novel strategies for solid-phase construction of small-molecule combinatorial libraries

1359-6446/01/$ – see front matter ©2001 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(01)02070-0

▼ The field of combinatorial chemistry hasreceived a great deal of interest for the rapidgeneration of novel and drug-like heterocyclicscaffolds. Today, chemists face increasinglyhigh demands for novel compound librarieswith drug-like properties for screening against a rapidly growing range of therapeutictargets resulting from genomics research.Combinatorial libraries, depending on theirutility, can be categorized into several classes,including broad and diverse discovery libraries,targeted libraries and focused libraries.Therefore, the strategies for design and synthesis of these libraries are implementedin different ways1. However, the followingchallenges and problems in generating asmall-molecule combinatorial library are al-ways encountered regardless of whether it is amixture- or single-compound-based library:• Solid-phase vs solution-phase synthesis;• Drug-like properties;• Novelty and patentability;• Molecular diversity;• Efficiency of synthesis;

• Purity of compound libraries;• Cost of production; and• Compatibility with automation.

Although there has been a rapid growth ofliterature dealing with the development ofnovel strategies for addressing these issues,the scope of this article is limited. Thus, thisreview can only highlight the recent and rep-resentative examples with a combination ofthe author’s own work and current interests,primarily focused on novel synthetic strategiesfor rapidly generating heterocyclic scaffoldsand combinatorial libraries on a solid support.The strategies relating to the development ofnovel linkers for solid-phase synthesis2, high-throughput purification of combinatorial libraries3 and rational approaches in librarydesign4 are not reviewed here.

Template-based approachThe concept of ‘privileged structures’ was introduced by Evans and coworkers in 1988(Ref. 5), and recently updated by Patchett6. Aprivileged structure is ‘a single molecularframework able to provide ligands for diversereceptors’. A classic example of privileged struc-ture is the benzodiazepine moiety that is foundin a variety of therapeutic agents. To exploitmolecular diversity and generate drug-likecombinatorial libraries for various biologicaltargets, these privileged structures have beenused as templates from which functional varia-tions can be achieved at multiple diversificationpositions using combinatorial approaches.These libraries are used for screening in a vari-ety of biological assays and exploring theirability to affect particular pathways in cells ororganisms, hopefully leading to the discoveryof highly specific and effective molecules.

Novel strategies for solid-phaseconstruction of small-moleculecombinatorial librariesBoliang Lou

Boliang LouAdvanced SynTech

9800 Bluegrass ParkwayLouisville

KT 40299, USAtel: +1 502 499 0122fax: +1 502 499 0078

e-mail: [email protected]

During the past decade we witnessed a rapid advance in the new field

of chemical science, combinatorial chemistry. The pharmaceutical industries

invested heavily in accelerating the development of this new technology.

As a result, it has become an extremely important tool in lead

identification and optimization in current pharmaceutical research. It

also quickly crossed the boundaries of the original chemical discipline

and demonstrated great potential in many other important areas, such

as searching for novel and highly efficient catalysts and superconductive

material. Researchers from both academic and industrial laboratories have

directed great effort towards the development of novel strategies for

combinatorial synthesis.

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The purine structure can be found in many agonists, antagonists and sub-strates7,8, and it plays a crucial role inmany cellular processes. Therefore, theexploration of chemical diversity basedon the purine template and the devel-opment of practical synthetic proto-cols was an attractive objective; thereare several approaches reported in theliterature (Fig. 1)9–16. The most impres-sive was the solid- and solution-phasecombination strategy developed bySchultz and coworkers9,10,12,14, whichenables the complete diversification atthe C2, C6 and N9 positions on thepurine template. From the libraries,the same group then identified a seriesof highly potent and selective CDK2-kinase inhibitors. The most potent inhibitor has an IC50 value againstCDK2-cyclin A of 6 nM (Ref. 9).

The common features in both thesolid- and solution-phase synthesesshown in Fig. 19–15 are the Mitsunobualkylation at the N9 position, the nucleophilic amination at the C6 position and the Mitsunobu alkylationor nucleophilic amination at the C2 position. However, the order of thesereactions might vary in the differentprotocols.

More recently, 2,6,8-trisubstitutedpurines were synthesized from 2,6-dichloropurine bound to Rink resin atthe N9 position16. Following conven-tional aminations at the C2 and C6 positions, the C8 substitutes were thenintroduced by bromination at the C8position and a palladium (Pd)-mediatedcross-coupling reaction.

An alternative strategy to the con-struction of the diverse combinatoriallibraries is based on natural-product-like templates. These templates haverigid conformations and the potentialfor multisite functionalization. Theyare usually assembled by highly effi-cient solid-phase chemistry as reportedby Schreiber and coworkers (Fig. 2)17,18.The same group proposed the diver-sity-oriented organic synthesis concept

Figure 1. Solution- and solid-phase syntheses of combinatorial libraries based on thepurine template.

N

N N

N

N

N

R1

R3 R2

R4

R5

N

N NH

N

Cl

(Cl)F

N

N NH

N

NH

A = SNAr aminationM = Mitsunobu alkylationB = BrominationC = Cross-coupling

Cl

N

N NH

N

N

F

R1

N

N NH

N

Cl

NR4

R5

N

N N

N

NH R1

Cl

O

CF3

CF3

O

(Ref. 14)

N

N N

N

Cl

R1

Cl

(Refs 15,16)

(Refs 9,10)

(Refs 9−11)(Refs 12,13)

(Ref. 14)

B & C

R6

A

MA

A

MM

MA

M

A

M

A

A

Drug Discovery Today

A

Figure 2. Combinatorial synthesis based on a synthetic polycyclic template17,18.Abbreviations: DIPEA, N,N,diisopropylethylamine; PyBOP, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate.

Nucleophilic addition

HO

O

OH

O

H2N+

PyBOPDIPEA HO

O

NH

O

HO2C N+

R

O−

O

O

N

O

O RH

HH

HN

O

Electrophilic

capping

Electrophilic capping Nucleophilic

addition

Electrophiliccapping

Reductive cleavage

Electrophilic

capping

Various substituents

Various scaffoldsDrug Discovery Today

and demonstrated the importance of novel and structurallycomplex templates for generating the small-molecule libraries that are useful for exploiting chemical genomics19.

Versatile precursor-based approachThe use of highly versatile polymer-bound precursors forthe rapid generation of multiple scaffolds became an effec-tive method for quick access to diversity combinatorial libraries. These polymer-bound building blocks are usually

readily prepared from commerciallyavailable starting material, and containmultiple functional group(s) and/or reactive sites suitable for exploringstructure diversification. Unlike thetemplate-based approach, these pre-cursors undergo higher degrees ofstructure variations through a series ofchemical reactions and proliferatestructurally diverse and biologically interesting heterocyclic scaffolds.

These polymer-bound versatile pre-cursors were often developed based onclassic organic synthesis. For example,in addition to its utility in reductivealkylation, the imine moiety has beenwidely used in the formation of diversenitrogen-containing heterocyclic rings

through cycloadditions, condensation reactions and othernucleophilic additions. Several laboratories then adaptedthese conventional transformations to solid-phase synthe-sis using resin-immobilized imines via the condensation oftethered amino acids with aldehydes, generating 4-thiazol-idinone, β-lactam, pyrrolidine and polycyclic scaffolds(Fig. 3)20–23.

Armstrong24 proposed that a multiple core structure library (MCSL) generated from a common precursor

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Figure 3. Resin-immobilized imines as precursors for rapid generation of multipleheterocyclic scaffolds.

X

O

R1

N R2

X

O

R1

N S

O

R2

R3

X

O

R1

N

O R3

R2X

O

R1

NH

R3

R2

X

O

N

HNR2

R3

Pg

(Ref. 21)

(Ref. 20)

(Ref. 22)

(Ref. 23)


Figure 4. Armstrong’s solid- and solution-phase strategies for the rapid generation of Multiple Core Structure Libraries (MCSL)24,25.

XBu3Sn

O

O

O

+

O

O

R

O

OH

O

OH

OAc

HO

O

O

HN

R

HO

N

O

O

HO

R1

R2

O

Ar

O

OHO

R1 N

O

R2

R3 HN

O

NH

N

O

R3

O

R2

R

O

HO

RORO

N

O

R2R1

NR1

R5 R6

R3

R2

R1 N

O

R2

R3

OH

O

Solid-phase Solution-phase


O

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possesses a higher degree of diversitybecause of the structure variations notonly from the functionalities but alsofrom the orientation of the display. Asingle-core structure-based library gen-erates different compounds by chang-ing only the functionalities that aredisplayed. Squaric acid was identifiedas a versatile precursor and then at-tached to a solid support via an arylether linkage. Transformations involv-ing the polymer-bound squarates gavea variety of fused aromatic and hetero-aromatic scaffolds as shown in Fig. 4.

The same research group also applieda similar strategy to solution-phasecombinatorial synthesis. By using a ‘universal isocyanide’, 1-isocyano-cyclohexene, in the Ugi reaction, theproduct cyclohexenamides can serve as a powerful precursor to a variety of scaffolds25. An oxazolinium-5-one(münchnone) was proposed as an active intermediate that reacts withmany nucleophiles to yield the productsillustrated in Fig. 4.

Jung reported a method for the rapid expansion of ascaffold collection based on polymer-bound 3-hydroxy-2-methylidenepropionic acid26, which was prepared via theBaylis–Hillman reaction of chlorotrityl-resin-bound acrylicester with aldehydes. The presence of two functionalgroups of the precursor enabled a wide range of post-mod-ifications, such as the Michael addition, 1,3-dipolar cy-cloaddition, dehydration and electronic capping resultingin an array of interesting scaffolds (Fig. 5).

During the past several years, many laboratories inde-pendently reported the formation of various heterocyclicscaffolds using resin-immobilized 4-fluoro-3-nitrobenzoicacid. A common synthetic strategy adapted in the synthe-ses is illustrated in Fig. 6 (Refs 27–36). The first step is thedisplacement of fluoride at position 4 by various nucleo-philes, such as amines and thiols. Subsequent reductionsof the nitro-intermediates followed by various cyclizationprotocols led to different heterocyclic structures, such asbenzimidazolone, benzimidazole, benzopiperazinone, ben-zodiazepine, benzothiazepinone and tetrahydroquinoxa-linedione. A representative set of scaffolds derived fromthis building block is shown in Fig. 6.

Recently, our laboratories and others reported a similarapproach to constructing biologically important heterocyclesusing polymer-bound 4-(bromomethyl)-3-nitrobenzoate and

the corresponding amides (Fig. 7)37–39. The building blockundergoes nucleophilic displacement followed by reductionand cyclocondensation reactions to afford 3,4-dihydro-quinazolines37, benzodiazepin-2-one38, tetrahydroquina-zolinone39 and many other heterocyclic scaffolds (Fig. 7)(Zhang, J. et al., unpublished).

The ‘libraries from libraries’ conceptProposed by Houghten in 1994 (Ref. 40), the ‘libraries fromlibraries’ concept has been widely practiced in combina-torial synthesis. The central feature of the approach is theconversion of libraries into new libraries while the com-pounds remain attached to the solid support. The secondgeneration of libraries produced by this process shouldhave markedly different physical, chemical and biologicalproperties compared with the libraries from which theywere derived. Houghten demonstrated the concept by con-verting a peptide library into a permethylated one in whichthe typical –CONH– peptidic amide bond was modified byN-methylation40.

The same laboratory has extended this approach to theconstruction of small organic compound libraries. The ex-isting resin-bound peptide libraries have been successfullymodified by reduction of amide bonds followed by a seriesof further chemical manipulations to afford the secondgeneration of libraries. The linear dipeptide libraries were

Figure 5. Polymer-bound 3-hydroxy-2-methylidenepropionic acids for synthesis ofMultiple Core Structure Libraries (MCSL)26.

O

ORCHO

O

O

R1

OH

O

O

O

R1

O

O

NR7

R6

O

O

R1

OH

O

O

R1

OH

NH

R5

O

O

R1

NH

R5

O

R1

OR2

O

O

O

R1

NN

R3

O

R4

O

O

R1

NN

R3

O

R4

OH

Michael additionand further modification

Dehydrationor electrophiliccapping


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used for the generation of small hetero-cyclic compound libraries, such as cyclicureas, thioureas, bicyclic guanidines,imidazol-pyrido-indoles, hydantoinsand thiohydantoins (Fig. 8)41–45.

Based on the same concept, a solid-phase synthesis of a piperazine libraryfrom the corresponding diketopiper-azine library has been recently demon-strated (Fig. 9a)46. The reduction of thediketopiperazines by a BH3–THF com-plex on solid support was performed inAres™ reactors on automated synthe-sizers (Advanced ChemTech, Louisville,KY, USA). A similar approach was un-dertaken to generate a highly diversifiedpiperazinone library. In this synthesis,the Ugi four-component condensationreaction was carried out on various α-amino acid Wang resins under standardconditions. An array of resin-bound

Figure 6. Polymer-bound 4-fluoro-3-nitrobenzoic acid as a versatile precursor for rapid generation of multiple heterocyclic scaffolds.

H2N

O

N

NS

R1

R2

NH

O

N

N

R3

O

R2

R4

R1

X

O

N

NR2

R1

HO

N

NO

R1

R2O

XNO2

F

O

NH

O

N

N

R2

O

R1

R3

O

X

O

N

N

R2

R3

O

R1

X

O

N

N

R1

O

ONu

H2N

O

N

NNH

R1

R2

X

O

S

N

R2

O

NHR1

Nucleophilic displacement

Reduction

Heterocyclicring formation

(Ref. 28)

(Ref. 29)

(Ref. 30)

(Refs 31,32)(Ref. 33)

(Ref. 34)

(Ref. 35)

(Ref. 36)

(Ref. 27)


Figure 7. Polymer-bound 4-(bromomethyl)-3-nitrobenzoic acids as a versatile precursorfor rapid generation of multiple heterocyclic scaffolds.

XNO2

O

Br

HX

O

NR1

OHN

HX

O

N

NO

R1

R2

R3

O

N

N

R1

R2

HX

Nucleophilic displacement

Reduction

Heterocyclicring formation

(Ref. 38)

(Ref. 37)

(Ref. 39) Drug Discovery Today

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Ugi-products were then subjected tothe reduction by using BH3–THF at65°C for 6 h. The piperazinones werereleased via intramolecular cyclizationin the presence of 5% HOAc indichloromethane (Fig. 9b)47. The Ugireduction–cyclization strategy offers a practical extension of the repertoire of Ugi-chemistry in combinatorial synthesis.

ConclusionsThe evolution of combinatorial chem-istry has provided access to greatly ex-panded chemical collections useful forlead identification in pharmaceuticalcompanies. Several new chemical enti-ties generated from combinatorial li-braries are currently being evaluated inthe clinic for the treatment of varioushuman diseases48–50. The current trendto explore chemical diversity has shiftedfrom merely increasing the number of new compounds synthesized, gener-ating huge libraries and exploring relatively simple reactions to creating biologically relevant and information-rich combinatorial libraries in a muchmore defined and rational fashion.

Although the pharmaceutical indus-tries still continue to mainly adapt theparallel synthesis technologies for thegeneration of combinatorial libraries,the mix-and-split method devised withingenious encoding methods, such asradiofrequency, has also demonstratedgreat value. Recently, several new tech-niques, such as string synthesis51 and Euclidean shape-en-coded synthesis52, were reported to combine the high effi-ciency of the split synthesis with the advantage of theparallel method. However, putting them into real practicein pharmaceutical laboratories remains to be seen.

Developing new concepts to create novel and biologi-cally relevant scaffolds and engineering efficient strategiesto accelerate the syntheses of combinatorial libraries areimportant in the discovery of lead molecules against vari-ous new targets validated from genomics and proteomicsresearch. The combination of combinatorial chemistry, rational drug design and classic medicinal chemistryoptimization techniques is the key to delivering high-quality drug candidates in the most cost-effective manner.

Integration of innovative chemistry technologies andstate-of-the-art automation is equally important to achievethese goals.

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Figure 8. Houghten’s ‘libraries from libraries’ approaches to rapid generation of multiplelinear and heterocyclic-based libraries.

NH

O

R1

HN

O

NH2

R2

H2N

O

R1

N

HNX

O

R2

H2N

R1

HN

NH2

R2

N

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R3

R1

H

+

HN

R1

N

R3

N

R2

X

R4

X = O, S

X = O, S

NH

N

N

R3

R2

ONH2

R(Ref. 44)

(Ref. 46)

(Ref. 45)

(Ref. 42)

(Ref. 43)


Figure 9. (a) Solid-phase synthesis of piperazine derivatives from the correspondingdiketopiperazine library47. (b) Solid-phase synthesis of piperazinone derivatives based onthe Ugi reduction–cyclization strategy48.

X L

O

R1

R2

O

R3

N

N

O

R1

N

R2 O

R3

NH

OR4

O

BH3−THF

N

N

R4

R3

O

R1

R2

N

R1

R2

R3

N

1 BH3−THF65˚C, 4−6 h

2 Cleavage

(a)

(b)

65˚C, 4−6 h

Cleavage


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novel strategies for solid-phase construction of small-molecule combinatorial libraries

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