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BIOCATALYSIS Biocatalytic synthesis of planar chiral macrocycles Christina Gagnon, Éric Godin, Clémentine Minozzi, Johann Sosoe, Corentin Pochet, Shawn K. Collins* Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations that provide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. In many cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality. The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methods to impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy for enantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles can be formed with high enantioselectivity from simple building blocks and are decorated with functionality that allows one to further modify the macrocycles with diverse structural features. M acrocycles are capable of simultaneously displaying extended molecular frame- works while retaining some conforma- tional bias ( 1, 2). The cyclic skeleton can even impart severe restrictions on bond rotations that can lock functional groups or other molecular fragments in conformations that would be otherwise unfavorable in an acyclic analog (3, 4). Such is the case in planar chiral cyclophanes, a subset of macrocycles for which conformation (or size) limits the rota- tion of an aromatic unit within the skeleton. The presence of planar chirality in natural product terpenes as well as macrocyclic pep- tides is well documented, and atropisomerism has become increasingly apparent in drug dis- covery (Fig. 1A) (57). As such, methods for forming peptidic cyclophanes have attracted increased attention. However, in most cases, synthetic methods face the steep challenge of having to form the rigidified and often strained macrocycle itself while simultaneously impart- ing high levels of enantioselection. Consequently, atroposelective macrocyclizations are rare and can be classified into two synthetic strategies (Fig. 1B). Most protocols employ auxiliaries that enforce conformations of the acyclic precursor through noncovalent interactions ( 8, 9). Much more rare are instances in which catalysis is exploited to induce asymmetry during the for- mation of the cyclophane (10, 11). Although macrocyclization has been exam- ined via biocatalysis ( 1216), the preparation of prevalent planar chiral macrocycles has largely been ignored. This is surprising given that bio- catalysis has had a profound impact on the syn- thesis of crucial chiral building blocks such as secondary alcohols and amines (1721). In par- ticular, the dynamic kinetic resolution (DKR) de- veloped by Bäckvall and co-workers is a strategy involving transition metal catalysis and bio- catalysis working in concert. The process in- volves a transition metal complex that catalyzes racemization of a substrate (in general, a second- ary alcohol or amine) and an enzyme (typically a lipase) that selectively acylates one enantiomer forming an ester or amide (22). A subsequent step is then required to access the desired alco- hol and amine through deacylation (Fig. 1C). In examining whether an analogous process could be applied to the preparation of planar chiral macrocycles, several differences from the standard DKR are apparent (Fig. 1D). First, in DKR protocols, the acylation is only tempo- rary, as the free alcohol or amine is typically desired. In addition, the acylating agent can be added in excess to improve reaction rates and yields. In a macrocyclization process, the acylation is inherent in the final product and the stoichiometry between alcohol and acylating agent is naturally fixed. Second, in the absence of secondary alcohols, a different racemization process must be used. Despite the challenges, a biocatalytic DKR process to access planar chiral cyclophanes has consid- erable potential: The thermal stabilities and high enantioselectivities observed with com- mercially available lipases make them ideal for macrocyclization processes, and the simple building blocks required allow one to rapidly build complexity in a chiral architecture. A key goal in the development of a chemoen- zymatic synthesis of planar chiral macrocycles was to permit synthesis from common and simple building blocks. As such, we envisioned exploiting common diacids or diesters as ali- phatic linkers (A, Fig. 1D). The chemoenzy- matic macrocyclization would take place via sequential acylations using a lipase on an aromatic diol B (Fig. 1D) that possessed core functionality amendable to diversification and applicability to drug discovery efforts. In contrast to the classic DKR process, race- mization of intermediate C occurs through free rotation of the aromatic ring. Several chal- lenges exist for the chemoenzymatic macro- cyclization. The ring-closing event would result in a rigidified macrocycle, and the enzyme must be able to promote such a ring closure. We expected that elevated temperatures could be used to promote macrocyclization, but we were conscious of possibly degrading the en- zyme or affecting the conformational stability of the cyclophane (i.e., at what temperature the ansa-bridge would be able to freely rotate and racemize the desired macrocycle). To help favor macrocyclization, longer diesters A could be employed, but the aromatic substi- tuents R 1 would have to be bulkier to restrict the rotation of the ansa-bridge. The size of the R 1 substituents is also critical, as they must affect the selectivity of the enzyme but not negatively influence the reactivity. Given the previous success of the serine hydrolase Candida antarctica lipase B (CALB) (23, 24) in DKR of secondary alcohols (25, 26), we used the enzyme in our synthesis of [13] paracyclophanes by macrolactonization of benzylic diols (Fig. 2A). We tested a molecule with an unsubstituted aromatic core (1a) and isolated the desired achiral macrocycle 3a in reasonable yield. Having demonstrated that CALB could promote the macrocycli- zation, we examined a subsequent cyclization having an aromatic core substituted with OMe (methoxy) groups (1b), but the yield of the corresponding [13]paracyclophane 3b was only 10%. In addition, variable temperature nuclear magnetic resonance (VT NMR) anal- ysis of the benzylic proton signals (highlighted in green, Fig. 2A) showed coalescence of the signals at 50°C. Macrocyclization employing larger bromo substituents (diol 1c) was even less successful, most likely due to an unfavor- able steric clash between the ortho-substituted benzylic diol and the enzyme active site. We redesigned the starting diol with an inserted methylene group next to the aromatic core (5, Fig. 2B). With the extended diol, we obtained the desired [14]paracyclophane 6 in good yield and high enantioselectivity. VT NMR analysis of the benzylic proton signals of 6 showed no coalescence of the signals even at 100°C. Although lowering the temperature decreased the yield of 6, raising the temperature had no beneficial effect on yield and did not promote rotation of the ansa-bridge, which would lower the overall enantiopurity. Although CALB tends to favor acylation of R-centered carbon chiral centers (27), it was unknown how the CALB active site, which has naturally evolved to differentiate the ge- ometry of tetrahedral carbons centers, would accommodate the prochiral aromatic plane of the forming macrocycle. To better under- stand how the active site environment might engage different conformations of the cyclo- phane substrate, we performed docking with the program Fitted ( 28, 29) from the FORECASTER computational platform (Fig. 2C) (30). Lee and co-workers previously reported an x-ray crystal structure of CALB bound to a phos- phonate inhibitor (PDB ID 5GV5) (31). We replaced the phosphonate inhibitor with each atropisomer of the macrocycle and examined RESEARCH Gagnon et al., Science 367, 917921 (2020) 21 February 2020 1 of 5 Département de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec H3C 3J7, Canada. *Corresponding author. 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Page 1: BIOCATALYSIS Biocatalytic synthesis of planar chiral macrocycles · Biocatalytic synthesis of planar chiral macrocycles Christina Gagnon, Éric Godin, Clémentine Minozzi, Johann

BIOCATALYSIS

Biocatalytic synthesis of planar chiral macrocyclesChristina Gagnon, Éric Godin, Clémentine Minozzi, Johann Sosoe, Corentin Pochet, Shawn K. Collins*

Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations thatprovide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. Inmany cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality.The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methodsto impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy forenantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles canbe formed with high enantioselectivity from simple building blocks and are decorated with functionalitythat allows one to further modify the macrocycles with diverse structural features.

Macrocycles are capable of simultaneouslydisplaying extended molecular frame-works while retaining some conforma-tional bias (1, 2). The cyclic skeleton caneven impart severe restrictions on bond

rotations that can lock functional groups orother molecular fragments in conformationsthat would be otherwise unfavorable in anacyclic analog (3, 4). Such is the case in planarchiral cyclophanes, a subset of macrocycles forwhich conformation (or size) limits the rota-tion of an aromatic unit within the skeleton.The presence of planar chirality in natural

product terpenes as well as macrocyclic pep-tides is well documented, and atropisomerismhas become increasingly apparent in drug dis-covery (Fig. 1A) (5–7). As such, methods forforming peptidic cyclophanes have attractedincreased attention. However, in most cases,synthetic methods face the steep challenge ofhaving to form the rigidified and often strainedmacrocycle itself while simultaneously impart-ing high levels of enantioselection. Consequently,atroposelective macrocyclizations are rare andcan be classified into two synthetic strategies(Fig. 1B).Most protocols employ auxiliaries thatenforce conformations of the acyclic precursorthrough noncovalent interactions (8, 9). Muchmore rare are instances in which catalysis isexploited to induce asymmetry during the for-mation of the cyclophane (10, 11).Although macrocyclization has been exam-

ined via biocatalysis (12–16), the preparation ofprevalent planar chiral macrocycles has largelybeen ignored. This is surprising given that bio-catalysis has had a profound impact on the syn-thesis of crucial chiral building blocks such assecondary alcohols and amines (17–21). In par-ticular, the dynamic kinetic resolution (DKR) de-veloped by Bäckvall and co-workers is a strategyinvolving transition metal catalysis and bio-catalysis working in concert. The process in-volves a transition metal complex that catalyzes

racemization of a substrate (in general, a second-ary alcohol or amine) and an enzyme (typically alipase) that selectively acylates one enantiomerforming an ester or amide (22). A subsequentstep is then required to access the desired alco-hol and amine through deacylation (Fig. 1C).In examining whether an analogous processcould be applied to the preparation of planarchiral macrocycles, several differences from thestandard DKR are apparent (Fig. 1D). First, inDKR protocols, the acylation is only tempo-rary, as the free alcohol or amine is typicallydesired. In addition, the acylating agent canbe added in excess to improve reaction ratesand yields. In a macrocyclization process,the acylation is inherent in the final productand the stoichiometry between alcohol andacylating agent is naturally fixed. Second, inthe absence of secondary alcohols, a differentracemization process must be used. Despitethe challenges, a biocatalytic DKR process toaccess planar chiral cyclophanes has consid-erable potential: The thermal stabilities andhigh enantioselectivities observed with com-mercially available lipases make them idealfor macrocyclization processes, and the simplebuilding blocks required allow one to rapidlybuild complexity in a chiral architecture.A key goal in the development of a chemoen-

zymatic synthesis of planar chiral macrocycleswas to permit synthesis from common andsimple building blocks. As such, we envisionedexploiting common diacids or diesters as ali-phatic linkers (A, Fig. 1D). The chemoenzy-matic macrocyclization would take place viasequential acylations using a lipase on anaromatic diol B (Fig. 1D) that possessed corefunctionality amendable to diversification andapplicability to drug discovery efforts.In contrast to the classic DKR process, race-

mization of intermediate C occurs throughfree rotation of the aromatic ring. Several chal-lenges exist for the chemoenzymatic macro-cyclization. The ring-closing event would resultin a rigidified macrocycle, and the enzymemust be able to promote such a ring closure.We expected that elevated temperatures couldbe used to promote macrocyclization, but we

were conscious of possibly degrading the en-zyme or affecting the conformational stabilityof the cyclophane (i.e., at what temperaturethe ansa-bridge would be able to freely rotateand racemize the desiredmacrocycle). To helpfavor macrocyclization, longer diesters Acould be employed, but the aromatic substi-tuents R1 would have to be bulkier to restrictthe rotation of the ansa-bridge. The size of theR1 substituents is also critical, as they mustaffect the selectivity of the enzyme but notnegatively influence the reactivity.Given the previous success of the serine

hydrolase Candida antarctica lipase B (CALB)(23, 24) in DKR of secondary alcohols (25, 26),we used the enzyme in our synthesis of [13]paracyclophanes by macrolactonization ofbenzylic diols (Fig. 2A). We tested a moleculewith an unsubstituted aromatic core (1a) andisolated the desired achiral macrocycle 3ain reasonable yield. Having demonstratedthat CALB could promote the macrocycli-zation, we examined a subsequent cyclizationhaving an aromatic core substituted withOMe (methoxy) groups (1b), but the yield ofthe corresponding [13]paracyclophane 3bwasonly 10%. In addition, variable temperaturenuclear magnetic resonance (VT NMR) anal-ysis of the benzylic proton signals (highlightedin green, Fig. 2A) showed coalescence of thesignals at 50°C. Macrocyclization employinglarger bromo substituents (diol 1c) was evenless successful, most likely due to an unfavor-able steric clash between the ortho-substitutedbenzylic diol and the enzyme active site. Weredesigned the starting diol with an insertedmethylene group next to the aromatic core (5,Fig. 2B). With the extended diol, we obtainedthe desired [14]paracyclophane6 in good yieldand high enantioselectivity. VT NMR analysisof the benzylic proton signals of 6 showedno coalescence of the signals even at 100°C.Although lowering the temperature decreasedthe yield of 6, raising the temperature had nobeneficial effect on yield and did not promoterotation of the ansa-bridge, which would lowerthe overall enantiopurity.Although CALB tends to favor acylation of

R-centered carbon chiral centers (27), it wasunknown how the CALB active site, whichhas naturally evolved to differentiate the ge-ometry of tetrahedral carbons centers, wouldaccommodate the prochiral aromatic plane ofthe forming macrocycle. To better under-stand how the active site environment mightengage different conformations of the cyclo-phane substrate, we performed docking withthe program Fitted (28, 29) from the FORECASTERcomputational platform (Fig. 2C) (30). Leeand co-workers previously reported an x-raycrystal structure of CALB bound to a phos-phonate inhibitor (PDB ID 5GV5) (31). Wereplaced the phosphonate inhibitor with eachatropisomer of the macrocycle and examined

RESEARCH

Gagnon et al., Science 367, 917–921 (2020) 21 February 2020 1 of 5

Département de Chimie, Centre for Green Chemistry andCatalysis, Université de Montréal, CP 6128 StationDowntown, Montréal, Québec H3C 3J7, Canada.*Corresponding author. Email: [email protected]

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the binding mode suggested by docking (32).The major product (−)-6 is oriented with itscarboxyl groups toward the nearby catalyticserine residue (Ser105), with one of the bro-mine substituents pointing toward the exteriorof the active site. The opposite enantiomer istranslated by >2.5 Å in the docking model,which suggests that the serine-catalyzed re-action would be geometrically challenging.The projected translation of (+)-6 results froma clash between a bromine atom and Leu140,precluding binding of the bromine atom intothe hydrophobic site delineated by Leu140,Ala141, and Leu144. In a docking of the startingdibromo diol 5, it fits into the cavity with its

alcohol extending toward the catalytically ac-tive serine. Indeed, even a monoesterified in-termediate orients itself within the active sitewith its carboxylate toward the serine residueand the bromine substituents in a conforma-tion mirroring that of the desired cyclophane.The biocatalytic synthesis of [14]paracyclophane6 could be easily reproduced on the gramscale (see supplementary materials), and weproceeded to explore the substrate scope withregard to ring size. Although the dibromo cy-clophane 6 could be obtained by using adiacid with a 6-methylene spacer [-(CH2)6-],reducing the spacer to four or five methyleneunits did not substantially increase ring strain,

and the resulting [12]- and [13]paracyclophaneswere obtained in good yields and high enan-tioselectivities (Fig. 3). This series of macro-cycles could be prepared with chlorine oriodine atoms replacing the bromine substitu-ents. The resulting [12]-, [13]-, and [14]para-cyclophanes (10→12) were all isolated withcomparable yield and enantiopurity, despitevariation in the size of the halogen substituent.Extending the ansa-bridge by an additional

methylene spacer provided a good yield of[15]paracyclophane 9; however, the productwas isolated as a racemic mixture, suggestingthat the larger aliphatic ring no longer con-strained rotation of the planar cyclophane. The

Gagnon et al., Science 367, 917–921 (2020) 21 February 2020 2 of 5

Fig. 1. Planar chirality in macrocycles. (A) Examples of planar chiral macrocycles in natural products and pharmaceuticals. (B) Methods for installing planarchirality in macrocycles. (C and D) Notable concepts for a proposed chemoenzymatic synthesis of planar chiral macrocycles. Me, methyl; p-tol, p-toluene;Cy, cyclohexyl; Ph, phenyl; Ts, tosyl; R, H, aryl; R1, alkyl, aryl, halogen; R2, alkyl, aryl; rt, room temperature; krac, rate of racemic reaction.

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larger size of the iodine allowed for the synthe-sis of the enantioenriched [15]paracyclophane17. To investigate whether the active site ofthe enzyme could tolerate more functional-ized ansa-bridges, we prepared two differentmacrocycles that have rigidified 1,3-diynes intheir backbones with phenyl-substituted (18)and alkynyl-substituted (19) cores, as well asa [14]paracyclophane 20 that has a disulfidebridge, a common motif found in bioactivemacrocyclic peptides (33). A series of func-tionalized aromatic diols were also well tol-erated in the macrocyclization process. Theterphenyl-basedmacrocycle21 could be formedviamacrocyclization as could similarly substi-

tuted p-anisoyl and m-anisoyl cyclophanes(22 and 23, respectively) with high enantio-selectivity. We were also able to synthesize[14]paracyclophanes 24 and 25, which havecores with either phenylalkynyl or hexynylsubstituents. Heteroatom-containing functionalgroups such as the p-methylaniline substitu-ents present in macrocycle 26 could also beinstalled within the chiral macrocyclic frame-works. Finally, C1-symmetric derivatives wereformed in high enantioselectivity. Macrocycle27 was isolated with one iodide substituentand one alkynyl unit, whereas macrocycle 28was isolated with one bromide substituentand a Csp

3-hybridizedmotif (benzyl). Notably,

the halogen-containing planar chiral macro-cycles can act as a platform for the synthesisof other derivatives through modern cross-coupling techniques (34). For example, themacrocycle 29 was prepared having Bpin(pinacolatoboron) functionality via Miyauraborylation. The bromo-substituted cyclophane6 could be subjected to Heck coupling to formmacrocycle 30. The macrocycle 30 could beformed via the biocatalytic route in highselectivity but lower yield (19%). As such, theability to exploit the “platform”macrocycles isparticularly powerful for accessing other sub-stitution patterns that may not be compatiblewith the CALB enzyme (35–37). Other cross-

Gagnon et al., Science 367, 917–921 (2020) 21 February 2020 3 of 5

Fig. 2. Biocatalytic synthesis of planar chiral macrocycles employing a lipase CALB. (A and B) Development of the biocatalytic macrocyclization. Greenhighlighted areas indicate methylene units monitored by VT NMR. aIsolated yields (0.1-mmol scale). bDetermined by chiral SFC high-performance liquidchromatography analysis. See supplementary materials for details. cExtending reaction time to 48 hours: 81% 6, >99% enantiomeric excess (ee). dUsing MeCN assolvent: 16% 6, >99% ee. e[2.5 mM]. f[10 mM]. (C) Computational docking of products and intermediates to CALB.

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coupling techniques were also viable for diver-sification of the macrocycles: Suzuki-couplingformed the terphenyl-based macrocycle 21from the Br-substituted cyclophane 6, whereasSonogashira coupling on the iodo-substituted

cyclophane 16 afforded macrocycle 25 in highyield with little loss of enantiopurity, exemplify-ing the resistance of the macrocycles to cleavageeven when heated in basic aqueous conditions.The preparation of a series of functionalized

planar chiralmacrocycles that have halogen orborylated substituents opens avenues for di-versification outside the boundaries of whatmay be tolerated by the enzyme active site. Thechallenge in the preparation of planar chiral

Gagnon et al., Science 367, 917–921 (2020) 21 February 2020 4 of 5

Fig. 3. Scope of the biocatalytic macrocyclization to afford planar chiral cyclophanes. All macrocyclizations were performed under standard conditions.Variations in reaction time are indicated when necessary. Detailed reaction conditions for the derivatizations of 6 are presented in the supplementary materials.

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macrocycles in drug discovery is now wellrecognized. With the pervasive awareness ofenvironmental issues, it would seem apt thatbiocatalysis provides an innovative solution.

REFERENCES AND NOTES

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(2015).23. C. R. Johnson, H. Sakaguchi, Synlett 1992, 813–816 (1992).24. C. Ortiz et al., Catal. Sci. Technol. 9, 2380–2420 (2019).25. G. Zhi-wei, T. K. Ngooi, A. Scilimati, G. Fulling, C. J. Sih,

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ACKNOWLEDGMENTS

We thank N. Moitessier for help with the FORECASTER program.Funding: This work was supported by the Natural Sciences andEngineering Research Council of Canada (NSERC, Discovery grant1043344), American Chemical Society Petroleum Research Fund(ACS PRF 60211-ND1), Université de Montréal, and the Fondsde Recherche Nature et Technologie via the Centre in GreenChemistry and Catalysis (grant FRQNT-2020-RS4-265155-CCVC).Author contributions: C.G., E.G., C.M., J.S., and C.P. synthesizedprecursors and macrocycles. C.G. performed docking experiments.S.K.C. designed and directed the investigations. S.K.C., C.G., J.S.,and E.G. wrote the manuscript. Competing interests: Nonedeclared. Data and materials availability: All data needed toevaluate the conclusions in the paper are available in the main textor the supplementary materials.

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/367/6480/917/suppl/DC1Materials and MethodsNMR SpectraReferences (38–52)

4 October 2019; accepted 21 January 202010.1126/science.aaz7381

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Biocatalytic synthesis of planar chiral macrocyclesChristina Gagnon, Éric Godin, Clémentine Minozzi, Johann Sosoe, Corentin Pochet and Shawn K. Collins

DOI: 10.1126/science.aaz7381 (6480), 917-921.367Science 

, this issue p. 917Sciencehow using an enzyme as the catalyst for sequential acylation reactions can impart the observed stereochemistry.synthesis of planar chiral macrocycles with handles that can be easily functionalized. Computational docking suggests

developed aet al.it can hold the molecule in functional conformations. Using a well-established lipase enzyme, Gagnon becausechirality when substituents of the ring cannot rotate freely. Restricted rotation is generally valued in macrocycles

are often conformationally constrained, and some exhibit planar−−macrocycles−−Molecules with very large ringsEnzymes lock in planar chirality

ARTICLE TOOLS http://science.sciencemag.org/content/367/6480/917

MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2020/02/19/367.6480.917.DC1

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