Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.The research leading to these results has received funding from the European Research Council under the European UnionÏs Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. [279337/DOS]. The authors also thank AstraZeneca, the EPSRC, the BBSRC, the MRC and the Wellcome Trust for funding. F.N. and D.L.K. thank the Gates Cambridge. F.N. also thanks Trinity College for a Krishnan-Ang Studentship. D.W. thanks the DFG for a postdoctoral fellowship (WI 4198/1-1). S.B. thanks the Herchel Smith Fund. The authors thank Dr John Davies for X-ray crystallography and Dr Andrew Bond for refinement (both from the University of Cambridge)

Bartlett, S

Galloway, WRJD

Kunciw, DL

Nie, F

Sore, HF

Spring, DR

Stokes, JE

Wilcke, D

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape

Bartlett, Sean

ORA - Oxford University Research Archive

A multidimensional diversity-oriented synthesis strategy for structurally diverse and complex macrocycles

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Angewandte Chemie International Edition

Apollo (Cambridge)

German Edition: DOI: 10.1002/ange.201605460Synthetic MethodsInternational Edition: DOI: 10.1002/anie.201605460A Multidimensional Diversity-Oriented Synthesis Strategy forStructurally Diverse and Complex MacrocyclesFeilin Nie, Dominique L. Kunciw, David Wilcke, Jamie E. Stokes, Warren R. J. D. Galloway,Sean Bartlett, Hannah F. Sore, and David R. Spring*Dedicated to Professor Stuart L. Schreiber on the occasion of his 60th birthdayAbstract: Synthetic macrocycles are an attractive area in drugdiscovery. However, their use has been hindered by a lack ofversatile platforms for the generation of structurally (and thusshape) diverse macrocycle libraries. Herein, we describe a newconcept in library synthesis, termed multidimensional diver-sity-oriented synthesis, and its application towards macro-cycles. This enabled the step-efficient generation of a library of45 novel, structurally diverse, and highly-functionalizedmacrocycles based around a broad range of scaffolds andincorporating a wide variety of biologically relevant structuralmotifs. The synthesis strategy exploited the diverse reactivity ofaza-ylides and imines, and featured eight different macro-cyclization methods, two of which were novel. Computationalanalyses reveal a broad coverage of molecular shape space bythe library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecularshape.Macrocyclic compounds are associated with a diverse rangeof biological activities and they have proven therapeuticpotential.[1] However, synthetic macrocycles are widely con-sidered to be underexplored within drug discovery. This hasbeen attributed to concerns regarding synthetic tractability.[2]Despite the success of early work on macrocycle librarysynthesis,[3] there remains a dearth of robust synthetic plat-forms for the efficient generation of macrocyclic libraries withhigh levels of structural diversity; in particular, variation inthe nature of macrocyclic ring scaffolds is often limited.[2b–c,4]This is significant in the context of biological screening, sincethe range of biological activities displayed by a librarycorrelates to its overall shape diversity, which in turn isdirectly related to its structural (principally scaffold) diver-sity.[5–7] Diversity-oriented synthesis (DOS) targets structur-ally (including scaffold) diverse molecule collections.[5,8]Several DOS-type strategies specifically aimed at macro-cycles have emerged, including two-directional synthesis,[2c]ring-expansion methods[9] and domain shuffling.[10] Manymacrocycle DOS campaigns are based around the three-phase build/couple/pair (B/C/P) strategy.[7,11] Recently, wereported the development of multidimensional coupling,which involves the use of a diverse set of branching reactionson a pluripotent functional group in the couple phase andleads to a greater structural (including scaffold) diversity inthe final macrocycle library.[4] We envisaged a more advancedDOS concept featuring the extensive application of branchingmultidimensional diversification throughout the synthesis(Scheme 1). Starting from a pluripotent functional groupScheme 1. Outline of the multidimensional DOS concept applied tomacrocycles. Multiple arrows represent many branching reactions, butonly one representative product is shown at each stage.[*] F. Nie, D. L. Kunciw, Dr. D. Wilcke, Dr. J. E. Stokes,Dr. W. R. J. D. Galloway, S. Bartlett, Dr. H. F. Sore, Prof. D. R. SpringDepartment of Chemistry, University of CambridgeLensfield Road, Cambridge CB2 1EW (UK)E-mail: spring@ch.cam.ac.ukSupporting information for this article can be found under:http://dx.doi.org/10.1002/anie.201605460.Ó 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.KGaA. This is an open access article under the terms of the CreativeCommons Attribution License, which permits use, distribution andreproduction in any medium, provided the original work is properlycited.AngewandteChemieCommunications11139Angew. Chem. Int. Ed. 2016, 55, 11139 –11143 Ó 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim(the primary branching point), compound generation wouldbe associated with the concomitant installation of functionalgroups that could act as pluripotent handles for furthermultidimensional diversification. This would enable the use ofpluripotent handles in the couple phase (for further rounds ofmultidimensional coupling or as additional branching points),in the pair phase (for divergent cyclizations) and modificationphase (for divergent scaffold modifications). It was antici-pated that application of this multidimensional concept tomacrocycle library synthesis would facilitate the rapid gen-eration of high levels of structural complexity and diversity.Herein, we report the development a multidimensionalDOS strategy towards highly functionalized macrocycleswhich uses fluorous-tagged azido building blocks and exploitsthe pluripotent reactivity of aza-ylides and imines(Scheme 1).The DOS commenced with the transformation of buildingblock 2 into 3a,b. The aza-ylide group served as the primarybranching point and 3a,b were reacted in situ in diverse aza-Wittig-type transformations to form 4–9 (Scheme 2). Afurther round of multidimensional coupling with 5 generated11–14, with various handles installed concomitantly to enablediverse macrocyclizations in the pair stage of the DOS. Theimine functional group was identified as a suitable secondarybranch point for the one-pot generation of an extensive set ofstructurally diverse and bio-relevant coupling motifs. Accord-ingly, 3b was converted to imines 15–16. An Ugi multi-component reaction of 15 afforded 17, and Staudinger ketenecycloaddition and Strecker reactions of 16 generated 18 and22, respectively. Compound 16 was also subjected to variousaza-Diels–Alder reactions to access 19–21, which featureda range of stereochemically and structurally diverse couplingmotifs. Pure samples of the Povarov reaction products 21aand 21d were isolated and the mixture of 21c,d was used inthe pair phase. Full stereochemical assignment of 21a–d wasmade retrospectively by NMR analysis of their macrocyclicproducts (see Figures S2–4 in the Supporting Information)and X-ray crystallography of one product (49b, Figure S5).[12]In the pair stage of the DOS, the linear cyclizationprecursors were “folded” into diverse macrocycles withScheme 2. The couple phase of the DOS. Reagents and conditions: i) PBu3 or PPh3, 4 ç molecular sieves, THF, RT; ii) THF, RT, then quenchedwith MeOH-H2O; iii) CO2, DIPEA, THF, RT; iv) CO2, THF, RT; v) Lindlar catalyst, HO(CH2)2S(CH2)2S(CH2)2OH, H2, MeOH, RT; vi) 40 8C, THF;vii) 8-azidooctanoic acid, 60 8C, 1.5 h, then isocyanocyclohexane, 60 8C, MeOH; viii) methoxyacetyl chloride, NEt3, 0 8C then 40 8C, CH2Cl2 ;ix) Danishefsky’s diene, Yb(OTf)3, 40 8C, THF; x) 2-cyclohexen-1-one, Yb(OTf)3, 40 8C, THF; xi) 3,4-dihydro-2H-pyran, Yb(OTf)3, 40 8C, THF;xii) TMS-CN, Yb(OTf)3, 55 8C, THF. RF=CH2COO(CH2)2C8F17. Stereochemistry of 20 detemined by NOESY (see Figure S1; DIPEA=diisopropyl-ethylamine, OTf= triflate, and TMS= trimethylsilyl).AngewandteChemieCommunications11140 www.angewandte.org Ó 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2016, 55, 11139 –11143different ring architectures making use of the pluripotency ofalkynes. Six known macrocyclisation methods were usedinitially (Scheme 3a–f). The Pauson–Khand reaction hasbeen used in the synthesis of medium rings (up to 11atoms),[13] but it has not yet been extended to macrocycles.We investigated it as a new method for macrocyclization of 4(Scheme 3g). After fluorous solid-phase extraction (F-SPE),optimized Pauson–Khand conditions (see Table S1) produceda mixture of structurally unusual macrocycles 23a,b contain-ing a cyclopentenone motif; these can be separated by HPLC,but we used the mixture in the modify phase).Iodo-alkynes may be cyclized into their corresponding 5-iodotriazoles, thereby generating another handle for macro-cycle functionalization. Current strategies require the syn-thesis of the linear iodinated analog.[14] Here, the directcycloaddition of azido-alkyne 6 into 5-iodotriazole 24c wasachieved using an external iodide source[15] (Scheme 3h). Thecomplete list of divergent macrocyclizations is presented inScheme S1 and Tables S2 and S3 in the Supporting Informa-tion. Attempted RuAAC macrocyclization of the linearprecursors featuring amine linkers resulted in decompositionof the starting material, and as such was not pursued.The macrocyclic scaffolds could be modified divergentlyby use of their latent functionalities. The fluorous tag wascleaved by transesterification, ester–amide exchange (exam-ples in Scheme 4a), ester reduction, and ester hydrolysis (seeTables S4 and S5). Annulation of the alkyne in 54a to form 61was achieved using RuAAC (Scheme 4a). Sonogashira cou-pling of 44a yielded 62 (Scheme 4b), dihydroxylation of 53aafforded 63, and acylation generated 64a,b (Scheme 4c).Overall, using the strategy outlined above and a limitednumber of building blocks, we synthesized a multidimensionalDOS library of 45 novel, structurally diverse and complexmacrocycles, based around a broad range of scaffolds andScheme 3. Representative examples of the macrocyclizations utilized inthe pair phase. Regiochemistry of 35 determined by NOESY (seeFigure S6).Scheme 4. Some examples of the divergent transformations used inthe modify stage of the DOS. Regiochemistry of 61 determined byNOESY (see Figure S7).AngewandteChemieCommunications11141Angew. Chem. Int. Ed. 2016, 55, 11139 –11143 Ó 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.orgincorporating a wide variety of biologically relevant structuralmotifs (see the Supporting Information for full details). Thepresence of a fluorous-tag on the common precursor 2allowed for generic purification during the DOS by F-SPE.[16] Final compounds were isolated in sufficient quantities(typically milligram) for unambiguous structural determina-tion and future screening in a variety of biological assays.Relative to our previous work,[4] the new strategy furnisheda library with a significantly greater variety of structuralmotifs and a larger range of macrocyclic ring sizes (15- to 33-membered rings).Principal moments of inertia (PMI) plots are commonlyused to visualize the shape diversity of compounds in“molecular shape space” spanned by the three basic extremeshape types “rod-like”, “disk-like” and “spherical”. Figure 1ais a PMI plot of a series of the DOSmacrocycles derived frommultidimensional coupling with 16 and which differ only inthe linking motif installed in the coupling phase at thesecondary branching point. The broad coverage of molecularshape space by this relatively small set of macrocyclesvalidates the use of a secondary branching point as anefficient means to generate shape diversity. Figure 1b showsthe shapes of three different groups of macrocycles (groups 1–3). The members of each group differ only in the nature of thepairing motif present. There is shape diversity present withineach group, which demonstrates that the pairing step caninfluence final molecular shape. Figure 1c shows the influ-ence of three series of post-pairing modifications uponmacrocycle shape: appendage and macrocyclic annulation(series 1), scaffold modification (series 2) and appendagereplacement (series 3). The members of each series differ onlyin the use or nature of any post-pairing modification. The dataindicates that post-pairing modification may influence molec-ular shape more significantly than previously thought andmay therefore represent a strategy for “tuning” the molecularshape (and thus target binding profile) of a given “parent”scaffold. A comparative PMI analysis of the DOS library withsome other molecular collections (see Supporting Informa-tion, Figure S8) indicated a high level of overall molecularshape diversity, which was comparable to that of a naturalproduct set, with more prominent spherical characteristicsthan a drug reference set.In summary, we have described a multidimensional DOSstrategy for the step-efficient generation of structurallycomplex and diverse macrocycles from simple and similarstarting materials. Macrocyles of this sort are of significantinterest from both a biological and synthetic perspective andtheir successful generation provides a validation of themultidimensional DOS concept. We report two new macro-cyclization methodologies (the Pauson–Khand reaction andCuAIAC with an external iodine source), which, we envisagewill prove valuable in a wider synthetic context. PMI analysisindicated that the library has a relatively high level of shapediversity, thus demonstrating the utility of the multidimen-sional approach for the compound-efficient coverage ofsubstantial molecular shape space. Interesting insights weregained into the impact that the various diversity-generatingelements of the DOS have upon molecular shape; this newFigure 1. PMI plots of some selected compounds. a) Compounds which differ only in the linking motif installed at the secondary branching point.b) Three different groups of macrocycles (groups 1–3), the members of which differ only in the pairing motif present. Members of each group arelinked together by a solid line. c) Three different series of compounds (Series 1–3) whose members differ only in the nature of any post-pairingmodification. d,e) Macrocycles shown in Figure 1a and b. Macrocycles in Figure 1c are shown in Scheme 4.AngewandteChemieCommunications11142 www.angewandte.org Ó 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2016, 55, 11139 –11143understanding may provide a basis for the deliberate synthesisof macrocycles with tailored molecular shapes.Multidimensional DOS integrates the B/C/P approachwith branching diversification. The result is a modular andhighly divergent concept for library synthesis that featuressystemic “product-equals-substrate” reactivity; functionalgroups generated in products become the new pluripotenthandles for the next stage of the synthesis, which facilitatesdiversification at every branching point. This allows for therapid generation of diversity and complexity from simple andsimilar starting materials. Thus, it is anticipated that themultidimensional concept will have broad strategic value inthe DOS of other molecular libraries. Work is underway toexpand this strategy to the synthesis of 12- to 14- memberedrings and to study the substrate scope of the new macro-cyclization methods reported herein.AcknowledgementsThe research leading to these results has received fundingfrom the European Research Council under the EuropeanUnionÏs Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. [279337/DOS]. The authors alsothank AstraZeneca, the EPSRC, the BBSRC, the MRC andthe Wellcome Trust for funding. F.N. and D.L.K. thank theGates Cambridge. F.N. also thanks Trinity College fora Krishnan-Ang Studentship. D.W. thanks the DFG fora postdoctoral fellowship (WI 4198/1-1). S.B. thanks theHerchel Smith Fund. The authors thank Dr John Davies forX-ray crystallography and Dr Andrew Bond for refinement(both from the University of Cambridge). Data accessibility:all data supporting this study are provided as SupportingInformation accompanying this paper.Keywords: diversity-oriented synthesis · macrocycles ·molecular diversity · synthesis design · synthetic methodsHow to cite: Angew. Chem. Int. Ed. 2016, 55, 11139–11143Angew. Chem. 2016, 128, 11305–11309[1] a) N. K. Terrett, Drug Discovery Today Technol. 2010, 7, e97;b) E. M. Driggers, S. P. Hale, J. Lee, N. K. Terrett,Nat. Rev. DrugDiscovery 2008, 7, 608; c) E. A. Villar, D. Beglov, S. Chenna-madhavuni, J. A. Porco Jr, D. Kozakov, S. Vajda, A. Whitty, Nat.Chem. Biol. 2014, 10, 723.[2] a) F. Giordanetto, J. Kihlberg, J. Med. Chem. 2014, 57, 278; b) C.Madsen, M. H. Clausen, Eur. J. Org. Chem. 2011, 3107;c) K. M. G. OÏConnell, H. S. G. Beckmann, L. Laraia, H. T.Horsley, A. Bender, A. R. Venkitaraman, D. R. Spring, Org.Biomol. 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These data can be obtained free of chargefrom The Cambridge Crystallographic Data Centre.[13] a) K. D. Closser, M. M. Quintal, K. M. Shea, J. Org. Chem. 2009,74, 3680; b) E. Comer, E. Rohan, L. Deng, J. A. Porco, Jr., Org.Lett. 2007, 9, 2123.[14] a) A. R. Bogdan, K. James, Org. Lett. 2011, 13, 4060; b) A. C.B¦dard, S. K. Collins, Org. Lett. 2014, 16, 5286.[15] W. S. Brotherton, R. J. Clark, L. Zhu, J. Org. Chem. 2012, 77,6443.[16] W. Zhang, D. P. Curran, Tetrahedron 2006, 62, 11837.Received: June 5, 2016Published online: August 2, 2016AngewandteChemieCommunications11143Angew. Chem. Int. Ed. 2016, 55, 11139 –11143 Ó 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

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A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

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