Towards the realisation of lead-oriented synthesis

DRUDIS-1297; No of Pages 7 Drug Discovery Today  Volume 00, Number 00  December 2013

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feature Towards the realisation of lead-oriented synthesis Richard Doveston1,2, Stephen Marsden1 and Adam Nelson1,2, [email protected]

Lead-oriented synthesis: a major challenge for synthetic chemists There is a strong link between the molecular properties of clinical candidates and the probability of successful development to yield marketed drugs [1]. Molecular properties that correlate with success in the development process include molecular size and lipophilicity (clogP) [2], the fraction of sp3-hybridised carbon atoms (Fsp3) [3] and the number of aromatic rings (nAr) [4]. Lead optimisation almost inevitably leads to increases in molecular weight and lipophilicity, and therefore tight control over the properties of initial lead molecules is advisable [5,6]. The concept of lead-oriented synthesis has recently been introduced to capture the specific problem of preparing diverse small molecules with lead-like molecular properties (Table 1) [7] (i.e. compounds that would serve as good starting points for lead optimisation). A recent study [7] found that >99% of commercially

available compounds are not lead-like. This study also found the vast majority of compounds that are reported in synthetic methodology papers are not lead-like either. The scale of the problem is further compounded by historically uneven and unsystematic exploration of chemical space: around half of all known compounds are based on just 0.25% of the known small molecule scaffolds [8]. This uneven exploration is reflected in the (lack of ) diversity of small molecule screening collections [9,10]. How, then, might large numbers of diverse, leadlike compounds be sourced to allow high-quality screening collections to be built and maintained? The realisation of lead-oriented synthesis will require the development of new synthetic methods and approaches that can deliver large numbers of diverse, lead-like small molecules. Indeed, the poor availability of diverse, lead-like small molecules might stem, in part, from the limited toolkit that is generally used to support

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Sourcing large numbers of lead-like molecules – compounds that would serve as good starting points for drug discovery programmes – is currently very challenging. The concept of lead-oriented synthesis has recently been articulated to capture the specific problem of preparing diverse small molecules with leadlike molecular properties. In this Feature, some methods that might be used to prepare lead-like molecular scaffolds are described, and presented in the context of diversity-oriented synthetic strategies that allow wide variation in molecular scaffold. It is concluded that the development of a wider toolkit of reactions that is reliable with more polar substrates will be required to allow genuine combination of molecular scaffold within lead-like chemical space.

drug discovery [11,12]. The challenge of realising lead-oriented synthesis should serve as a clarion call to the synthetic chemistry community; (for example, see [13]).

Learning from diversity-oriented synthesis We describe synthetic approaches that can assist the realisation of lead-oriented synthesis. We focus on approaches that could enable the synthesis of lead-like molecular scaffolds (i.e. scaffolds that can be decorated to yield large numbers of compounds that have lead-like molecular properties: such scaffolds need to be rather small, with up to 16 heavy atoms, so that lead-like properties are retained after decoration). Synthetic approaches that enable the combinatorial variation of the molecular scaffold will have particular value in lead-oriented synthesis. Although many diversity-oriented syntheses have tended to yield scaffolds that lie well outside lead-like chemical space, the underlying www.drugdiscoverytoday.com

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Drug Discovery Today  Volume 00, Number 00  December 2013

TABLE 1

synthetic strategies [14–17] might nonetheless also be exploited in lead-oriented synthesis. Indeed, diversity-oriented approaches have already been exploited in the synthesis of diverse central nervous system (CNS)-focused scaffolds [18] and in the synthesis of 3D fragments [19]. Fig. 1 illustrates three syntheses that exploit three important strategies for diversity-oriented synthesis. All three of these syntheses can be considered to exemplify the

Molecular properties and features proposed for lead-like small molecules [7] Molecular property and/or feature

Preferred values

Molecular size

14  heavy atoms  26a

Lipophilicity

1 < clogP < 3

Aromatic rings

nAr  3

Shape

More 3D shapeb

Substructures a

Absence of chemically reactive or redox-active groups b

3

Molecular weight  200–350 Da. Fsp can be a useful parameter for assessing three-dimensionality.

CO2Et

EtO2C

(a)

N O

a

EtO2C

H

CO2Et

2 EtO2C

b 1

N O CO2Et 3

(b)

N

O

O

N

CO2Me

N2

H

CO2Me

O N

O

O

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N

O

OTBS 4

O

O

O

OTBS

6

c OTBS

HN

H N

O

N

O

O

N2

H N

N

O

N

H

OTBS

O 5

7

(c) O RF

Ns N

O Si iPr 2

H

O

O OH NsN 10

HO

8 d

O Ns N

O

RF 9

O Si iPr 2

H

O N Ns

OH

OH

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FIGURE 1

Alternative diversity-oriented synthetic approaches. (a) An example of a branching pathway. (b) An example of a folding pathway. (c) An oligomer-based approach. (a) (i) NH3, NaBH4, Ti(OEt)4, EtOH; (ii) AcOH; (b) (i) NH2OHHCl, NaOAc, MeCN; (ii) toluene, 140 8C; (c) Rh2(O2CC7H15)4, benzene, 50 8C; (d) metathesis. RF denotes a fluorous-tagged linker. 2

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R

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NH2 12 (bi)

Boc N O NH

N

Steps

O CCl3

R1

R N Decoration

tri/ bi N Boc

CCl3

HN 13 (tri)

N

R2

15

14

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FIGURE 2

Synthesis of a bridged scaffold 14 from two building blocks. The scaffold 14 might be exploited in the synthesis of a wide range of final compounds 15. R = cumyl.

‘build-couple-pair’ approach [15], in which building blocks are prepared (built), linked (coupled) and cyclised (paired). The branching pathway strategy (Fig. 1a) involves the conversion of key intermediates (e.g. 1) into alternative molecule scaffolds (e.g. 2,

3) [20]; for another example, see [21]. The approach requires the design of intermediates that are functionalised such that many alternative cyclisation reactions are possible. In the case of 1, a total of 12 natural-product-like scaffolds were prepared. By contrast, folding pathways

(Fig. 1b) involve the conversion of alternative substrates (e.g. 4, 5) into distinct molecular scaffolds (e.g. 6, 7) under common reaction conditions [22]; for another key example, see [23]. Here, the substrates must be designed such that alternative scaffolds are obtained. In the

CN

(a)

(II)

(I) CN

N Bn 16 (bi) Br F3C

Ph

N Ph N Cbz

N F3C

O

20

19

N Bn

18

N H

Ph N

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bi/ uni (a)

Ph

PMP N

HN

21

17 (uni)

(b) NH2

(I)

(II) NH

Br 22 (bi)

bi/ bi (b)

O

OH

O N

N H

HN

O

NBn NH

N H

N H 25

24

23 (bi)

H N

N

Ph O

O

Ph

26

27

(c) (I) 28 (bi) O

29 (bi) Cl

30 (bi)

(II)

Ns N

NsNH2 bi/ bi/ bi (c)

O 31

Ns N

Ns N

Cl BocN

O

Cl

O

Cl

AcO 32

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FIGURE 3

Syntheses of lead-like molecular scaffolds. (a) Synthesis of heterocyclic scaffolds using aminoarylation reactions. (I) Illustrative synthesis of a piperazine; (II) examples of other heterocycles prepared using a similar approach. (b) Synthesis of medium-ring lactams by Cu-catalysed amination and transamidation. (I) Illustrative example of the approach; (II) examples of other lactams prepared using similar approaches. (c) Synthesis of spirocyclic scaffolds using multicomponent reactions. (I) Illustrative example of the approach; (II) examples of other spirocycles prepared using the approach. (a) 1 mol% Pd2(dba)3, 8 mol% P(2-furyl)3, NaOtBu, toluene, 105 8C; (b) 5 mol% CuI, K2CO3, toluene, 110 8C; (c) (i) NBS, 0 8C ! rt; (ii) K2CO3, MeCN. www.drugdiscoverytoday.com

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illustrated example, the substrates each contained an imide, an indole and a diazoketone; presumably, generation of a carbonyl ylide was followed by intramolecular 1,3-dipolar cycloaddition with the indole ring to give the alternative molecular scaffolds.

(a) (I)

An oligomer-based approach (Fig. 1c) has yielded natural-product-like molecules of unprecedented scaffold diversity (over 80 distinct scaffolds) [24]; for another example, see [25]. Simple unsaturated building blocks were iteratively attached to a fluorous-tagged linker to

N

CN

N R N

R N

34 (II)

yield metathesis substrates (e.g. 8, 9). Metathesis cascade reactions then ‘reprogrammed’ the molecular scaffolds to give, after deprotection, skeletally diverse products (e.g. 10, 11). A wide range of alternative molecular scaffolds was accessible through variation of the specific

N

R N 36

35

6 5 4 34

3

AlogP

2 35 1 0 -1

25

20

15

10

30

36

40

35

-2 Features  PERSPECTIVE

Heavy atoms

-3 (b) R

(I)

HO H

H H H

(II)

HO

N

OH

O

H O

H H H

HO OH

N

O

O 37

38

R

O

N H

R

Ph

39

6 5 4 37 3

38

AlogP

2

39

1 0 -1

10

15

20

25

30

35

40

-2 -3

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FIGURE 4

Molecular properties of virtual libraries based on the scaffolds 34–39. (a) (I) Structure of the scaffolds 34–36. (II) Molecular properties of virtual libraries based on the scaffolds 34–36. (b) (I) Structure of the scaffolds 37–39. (II) Molecular properties of virtual libraries based on the scaffolds 37–39. 4

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Extension to lead-like molecular scaffolds The value of lead-oriented synthetic approaches should be assessed in terms of the diversity and the molecular properties of the resulting compounds. Although emphasis is placed here on the synthesis of molecular scaffolds, it is important to consider the properties of the range of final compounds that might ultimately be prepared. An example is illustrated in Fig. 2. Ircatalysed amination of the bis-allylic trichloroacetimidate 13, followed by ring-closing metathesis, yielded the bicyclic, differentially protected scaffold 14 [26]. The value of the approach should be assessed in terms of the diversity and molecular properties of final compounds 15 that might be prepared from the scaffold 14. Synthetic approaches that enable combinatorial variation of molecular scaffold therefore have particular value because of the

higher diversity of the compounds that might be prepared. Throughout this article, we use a conceptual framework that we have developed to assess the power of synthetic approaches to molecular scaffolds [27]. The framework is hierarchical, and captures the relative power of alternative synthetic approaches in terms of the number of new bonds that are formed to each starting material (note that new bonds formed within a starting material are counted only once). Synthetic approaches are judged to be more powerful if more bonds are formed to individual starting materials, or if more starting materials are used. In the case of the synthesis of the bridged scaffold 14, the bi-connective amine 12 is combined with the tri-connective substrate 13. The synthesis of 14 from 12 and 13 thus receives a tri/bi classification. Three approaches that could have value in the synthesis of lead-like molecular scaffolds are illustrated in Fig. 3. In each case, an illustrative

synthesis of a scaffold is provided, together with examples of additional scaffolds that have also been prepared. The power of the synthetic approach is captured in terms of the connectivity of the starting materials used. Palladium-catalysed aminoarylation reactions are powerful in the synthesis of a wide range of molecular scaffolds (Fig. 3a) [28–31]. The approach usually involves the reaction between a bi-connective unsaturated amine derivative and a uni-connective aryl bromide (e.g. 16 + 17 ! 18). The approach is powerful because a wide range of molecular scaffolds is accessible through variation of the size of the ring formed (e.g. !19), the specific aryl (or hetaryl) bromide used (e.g. !19) or through the use of cyclic unsaturated amine substrates (e.g. !20 or 21). Aminoarylation reactions have also been exploited in the synthesis of more complex molecular scaffolds [32,33]. Approaches that combine pairs of bi-connective starting materials [34–36] can be

H2N

Boc N

O

N Features  PERSPECTIVE

building blocks used, and linkages between the building blocks.

PERSPECTIVE

N 41

Amino-

N

34a F3C

Boc N

1. Deprotection

Arylation

2. Decoration

S N

O O

BocHN N N

N

40

N 35b

42

O N Boc N

HN

O

N

CN 43

36c

CN

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FIGURE 5

Proposed synthetic approach to libraries 34–36. Aminoarylation of the unsaturated amine derivative 40 would yield pyrrolidines such as 41–43. Subsequent deprotection and decoration (for example by amide formation, sulfonylation, urea formation, (het)arylation and reductive amination) would yield potential screening compounds. www.drugdiscoverytoday.com

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extremely valuable because variation of the resulting molecular scaffold is often possible; such reactions have been dubbed ‘ambiphilepairing reactions’ [34]. A range of benzo-fused medium-ring lactam scaffolds has been prepared by Cu-catalysed amination, followed by ring expansion by transamidation (Fig. 3b) [37]. Through minor variation of the reaction conditions, the approach enabled variation of the size of the lactam ring formed (e.g. !26 or 27), and the incorporation of a fused hetaryl ring (e.g. !26). The power of synthetic approaches is greatly increased when more than two starting materials are used. An approach involving three biconnective building blocks has been exploited in the synthesis of a range of morpholine derivatives (Fig. 3c) [38]. Variation of the alkene used enabled the synthesis of scaffolds with alternative spiro-fused rings (e.g. 32, 33).

Concluding remarks and future outlook

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In this article, some methods that could have value in the synthesis of lead-like molecular scaffolds have been described. In each of the examples illustrated, some variation of the structure of the product scaffold was possible. However, we highlight two current barriers to lead-oriented synthesis supporting drug discovery programmes. First, synthetic chemists must demonstrate the value of new methodology in the synthesis of lead-like scaffolds and molecules. As an example, we have considered the lead-likeness of libraries based on six nitrogen heterocycles: three that might be prepared using an aminoarylation reaction (34–36) and three that we have previously prepared using a diversity-oriented [39] synthetic approach (37– 39; Figs 4 and 5). To allow direct comparison, a small library was enumerated in each case by virtual decoration of the nitrogen heterocycle with the same range of substituents (Fig. 4). Assessment of the molecular properties of the virtual libraries 34–36 revealed that the libraries 34 and 35 could target lead-like chemical space more effectively than library 36 (Fig. 4a). Interestingly, this analysis also revealed that the library 38, based on a scaffold prepared using a diversity-oriented synthetic approach [39], could also target lead-like chemical space. This type of analysis could be used by synthetic chemists to guide which specific examples are used to illustrate the scope and limitations of methods, thereby expanding the toolkit of reactions that can yield lead-like scaffolds. Such studies might also yield reactions that are more reliable with more polar substrates, minimising the systematic failed synthesis of the more polar 6

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compounds in designed arrays (log P drift) [7]. However, the cheminformatic tools needed to direct such research are very rarely embedded in academic synthetic organic groups. Second, it will be necessary to translate new methods that have been validated in the synthesis of lead-like small molecule scaffolds. Most likely, the establishment of innovative partnerships between academic synthesis groups and compound suppliers will be needed to increase the availability of diverse lead-like small molecules. Such molecules would provide better starting points for discovery programmes, and could thereby help to address the grand challenge [40] of improving research and development productivity in the pharmaceutical industry. References 1 Wenlock, M.C. et al. (2003) A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem. 46, 1250–1256 2 Leeson, P.D. and Springthorpe, B. (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov. 6, 881–890 3 Ritchie, T.J. and Macdonald, S.J.F. (2009) The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design? Drug Discov. Today 14, 1011–1020 4 Lovering, F. et al. (2009) Escape from Flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 5 Oprea, T.I. et al. (2001) Is there a difference between leads and drugs? A historical perspective. J. Chem. Inf. Comput. Sci. 41, 1308–1315 6 Keseru¨, G.M. and Makara, G.M. (2009) The influence of lead discovery strategies on the properties of drug candidates. Nat. Rev. Drug Discov. 8, 203–212 7 Nadin, A. et al. (2012) Lead-oriented synthesis: a new opportunity for synthetic chemistry. Angew. Chem. Int. Ed. 51, 1114–1122 8 Lipkus, A.H. et al. (2008) Structural diversity of organic chemistry. A scaffold analysis of the CAS registry. J. Org. Chem. 73, 4443–4451 9 Shelat, A.A. and Guy, R.K. (2007) Scaffold composition and biological relevance of screening libraries. Nat. Chem. Biol. 3, 442–446 10 Krier, M. et al. (2006) Assessing the scaffold diversity of screening libraries. J. Chem. Inf. Model. 46, 512–524 11 Roughley, S.D. and Jordan, A.M. (2011) The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451– 3479 12 Cooper, T.W.J. et al. (2010) Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries). Angew. Chem. Int. Ed. 49, 8082–8091 13 Wild, H. et al. (2011) The importance of chemistry for the future of the pharma industry. Angew. Chem. Int. Ed. 50, 7452–7453 14 Dow, M. et al. (2012) Towards the systematic exploration of chemical space. Org. Biomol. Chem. 10, 17–28 15 Nielsen, T.E. and Schreiber, S.L. (2008) Towards the optimal screening collection: a synthesis strategy. Angew. Chem. Int. Ed. 47, 48–56

16 Burke, M.D. and Schreiber, S.L. (2004) A planning strategy for diversity-oriented synthesis. Angew. Chem. Int. Ed. 43, 46–56 17 Galloway, W.R.J.D. et al. (2010) Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat. Commun. 1, 80 18 Lowe, J.T. et al. (2012) Synthesis of profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries. J. Org. Chem. 77, 7187–7211 19 Hung, A.W. et al. (2011) Route to three-dimensional fragments using diversity-oriented synthesis. Proc. Natl. Acad. Sci. U. S. A. 108, 6799–6804 20 Robbins, D. et al. (2011) Synthesis of natural-productlike scaffolds in unprecedented efficiency via a 12-fold branching pathway. Chem. Sci. 2, 2232–2235 21 Kumagai, N. et al. (2006) Short synthesis of skeletally and stereochemically diverse small molecules by coupling Petasis condensation reactions to cyclization reactions. Angew. Chem. Int. Ed. 45, 3635–3638 22 Oguri, H. and Schreiber, S.L. (2005) Skeletal diversity via a folding pathway: synthesis of indole alkaloid-like skeletons. Org. Lett. 7, 47–50 23 Burke, M.D. et al. (2004) A synthesis strategy yielding skeletally diverse small molecules combinatorially. J. Am. Chem. Soc. 126, 14095–14104 24 Morton, D. et al. (2009) Synthesis of natural-product-like molecules with over eighty distinct scaffolds. Angew. Chem. Int. Ed. 48, 104–109 25 Marcaurelle, L.A. et al. (2010) An aldol-based build/ couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors. J. Am. Chem. Soc. 132, 16962– 16976 26 Brawn, R.A. et al. (2012) An efficient synthesis of bridged heterocycles from an Ir(I) bis-amination/ringclosing metathesis sequence. Org. Lett. 14, 4802– 4805 27 MacLellan, P. and Nelson, A. (2013) A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds. Chem. Commun. 49, 2383–2393 28 Nakhla, J.S. et al. (2009) Palladium-catalyzed alkene carboamination reactions for the synthesis of substituted piperazines. Tetrahedron 65, 6549–6570 29 Bertrand, M.B. et al. (2007) Mild conditions for the synthesis of functionalized pyrrolidines via Pdcatalyzed carboamination reactions. Org. Lett. 9, 457– 460 30 Bertrand, M.B. et al. (2008) Mild conditions for Pdcatalyzed carboamination of N-protected hex-4enylamines and 1-, 3-, and 4-substituted pent-4enylamines. Scope, limitations, and mechanism of pyrrolidine formation. J. Org. Chem. 73, 8851–8860 31 Leathen, M.L. et al. (2009) New strategy for the synthesis of substituted morpholines. J. Org. Chem. 74, 5107–5110 32 Ney, J.E. and Wolfe, J.P. (2005) Selective synthesis of 5or 6-aryl octahydrocyclopenta[b]pyrroles from a common precursor through control of competing pathways in a Pd-catalyzed reaction. J. Am. Chem. Soc. 127, 8644–8651 33 Schultz, D.M. and Wolfe, J.P. (2011) Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives. Org. Lett. 13, 2962–2965 34 Rolfe, A. et al. (2010) Formal [4 + 3] epoxide cascade reaction via a complementary ambiphilic pairing strategy. Org. Lett. 12, 1216–1219

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PERSPECTIVE

Richard Doveston1,2 Stephen Marsden1 Adam Nelson1,2 1 School of Chemistry, University of Leeds, Leeds LS2 9JT, UK 2 Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK

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