Alcohols can be coupled to 35 using NIS in DCM, 105 with 9:10:1 TFA/DCM/HzO being used for cleavage (Scheme 18).
SEt O
R'O
O 9:10:1 TFA/DCM/H=O =" HO-R
Scheme 18 Wan= Linker: As discussed above in Section 6.1,
cleavage of the alcohol
attached via an ether bond to a
Wang derived linker, 20, using 10-50% TFA has been reported. 57 TFA ester formation was found to be a common side reaction during cleavage. The alcohol can be attached either by treatment of the Wang chloride 36 with sodium alkoxide 57 or by conversion of the Wang alcohol 19 to the trichloroacetimidate 37 then treatment with the alcohol and boron trifluoride etherate (Scheme 19).63
e
O
36
c,
o.o. "
O
20
"
HO-R
l.o.,.F:.O.,=
.OH
19
CI3CCN
--~"~"'~'O'~ CCi3
37
Scheme 19
4871
Rink linkr: The Rink linker has been derivatized as the chloride 27 for the attachment of alcohols (Scheme 20). 84 Cleavage is achieved with 5% TFA/DCM
o.Me
O.Me
A~C
o
"cl
O'Me ROH,DIEA
o
~L~o'Me
R
5% TFNDCM
HO-R
,,
,
Scheme 20
Siloxy linkers: The trialkyl silyl ether 38 is acid labile (Scheme 21). 16,17 The attachment, using pyridine (R = Me) or imidazole (R = Et, Bu), is selective for primary over secondary alcohols and secondary over tertiary alcohols. Cleavage is successfully achieved using I-IF (R = Et), HF/py (R = Me, I06 Bu) 108 or 6:6:1 AcOH/THF/H20 for primary alcohols (R = Me), 16 whereas cleavage with TBAF was found to be sluggish. 107 Although the early reports claim the solid phase bound silyl chloride to be relatively stable, 109 recent papers have discussed ways of masking the silyl chloride in a stable form such as the silane 16,11 or an electron rich aryi silane. 111
Si-cl X X
,
ROH, base ,. ~../.....si.O. R

,
X X
38 X = Me, Et
,. HO-R AcOH/THF/H20
or
HFIpy
X = Me, Et
Scheme 21 Triaryi siloxy ethers 39, which are discussed below as base labile linkers, are also cleaved under acidic fluoride conditions (Scheme 22). Cleavage conditions include HF.pyridine with an anisole scavenger, 112 or TBAF and AcOH in THF. 113,114 The diisopropylaryl siloxy ethers have been reported to he superior to the triarylsilanes 1t5 The alcohol is attached using DMAP catalysis with cleavage achieved using TBAF/AcOH in THF 116-118
X ~ ~ i - C l X X = Ph or iPr
ROH, DIEA ~h~._ X , or - //Si-O-R ~ \\ ROH, DIEA, DMAP 39 X = Ph or ipr

Scheme 22
TBAF, AcOH THF
HO-R
Carbonate linker: Similar to the attachment of amines via a carbamate (Section 7.8), alcohols have also been attached to 4-hydroxymethylpolystyrene via a carbonate 40 (Scheme 23). 72 The carbonate was formed by reaction with DSC/DMAP then the alcohoi/DMAP. The relatively electron poor benzylic systems required l i t
4872
treatment for cleavage. It would be expected that the carbonate would be unstable to strongly nucleophilic conditions although it is stable to basic conditions such as 5% DIEA treatment.
~
4O
7.1.2. Base Labile
OTR -]'O
O
Scheme 23
HF
HO-R
Ester Linker: Hydrolysis of an ester can be used to cleave alcohols from the solid phase. The succinate linker 41 has been utilized in this manner by a number of groups (Scheme 24). The alcohol is attached via solution phase 119 with the succinate 42 attached to the solid phase as the amide. Hydrolysis of the ester to release the alcohol is achieved using ammonia in McOH or hydrazine in DMF. Oligosaccharides have been prepared using a succinamide linker at the C-2, C-3120 and C-6121 positions. Cleavage was achieved using concentrated aqueous ammonium hydroxide or NaOMe in MeOH/dioxane.
DMAP PY = H O ~ ~
O O"R
ROH
O
O 42
DIC/HOBt H ~ 9~f, Nl'h =' O 1 I I O 41

Scheme 24
O O"R
NPkj or N2H4 =' HO-R
The benzylic ester 43 has frequently been used to attach alcohols. The alcohol is attached to the solid phase bound acid chloride 44 using DMAP, TEA 122 or pyridine (Scheme 25).123,124 A wide range of cleavage conditions have been developed including: NaOMe in THF/MeOH(4:l)123,125 or dioxane, 126"125 NaOH in HzO/EtOH/dioxane, 129 NH4OH in H20/dioxane, 130,131 KzCO3 in 1:2 MeOH/THF,122,132 or Bu~CI, KOH in H20/THF. 124 Synthesis examples: isoxazoles, 125 isoxazolines 12~ and polyisoxazolines, 123 cyclopentenones via the Pauson-Khand reaction. 124 O
O
DMAP/rEARoH"~ ~ J J ~
O'R NaOMe= HO-R
Scheme 25 Silvi Linker: Triaryl siloxy ether linkers described above are not only acid labile but also base labile. 109 The silyl chloride 45 was formed on the solid phase and the alcohol attached as the siloxy ether 46 using DIEA or pyridine as the base (Scheme 26). Primary alcohols are attached in preference to secondary alcohols. After synthesis, the alcohol is cleaved using TBAF. Further manipulation (in this case flash chromatography) is necessary to remove the fluoride salts.
L W. James/Tetrahedron 55 (1999)4855-4946
4873
P"si'C=
"Ph
46
py. ROH
,=
Ph, O ,~"',v SI, "R " Ph
TBAF
= HO-R
Scheme 26 Carbonate: A fluoride labile carbonate linker 47 has been developed. 133 It is formed via the imidazolide carbamate, which is subsequently treated with the alcohol and DBU. CsF in DMF at 90C is used for cleavage (Scheme 27).
1) CDI, py
Y O-R
CsF, DMF,9(PC
2) ROH,DBU MS
47
"
HO-R
MS
Scheme 27
7.1.3. Photolabile
The carbonate 48 has been used for the preparation of alcohols.72 Attachment is as described for the acid labile carbonate linker and cleavage is achieved by photolysis at 350nm (Scheme 28).
~
48 NO2
O
Scheme 28
HO-R
7.1.4. Reductive Cleavage
KSCOR
N
,. ~ ~ . S , ~ R
NaOzCR
DIBAL
=, HOuR
3 0 ~ R ~ o
RCO2H
19
DIG.DMAP OH Scheme 29
O.~R
o
4874
I.W. James I Tetrahedron 55 (1999) 4855--4946
Thioesters 49 may be used as reductively labile alcohol linkers.21,134,135. The salt of the thioacid was used to attach the linker to Merrifieid resin 50, with cleavage then achieved using LiBI-h (Scheme 29). The Wang esters 4,136 benzylic esters 3,137 and alkyl esters138,139 also have been reductively cleaved with DIBAL to give the alcohol. For all of these examples, purification would be required to remove the excess reductant from the cleavage solution prior to screening of the products.
7.1.5. Oxidative Cleavage
Wang Linker: As already stated, alcohols have been attached directly to the Wang linker via an ether 20. 57 These can be cleaved with TFA, however, the TFA ester was found to be a common impurity (20-30%). To avoid this side reaction, cleavage can be achieved oxidatively using DDQ in 20:1 DCM/I'hO (Scheme 30). 57 Excess DDQ and DDQH is removed using an ion exchange resin added directly to the resin/cleavage mixture. It was reported that no DDQ derived residues were observed by HPLC analysis of the samples resulting from this approach.
~' O O 20 Scheme 30 7.1.6. Enzymatic Cleavage
= HO-R
As an interesting addition to the range of methods available, enzymatic cleavage has recently been reported. The carbonate linker 51 can be cleaved to release the alcohol using lipase RB 001-05 in 50raM MES buffer/methanol (80/20) with 0.2M NaHSOs at pH 6.5 at 30C (Scheme 31). 140 This actually involves enzymatic hydrolysis of the acetate followed by elimination of the carbonate then decarboxylation. 141 The alcohol would need to be isolated from the cleavage solution using purification techniques, although separation should be relatively straight forward. This method has been demonstrated for a range of functional groups and these are reported in the relevant sections. It should be noted that this cleavage method has been performed on a relatively hydrophilic polymer, polyethyleneglycol grafted polystyrene.
O OAc ~O (,,..? H 7
(~O~
lipaseRB 001-05
_~I.~O~I-o.R 0.2MNaHSO3,pH 6.5, 30C St Scheme 31
7.2. Aldehyde
7.2.1. Acid Labile
1,2-Diols 52 have been used to attach aldehydes to the solid phase. 142-146 The aldehyde is attached using
p-benzenedisulfonic acid in dioxane orpTsOH in benzene, with azeotropic removal oftbe water released during the reaction (Scheme 32). Cleavage is achieved by acid hydrolysis using HCI orpTsOH in aqueous dioxane. The
1,3-diol has also been used an aldehyde linker. 147 Attachment via solution phase is used and cleavage is achieved with 90% TFA.
4875
O~s2OH
HO.3S-.~SO.,,J-I O ~ O R Ill o OH R,,JJ,,H O

Scheme 32
l.-IC,,dloxmno(m.)R..j~..H II
A recent alternative to the acetal linkers involves the use of threonine or serine on the solid phase 53 to form an oxazolidine linker 54 when reacted with an aldehyde (Scheme 33). 148 The linker is stable to both basic and strongly acid conditions, but it is cleaved in mild aqueous acid. Therefore, acid labile protecting groups may be removed with neat TFA then the product cleaved with 0.1% TFA in 60% MeCN/I-I20.
HOy, x
H2N'~o N\O =H, Me
53
i) TFA ii) 0.1%TFA In 60% M e C I ~ . 60C

im
MeOH, 00C " R~ ' N ~ o N"O
R.,'~ H
X=H, Me
Scheme 33
54
Semicarhazones 55 have also been used (Scheme 34), 149 The aldehyde is attached to the linker via solution phase and cleavage of the final product is achieved using formaldehyde in dilute aqueous acid. O r,"'.,,,t~N'~L'N'N ~,."R
O=CH2, O, H+ H2
NH~
O 55
H H
Scheme 34
"
H.,~ R
7.2.2. Photolabile
Nitroaryldioxalanes 56 have been used as photolabile aldehyde linkers. 150 Formation of the acetal is catalyzed withpTsOH in benzene (Scheme 35). Cleavage is achieved with visible light (Pyrex filtered Hg lamp) in typically 34 - 97% yield after 7 hours.
0 0
oH + O H . qr o o .
H
hv
O
" R,~H
56
Scheme 35 7.2.3. Reductive
Reductive cleavage of solid phase bound Weinreb amides 57, thioesters 49 and phenacyl esters 58 has been used to yield aldehydes (Scheme 36). The Weinreb amide 57 is prepared by coupling the carboxylic acid to the solid phase bound methoxyamine 59.151,152 At the end of the synthesis, it is cleaved with LiAIH4 to give, after collapse of the tetrahedral intermediate, the aldehyde in solution. This procedure requires the use of an aqueous
4876
solution to collapse the intermediate. This may lead to solvation problems with hydrophobic polystyrene and hence potential reduction in yields. DIBAL reduction of thioesters 49153 and LiAlH(OtBu)3 reduction of phenacyl esters 58152 have also been used to yield aldehydes. Over-reduction to the alcohol was reported as a side reaction for the phenacyl derived linker. For all approaches, it is necessary to remove the aluminum salts after the cleavage to achieve clean samples. This adds to the complexity of post cleavage manipulations.
Me-.0 Me,. O RCO2H _---~L..,.~I~I,,~R ~ , , - I ~ 1 - H BOP,DIEA

59 57 0
Me..O LiAIH4 " ~ 1 ~ 1
/
omAL
KHSO,(~)
"
50
s.. R
49 0
o
H.X.R
BOP, DIEA NH2 O

58
/~H(O~u)s
Scheme 36
7. 2. 4. Oxidative
O R..JL-H
"
R
6t
OH
MBHA resin
I)0 3 R -....~C(NH2)2
ii) RCHO
62
Scheme 37 Alkenes on the solid phase may be cleaved oxidatively to give aldehydes (Scheme 37). 154 The alkene 60 can be prepared in solution by first forming the a,l~-unsaturated acid 61 then coupling this to the solid phase. 155 Ozonolysis of 60 gives the free aldehyde+ The resulting solution requires aqueous workup to remove the excess thiourea. Alternatively, the alkene 62 can be prepared directly on the solid phase using Wittig chemistry. 156 In this case, the ozonide is treated with Me2S to produce the aldehyde. The cleavage reagent is volatile hence removing the need for any aqueous work up, which may be problematic for simultaneous cleavage of large numbers of samples.
4877
7.3. Alkene The Wittig reaction can be used to cleave solid phase bound phosphonium salts. 157 The phosphonium salt 63 is prepared by treatment of solid phase bound triaryl phosphine 64 with a benzyl halide (Scheme 38). Treatment with base (NaOMe) and aldehyde results in cleavage of the product as the alkene. Excess aldehyde is removed by either derivatization as a water soluble hydrazone and aqueous work up, or formation of the imine with aminomethylpolystyrene. The latter is a simple method, which, if successfid, may be performed relatively easily in large numbers.
64
63
Scheme 38
Ring closing metathesis reaction has been used to cleave alkenes. 15s Attachment via solution phase is used, then treatment with Grubb's reagent forms the cyclic alkene on the solid phase and releases the desired alkene into solution (Scheme 39).
(CY3P)2CI2Ru=CHPh R
Scheme 39
~-Elimination of a cysteine-derived linker 65 has been used to prepare dehydroalanines. 159 The sulfide is oxidized to the sulfone 66 with mCPBA, then elimination and release of the product is achieved using DBU in DCM (Scheme 40).
fS
R-N~f.R
mCPBA
R.
N S~~
R'
66
DBU .
R.
O
R'
H~
615
Scheme 40
7.4. Allyl For linkers that cleave to give an allyl functionality, see Section 8.3.
4878
I. W. James / Temhedmn 55 (i 999) 4854946
7.5. Ally1 Bromide 7.5.I. Acid Labile
-R
HBrlHOAc
Br-R
67 Scheme 41 Treatment of an ally1 alcohol attached to trityl resin 67 with anhydrous HEk in Ac0I-I results in release of the product as the bromide (Scheme 41).s8 Note that this is not a clean reaction, as removal of the acetate byproduct is required. 7.6. Amide 7.61. Acid Labile
B,& One of the most common linkers used to access primary amides is the Rink l&x.80*81 The nitrogen
of 25 can be acylated by a carboxylic acid using a range of acylating reagents such as DUDMAP achieved with 50% TFA/DCM, although lower concentrations (Scheme 42).*2
or
HOBt/BOP, although more forcing conditions may be required to prepare bulky amides. Cleavage is typically of TFA may be used, e.g. 2o%TFA/DCM
Scheme 42
riy b.,,
26
R. #
1 R
Scheme 43
I. W. James/Tetrahedron 55 (1999) 4855-4946
4879
The secondary amine derivative of the Rink linker 68 can be prepared either by amination of Rink chloride 2784 or reductive alkylation of the Rink amine 25 (Scheme 43). 87,160 Reactive reagents, such as the acid chlorides, are required for the acylation and the product is cleaved by 5%TFA/DCM to give the secondary amide. Synthesis examples for Rink amide linker: benzimidazoles, 161 1,4-benzodiazepine--2,5-diones, 162 benzofurans, 163 benzofurans via SmI2 radical cyclization, 164 dihydropyrimidines,g2 imidiazo[l,2-a]azines, 165 2imidazolidones, 166 indoles,163,167 isoxazoles,168,169 isoxazolidines, 170 isoxazolines, 169 2-oxindoles, 171 2oxopiperidines, 172 pyrazoles,S2,168,173 pyrazolines, 174 pyridinium salts, 175 pyrimidines,82 pyridines, 82 pyrroles, 176 tetrahydroimidazopyridines, 177 tetrahydroisoquinolines, 177 quinolines, 178 and 1,2,3,4tetrahydroquinoxalin-2-ones. 179 Sieber: The amine of the Sieber linker 69 is not as hindered as that of the Rink linker and is readily acylated (Scheme 44).180 The amide 70 is very acid labile, cleaving in 1% TFA/DCM. lsl The linker can also be used to prepare secondary amides. 182 The amine is reductively alkylated then acylated by a carboxylic acid using HATU/HOAt. Although 90% TFA was used for cleavage in this example, this was primarily to ensure complete removal of protecting groups and a significantly weaker acid such as 1-2% TFA should be sufficient.
I I
RCO2H HN ~I'R acylation " t ~ . O ~
1%TFA/DCM O " H2N~'R
69 l i) RCHO i~ NaBH4
7O O RCO2H R~'~N"~ R HATUHOAt" t ~ . O ~
R~-NH
TFA
O "R~NtU~RH
Scheme 44
Sasrin: The dialkoxy Sasrin linker has been modified to attach secondary amides. 183-185 The aldehyde 71 is reductively aminated with a primary amine, then acylation with either symmetrical anhydrides or acid chlorides gives the amide 72 (Scheme 45). Cleavage is achieved with 30% TFMDCM. This approach also has been used to link sulfonamides, ureas and carbamates. 183 The amine itself does not cleave in TFA, hence even if incomplete acylation (sulfonylation etc) occurs, only the desired amide (sulfonamide etc.) will be cleaved from the solid phase. Thus, the purity should remain high, although the yield may vary.
.
~/O~O
reduc'dve amination
O~C)
Me
ye
RCOCI O. ~ -0 R 5%TFA/DCM H ,
71
H
Scheme 45
72
4880
PAL: The trialkoxy PAL linkerlS6,187 can be used to generate primary amides 73 and is cleaved in 70-4TFA/DCM (Scheme 46). The related secondary amide linker has been developed by reductive amination of the aldehyde 74 then acylation (Scheme 47). 1$S,lS9 Cleavage of the secondary amide is achieved with 90,4 TFA. Synthetic examples: 1,4-benzodiazepine-2,5-dioneslS9and diketopiperazine.19o O Me O Me
R
acylation
"
"f 0
PALlinker
Me--o Scheme 46
Me..O 73
iMe reclucUve ~ ~,O..~,~O aminatlon9D~O

~,~,~.O Me..O H 74 Me...O
Me Me _O..,,,~ .~R ~ R'CO2H, O EDC lq,~R' 90%TFA R_I~,,~, R, ""R ~O

Me..O O Scheme 47
The Wang linker has been used for preparation of secondary amides.191 Preparation of the amide 22 from the aldehyde 75 is similar to that d~'~ribed above (Scheme 48). Cleavage is achieved using 97.5% TFA?I~S. Alternatively, the Wang bromide 76 can be aminated then acylated with acid chlorides to give 22. 61 Cleavage is achieved using 95%TFA/H20.
~ " O ~
reduclJve HATU O t or R'COCI R' 22 O 97.5%TFA H R' " R'N~ O
76 Scheme 48
Lewis acid (AICls or ZrCI4) catalyzed aminolysis of the Wang linker 4 with a secondary amine has been used to cleave secondary amide products (Scheme 49).77 Solid phase extraction w u necessary to remove the aluminum or zirconium residues.
HNR'R" R'"N,,~ R AIClaor ZtC,4

4 O Scheme 49 O
4881
Indole: An indole derived linker 77 can also be used for secondary amides. 192 The aldehyde 78 is reductiveiy aminated then acylated (Scheme 50). Cleavage is achieved with 50% TFA/DCM, with the cation formed on the solid phase stabilized by the indole group.
o =
R' 50%TFA/DCM O
R.~'-N.R
78
77
Scheme
50
Benzhydryi: The benzhydryl amine 79 and related p-methyibenzhydryl amine linkers are also used for the preparation of primary amides. Being significantly less electron rich than the alkoxy substituted linkers such as Rink and PAL, the strong acid HF is required for cleavage (Scheme 51) 193,194 Synthetic examples: cyclic ureas, 193 3,4-dihydro-2(1H)-quinolinones, 195 perbydro-l,4-diazepine~2,5diones, 194 and thiomorpholinones. 196
acylation,
Nh~
79
~ O N. R 7
HF = H2N.~X R
Scheme 51
B-Silvl Linker:
0 HN.~J~R H ~ T M S
O 8O
TFA/EDT/PhOH/PhOMe O 90:5:3:2 ="H2N~R
Scheme 52
As mentioned in Section 5, the carbocation formed on the solid phase may react with the molecule being cleaved. To reduce this, the l~-silyl linker 80 was prepared (Scheme 52), with [3-elimination of the trimethylsilyl group acting as an internal scavenger. 197 With an indole present in the molecule (tryptophan), the linker gave improved results over both the Sasrin and Rink linkers, although scavengers such as EDT, phenol and anisole were found to improve the yield of cleaved material greatly.
4882
L W. James/Tetrahedron 55 (1999) 4855--4946
7.6.2. Base Labile
The benzylic ester linker can be treated with an unhindered amine to cleave the product as an amide incorporating the amine used for cleavage (Scheme 53). Primary amides can be prepared by the aminolysis of the HMB $1198 and glycolamido 82199,200 linkers with the glycolamido linker being preferable for hindered compounds. 199 Similarly, treatment with a primary amine has been used to achieve secondary amides. Examples using the PAC ester g3201, the HMB ester 81, 202 and the Merrifield ester203,24 have also been reported. Typically an excess of amine is required, therefore the use of less volatile amines may introduce the need for a purification step.
j ""
O H ~ ' ~ "~O'~'R NH3 ~, I~ N ~ vapouror in MeOH H NJ~'R O 81 ~ R'NH-~ 2
NH 3 vapour
0 H "J~R N 0" "[~O

O 82
"-~
H ~N.,~O
O
~F~...O...J~. R ~,~
83
R,NH 2
O
= R'.N.~-. R ,.
R,NH ~ ~ r ~ 3 0 . ~ 2
Scheme 53 The thioether 84 was prepared as a safety catch linker, and activation by hydrogen peroxide oxidation of the thioether to the sulfone 85 followed by cleavage with a primary amine gives the amide (Scheme 54).205,206 Recent studies though have shown that oxidation of the thioether is not necessary for effective cleavage even when using limiting amounts of the amine.27 Excess amine in pyridine may be used to achieve more rapid cleavage, although solid phase extraction of the cleavage reagent is then required. 16 O
R' N.~I,. R
R'NH2
Scheme 54
Kaiser Linker; Kaiser's oxime linker 86 has been used to couple carboxyfic acids, which then may be cleaved with nucleophiles. For example, treatment with ammonia gives primary amides208,209 or with primary amines and anilines gives secondary amides (Scheme 55). 21 As above, the excess amine needs to removed from the cleaved product, which may be problematic if the amine is not volatile. Synthesis example: 1,2,3,4-tetrahydro-13-carbolines 211
4883
NO=
R'NH2
R," N ' , ~ R
O O
Scheme 55
7. 6.3. Photolabile
2-Nitrobenzyl amide linkers have been used as photolabile amide linkers (Scheme 56). As discussed in Section 3.3, the or-methyl derivative 87a gives superior cleavage kinetics compared with the non-methylated linker 87b.29,212 Although alkoxy substitution on the aromatic ring usually improves the cleavage step, linkers without the electron donating groups on the aromatic ring have been used successfully for both primary27,213,214 and secondary 215 amides. Cleavage is typically achieved using a 350 - 365nm fight source. O
350nm
0
>350nm 0 365nm
.
H2N,,,~ R "
%"
87a Y = Me bY=H
Scheme 56
7.6.4. Other
A linker has been developed to give tertiary amides upon cleavage (Scheme 57). 216 A secondary amine is attached to the Wang linker. Treatment with an acid chloride acylates the tertiary amine 88 which is cleaved fi'om the solid phase to give the tertiary amide, probably via a mechanism involving the chloride ion. The excess acylating agent is removed using aminomethyl polystyrene.
R"COCl R'
V~L"--/N" R /
88
,+1
II
0
R"
cr-~o"J~R"J
R" .,u,,.N" I R
Scheme 57
4884
I.W. James / Tetrahedron 55 (1999) 4855--4946
7.7. Amidine
The PAC linker 89 has been convened to the amidoxime 90 via the p-nitrophenylcarbonate 91 (Scheme
---58). 74,217Cleavageis achievedwith either50%TFAand 5%H20in DCM or 95%TFA/H20. H o l/j~,"'~ OH C,-~'.O_.~.NO2 PY ~ H~O~:"~'O O NH I~.003or TEA NH H2N'~'-Ar 50%TFA O f,,~"~/NO2 ~"J~J
( ~ N O~ O ~ 89
tr"Co
Scheme 58 7.8. Amine 7.8.1. Acid Labile
There are two main routes to attach an amine to solid phase so that it may be cleaved using acid. The first involves attachment directly to a linker, such as the 2-cldorotrityl or Rink derived linker, which can be cleaved with TFA. The second involves attachment of the amine through a carbamate to linkers originally developed to attach carboxylic acid. The linker is cleaved using similar conditions to those used to cleave the carboxylic acid. When TFA is used in the cleavage reaction, the products are generally isolated as the TFA salts.
~
~"~ ~
CI RNH2
31 o.Me ~,, l~o'Me

NH 5%TFA
50-95%TFA
" H2N-R
95%TFA
OA%..~
"
Scheme 59
!. W. James/Tetrahedron 55 (1999) 4855--4946
4885
Direct Attachment: Amines are attached to the 2-chiorotrityl linker 31 either using only a slight excess of the amine with DIEA in DMF 218 or by using a large excess of the amine and no other base (Scheme 59).219,220 Cleavage is achieved with 50-95%TFA/DCM. As has already been illustrated in the preparation of secondary amides, the Rink linker has been derivatized as an amine linker 68 either by amination of the Rink chloride ~ or by reductive alkylation of the Rink amine. The linker is cleaved with 5% TFA/DCM. The PhFl linker 92, based on the 9-phenylfluoren-9-yl protecting group, has recently reported.221, 222 This linker is more acid stable than either the 2-chlorotrityl or Rink derived linkers, requiring 95% TFA/H20 for cleavage. Amines have been directly attached to the PAL and Rink linkers in the synthesis of 1,4-dihydropyridines (Scheme 60). 223 Cleavage is achieved with 95% TFA/DCM for the PAL linker and 3% TFA/DCM for the Rink linker. These amines are in conjugation with an ester and this may render them more acid labile than unconjugated amines.
~ R20~ "0
~" Rink or PALlinker R! I ~"~" Ar " O~
Ar 0
Scheme 60
Carbarnate Attachment: A number of linkers initially used to attach carboxylic acids have been adapted to attach amines in the form of a carbamate. Cleavage involves initial release of the N-substituted carbamate then decarboxylation. The conditions for cleavage of the carbamate amine linker are usually similar to those used to release the carboxylic acid. The carbamate of the Wang linker, 24, is formed via either the chloroformate,68 the imidazolide carbamate,68 or the p-nitrophenylcarbonate (Scheme 61). 69,224-226 Typically, cleavage to give the amine is achieved with 50% TFA/DCM. Treatment with LiAl_I-hwill also cleave the linker to give the methyl amine. 71 Successful use of mCPBA has been reported when using the Wang linker,227 although in another instance unwanted cleavage was reported using similar conditions. 59 Synthesis triazoles, 231 O O examples: benzoxazoles,228 2,3-dihydrothiazoles, 229 thiofurans, 230 thiophenes, 229 and
Q o ~ O H
.~....v....~o1J~y RNH2=. Y =p-NO2-CeH4-, CI Im,

Scheme 61
.~...........~.O..,U~N.R TFA/DCM 50%
The PAC linker has been similarly derivatized for the attachment of amines. 232,233 Cleavage is achieved using 75-92% TFA with scavengers. Hydroxymethylpolystyrene has also been adapted for the attachment of anilinesTM with I-IF being required for cleavage.
4886
L W. James / Tetrahedmn 55 (1999) 4855--4946
Derivatization oftbe hindered handle 9 has also been used. 235,236 The linker is prepared via either thepnitrophenyicarbonate or the imidazolide cerbamate 93, which requires alkylation with methyl Uff]ate prior to 136 treatment with an amine for efficient formation of the carbamate 94 (Scheme 62). 235 10-20% TFA/DCM is required for cleavage. The steric hindrance of the dimethyl substituent would reduce the probability of nucleophilic attack on the carbamate that leads to undesired cleavage.
~ O H
9
CD, . ~ O DMAP
~,/~. N N..~. Y O
93
1) MeOTf 2) TEA
oyN-%
I RR'NH R' I
94
R' I
H.N.R q
10%TFA
Scheme 62
7. 8. 2. Base Labile
Carbamate Attachment: The carbamate linker approach has also been applied to hydroxymethylpolystyrene to prepare pyfidyl derivatives (Scheme 63).237,238 The chloroformate 95 is treated with pyridine to form the reactive acylium complex 96, which is immediately treated with a Grignard reagent. If any of the acylium complex does not react in the second step, it is cleaved from the product in the acidic work up used, leaving only the cyclic amine attached to the solid phase 97. The linker itself is cleaved with NaOMe in MeOH, although it would also be labile to I-IF treatment as described above.
O CI N ~ O M e ~
O A Jl + A
I~oMe 96
RMgX, O+3 THFI.1 then
O~.N
R 97
~O NaOMe/MeOH,=
R
Labileto 1-13 O+
Scheme 63
Stableto H30+
The carbamate linker 98 has been developed and it is fluoride labile (Scheme 64). 133 Either TBAF in DMF at 60C or CsF in DMT at 90C can be used for cleavage.
OH 1) CDI,py 2) RNH2,PY
MS
O..~ON. R TBAF, DMF,60C t. R-NH2 or CsF, DMF,90"C

98 MS
Scheme 64
4887
Hofrnann Elimination Linkers: A suite of amine linkers has been developed based around Michael addition and Hofmann elimination. Michael addition of a secondary amine to an acrylate ester 99 on the solid phase is used as the attachment process (Scheme 65).22, 23 The cleavage involves a 2 step process. The tertiary amine 100 is treated with an active alkyl halide (e.g. benzyl or allyl bromide) to form the quaternary ammonium salt 10, which is then eliminated using DIEA in either DMF or D C M This Hofmann elimination releases the tertiary amine and reforms the acrylate ester on the solid phase, which may be recycled. Aqueous work up is used to help purify the products. Alternatively, the cleavage may be performed using either Ambedite IRA-95 ion exchange resin or Rink resin in DMF. 239 The basic resin is sufficient to achieve cleavage and avoids the need for aqueous work up. This surprising two resin result may be explained by thermal elimination of the amine as the hydrobromide salt. The basic resin then frees the amine to catalyze the 13-elimination. Alternatively, it may also be due to trace base, either present in the solid phase from previous steps, or as trace dimethylamine in the DMF. O
HNR'R".
e
O~
100 R"
R"X.
O/""/"~ I~I'+, DIEA R"N'R "R''

10 I~" R
99
Scheme 65
The sulfone derivative has also been explored24, 25 with similar attachment and cleavage methods being used. It has been reported to be much more stable than the acrylate derivative to nucleophiles such as PhMgBr. 7.8.3. Reductive Cleavage The Wang derived carbamate linker 24 may be reduced with LiAlFh in refluxing THF to form the methyl amines (Scheme 66). 71 Aqueous workup and solid phase extraction are used to remove aluminum salts.
~~
7. 8. 4. Pd Catolyzed Cleavage
"~-O~-HN. R
24
LiAII"I4
Me.N.R H
Scheme 66
Carbamate methodology has also been used to attach amines to an allyl linker. 70 The carbamate 101 is formed using the p-nitrophenylcarbonate method, and cleavage is achieved using palladium-catalyzed allyl transfer (Scheme 67). Purification is necessary to remove the cleavage reagents.
4888
L W. James / Tetrahedron 55 ( ! 999) 4855--4946
c,~o~
OH
0 'K,#K O N2 Me0 Me DCM

(Ph3P)2PdCI2, Bu3SnH DCM, DMSO, AcOH
DCM
H2N-R
H2NR, DIEA
O'.~N- R
'10'1 O
Scheme 67 Conversely, solid phase bound allyl esters 102 may be cleaved as the allyi amine (Scheme 68). 240 Both secondary and tertiary amines have been prepared this way.
R R
0
-qF~ O ~ . ~ ~102
v~
Pd(PPh3)4 NHR'R" " R' R , . - N ~ f -.~
Y -O
O
Scheme 68
7.8. 5. Enzymatic Cleavage
The carbamate linker 103 can be cleaved using lipase RB 001-05 in 50mM MES buffer/methanol (80/20) at pH 5.8 at 40C to release the amine (Scheme 69). 140 (See also Section 7.1.6.)'
0 OAc lipase RB 001-05 0 i,
~['~0"'/~ HN'~
~..'OUN. R 50mMMESpHbUffer/MeOH5.8, L.. 4(PC (80/20) 1-12N-R t03 H

Scheme 69
7.8.6. Others
Merrifield Amine: Secondary ~ n e s have been cleaved from Merrifield re~in as the HCI salts using ctchloroethyl chloroformate (Scheme 70). 241 Heating in MeOH is required to decompose the cm~o~nate intermediate 104 that is the initial cleavage product. All of the by-products are volatile, so high purity products can be achieved aRer evaporation. The use of heating, though achievable, does increase the complexity of the cleavage step if large numbers of individual compounds are being prepared.
4889
Me'T'OyCI CI NHR'R" NMP, 50C=
~ N "
RII
Cl 0
F
.
Cl"
~0~ "
H.N.R,
R"
,I
MeOH, 50"C
1
,
-CO2
R,.NyO...F..Me
O
104
.CH3CH(OMe)2 Scheme 70
Cl
Formamidine Linker Transamination can be used to attach secondary amines to fotmamidines on the solid phase (Scheme 71).242,243 Cleavage is achieved using hydrazine and acetic acid in ethanol at 60C Aqueous work up is used to remove excess cleavage reagents. As above, the use of heat during the cleavage step adds to its complexity. LiAlI-h, KOH in MeOH or ZnCh in EtOH are also reported as cleavage reagents.
N.-....,,N.Me
Me
HNR'R" a O
N.-.....,N.R,
R"
H4N2, AcOH H.N.R'

,-
Scheme 71 Dimedon Linker: Attachment via solution phase is used to attach amines to a linker derived from aoetyldimedone (Scheme 72). 244 The linker 105 is stable to bases such as piperidine and DBU and to acidic conditions, however, it is cleaved rapidly with 2% hydrazine in DMF. The related linker 106 is prepared in a similar manner and cleaved with 5% hydrazine in 50% THF/H~O.245 o
HO acyiation
o
.
.N.
J~
.N. R
'qw
N
105
O
-R
JN / \
Scheme 72 7.9. Aminosulfonylurea Attachment to the Wang linker using the carbamate method used to attach amines has also been used for the aminosulfonyl moiety (Scheme 73). 73 The linker 107 would probably be acid labile giving the aminosulfonamide a~er decarboxylation, but in the reported example it is used to prepare the aminosuffonylurea by treatment with a primary or secondary amine in refluxing THF, The amine used for cleavage is the limiting reagent and is mostly consumed in the reaction, hence giving high purity products following evaporation of the cleavage solution(s)
4890
OCN~..Cl ,sj
o o
0 O0
HNRIR DCM,RT R2 -v H ! R4"N~'~N-S~ "N'RI " O OO

R3
HNR3R 4 THF reflux
trY
o . "/K"..~'K',.I,..rF. N.RI N:s~.

1070
OO
Scheme 73 7.10. Aniline

7.10. L Acid Labile
A derivative of the PAL linker has been used to attach anilines to the solid phase. 246 The aniline is attached by reductive amination of the aldehyde 74 and cleavage is achieved with 90%TFA/5%Me2S/5%H20 (Scheme 74). The chloride 27 has been used as a means of attaching anilines to the Rink84 and PhFI linkers. 221,222 Cleavage is achieved using 5% TFA/DCM and 20% TFA in 9:1 DCM/MeOH respectively.
O
N~J~.O~
74
Me )
H2 NAt , , t ~ . N . ~ ? MetO
Me --R ~ 90%TFA
Me/O O"Me
.,.,,~~ O "
Me ArNH2.DIEA.
~ ' ~ O " Me 5%TFA/DCM
/ ~
,"
PhFIlinker
Scheme 74 Hydroxymethylpolystyrenehas been adapted for the attachment of anilines using the carbamate method. 234 The carbamate is prepared via the chloroformate and HF is used for cleavage.
L W. James / Tetrahedron 55 (1999)4855--4946
4891
7.10.2. Base Labile
A safety catch version of the carbamate linker has been used to attach anilines.247 The linker I N is activated by oxidation of the thioether to the sulfone, 109, with mCPBA (Scheme 75). Treatment with NH4OH cleaves the product either by J3-elimination and decarboxylation or by direct attack of the hydroxide on the carbamate. H
x,. ~-~ ~ O H H j~/ "~ "S '/ ~j ArNCO . NO~ ~ dibutyffindilaurate
I mCPBA
I"IzN'~__R
NI"~OH
~,,~-~j~iS..~,...~O .N. A
I.
6;,o
Scheme 75 7.11. Aromatic Group
A number of traceless linkers have been designed which give aromatic groups on cleavage See Section
8.1.
7.12. Aryl Bromide Electrophilic bromination with Brz/pyridine may be used to cleave the aryl silane linker 110, which was developed as a traceless aromatic linker. The product is the aryl bromide (Scheme 76). 245 Awl germanium linkers may also be cleaved to give the aryl bromide. 30
~-.,~0~-~ 0/~- Si~'-- R

S O ~,J 110
Scheme 76
Br2/PY Br
M; "Me
-~-/-, R
7.13. Aryl Iodide Aryl triazines 111 have been cleaved with MeI at 110C to form the aryl iodide (Scheme 77). 249,250 The excess alkylating agent would have to be removed prior to screening
~N.N~N.A r
111
Me1110C ~" I--At
Scheme 77
4892
The aryl silane linkers 110, 112, developed as traceless aromatic linkers, may be cleaved by electrophilic iodination using ICI to obtain the aryl iodide (Scheme 78). 248,251
~OAO~Si
~ 0 ~.,~..~J
~ - ~' - R Me Me
ICI "l
~,~
R-'
ICl I ~ . / N ~ S i ~
Me, Me
I~'R
110
Scheme 78
1t2
7.14. Carbamate
7.14.1. Acid Labile
The Sasrin linker 183 and the indole linker 192 have been modified for the preparation of carbamates. For both, the solid phase aldehyde is reductively aminated, and treated with a chloroformate to form the carbamate (Scheme 79). Cleavage from the Sasrin linker 113 is achieved with 5% TFA/DCM, whereas 5 0 e TFA/DCM is required for cleavage from the indole linker 114.
Me _ O..i:...0
Me
reductive amination
R'OCOCI
.,
7t
'/%/_-)'-,~N,.~,O-R. t13 O
OyO'R'
5%TFA/DCM
50% TFNDCM R HN.,~O.R,
0
78
t t4
Scheme 79
7.15. Carboxyli Acid

7.15.1. Acid Labile
The carboxylic acid group of a given alkoxybenzyl linker is more acid labile than the corresponding amide derivative. For example, cleavage of a carboxylic acid from the Rink linker is reported to require as low as 10% AcOH/DCM whereas 5-50% TFA/DCM typically is used for an amide.80 The monoalkoxy benzyl linker, the Wang linker 4,49 which is cleaved with 50% TFA/DCM, is more frequently used than the Rink linker for carboxylic acids. Other acid labile linkers used to attach carboxylic acids are the PAC ester 83, cleaved with 95% TFA,198,252 the dialkoxy benzyl Sasrin linker 5,253*255 and 1155o both of which are cleaved with 1-3%
1. W. James / Tetrahedron 55 (1999) 4855-4946
4893
TFA/DCM (Figure 4). The trialkoxy benzyl HAL linker 116 requires only 0.05-0.1% TFA or 10% AcOH. 256 The benzylic ester with no alkoxy group 3, usually derived from chloromethyl- or hydroxymethyipolystyrene, and frequently referred to as the Merrifield linker, is significantly more acid stabile. It can withstand high concentrations of TFA and requires the use of HF,~I, 52 HBr/AcOH/TFA, 257 or HBr/TFA25S,259to cleave the desired compound. AICI3 in DCM/MeNO2260 may also be used, although removal of the aluminum salts is not as simple as removal of the other cleavage reagents which are removed by evaporation. The PAM linker 114 is slightly more stable to acid than the Merrifield linker 3 but is also readily cleaved with HF. 261 In all cases, ester formation to attach the carboxylic acid is typically achieved with DIC/DMAP, or using the acid chloride and base, although the other methods described below for the base labile linkers may also be used. As with all esters, these linkers are not only acid labile, but may also be cleaved by nudeophilic attack on the ester, hence undesired cleavage may occur if unhindered nudeophiles for example, NaOMe, 53 are used in the synthesis. Prolonged treatment with (Bu3Sn)20 has been reported to cleave the Wang and PAM linkers to release the acids. 262 The PAM linker is also labile to TBAF.3H20. 263
o
'
3
hydmxymethyl polystyrene HF O
114
PAM linker HF
4
Wang linker 50% TFAK)CM O
$
Sasdn linker 1-3% TFAJDCM
83
PAC linker 95% TFAK)CM
115
1-3% TFMDCM
~XN-~O-.
H
4 ~
~/OT
~
9
OyR O
116 HAL linker 0.05-0.1% TFA/DCM
O.Me
Hindered handle 95% TFA/DCM
Figure 4
The t-butyl based hindered handle 9264 is cleaved by 95% TFA, but it is sterically hindered and hence resistant to nucleophilic attack and unwanted cleavage. The esterification to attach the first residue requires forcing conditions, such as the use of the acid chloride.
4894
L W. James / Tetrahedron 55 (I999) 4855-4946
RCO2HDIEA ~'~"~:O
10-20% AcOH 10-20% AcOH O 20% TFA
HO~R ~
118
10-20% ACOH
PhFI linker
119
Scheme 80
When using trityl linkers to attach carboxylic acids, the 2-chlorotrityi linker 117 is used instead of the unsuhstituted trityl linker as the latter is generally too labile. Attachment is performed using DIEA and cleavage is achieved using 1:1:8 AcOH/trifluoroethanol/DCM, 265-265 5% TFA/DCM, 269 or 2:1:7 AcOH/TFA/I~M (Scheme 80). 270 The chloride of the 2-chlorotrityl linker 31 is highly reactive and, unlike most linkers where excess of the acid being attached is used, effective loading can be achieved even when limited amounts of the acid are used. This technique has been used in the synthesis of TaxolTM derivatives to limit the use of the expensive baccatin-III derivative. 270 The 2-fluorotrityl 118271 and the 4-(carboxamide)trityl 119 linkers272 can be used in a similar manner to the 2-chiorotrityl linker. The PhFI linker 120, based on the 9-phenylfluoren-9-yl protecting group, is more stable than the 2-chlorotrityl linker. 221,222 It is stable to AcOH, but it is cleaved with 20% TFA in 9:1 DCM/MeOH. Synthetic examples using the Wang tinker: benzimidazolones,273 benzopiperazinones,274 1,3-benzoaxazine-2-ones,275 coumarins, 276 yciopentenones,277 cyclopropanes,278 dihydropyrimidin~ 279 3,4-dihydroquinazolinas, 280 imidazoles,281, 282 indoles, 283 isoxazolines, 284 pyridines,254 pyridopyrimidines,254 quinazolinones, 285 quinolones, 286 tetrahydro-[3-carbolines,287 and tetrahydroquinolines. 288,289 Hydroxymethylpolystyrene derived (Merrilield) linker: dihydro- and tetrabydro-I~-carbolines51 and indazoles.257 Sasrin linker: ~,lactl~ms,290,291 pyrrolidines,292 2,4-diones, 293 and ~-sultams. 294 PAC linker: pyrazoles295 and tropanes. 296 2 -Chlorotrityi linker: isoxazolidines 17o pyridines,254 pyridopyrimidines,254 quinazolin~
4895
7.15.2. Base Labile
Solid phase bound esters may be cleaved by hydrolysis to give carboxylic acids. The acid can be attached to the solid phase hound alcohol using Mitsunobu conditions,297,298 or by means of the acid chloride 299 or anhydride (Scheme 81). 198 An alternative method for the attachment is displacement of the solid phase alkyl bromide or chloride with the cesium salt of the acid. 300 A range of esters have been used as base labile carboxylic acid linkers, including (with cleavage conditions in brackets): the ester of hydroxymethylpolystyrene or Merrifield linker 3 (0.85M Bu4NOH in THF,299,301 LiOH in 5:2:1 THF/IVIeOH/H20,302 K2C03 in MeOH301,303), the hydroxymethylbenzylamide or lIMB linker 81 (0.1M aqueous NaOH), 21 the glycolamido linker 82 (NaOH in 70% iPrOH/water),3 and 121 (3% 1M aqueous NaOH/PrOH at 50C) (Figure 5). 297,298 The oarboxylic acid is released as the salt and can be neutralized by treatment with a volatile acid.
~,~Br
tl.jOyR
O
1) base HO..y.R II 2) I-~ O
Scheme 81
~ O ~ . . R Merrifield linker 0.85M Bu4NOHin THF

3
I
81
O...~ R
O
HUB 0,1M NaOH (aq.)
O 121 PS-PEG-OH 3% 1M aq. NaOH in iPrOH at 50C

Figure 5
82
glycolamido 0.01M NaOH in 70% iPrOH/H20
Thioesters can be prepared on the solid phase by acylation of the thiol 122 with the acid chloride (Scheme 82). 153 Treatment with 20% 1M aqueous NaOH in dioxane releases the product acid.
S H
t22
RCOCI ~ D _ _ ~
0 1) 0.2M NaOH. 0 S~ " R 2) H HO" ~ R
Scheme 82
4896
!. W. James I Tetrahedron 55 (1999) 4855-4946
N-Acylated chiral oxazolidinones 123 have been used as a base labile acid linkers.304-307 The acid is attached using either the anhydride34,307 or the acid chloride (Scheme 83). 305,306 On completion of the synthesis, the acid is cleaved from the solid phase by treatment with LiOH in 75% THF/H20. This process also
regenerates the chiralauxiliary/linker.

0
; (RCO)20, DMAP, TEA or BuLl then RCOCl "
O
UOH in 75%THF/I-~O O HO'~R
O~L-~-/N'J~'R
Scheme 83
A fluorene derived linker 124 has been developed with cleavage achieved by morpholine or piperdine in DMF (Scheme 84).308,309
DIC, DMAP
HO" ~ R
M
124 Scheme 84 A fluoride labile, silicon derived linker 126 has been developed. 133 Carboxylic acids are coupled to the alcohol 126 with DIC/DMAP (Scheme 85). Cleavage is achieved via 1,6-dimmation using either TBAF in DMF at 65C or CsF in DMF at 90C Further work up would be required after cleavage to remove the fluoride salts.
The related linkers 12731o and 128311 have also been reported. Attachment of the acid is via solution phase and cleavage is achieved with TBAF in DMF. Linker 127 is also labile to I% TFA/DCM.
O I _C I O =" I II R ...._ TBAF DMF 65(3 TBAF D M F /
~. A
~
.TM$ "
C~/~R
or 1% TFA/DCM
127
Scheme 85
4897
Carboxylic acids are attached to silyl linker 129 via solution phase.312 The linker is labile to both 50% TFA in I)CM and TBAF (Scheme 86). Apart from the desired carboxylic acid, this linker also releases the quinone methide 130, which is scavenged by thiophenol in the cleavage solution. The final product has to be
purified from this by-product.

O
.H.
tBu Ph I ~ " ~ ~OAR H A :Si' ~ ~1

129 Scheme 86
TBAF .
O HO~R.. + ~"~/=--O
7.15. 3. Photolabile
The 2-nitrobenzyl 131,26,313 -methyl-nitrobenzyl 132,314 2-nitrobenzhydryl 133,315 and 4,5-dialkoxy-2nitrobenzyl 13420,29,316 photolabile linkers have all been used to attach carboxylic acids (Scheme 87). Cleavage is performed by irradiation at 350-365nm. Synthesis examples: I~-lactams291 and J~-sultams.294
o
~ H
~-~'~"~Br
N'~'~k-NO l O
. R RCO2H' i ~ " i N H~ ~ O ~ " N 2 ~ TEA J O O131 O RCO2H, DCC ~ ~

133
O...~.R 132Me O X ~ J 350nm m 3 5 0 "
O " HOWl..R
Me Me...O~,~OH ~..-~OA~...~NO2
7.15. 4. Oxidative Cleavage
Me O RCO2H Me..O,~A~O.~ R DIC,HOBT, ~ ~OA~J~.NO 2 DMAI 134

Scheme 87
3~~Snm
The phenyl hydrazide 135 has been used as an oxidatively labile linker for carboxylic acids.31"#The add is coupled to the hydrazine 136 using DIC/HOBt (Scheme 88). Cleavage is achieved using copper(lI) and oxygen.
~S~.
o,, p
N z C zDIC, HR O H HOBT~ . . S . ~ ,
13S
Scheme 88
op
C ( O )O uS 4, 2 O N.NH R py, DIVlF, D HO'~R ACOH, H20

H O
4898
L W. James/ Tetrahedron 55 (1999)4855--4946
Z 15.5. Reductive Cleavage
Esters attached to hydroxymethylpolystyrene may be cleaved by palladium catalyzed hydrogenation (Scheme 89).318,319 Treatment with Pd(OAc)2 in DMF at 40C under 4 atmospheres of hydrogen may be used. 318,319 Alternatively cyclohexene may be used as the hydrogen source with the cleavage performed at 70oC.320
~
H
O~'-R
Pd(OAc)2, DMF, H2, 40'C or Pd(OAc)2, ~ ,

Scheme 89
O =' HO.JI,. R
DMF, 70C
One of the few linkers based on metal complexes involves the use of the cobalt(m) to attach acids (Scheme 90).321 The complex with either bis(ethylene diamine) or tetraammonia ligands and the carboxyfic acid is prepared in solution then attached to the solid phase. Cleavage is achieved using DDT and DIEA in DMF. The cobalt-sulfide by-product is removed by precipitation and the excess DDT is removed by extraction. L,4 O .~x-..."X'HN'CO-o/~LR
DDT, DIEA, DMF O
L4 = (HzNCH=CH2NH2)2 or (NH3)4
Scheme 90
7.15.6. I'd Catalyzed Cleavage 0 0
~.N ~ B r
L
H-'3 137
DMF/DM7 PdCI2(PPh3) 2 O HO'J~R
138
139
Bu3SnH
Scheme 91
4899
Linkers based on palladium catalyzed allyl transfer have been used to attach carboxylic acids (Scheme 91). 322-324 Attachment of the carboxylic acid to give 137 is performed in solution phase and cleavage is achieved using Pd(PPI~)4 and morpholine in 50% DMF/DMSO. Purification is required to separate the desired product from the palladium catalyst. This ethylene glycol linker was found to be more stable to nucleophilic conditions such as secondary amines than the initially developed crotonyl derived linker 138.325 Usin8 a similar approach, linker 139 is cleaved with PdCI2(PPh2)2 and Bu3SnI-I,326 or Pd(PPh3)4 and morpholine in 2:2:1 THF/DMSO/0.5M HCI.327
7.15. 7. Enzymatic Cleavage
The ester linker 140 can be cleaved using lipase RB 001-05 in 50mM MES buffer/methanol (60/40) at pH 5.8 at 30C to release the acid (Scheme 92). 140 Tetrahydro-[3-carbolines have been prepared using this linker. (See also Section 7.1.6.)
O OAc
lipase RB 001-05
D
50raM MES buffer/MeOH (60140) 140 ~O~R
pH5.8,30"C
Scheme 92 7.16. Carboxylic Ester 7. ! 6. I. Base Labile
The ester based linkers used to attach carboxylic acids to the solid phase may be deavedby saponification with an alkoxide to release the product as the ester (Scheme 93). Published examples of this reaction are mainly restricted to formation of the methyl ester. The Merrifield linker 3 is cleaved with MeOH and TEA or NMM24,328 or with NaOMe in THF at reflux.329,330 The HMB linker 81 is cleaved with 9(FA MeOH/TEA at 50C331,332 and the Wang linker 4 with NaOMe, 53 TEA/MeOH/KCN, 54 or LiBr/DBU/MeOH. 333 The PAM linker 114 is also cleaved with LiBr/DBU/MeOH.333,334 Synthesis examples: dihydropyrans 329 indoles,331,332 and tetrahydro-1,4-benzodiazepine*2-ones. 53
O
o
MeOH~E.A ~ "
o
MeOH/TEA
Scheme 93
4900
A solid phase bound N-acylated chiral oxazolidinone 123 has been used as a base labile carboxylic ester linker (Scheme 94). 305,307 Cleavage with NaOMe/THF305 or lithium benzyioxide generates the methyl ester or the benzyl ester respectively. This process regenerates the chiral auxiliary/linker.
O~NAR
LiOBn or NaOMe
mr
I I
XO"u" R X = Bn, Me
Scheme 94
7.17. Diol
7.17.1. Acid Labile
The 5-membered cyclic ketal 141 has been used as a linker for 1,2-diols. Attachment via solution phase can be used and cleavage achieved using 95% TFA/water (Scheme 94). 102
HO'~'IF ~
" " . Ho H-toO.

R R'
O,C.HOB, Q ' O
R' 141
9~'rFA.-~O
HO OH "R) ~,
Scheme 95 Alternatively, 1,2-335,336 and 1,3-diols 337 can be attached using pTsOH directly to a solid phase bound benzaldehyde 142 (Scheme 96). The 1,2-diols are cleaved with 1% AcCI/MeOH or 1% TFA in 80% AcOH/H20 whereas the 1,3-diols required 90% TFA/water.
RI
H O
142
HO .
In
R'
. .
R' or 90% TFA/H~C)=' HO-'~ ) n n = 0,1

R
pTsOH,-HzO
n = 0,1
)n
R
Scheme 96
Solid phase bound boronic acids 143 can also be used to attach 1,2- and 1,3-diols338 using azeotropic removal o f the water (Scheme 97). The linker 144 is water sensitive and cleavage is achieved using 20%
HzO/MeCN.
R*
HoHO~ )n
O
R'
,
R' H In
R
H 143
"1-120
144 R n = 0,1
n=0,1
Scheme 97
I. W. James/Tetrahedron 55 (1999) 4855-4946
4901
7.18. Furan For a linker which cleaves to give a furan, see Section 8.6.
7.19. Guanidine 7.19. I. Acid Labile
The acid labile guanidine linker 145 is prepared using the attachment via solution method (Scheme 98). 339 The linker is stable to at least 20% TFA in DCM, but is cleaved by triflic acid in TFA at 40C. The Wang linker has also been modified to attach guanidines (Scheme 99). 340 The imidazole carbamate 146, derived from the Wang linker, is converted to the thiourea derivative 147, which is then protected and treated with an amine to form the solid phase hound guanidine. Cleavage using 49/0 TFA in DCM gives the unprotected guanidine.
0 R R
~" N 2 H
R R ~ IO1 , I O , IF"N"'~"v'O"~/"~HNH ~'NH II I DIC, o t HB O q'~'L~',S~ N 145 o O

e-..~-S:N
IR
TfOH,TFA,40'~., HN..~.,I~IH N H
Scheme 98
'
148 0
i~ (aoc)20
"
'/IL"'~K'~O'~" N'~ N'BOC 0 S

RR'NH,TEA
R'N'R
, -
TFArrlPS/DCM j O . . . ] ~
- .
H H
NyN.Bo c
H2"I~NH2
Scheme 99
O 147 R"N'R'
An indole derived linker 148 has also been used for guanidines. 192 The aldehyde 78 is reductively aminated then treated with BOC protected thiourea (Scheme 100). Cleavage to give the unprotected guanidine is achieved with 50% TFA/DCM,
0 ~ ,, ~
BOCN~"/'"NHBOC ~ N N,R NH 50%TFA/DCM,. H2N~LN.R..
78 H
148
Scheme 100
4902
7.19.2. Base Labile
The thiopseudourea 149 has been used as a base labile guanidine linker.341 It is prepared from chloromethylpolystyrene using thiourea, protected with (BOC)20 then alkylated using Mitmnobu chemistry (Scheme 101). Cleavage is achieved using a primary amine in DMF at 50C. The BOC protecting groups can be removed after cleavage by treatment with TFA.
""~CI SC(NH2)2 ,.
'OMF, 7S.c
50
sI~" H N2
~IIH .HCI
NBOC
s
149
O ~
R'NH2
NBOC
Scheme 101
7.20. Hydroxamic Acid

7. 20.1. Acid Labile
~
30X
remove ~ t
..~-
3, x:c,
Linker gN-prot
-"
pr~ecllng group = O L i n k e r _ o , NH2
X /"~HONH-prot [ ~ . , ~ O H / P P h 3,DEAD
4X=H $ X OMe
l acylatlon
Q_unker_o. -<
Me'O . acylatlon . ~ O ~"~O
150
~'O '1~
Me" O ~~O Mel
N-O
~O N R
.e'
2.5%TFA 1%H2OInDCMHO.N~1~R O = H
Scheme 102
A range of acid labile hydroxamic acid linkers have recently been published. Typically, the nitrogen of hydroxylamine is protected with either the Fmoc group342 or as the phthalimide.293,343-345 The protected hydroxylamine can be attached through the oxygen to the trityl 30344 or 2-chiorotrityl 31 linkers342 by displacement of the halide or mesylate, or to the Sasrin 5293 or Wang 4343,345 linkers using the Mitsunobu reaction (Scheme 102). The protecting group is removed either with piperdine for the Fmoc group, or hydrazine for the phthalimide, and the nitrogen acylated with standard conditions, e.g. DIC, HOBt. The linkers are cleaved with acid: trityl, 25% formic acid; 2-chlorotrityl, 5% TFA/DCM; Sasrin, 1% TFA/DCM; and Wang,
I. W. James I Tetrahedron 55 (I 999) 4855-4946
4903
70%TFA/DCM The nitrogen of the hydroxymate is very nucleophilic and, for relatively unhindered tinkers such as that derived from Sasrin, may participate in side-reactions. The bulk of the trityl group can hinder the reactive nitrogen, reducing these unwanted reactions. An alternative approach involves the trialkoxy benzyl PAL linker.346 The hydroxylamine is O-protected with a THP group and attached through the nitrogen (Scheme 102). The nitrogen is then acylated with either the acid chloride or the symmetrical anhydride. The tertiary nitrogen formed in 150 is unlikely to be involved in sidereactions. The THP protecting group is removed during cleavage with 2.5% TFA and 1% H20 in DCM releasing the deprotected hydroxamic acid. The Rink linker has been used to prepare N-substituted hydroxamic acids. Rink chloride 27 is treated with N-Fmoc-N-alkyl hydroxylamine and DIEA, deprotected then acylated with an acid (Scheme 103). On the completion of synthesis, cleavage is achieved with 90%TFA at 30C. 85
Fmoc DIEA
i ~ O ~ O . M e Fmoc--N.O O-Me
R 1) pipeddine 2) acylation
27
CI O.Me
r ' O ~ O HO.NIU-.R, I R 90%TFA

R.N.O
O"Me
O.Me
R'"]%O 29
Scheme 103
7.20.2. Base Labile
Treatment of Kaiser's base labile oxime linker 86 with tert-butyldimethylsilyl O-protected hydroxylamine in DCE cleaves the product as the protected hydroxamic acid (Scheme 104).347 The protecting group can be removed by treatment with TFA.
O,~R N,, 0
TBDMSONI"I2 0 TBDMSO~ ~ R N DCE,83"C H TFA " HO'N H R
Scheme 104 7.21. Iodide
The sulfonate ester 151 has been used to attach compounds through an alcohol resulting in the iodide after cleavage 34s The solid phase sulfonyl chloride 152 is prepared from the sulfonic acid 153 using SO2C12then the alcohol is attached using TEA as the base (Scheme 105) 349 Alternatively, attachment via solution phase can be
4904
L W. James /Tetrahedron 55 (1999) 4855--4946
used. 348 Cleavage to give the iodide is achieved via nucleophilic displacement using NaI. This linker could be used to give other functionalities if treated with suitable nucleophiles, such as NaOAc or NAN3. It has also been used as a traceless linker using intramolecular attack by a carbon nucleophile.348
~ , ; H 183
SO2CI2, PPh3
d~I.~s.CI
ROH, TEA
~tSfoO. tl;1
Nal
~ o
152
Scheme 105
7.22. Isoquinoline An isoquinoline linker has been developed based on Reissert compounds.350,351 Treatment of resin bound benzoyl chloride 44 with isoquinoline and TMS-CN results in the Reissert linker 154 attached via the acyl group at the 2-position (Scheme 106). The 1-postion was then alkylated using LDA as base. Cleavage to release the isoqulnoline is achieved by heating with KOH in 33% H20/THF. Aqueous work up is required after cleavage.
It~[~R'~ Cl
44 TMS-CN
CN
R' R
Scheme 106
.O. R" CN
= R R'
1M KOH
="
R"
R' R
7.23. Ketone
7.23.1. Acid Labile
Ketals: In similar manner to the attachment of aldehydes, ketones have been attached to the sofid phase as the 5-membered cyclic ketal 155.144,352 Attachment of the ketone is performed using pTsOH and cleavage is achieved using 2M HCI in 50% dioxane/water 352 orpTsOH in 20% dioxane/water (Scheme 107). 144
.'r.o.
OH O R.JI-R, = 1S5
X
Q R R'
.C,, ,,ox..e <%
0
RJJ.. . R,
Scheme 107 Enamines: 2-Aminobutediene derivatives have been used to give c~,l~-unsaturated ketones. The diene 1S6 is formed by treatment of secondary amine 157 with propargyl triphenylphospine bromide followed by a Wittig reaction (Scheme 108). Treatment with 3%TFA/DCM cleaves the product as the ketone.353,354 The diene can be further reacted resulting in an enamine linker 158, which also cleaves in 3% TFA/DCM to give the ketone. 354
1. W. James/Tetrahedron 55 (1999) 4855--4946
4905
//~"pph3+Br i=
i) KOtBu ii)RCHO
17 S 3%TFA/DCM
R"
t.'[ ~
3%TFA/DCM
158 Scheme 108
"~
Enol Ethers: 1,3-Diones have been attached to hydroxymethylpolystyrene as the enol ether 159. 355 The ketone moiety not involved in binding to the solid phase can be transformed using various reactions. The linking ketone is released by treatment with 3-5%TFA (Scheme 109).
OH CSA I,
o
RMgBrrRLi=.
R OH
R OH
~ T~.. o ~
R'
Rt
159 ~
5%TFA/DCM,,O ~
Scheme 109 I~nes: Ketones have been attached to amines on the solid phase as the imine 160 with cleavage achieved using the mild conditions of buffered aqueous acetic acid (Scheme 110). 356,357 O
R.,~R,
.eel_
160 Scheme 110

7.23.2 Others
R~II~R,
Treatment of a thioester linker 161 with a Grignard reagent leads to the formation of the tetrahedral intermediate 162 (Scheme 111). This can be washed with dry THF to remove the excess Grignard reagent then release of the product from the solid phase as the ketone is achieved by treatment with a proton donor such as formic acid. 35s Filtration is used to remove the magnesium salts. No tertiary alcohol products were reported as by-products in the cleaved samples.
4906
R'MgBr 161 O
e'N'AR 1
H 162 R' OMgBrJ
Scheme 111
HCO2H
O R~R,
7.24. Phenol
7.24.1. Acid Labile
The phenol group may be attached to the Wang Linker 19 using Mitsunobu chemistry (Scheme 112).65 Cleavage of 163 is achieved with 10-50% TFA in DCM. This method can be problematic with the loading being highly dependent on the substrate. Also, hydrazinodicarboxamide derivatives have been reported as impurities in the cleaved product when using this method of attachment. 359 An alternative method for preparing 163 involves first treating the Wang linker 19 with trichloroacetonitrile and DBU to form the trichloroacetimidate 37. This is then treated with the phenol and boron trifluoride etherate. 63 Synthesis examples: 2,3-dihydro-4-pyridones 360 and imidazoles.252
eo
OH ArOH,PPI~,DEAD 19CI3CCN~
OBU"',~
-Co
~H"OA r 163
O~ ] ~
50%TFA/DCM
~H / BF3.OEt 2
37
Scheme 112 The monoalkoxy benzyl PAC linker also can be used as a phenol linker (Scheme 113). Usually the phenol is attached via solution phase, 31,67 hence removing the problem of variable loading and impurities that can be encountered when using Mitsunobu chemistry to attach to the linker. Cleavage is achieved using 95% TFA/H20. Synthesis examples: benzimidalones,66 1,4-benzodiazepines, 361 indoles362 and quinazoline-2,4-diones. 67
-.
HO
.~~O
coupling 50%TFA/DCM
Scheme 113
4907
Phenols can be attached to the Rink (166), 84 trityl (164), 363 and 4-carboxamidetrityl (165) linkers (Scheme 114)) 64 The Rink linker is cleaved with 5% TFA/DCM and the trityl linkers are cleaved with 1 and 10% TFA/DCM respectively.
O-Ar
164 O.Me
o, Me Me ArOH,DIEA ~ O "Me 5%TFA/DCM

k
1%TFA/DCM HO---~R l l 0%TFA/DCM
~,.~O
o 'C'
16S Scheme 114
The DHP linker 33 has been used as a phenol linker using similar attachment and cleavage procedure to those used for alcohols (Scheme 115). 103 OH
'0 33
ArOH P
PPTS,80*L;
Scheme 115
1:1:5
7.24.2. Bose Labile
Phenols have been attached to a solid phase benzoic acid 167 as the ester 168 (Scheme 116)) 65 After completion of chemistry, the ester bond is cleaved by hydrolysis with NaOH in dioxane, 366,367 NaOMe/MeOH/THF365 or K2CO3 in MeOH. 365 Salts can be removed by filtration from organic solvent.
= R NaOMe, MeOH or K2CO3, MeOH" H O - - ~ R
H
167
DMAP, py
168
Scheme 116
4908
The phenols can be attached to the fluoride labile linker 169 via solution phase 368 Treatment with IM TBAF in THF deprotects the alcohol of the linker, which then cyclizes to form the solid phase bound oxazolidinone and releases the phenol (Scheme 117). Aqueous work up is used to remove the fluoride salts.
HN o~N/U..o.Ar
t65
1MTBAF/THF,
~N H
.Ar
,. HO~ - - ~ R
Scheme 117
7.24.3. Photolabile
Photolabile cleavage has been used for phenols. 369 The phenol is attached to the 170 using Mitsunobu chemistry then cleaved using standard photolysis conditions (Scheme 118).
OH DIAD,DIEA,THFJ" "~" 170

Scheme 118
Ar
Ar
7.25. Phosphonate The Wang linker has been used to attach phosphonates.76,37 The phosphorus is attached using 2-chloro4H-1,3,2-benzodioxaphosphorin-4-one (Scheme 119). It is further manipulated to form the solid phase bound phosphonate 171 which is cleaved with 10% TFAfDCM.
O
10%TFA/DCM, HO-,P x py, DCM O 4 171 R

!
,o
O,R' R
Scheme 119
7.26. Phthalhydrazide Phthalamides can be attached to chloromethylpolystyrene 50 using the potassium salt (Scheme 120)) "11 Treatment of the attached phthalamide 172 with aliphatic hydrazines releases the product as the
phthalhydrazide. 372 o
'CI 50
K~--R O : ~ 0 DMF,100eC ~. ~ r ~N
172 R
O R'HNNHR"~. R~" ~ / _ _ N J, R" N

O
Scheme 120
4909
7.27. Purine The purine group has been attached through the 9-position to the solid phase using the DHP linker 33. 373 Attachment is catalyzed by CSA and the linker cleaved using 89% TFA/DCM (Scheme 121).
CI N N N N CI ~ CSA,DCE,65C
33
CI
(~,.~ ~NI/j... H
R'
.89% TFNDCM
R' Scheme 121
7.28. Pyrimidine Aromatic nudeophilic substitution by a solid phase bound thiol onto a 2-chloropyrimidine has been used to
attach pyrimidines to the solid phase (Scheme 122). 38 On the completion of the synthesis this safety catch linker 173 is activated by oxidation of the aromatic thioether with mCPBA to the sulfone 174 then cleaved by aromatic substitution by an amine to release the pyrimidine as the 2-amino derivative. A limiting amount of the amine (i.e, no excess reagent) is used so no impurities are introduced from the cleavage step. Most primary and secondary amines are reported to give generally acceptable yields (>80%) whereas anilines are not as successful (-50%).
N=~R
mOPBA.
122
R,.I~I-R ,,
,,
N~, _
R'~N.~N ~--Ix .
TEA
173
~ )
174
Scheme 122
7.29. Saccharide
A number of linkers have been developed to link saccharides through the anomeric centre. Linkers used to attach saccharides through hydroxyls at other positions are included with the alcohol linkers (Section 7.1). Thioether Linker: By attaching through the anomeric centre, sugars can be attached to the alkylthiol 175 using the trichloroactamide as an activating group. 374-376 The methyl ether at the anomi,'ric centre is obtained by cleaving using either dimethylthiosulfonTum triflate in DCM/MeOH 375 or NBS in THF/MeOH (Scheme 123). 376 Using NBS in acetone/H20 for cleavage, the anomeric alcohol can be obtained. 376 The phenyl thioether 176 has also been used. 377 Attachment via solution phase is used, and mercuric trifluoroacetate is used for cleavage (Scheme 124). Post-cleavage purification is required to remove the mercury salts.
4910
O~NH
HS~ X-~
C b C
RO
~-~_q
OH
TMSOTf
175 X=SorO
RO~'~ S~
~ X'--~
X=SorO 90%DCM/MeOH Ro~OO~ or 91%THF/MeOH

Scheme 123
NBSDTBP
O-Me
r~.~O ~ - ~ RO<-~'-4~S--~ OCs "- ~,....jO
~,,,-~O,,,~
176
Hg(OCOCF3)2
Scheme 124 Wan= Linker: The Wang linker 177 has been used to attach sugars through the anomeric center.75, 378 The first sugar is attached to the linker in solution then the combined linker-sugar attached to the solid phase (Scheme 125). Cleavage is achieved using TrBF475 or 10%TFA/DCM. 378 oH v-._.O
Cl~.~
RO~-~.O~ . ~-~O Cs2CO3DMF 50=C RO__ ~ O
~ . O ~ ~.t~ ~
TIBF4 DCM . : ~:/0 or 10%TFA/DCm RO~ - ~ O H ~v
t77
Scheme 125
B-Silvl Ethyl Linker: The I~-silyl ether linker 178 may be used to attach saccharides via solution phase. 379 Treatment with BF3.OEt2 and acetic anhydride in toluene releases the saccharide as the acetate (Scheme 126).
RO~_~O~
$iO
Ao20, BF3.OEt2 ~, R o ~ O . ~
O
Scheme 126
~ t78 Me "Me
7.29.1. Photolabile Saccharides have been attached to the solid phase through the anomeric oxygen using a number of
photolabile linkers 179, 380 180, 381 181, 382 152383 with cleavage generally being performed using irradiation at 350nm for 12 - 15h (Scheme 127). Both solution phase synthesis 381 and direct coupling of the saccharide to the linker already on the solid phase 380,383 have been used to attach the saccharide. Although a number of linkers are reported, surprisingly, the or-substituted version, such as in 182, 383 generally has not been utilized. This is
L W. James I Tetrahedron 55 (1999) 4855-4946
4911
despite this being reported as being beneficial for the cleavage of amides and carboxylic acids from photolabile linkers. 29,212
O~N.~O-O
HO-,v-'J'~O.Me
,,
R ~ O . ~ Br PY
179
Me
RO~.~ O ' . v ~ O O
180
0
hv
'~ R O ~ , ~ O
JhV ~...~0
hv
ON 2
OI
T
hv
0
NIS, TESOTf
182
Scheme 127
7.30. Silanol The siloxy linker 183, used as a traceless linker for aromatic groups,384 (Section 8.1.2) can be cleaved with TFA to give the silanol (Scheme 128).
~/"OH
ClSi~Pr)2Ar Im, DMF
iPr iPr ~.,~...O, Si...r.,~ ~ ~ ~1.~-:-' R
TFA
, HO, S i ~ , / ~ ~
~L.~----'R
IPr IPr
t83
Scheme 128 7.31. Sulfonamide
7.31.1. Acid Labile
o.Me ~..~ ~0" Me

RSO2CI, py, DCM ,~ z . ~ ~
O. Me
O'Me
20% TFA/DCM
0,,,9
"- H2N.S.R
Scheme 129
4912
I.W. James / Tetrahedron 55 (1999) 4855-4946
The Rink linker 25 may be treated with sulfonyi chlorides to form the sulfonamide 26 (Scheme 129). 83 The linker is stable to 50% AcOH/DCM but is cleaved in 20% TFA/DCM to give the primary sulfonamide. The Wang linker has been used as a linker for secondary sulfonamides.61, 62 The alcohol 19 is converted to the halide (chloride, bromide or iodide), then treated with a suitable primary amine and finally a sulfonyl chloride to form the attached sulfonamide 21 (Scheme 130). Cleavage is achieved with 95% TFA. Reductive amination of the solid phase aldehyde 76 then sulfonylation has also been used to prepare the Wang derived secondary sulfonamide linker. 191 It was reported that the sulfonamide but not the amine is cleaved, so high purity is generally achieved even if the sulfonylation does not go to completion.
pPh.X~ ~ , . O ~ X "Br:~l 1 . f " " ~,~,.,.~X '
H NR
lamination
I~uct~ve
7e
X= C,, Br
-<~ v X = CI, Br
TL .:.L .x
I NMM |
I R, o c,
95% TFA 21 O O
Scheme 130 The Sasrin linker also has been modified for use as a secondary sulfonamide linker. 183 Attachment is via reductive amination then sulfonylation and cleavage is achieved with 5% TFA (Scheme 131). Note, though, that a similar linker 184 was reported to give slightly inferior yields to its Wang equivalent. 61
Me ~ ' O " ~ ~--'-'~O-1
reductive amindon _
u
O. ~
Me .()
_ _ R'SO2CI ~ / O y ~ O
,,
Me R
5%'I'FA/DCMp
,R
HN._.R'
'
~t
Me
"' 184
'/'C.....~.t~I~I R' ;ST

0 'O
Scheme 131
4913
Reductive amination then sulfonylation is also used to prepare the indole derived sulfonamide linker lg5 (Scheme 132). 192 Cleavage is achieved with 50% TFA/DCM.
O 0 : ~ R'
R
50% TFA/DCM
o,,o
R,-S-N-R
H
78 H N
186
Scheme 132
7.31.2. Base Labile
An alternative use of the Wang linker to attach sulfonamides is via the carbamate.385 The carbamate 24 is formed via the p-nitrophenylcarbonate (Scheme 133). Deprotonation of the carbamate and treatment with a sulfonyl chloride forms the sulfonamide 186, which can be cleaved with NaOMe in 50% MeOHfrHF. Aqueous work up is used to remove the salts. Being derived from the Wang linker, cleavage may also occur under acidic conditions, although a hydroxymethylpolystyrene (Merrifield resin) version of this carbamate derived linker that would avoid this problem is also described. 385
O o.
19
i) NMM, CI~I~O-'~NO2
o
lid
iJ) H2NR 0 LHMDS l then R'SO2C
H R-N "~S~R' OO
1.5M NaOMe 50% MeOH/THF
~ q ~ - - ~ O,,,r(.N.S. R' '

186~
(3' ~C)
Scheme 133
7.32. Tetrazole Tetrazoles can be attached to a DHP linker 187 using 1 equivalent of TFA (Scheme 134). 386 Cleavage is best achieved using 3%HCI in MeOH for 24h. The ester bond used to attach the linker to the solid phase allows the compound to be removed from the solid phase by LiOH in THF/I-I20 to give a protected tetrazole.
4914
N~'N<.fAr O N,:N,,f Ar N-N H TFA t87 LiOH ~ .N).~ Ar

N
3%HCI/MeOH
Q .N. _Ar ~
N-N,
H
Scheme 134
7.33. Thioacid
Z33.1. Acid Labile
A benzhydryl linker has been used to attach thioesters 387 Attachment via solution phase is used with cleavage on the completion of synthesis being achieved using I-IF (Scheme 135)
s~JJ-.R
0
NH2
i
HF O
J"HS.~,.R
0
Scheme 135
Z33.2. Base Labile
Treatment of the base labile oxime linker 86, initially developed as a carboxylic acid linker,208,388 with Me3Si-S-SiM~TBAF (an H2S equivalent) results in the cleavage of the product as the thioaeid (Scheme 136).389 Aqueous work up is used to remove the salts.
N''0
(TMShS, TBAF
.
,sAR
NO2
Scheme 136
I. W. James I Tetrahedron 55 (1999) 4855-4946
4915
7.34. Thiol
7.34.1. Acid Labile
Thiols may be attached to Rink chloride 27 using DIEA (Scheme 137).84 Cleavage is achieved with 5% TFA/DCM.
o.Me
o.Me [~O OA~.~Y R "Me 5%TFA/DCM
~:.. ~ C I O'Me RSH,DIEA O~ / ~ -CI
HS-R
,,
e
Scheme 137
7.34.2. Reductive Cleavage
The reductively labile dithiane linker 188 is prepared in solution and attached to the solid phase with the starting material attached (Scheme 138).39,391 After synthesis, the product is cleaved using tris(2carboxyethyl)phosphine to give the thiol. Purification is required to remove the phosphorus impurities.
Me Me
HO'~'s'S'R BOP,DIEA
H Me Me P(CH2CH2CO2H)3 O/ s'S~R = HS-R O 188

Scheme 138
7.35. Urea
7.35.1. Acid Labile
A modification of a Wang-aldehyde has been used to attach ureas. 64 The aldehyde 76 is reductively aminated with a primary amine (Scheme 139). Treatment with an isocyanate forms the urea 189, which can be cleaved from the solid phase with 95%TFA/TES. A similar approach has been reported using the Sasrin derived linker 190, with cleavage being achieved using only 5% TFA/DCM. 183
~,.o~x H 76X=H 71X = OMe
reductive amination
R'NCO J O ' ~ / ~
XR
H 5-95%TFA/DCM H H o
X= H,OMe
Scheme 139
O 189X=H 190X = OMe
4916
/. W. James / Tetrahedron 55 (1999) 4855--4946
7.35.2. Base Labile Isocyanates are used to form ureas on Kaiser's oxime linker.392, 393 The linker 191 is stable to treatment with amines at room temperature but cleaved with amines in toluene at 75C (Scheme 140). One equivalent of amine can be used to ensure reasonable purity of cleaved compounds. H N- R
NO ~ H
OCN'R = N2 O
N "0
191
Scheme 140
R'R"NH =. R"N.~.N.R toluene, 75C = H R' N2 O
The phenol 192 can be converted to the carbamate 193 via the p-nitrophenylcarbonate. Is Treatment with TEA and an amine results in cleavage of the product as the urea (Scheme 141), possibly by release as an isocyanate, which reacts with an amine present to form the urea, or by direct reaction of the amine with the carbamate as above. Excess amine is removed by treatment with an isocyanate resin. 18
OH 192 193 R'
MeCN, 60=C
I R"
I R'
Scheme 141
8. TRACELESS LINKERS The key definition of a traceless linker is a linker whereby a new C-H or C-C bond is formed during cleavage. This has been expanded to include linkers that cleave give an aromatic, alkyl, alkene or alkyne group without a heteroatomic linker site, hence including other reactions such as retro cydoadditions. Other examples sometimes described as traceless linkers, such as those involving SNAr with amines38 or tertiary amine linkers cleaved by Hofmann elimination, 22,23 are omitted from this section but are included in the relevant sections above.
8.1. Aromatic
8.1.1. Trialkylsilane Trialkylsilanes have been used as traceless tinkers for aryl groups with cleavage by electrophilic ipsosubstitution.30,31,24s,251 The acid required for cleavage is highly dependant on both the chemical nature of the linker and the electronic nature of the aromatic group (Schemes 142, 143). Fluoride cleavage may also be used, though extractive removal of the fluoride salts is required when using this method. A range of linkers has been developed. Linker 194 requires I-IF treatment to cleave the electron poor systems studied,3, 31 whereas CsF treatment at 100C failed. For more electron rich systems, weaker acidic treatment would probably suffice. HCI
4917
in DCM is sufficient to cleave electron rich systems from linker 195111 and 50% TFA/DCM will cleave them from linker 196,106 whereas for electron poor systems, TBAF achieves cleavage.
l~O/'-o~Si~ '-R
Me Me
~
~ H
O~/L.~l
Me Me 110 T 112
~"
FA/DCM Me Me Ny---v'si,.,~-~ TFA P C - - R 4 HCI/DCM

195
~TFA/DCM
197
t96
Scheme 142: Cleavage of Electron Neutral to Rich Aromatic Systems
195
TBAF
E( Et
194
CsF, 110eC
196
197
Me "Me
Scheme 143 Cleavage of Electron Poor Aromatic Systems
TFA is used for cleavage of electron rich systems from the a-alkoxy linker 197394 as well as 110. 248 TFA cleavage of 197 fails for electron poor systems, for which CsF treatment at 110C can be used. 394 An amazing rate enhancement is observed when a ]3-amide (relative to the silyl group) is introduced. 251,395 Treatment with 30% TFA/DCM for only 10 minutes is required for cleavage of aromatic systems that are only slightly electron rich (112), as opposed to the hours of treatment with stronger cleavage reagents required for
4918
the other traceless linkers mentioned above. It has been suggested that this rate enhancement is due to either intramolecular delivery of the proton from the protonated amide, or carbonyl coordination to the mildly Lewis acidic silane, hence weakening the silene-aromatic carbon bond to attack by the proton. Interestingly, the related linker 19g does not show this rate enhancement, requiring TFA treatment for 40h for complete cleavage (Scheme 142),396 possibly due to hindrance of the amide by the benzhydryl group preventing the I~-amide assistance. Electrophiles other than protons may be used so as to introduce further diversity. 1C1 may be used to obtain the aryl iodide from either 110 or 112 (Scheme 144).248,251 The aryl bromide may be obtained from 110 using Br2/pyfidine.248
~.~/H
Me, Me N. . ~ v . S i ~ . / ~ I O ~j-':-" R 112
ICI
"
~,--R I
ICI
O~ 1 110
Me Me
Br2/py
"Br~ ' - R
Scheme 144 The silyl chloride used to attach the aromatic group to the linker is quite unstable, so attachment via solution phase is usually used. A couple of ways of avoiding this have recently been reported. The linker can be attached as the anisyl silane 199, which is stable to storage. 111 The silyl chloride 200 is formed by brief exposure to HCI in DCM, which removes the anisole group (Scheme 145). Alternatively, the linker can be stored as the silane 201.106 Conversion to the silyl chloride 202 is achieved by treatment with 1,3-dichloro-5,5dimethylhydantoin (Scheme 146). In both cases, the silyl chloride is then treated with an aryl lithium species to attach the aryl group of interest.
[/~O'Me '199
HCI, DCM . ~ . ~ s i . C l Me ~le / 200

Scheme 145
ArLi ~,~R THF " ~'/'~S! Me Me /
Me Me O~N'CI
,"%
DCM
/ Et 201
202
Scheme 146
I. W. James/Tetrahedron 55 (1999) 4855--4946
4919
8.1.2. Dialkylsiloxy
The siloxy group also has been utilized as an aromatic traceless linker. 384 The chlorosilane with the aromatic residue was formed in solution then coupled to hydroxymethylpolystyrene as the siloxy ether 183 (Scheme 147). After synthesis the aromatic group is cleaved with TBAF at 65C Aqueous work up and filtration is required to remove excess cleavage reagent. TFA can be used to release the product as an dialkylarylsilanol.
~R CISiCPr)2Ar
Ira, DMF
183 ~
ipr ipr O.S: ip r ip r HO'Si-,,r~
Scheme 147
8.1.3. Trial~lgerraane
The more labile germanium analogue of the trialkylsilane linker has been used. 30 The germanium-carbon bond is significantly labile, such that TFA at 60C is sufficient for cleavage of even electron poor aromatic systems (Scheme 148).
R"
0
R**
~
/O R
=" R
R'
Scheme 148
8.2.
Alkyl
Intramolecular attack of a carbon nucleophile onto the alkylsulfonate linker resulting in cyclative cleavage (Section 9.4) is a form of traceless linkage that leads to an alkyl group.
8.3. Aliyl
The allyi silane linker 203 may be prepared using the metathesis reaction (Scheme 149). 397 It is cleaved with 3% TFA/DCM to release the allylic product.
O "siv'
Me, Me
(pc c,.R.=CHP. O "siv' :R

P
~/
Me, .Me
3% TFA/DCM
.
:,.jR
2O3
Scheme 149
4920
Alternatively, allylic groups may be attached to the solid phase through a sulfone 204. 398 This is prepared by lithiation of polystyrene then sequential treatment with sulfur dioxide and an allyi bromide (Scheme 150). Treatment with Cnignard reagents in the presence of copper iodide results in SN2' alkylation, cleaving the allyl group. The product must be purified from excess cleavage reagents.
ii) S02 " iii) allyl bromide
04
S c h e m e 150
"
CuI, TH;
The allyl ester 102 may be cleaved with
palladium and
a nucleophile. If a carbon nucleophile, such as
dimethyl malonate, is used then this acts as a traceless linker (Scheme 151). 240 Ammonium formate may be used as a hydride source for reductive cleavage of the product. R R
Pd(PPh),
MeO,,,l~OMe 0 o
MeO.. O
M e O ~ 0
HNEt3*HCO2" ( ~ 0 O 102
Scheme 151
8.4. A l k e n e
The alkene linkers described in Section 7.3 may all be considered traceless. Similarly, metathesis cyclization to release the product as the cyclic alkene (Section 9.5.1) also may be considered a form of traceless linker. 8.5. Benzyl The benzyl phosphonium salt 63 when treated with NaOMe in refluxing MeOH cleaves from the solid phase as the toluene derivative (Scheme 152). 157
O-PP
64
A : Br
DMFI70C ~
O--:Ph Br"
IXAr $3
S c h e m e 152
naO.e,UeOX
- Ar-Me
8.6, Furan
An interestingform of tracelesslinkerbased on a rctrocycloadditionhas been used for the preparationof furans.399, Treatment of the diazo carbonyl 205 with I~2(OAc)4 or Pd~(pfbm)4 at 80C leads to the formation 40 of the isom~nchone intermediate 206, which reacts with an electron poor alkyne to form the hicyclic intermediate 20"/(Scheme 153). This then undergoes retrocycloadditionreleasingthe furan. The catalystand excess alkyne have to be removed from the products. The cleavage, however, can be performed in two steps by
4921
treating with Rh2(OAc)4 and acetylene at room temperature to form the bicyclic intermediate 207. The sofid phase can then be washed to remove the catalyst and the retrocycloaddition with cleavage achieved by heating at 80C. R
RI12(OAc)4
eFN
205
'R'
O N o-R,
O" 206 E E O -E
E
!1
R.~O'R '
0
heat
0
2O7 Scheme 153
8.7. Active Methylene Groups
Under acidic conditions, carboxylic acids of activated methylene groups may undergo decarboxylation. Originally, ketones were prepared on hydroxymethylpolystyrene with cleavage and decarboxylatioo being achieved using HBrflTA (Scheme 154).401 More recently they have been prepared on the trityl linker, with prolonged treatment with AcOH used to achieve cleavage and decarboxylation (Scheme 155).402 Similarly, cyanoacetamidines (Scheme 156),403,44 and JS-cyanoketones (Scheme 157)401,42 were prepared using the Wang linker, with cleavage and decarboxylation being achieved using 50% and 70% TFA/DCM respectively. 0 R'
Scheme 154
N'
(3
0
IIL P
R'N'R'
AcOH, 8h
R.N.R'
Scheme 155
4922
I. 14/. James / Tetrahedron 55 (1999) 4855--4946
o
oH
m,
O R H
CN N.R' R"
50% TFA/DCM
+ t
-COz
"
" R"
Scheme 156
O
oH
I~O"
0~'" ph
-CO2
oCN
Ph
Scheme 157
9. CYCLATIVE CLEAVAGE
9.1. Cyclization onto Esters
Both acid and base catalyzed cleavage of esters involving the intramolecular attack of nudeophiles have been used to cleave products. As discussed earlier, if the nucleophile is incorporated late in the synthesis in a manner that is reliant on the success of previous steps, then generally the desired product can be obtained in high purity, although the yield may vary, 1.4-Benzodiazepine-2,5-diones: Cyclization of the aniline nitrogen onto the Wang linker ester of 208, forms the desired product and cleaves it from the solid phase (Scheme 158).405 The cyclization is achieved using NaOtBu in THF at 60C. Yields are moderate to good (50-80%) and purity is generally good to excellent (8198%).
0
t, IF O ~.~
R' ~
R O H2N THF 60=0
R',,N /?
R
20S Scheme158
Benzodiazeoinones Intramolecular amide formation has been used to prepare benzodiazepinonesusing cyclative cleavage32 Chloromethylpolystyrenewas used for the synthesis and the final cyclization was performed using TFA at 60C (Scheme ] 59) . ~ N ~ ~CI
0 R"HN R R
R"
R g*
TFA, 60"C
t ..~O
N
O1"'O" "
=" R / - - R ~ ~ N R
Scheme 159
Dihvdropyrimidine-2.4-diones: Urea cyclization onto the Wang ester of 209 has been used to cleave 5,6dihydropyrimidine-2,4-diones. 46 The cyclative cleavage is achieved using saturated HCl/toluene at 95C
4923
(Scheme 160). These conditions would probably cleave the Wang linker first, with cyclization occurring after cleavage. Heat is needed to obtain good yields of the cycfic product, as the uncyclized product is obtained by
treatmentwith 95%TFA/H20at roomtemperature.

O
N~NN ' ~R
R
/OH
,,
, < / ' ~ , , . ~ O . J ~ N..~ N.R,

209
95% TFA/H20
~
He
/IL.
N
R
,
N"R
Scheme 160
biketopiperizines (DKP): DKP formation is a side reaction in peptide synthesis and can occur after deprotection of the second residue, or during the attachment of the third residue, resulting in low yields. Many techniques have been developed to avoid this yield reducing process. It can, however, be used to prepare libraries of low molecular weight molecules. The first amino acid is attached through an ester. The second amino acid is attached with BOC protection on the or-nitrogen. To cleave the DKP, the BOC group is removed with TFA. The TFA salt is neutralized with 0.1M NH4HCO3 in 40% MeCN/H20407 or 0.1M sodium phosphate buffer,408,409 and cyclization occursin situ at room temperature (Scheme 161). Sonication can aid the cleavage when using NHffICO3.407 The TFA salt also can be neutralized with DIEA, with the cyclative cleavage being subsequently induced using either I%AcOH or 4% TEA in 1:1 toluene/EtOH. 410 Purity, using any of these methods, is generally >90%, as product will only cleave if the dipeptide is formed. Though the yields are highly dependent on the side-chains present. Substitution on the amide nitrogen generally aids the cyclative process. If an Fmoc amino acid is used for the second coupling, then cyclization with cleavage will occur in situ with Fmoc deprotection using piperidine.4] ] Replacement of the second amino acid with an (~-hydroxyacid realizes the diketomorpholines after cyclative cleavage in 5%TEA/DCM (Scheme 162).4]0
O
R O
R'
ii) neutralization
i) TFA
R'.
N.
H
N
1.O
R
Scheme 161
~/H,~
R
R'
5%TEA
R' .O
O,~. ~ . N H
Scheme 162
4924
L W. James / Tctrahedron 55 (1999) 4855--4946
Hvdantoins: Hydroxymethylpolystyrene resin has been used to prepare hydantoins via cyclization of the urea using 6N HCI, 32 KOtBu, 412 or bis(trimethylsilyl)trifluoroacetamide at 83C. 413 Cyclization of the urea onto the Wang ester of 210 using DIEA or TEA also has been used (Scheme 163).78, 79 Similar conditions are used to cleave an alkyl ester linkage. 414 In all these cases, cleavage only occurs if the urea has been formed, so again, products are generally obtained in high purity but variable yields.
O.~~
OH
.=
O R' H F . ~ X ~ o / ~ ' - f " N"~" N"R" DIEAor TEA
O RLN~N.R,,
Scheme 163 Alternatively, cyclization of the amide onto the carbamate 211 can be used. The cyclization is catalyzed by TEA in MeOH at SS-90C (Scheme 164). 415 Again mass recovery is variable but purity is generally good.
TEA, MeOH,A
R*
~'~'OH
= =~ O ' ~ ' N % N ' R ' O 211

Scheme 164
" OTN~O
R
Lactams: Kaiser's oxime linker has been used to form cyclic peptides. The peptide is prepared using BOC chemistry: TFA to remove protecting groups (amine remains as a TFA salt), then coupfing with m situ neutralization. This process limits the presence of the nucleophilic free amine. To achieve cyclative cleavage, the deproteoted peptide 212 is treated with DIEA (Scheme 165). A range of sizes of cyclic peptides have been prepared including 5-mers 416 and 10-mers. 417
R J ~ BocHN"'~"
..,6
i) TFA R ii) Boc-AA-OH Q, J . ,.., BOP, HOBt, D I E A ~-AAn-N:"~" repeat . TFA.I"I2N'~ H ,.:6
DIF-A --
HN'~ R
Scheme 165
Lactones: Lactone formation is demonstrated by the cyclative cleavage of alcohols using 213. 418 The alkene 214 is oxidized with mCPBA. The resulting epoxide 215 is opened with a nucleophile (e.g. Ns'), forming the alcohol 213. Treatment with TFA cleaves the desired product as the lactone. The ester 214 is not labile with TFA, so if the oxidation failed, no product would be released. Although the purity of the products was generally high, 75-95%, the yields were only moderate, 45 - 67%.
1. W. James/Tetrahedron 55 (1999) 4855--4946
4925
O HO~.~" Cs2CO3,KI
O
214
mCPBA
-
216
NAN3,NH4CI O
N3
213 Scheme 166
50%TFA/DCM
O
HO
Pvrazolones: Treatment of 13-ketoesters 216 with primary hydrazines produces the hydrazones 217 which then cyclize on treatment with 2% TFA/MeCN to release pyrazolones (Scheme 167).419 Heating at 100C in toluene also causes cyclative cleavage although this method is not as amenable to parallel synthesis. 420 Ar R
Oij (~ i-...~ H2NNHAr. O R'

R 216
O ~
~"~O R 217
N"NH 2% TFA/MeCN
R'
L ~"~ ~ R~.~, ~....O

N-N
or toluene,100*C
Ar
Scheme 167
2.4(1H.3H~-Quinazolinediones: The cyclization of an amide onto the carbamate linkage 218 has been used to prepare 2,4(IH,3H)-quinazolinediones. Cleavage is achieved by heating at 125C in DMF, 421 or by using TEA/MeOH at 60C (Scheme 168). 422 Purities are good although the yields vary significantly.
(~OH
RO ~ N'R' ",.O1O N ~O' "~/-- T A MMO 15 R,,~N'.~ "O ED F e 60~* , ' H2C ,=
R" ~'~ N'R' O
218
Scheme 168
Ouinolin-2-ones: The aniline nitrogen of 219 can cyclize onto the Wang ester or thioester linker releasing the product as the quinolin-2-one (Scheme 169). This is achieved by heating in toluene at 80C. 423 OH
~ X
C N ~ OO NH2 ~
2t9
toluene, 80C . ~:~J'N"~'O[~J~CN

H
X=O,S
Scheme 169
4926
Tetramic Acids: Deprotonation of the activated methylene of 220 results in cyclization onto the Wang ester with cleavage to form the tetramic acid (Scheme 170).19,424 Both tetrabutylammonium hydroxide and sodium ethoxide have been used as the base, with excess cleavage reagent removed by treatment with acidic ion exchange resin.
""
".o
-.,
R
19
220
Scheme 170
R'
X = CN, P(O)(OEt)2, 2-NO2-C0-14,SPh
9.2. Cydization onto Amides
Lactones: Iodolactonization onto an amide linker 221 using iodine in THF/HzO releases the product as the lactone (Scheme 171).425,426 This process regenerates the chiral linker. O
12,THF/H20 "
0_ ~ ''~Me
I---.4
221~
"~
Scheme 171 Lactones have also been prepared from the methionine derived linker 222.220,427 Cyanogen bromide is used to cleave the product as the homoserine lactone (Scheme 172).
0 N R BrCN, TFA (cat.) O J ~
s:2 CHC - o
Me--s
P O~ / N
"lr
0
222
Scheme 172
9.3. Cydization onto Tbioesters ~ctones: Removal of the silyl protecting groups from 223 with TBAF in AcOH and THF at 40C causes cyclative cleavage via attack on the thioester linker to form the 5-membered lactone (Scheme 173).42s
TBSO OH Q B n O ~ s , ~ , ~ OTBS TBAF, AcOH THF, 400C
HQ .~.~.~..O..~ O = BnO
223
Scheme 173
4927
9.4. Displacement of Suifonates
Alkanes: Removal of the acidic proton of 224 with LHMDS results in sulfonate releasing the product as the cyclic dialkene (Scheme 174). 34s
intramolecular displacement of the Et

o
Et 9~O'~SoO.~
2~'4
'o
LHMDS'dixane'100= CN, ~O
Scheme 174
9.5. Other Cydizations

9.5.1. Metathesis
A suitable diene on the solid phase, e.g. 225, and 226, may be treated with a metathesis catalyst (usually Grubb's reagent, CI2(PCy3)zRu==CHPh), so as to undergo intramolecular metathesis releasing the product as a cyclic alkene. This has been used for the formation of 6-membered dihydropyrans and te~ahydropyridines (Scheme 175), as well as 7-membered lactams429, 430 and to form 14-membered tripeptide derived macrocycles.431 Purification is required to remove the ruthenium catalyst and this may reduce this method's applicability to large libraries. It has been used, though, in an impressive solid phase synthesis of 16-membered cyclic epithilone derivatives (Scheme 176). 432,433
~..~..~
225 X=OorNR
R' (Cy3P)zCI2Ru=CHPh I~R,

X=O
orNR
Scheme 175
(CY3P)2CI2Ru=CHPh ,,.HO
"--
R"
H(~O" "i~O R" ~

226 Scheme 176
9.3.2. Wittig/Horner-Emmons Reaction
~ p+phzBr" '~NLAr DMF, Bu KOtuene tol H 227

S c h e m e 177
4928
Intramolecular Wittig reaction of the phosphonium salt linker 227 with an amide leads to formation of indoles (Scheme 177). 157 KOtBu is used as the base and strictly anhydrous conditions are required to avoid hydrolysis of the phosphonium salt. The intramolecular Horner-Emmons reaction can be used with a phosphonate ester linker 228 to give the cyclic alkene (Scheme 178).434 K2CO3 and 18-crown-6 in benzene at 65C are used to achieve the cydative cleavage.
I M ' O " P" Me OMe
,~ _
OMe ,~ n /O_../ 228 n=7,9 O
K2C03,18.C.6 ,,
CsH6, 65"C ( O n=7,9
Scheme 178
10. SAFETY CATCH LINKERS The previous sections have been categorised according to the products. This section is divided according to the chemistry involved in the activation and cleavage steps of safety catch linkers. Many of these potentially could be used to attach functional groups other than those mentioned here,
10.1. DKP Formation
O i) 50%TFA/DCM
ii) K2HPO4 buffer,pH 8 Boc 229 23O
4-
O o
HO~'O'JJ~" R I eMmindon 0 HO R "~"

Scheme 179
Utilizing the same principles as the DKP synthesis discussed above (which can also be described a safety catch method) a linker has been designed so that the DKP formed remains on the solid phase with the desired product cleaving into solution. 435 Activation of 229 is achieved by removing the BOC protecting group with TFA then cleavage is achieved by neutralization at pH 7-8 (K2I-IPO4)to release the phenol 230, which then
4929
undergoes elimination to give the acid (Scheme 179). A similar approach has been used with BOC protected imidazoles, which then cyclize cleaving the ester bond aRer deprotection then neutralization. 436
10.2. Cyclic Urea Formation
Linker 231 is stable to acidic and neutral conditions.437,438 It is activated by treatment with sodium phenoxide and forms the cyclic urea 232 via the isocyanate (Scheme 180). The linker is then labile to nucleophiles and can be cleaved with NaOH in 70% iprOH in water
H O R N "~ "T~N"~ , OHN/] L"v'N'~ F O.~O, Ph

231
R"~ O O PhONa, h H O N . ~ N PO ~ DMF " ~ '~ a.~,~ HN ~..,. 232

Scheme 180
O
NaOH O tPrOH/H20= R.~OH
10.3. Dehydration
Linker 233 is activated by dehydration using TFA (Scheme 181) 439 Treatment with a primary amine releases the product as the amide
HO
O O"~R
oy.R
TFA
=.
~"O F ~
HN ' 2R
R'N~ R H
233
Scheme 181
10.4. Dithioacetal Protection of Ketone
A photolabile linker has been converted into a safety catch linker by protection of the ketone as the dithioacetal 234. 44o Activation involves removal of the dithioacetal using mercury(H) percldorate and cleavage of the linker is achieved by irradiation at 350nm (Scheme 182) No discussion is given on ensuring complete removal of the toxic mercury residues, although bis[(trifluoroactoxy)iodo]benzene or periodic acid may be used in the activation step instead of the mercury salt. The linker can be used for attaching carboxylic acid via the ester linkage, or alcohols via the carbonate.
R s R
hv
~ ~S
9%H20/THF
350nm = HO-'~R
Scheme 182
4930
10.5. Oxidation of Thioether
A sulfide linker 173 has been used for pyrimidines. 3s It is stable to both acidic and basic conditions, however, once oxidized to the sulfone 174 with mCPBA, it can be cleaved by nucleophilic aromatic substitution by amines (Scheme 183).
~"~SH
Cl'~lN"T'CFs CF3 CF3 .CFs NJ~'~L'co2Et== N,?~S CO2Et mCPBAp N-~-~r tcO2Et R'RNH N ~ cO2Et 'TEA,DMFg~s/J~N ~J D C M ~ , ~ N ~J DCM "R,N,~N~ R' 173 174
I
Scheme 183
10.6. Oxidation of Hydrazide The diphenylhydrazide linker 235 is activated by oxidation with NBS (Scheme 184). 441 It is then base labile, being cleaved by treatment with an amine to release the product as an amide. The process can be performed in one step, using copper(R) acetate in the presence of the nucleophile and base. 442 O O
,-/~,~ ~1" ~" R N

0
235
NBS
0
(~-~ N-'NIU'~R
H2NR'
Scheme 184
10.7. Reduction of Sulfoxide Electron rich benzylic linkers, which normally contain methoxy substituents, can be protected by exchanging one or more of the methoxy groups for a sulfoxide. The linker is stable to acid whilst in the oxidized state. Reduction of the sulfoxide(s) to the thioether(s) with SiCI4/thioanisole/anisole results in a more electron rich benzylic linker, hence cleavage is achieved with TFA (Scheme 174). The reduction o f th e suifoxide(s) is typically performed under acidic conditions so the two processes actually occur in the one step. This methodology has been used for linking carboxylic acids 443 and amides. 444
R
SiCl4/MeSCsHs/MeOCeHs
90% TFNDCM
O
HO~1~ R
Me/S~o
Scheme 185
I. W. James / Tetrahedron 55 (1999) 4855--4946
4931
10.8. Kenner's Safety Catch Linker

The acyl suifonamide developed by genner 34 is stable to both acid and base prior to activation. Under basic conditions the acidic acyl sulfonamide proton of 236 is removed protecting the acyl group fi'om nucleophilic cleavage. To activate the linker for cleavage the nitrogen is alkylated with either diazomethall34,35 or iodoacetonitrile (Scheme 185).36, 37 It is then cleaved using nucleophiles, such as hydroxide to give the carboxylic acid,34, 35 or amines to give the corresponding amides. 34-37 0
(RCO)20
I
DMAP,
I
R
C1"12N2 or DIEA, ICH2CN O
HO" ~ R OO X = Me, CI-~CN O
I)MSO
R"
Scheme 186
11. CONCLUSION As the field of solid phase organic synthesis expands, so does the demand for new and novel linkers. Many of the linkers used were first developed for peptide synthesis. These have performed admirably and the synthesis of a large range of molecules has been achieved. They also have limitations though. The range of functionalities is limited and many are not stable to a wide range of organic reactions. Conversely, some require cleavage conditions that are too harsh for certain functional groups. Iti recent years, many protecting groups developed for solution phase synthesis have been translated for use as linkers for solid phase organic synthesis. These have greatly expanded the functionalities available for linkage and have a wide range of chemical stabilities and cleavage conditions. One of the key challenges in this area is to utilize cleavage reagents that are readily removed from the cleaved product. This is especially the case when preparing the large numbers of compounds required in combinatorial chemistry. Volatile reagents are ideal for this, although recently developed high throughput purification techniques such as solid phase purification reagents have increased the scope of this process. The area of cleavage techniques and methods of purification of the large numbers of compounds created by combinatorial chemistry will be one of great development over the coming years. The safety catch approach may prove useful here, using selective conditions for activation, then conditions for the cleavage which are easily worked up. The area of traceless linkers provides one of the biggest challenges as this is not based on common protecting group techniques. Already, great advances have been made with the silyl linkers for attaching aromatic groups. It will be interesting to see if these last the test of time, or if new, more labile linkers are developed. Although the universal linker, one which may be applied to any molecule, is an admirable goal, much
4932
L W. James/ Tetrahedron 55 (1999) 4855--4946
work needs to be performed before this will be possible, if indeed it is possible. Methods that are useful in specific cases, i.e. non-universal, will continue to be developed, and successfully applied. What is important is to understand fully the capabilities and short-comings of both current and new linkers. This can only be achieved by the open reporting of conditions that work, but also those that do not, or result in premature cleavage. As in all areas of solid phase and combinatorial chemistry, the area of linkers is rapidly developing, and although many of the linkers reported here may not end up finding wide spread use, they will lay the foundation for new, more effective, linkers to be developed in the future.
12. ABBREVIATIONS
BOC, tert-butoxyearbonyl; BOP, benzotriazol- 1-yloxy-tris(dimethylamino)phosphonium hexfluorophosphate; CDI, 1,1'-carbonyldiimidazole; mCPBA, 3-chloroperoxybenzoic acid; CSA, 10camphorsulfonic acid; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC, 1,3-dicylcohexycarbodiimide; DCE, 1,2dichloroethane; DCM, dichloromethane; DDQ, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone; DDQH, 2,3dichloro-5,6-dicyano-l,4-hydroquinone; DDT, dithiothreitol; DEAD, diethyl azodiearboxylate; DIBAL, diisobutylaluminium hydride; DIC, 1,3-diisopropylcarbodiimide; DIEA, N,N-diisopropylethylandne; DMAP, 4dimethylaminopyridine; DMF, N,N-dimethylformamide; DMSO, dimethylsulfoxide; DMTST, dimethylthiosulfonium triflate; DSC, N, N'-disuccinimidyl carbonate; DTBP, di-tert-butylpyridine; EDT, 1,2ethanedithiol; Fmoc, 9-fluorenyimethoxycarbonyl; Ira, imidazole; HATU, N-[(dimethylamino)-lH-1,2,3triazol[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HBTU, Obenzotriazol-l-yl-N,N,N',N'-tetrarnethyluronium hexafluorophasphate; HOAr, 1-hydroxy-7-azabenzotriazole; HOBt, 1-hydroxybenzotriazole, LDA, lithium diisopropylamide; LHMDS, lithium bis(trimethylsilyl)amide; IVIES, 4-morpholineethanesulfonic acid; NBS, N-bromosuccinimide; NIS, N-iodosuccinimide; NMM, 4methylmorpholine; NMP, 1-methyl-2-pyrrolidinone, pfbm, perfluorobutyramide; PPTS, pyridinium ptoluenesulfonate; pTsOH, p-toluenesulfonic acid; py, pyridine; TBAF, tetrabutylammonium fluoride; TBDMS, tert.butyldimethylsilyl; TEA, triethylarnine; TES, triethylsilane; Tf, trifluoromethanesulfonyl; TFA, trifluoroacetic acid; TI-IF, tetrahydrofuran; THP, tetrahydropyran; TIPS, triisopropylsilane; TMS, trimethylsilyl; Tr, trityl. 13. ACKNOWLEDGEMENTS The author gratefully acknowledges Andrew Bray, Geoff Wickham, and Nicholas Ede for valuable discussion and advice throughout the preparation of this manuscript. The author also thanks Matt Tozer, Mark Bradley, Beata Krywult and Susan Eagle for their help.
14. REFERENCES
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2.
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Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Voufloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387, 268-272. Nicolaou, K. C.; Vourloumis, D.; Li, T.; Pastor, J.; Winssinger, N.; He, Y., Ninkovie, S.; Sarabia, F., Vallberg, H.; Roschangar, F.; King, N. P.; Ray, M.; Finlay, V.; Giannakakou, P.; Verdier-Pinard, P.; Hamel, E. Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103. Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F. Jr. Am. Chem. Soc. 1998, 120, 5132-5133. Atrash, B.; Bradley, M. Chem. Commun. 1997, 1397-1398. Hoffmann, S.; Krank, R. Tetrahedron Lett. 1994, 35, 7763-7766. Sola, R.; Saguer, P.; David, M., Pascal, R. d. Chem. Soc., Chem. Commun. 1993, 1786-1788. Sola, R.; Mery, J.; Pascal, R. Tetrahedron Lett. 1996, 37, 9195-9198. Wieland, T.; Birr, C.; Fleckenstein, P. Liebigs ~Inn. Chem. 1972, 756, 14-19. Routledge, A.; Abeli, C.; Balasubramanian, S. Tetrahedron Lett. 1997, 38, 122%1230. Wieland, T.; Lewalter, J.; Birr, C. LiebigsAnn. Chem. 1970, 740, 31-47. MiUington,C. R.; Quarrell, R.; Lowe, G. Tetrahedron Lett. 1998, 39, 7201-7204. Kiso, Y.; Fukui, T.; Tanaka, S.; Kimura, T.; Akaji, K. Tetrahedron Lett. 1994, 35, 3571-3574 Patek, M.; Lebl, M. Tetrahedron Lett. 1991, 32, 3891-3894.
4946
Biographical sketch
Ian W. James
Ian James completed an Honours degree at Monash University in Melbourne in 1988. He received his doctorate in 1992, having studied the kinetics of radical additions to heteroatomic double and triple bonds under the guidance of Prof. Athel Beckwith at the Australian National University in Canberra. He then worked with Prof. Willie Motherwell for 2 years at both Imperial College and University College, London, studying the application of transition metal chemistry to methylene cyclopropanes. In 1994, he returned to Australia to work on HIV protease inhibitors with David Fairlie at the Centre for Drug Discovery and Development, University of Queensland. In 1995, he moved back to Melbourne to work with Chiron Technologies. Whilst there his main area of work has been on the development and application of solid phase technologies to the discovery of new therapeutic agents.

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Tetrahedron Report Number 489

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TETRAHEDRON Pergamon Tetrahedron 55 (I 999) 4855--4946

Tetrahedron report number 489

Linkers for Solid Phase Organic Synthesis

Received 8 February 1999

l. W. James/Tetrahedron 55 (1999) 4855--4946

Protecting Group-I--Functional Group--Molecule Polymer-Spacer--Linker-I--FunctiGroup--Molecule onal Deprotection 1Cleavage

L W. James / Tetrahedron 55 (1999) 4855--4946

L W. James / Tetrahedron 55 (1999) 4855--4946

O2N~ ' O O ~'~ "OMe

(a) X = O avoids the acidic amide proton present when Co)X = NH

I.W. James / Tetrahedron 55 (1999) 4855-4946

Hindered handle Trityl linker

3.2. Base Labile

L W. James I Tetrahedron 55 (1999) 4855--4946

L W. James / Tetrahedron 55 (1999) 4855-4946

I. W. James / Tetrahedron 55 (1999) 4855-4946

cleavage R' = Me, CH2CN

L W. James / Tetrahedron 55 (1999) 4855--4946

SpacermLinker Polymer--Spacer--Linker Substrate PolymermSpacer Linker~Substrate

purified by I traditional techniques]

Relies on effective formation of bond between linker and substrate

L W. James/Tetrahedron 55 (1999) 4855-4946

O DIC/DIVIA~o~O/~" R 50%TFA/DCM O =" HO~,~R

L !4/. James / Tetrahedron 55 (1999) 4855-4946

Mitsunobu reaction ~ ~o e n CI3CCN, DBUBF3.OEt2 " hr ROH,

R,,P = ~"~N'S'RR' " (ii)CISO2R

Cleavage: 95% TFN'FES

Cleavage: 95% TFNDCM

!. W. James I Tetrahedron 55 (1999) 4855-4946

Cleavage: 20-50% TFNDCM

Cleavage: 20% TFNDCM

L W. James / Tetrahedron 55 (1999)4855-4946

X=O, S R = alkyl, awl

O~N- R O'Me R"

!. W. James / Tetrahedron 55 (1999) 4855-4946

50%TFA/DCM ~CRI py CI ROH, ~~--~O-R TFA HO-R 1% DCM TFA/

L W. James/Tetrahedron 55 (1999) 4855-4946

0 ~' . H o ~ g O ' ~ r ' /

O 9:10:1 TFA/DCM/H=O =" HO-R

Scheme 18 Wan= Linker: As discussed above in Section 6.1,

cleavage of the alcohol

attached via an ether bond to a

L W. James / Tetrahedron 55 (1999) 4855--4946

ROH, base ,. ~../.....si.O. R

ROH, DIEA ~h~._ X , or - //Si-O-R ~ \\ ROH, DIEA, DMAP 39 X = Ph or ipr

TBAF, AcOH THF

L W. James/Tetrahedron 55 (1999) 4855-4946

DIC/HOBt H ~ 9~f, Nl'h =' O 1 I I O 41

NPkj or N2H4 =' HO-R

O'R NaOMe= HO-R

Ph, O ,~"',v SI, "R " Ph

7.1.4. Reductive Cleavage

I.W. James I Tetrahedron 55 (1999) 4855--4946

L W. James/Tetrahedron 55 (1999) 4855-4946

HO.3S-.~SO.,,J-I O ~ O R Ill o OH R,,JJ,,H O

i) TFA ii) 0.1%TFA In 60% M e C I ~ . 60C

MeOH, 00C " R~ ' N ~ o N"O

L W. James I Tetrahedron 55 (1999) 4855--4946

Me-.0 Me,. O RCO2H _---~L..,.~I~I,,~R ~ , , - I ~ 1 - H BOP,DIEA