Practical Medicinal Chemistry with Macrocycles: Design, Synthesis, and Case Studies

About the Contributors

Andrew D. Abell

Dr. Abell graduated from the University of Adelaide with B.Sc. (Hon) and Ph.D. degrees and then undertook a postdoctoral fellowship at the University of Cambridge. He held a professorship at the University of Canterbury before returning to the University of Adelaide in 2007, where he is currently a professor of chemistry and node director of the ARC Centre of Excellence for Nanoscale BioPhotonics. His research interests are concerned with understanding the fundamental link between the chemical structure and shape of key bioactive molecules and their biological function. While his work is very much driven by fundamental science, he has always had a keen interest in pursuing associated commercial opportunities. The seed for this was sown with a sabbatical leave working as a visiting scientist, consultant, and senior Fulbright fellow with SmithKline Beecham (now GSK) in Philadelphia. In Australia, he co‐founded an Adelaide‐based company (Calpain Therapeutics) to develop macrocyclic protease inhibitors as a potential treatment for cataract and other conditions. He served as the Head of School of Chemistry and Physics at the University of Adelaide and is a recent recipient of the Royal Australian Chemical Institute Adrien Albert Prize and the Alexander R. Matzuk Prize and Lecture in Drug Discovery (Baylor College of Medicine, Houston).

Madhu Aeluri

Madhu Aeluri was born in Telangana, India, in 1987. He completed his B.Sc. in 2007 and M.Sc. with specialization in organic chemistry in 2009 from Osmania University. He obtained his Ph.D. in chemistry in 2014 from the University of Hyderabad under the guidance of Professor Prabhat Arya at Dr. Reddy’s Institute of Life Sciences (affiliated to University of Hyderabad). After the completion of his doctoral studies, he served as an associate scientific officer at GVK Biosciences Pvt Ltd., Hyderabad, for 2 years. Currently, he is working as a postdoctoral fellow in Professor Prabhat Arya’s research group. His research interests are the synthesis of natural product‐inspired and natural product‐derived small molecules hunting for small molecule modulators of protein–protein interactions.

Prabhat Arya

Prabhat Arya was born in 1958 and grew up on the University of Delhi campus where he received his undergraduate and graduate training. Following postdoctoral tenures at Cambridge and McGill Universities, he joined the National Research Council of Canada in Ottawa and worked with this organization for nearly 20 years. Later, he also had a short stint at the Ontario Institute of Cancer Research helping build the Medicinal Chemistry Program. In July 2009, he decided to follow an adventurous path and moved back to India with the objectives of establishing an integrated chemical biology program and thoroughly connecting his academic program to society and the business world. For him, this has been an exciting journey and a good learning path so far. He enjoys spending time with students and teaching Stereoselective Organic Synthesis to a wider audience in India. Overall, his research is focused on developing synthesis methods that allow building a chemical toolbox with compounds that are closer to bioactive natural products. These compounds can be classified as natural product‐inspired and hybrid natural products. The ultimate interest is in addressing challenging biological questions related to protein–protein interactions and pathways with an extensive use of small molecules emerging from his group. Prior to moving back to India (that he does not regret so far), he was also an adjunct professor at the Department of Biochemistry of McGill University, OHRI in Ottawa, and the Department of Chemistry and the Department of Biochemistry, Microbiology and Immunology of the University of Ottawa.

Richard Bartelt

Richard Bartelt was born in Wilhelm‐Pieck‐Stadt Guben, Germany, in 1987. He studied biochemistry at the Martin Luther University Halle‐Wittenberg, received his bachelor’s degree in 2011 on the topic of 3D‐QSAR of Substrates of the Human Amino Acid Transporter hPAT2, and continued his studies until 2014. Under the supervision of Prof. Wessjohann and docent Dr. Brandt, he prepared his master’s thesis—Homology Modelling of Prenylating Enzymes and Elucidation of Their Catalytic Mechanism—at the Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry (IPB), Halle. Since then, he has focused on chemoinformatic analyses of macrocycles in the same research group.

Anne‐Catherine Bédard

Anne‐Catherine Bédard was born in Québec, Canada, in 1987. She received her B.Sc. in Biopharmaceutical Sciences from the University of Ottawa in 2010 and her Ph.D. from the Université de Montréal under the supervision of Prof. Shawn K. Collins in 2015. She is currently an NSERC postdoctoral fellow in the laboratories of Prof. Tim F. Jamison at MIT.

François Bédard

François Bédard has completed a B.Sc. in Biochemistry and an M.Sc. in Pharmaceutical Sciences at Université Laval. He then commenced his Ph.D. studies in pharmaceutical sciences under the guidance of Prof. Éric Biron and Prof. Ismail Fliss at the Institute of Nutraceuticals and Functional Foods at Université Laval in 2014. As a Fonds de recherche du Québec – Nature et technologies (FRQNT) scholar, he is currently working on the synthesis, characterization, and pharmacokinetic studies of antimicrobial peptides from the bacteriocin family. His research interests include the synthesis and applications of natural cyclic peptides with antimicrobial activities and the design and development of antimicrobial peptide mimetics.

Éric Biron

Éric Biron obtained his Ph.D. in Chemistry under the direction of Prof. Normand Voyer at Université Laval, Canada, on the design and synthesis of functional peptidic nanostructures as artificial ion channels and DNA intercalators. After his Ph.D. in 2003, he moved to the Technische Universität München in the laboratory of Prof. Horst Kessler as a postdoctoral Alexander von Humboldt fellow. During his stay, he worked on the synthesis of N‐methylated peptide macrocycles and studied the effects of multiple N‐methylations on the conformation and activity of bioactive cyclic peptides. Upon conclusion of his postdoctoral studies, he returned to Québec and joined the Faculty of Pharmacy at Université Laval as a junior research scholar from the Fonds de recherche du Québec en Santé (FRQS). His research program focuses on the design and synthesis of cyclic peptides and macrocyclic peptidomimetics with antimicrobial activities and the development of new strategies to prepare and screen combinatorial macrocycle libraries. Prof. Biron is currently an associate professor at the Faculty of Pharmacy of Université Laval and a researcher at the Laboratory of Medicinal Chemistry at the Centre de recherche du Centre hospitalier universitaire de Québec in Québec City, Canada.

Andrew T. Bockus

Andrew T. Bockus earned his B.A. in Chemistry from Skidmore College in 2008 where he engaged in enzymology research with Professor Michelle Frey. In the following year as an instructor of English at China University of Petroleum in Beijing, Andrew joined the lab of Professor Scott Lokey at the University of California, Santa Cruz, to study the structure–permeability relationships of cyclic peptides, completing his Ph.D. in 2015. He continued his academic career postdoctoral work at Trinity University, where he taught undergraduate courses and studied the molecular recognition of peptides and proteins by synthetic hosts under the guidance of Professor Adam Urbach. Andrew currently works on the development of cyclic peptide therapeutics at Circle Pharma, Inc.

Wolfgang Brandt

Wolfgang Brandt studied chemistry at the Martin Luther University Halle‐Wittenberg in Halle (Germany), where he received his degree in Chemistry in 1979 and his Ph.D. in 1982 for studies on structure–activity relationships of auxins under the supervision of Professor Alfred Barth. From 1985 to 1986, he was a scientific coworker at the Institute of Neurobiology and Brain Research Academy of Science of the GDR (then East Germany) in Magdeburg. In 1987, he became head of the research group Molecular Modeling—Drug Design at the Department of Biochemistry/Biotechnology of the University of Halle. In 1992, he was on sabbatical leave at the Clinical Research Institute of Montreal, Canada (Prof. Dr. P. W. Schiller). He received his Habilitation (Asst. Prof.) in 1997. In August 2001 he moved to the Department of Bioorganic Chemistry headed by Prof. Ludger Wessjohann at the Leibniz Institute of Plant Biochemistry in Halle as a group leader for computational chemistry. His research interests cover all fields of computational chemistry and molecular modeling. He has published over 170 scientific papers, books, and some licensed patents.

Shawn K. Collins

Shawn K. Collins obtained a B.Sc. degree from Concordia University in 1996 and his Ph.D. at the University of Ottawa (Prof. A. G. Fallis) in 2001. After an NSERC postdoctoral fellowship with Professor L. E. Overman (University of California, Irvine), he joined the faculty at Université de Montréal in September 2003 and was promoted to Full Professor in 2015. Professor Collins’ research group is interested in the development of novel synthetic methods, particularly involving catalysis, photochemistry, and continuous flow methods.

David J. Craik

David J. Craik obtained his Ph.D. in Organic Chemistry from La Trobe University in Melbourne, Australia, and undertook postdoctoral studies at Florida State and Syracuse Universities before taking up a lectureship at the Victorian College of Pharmacy in 1983. He was appointed Professor of Medicinal Chemistry and Head of School in 1988. He then moved to University of Queensland in 1995 to set up a new biomolecular NMR laboratory and is currently an NHMRC senior principal research fellow and group leader in IMB. His research focuses on applications of circular proteins, toxins, and NMR in drug design. He is also a fellow of the Australian Academy of Science and has received numerous awards for his research, including the Ralph F. Hirschmann Award from the American Chemical Society. He is an author of more than 600 scientific papers and has trained 60 Ph.D. students.

Patrick G. Dougherty

Patrick G. Dougherty completed his B.S. in Chemistry and Biochemistry at Florida State University in 2013. He joined the Pei group at the Ohio State University in 2014. His research currently focuses on integrating chemical biology and computational chemistry approaches for macrocyclic drug discovery and lead optimization against therapeutically relevant intracellular PPIs.

Ian J. S. Fairlamb

Ian J. S. Fairlamb was appointed as lecturer in York in 2001, following a Ph.D. with Dr. J. M. Dickinson in Manchester (1996/1999) and postdoctoral research with Prof. G. C. Lloyd‐Jones in Bristol (2000/2001). He was a Royal Society URF (2004/2012) and promoted to Full Professor in 2010. He leads a talented research group interested in catalysis, mechanism, and synthesis. Recent work includes Pd and Mn catalyst and ligand design, involvement of higher‐order Pd species (e.g., nanoparticles), and exploitation of mechanistic understanding in purine and amino acid C–H functionalization. He has interests in the application of Pd and Au catalysis in macrocyclic ring synthesis, for example, phacelocarpus 2‐pyrone A.

Rudi Fasan

Rudi Fasan was born in Italy and studied pharmaceutical chemistry at the University of Padua, where he received his undergraduate degree (B.S.) with the highest honors in 1999. In 2001, he joined the group of Prof. John A. Robinson at the University of Zurich (Switzerland) as a graduate student, working on the design and synthesis of beta‐hairpin protein epitope mimetics. In 2005, he joined Prof. Frances H. Arnold’s group at the California Institute of Technology as a Swiss National Science Foundation postdoctoral fellow, working on the directed evolution of P450 enzymes for alkane oxidation. Dr. Fasan began his independent career as a member of the Department of Chemistry of the University of Rochester in 2008 and was promoted to the rank of Associate Professor in 2014. His research interests lie in the area of bioorganic chemistry, chemical biology, protein engineering, biocatalysis, and chemoenzymatic synthesis. His research group currently focuses on the synthesis, evolution, and application of macrocyclic peptides and organo‐peptide hybrids for targeting and modulation of cancer‐related protein–protein interactions and on the design and investigation of engineered and artificial metalloenzymes for selective late‐stage C–H functionalization and for asymmetric synthesis of carbon–carbon and carbon–heteroatom bonds. His awards include a Swiss National Science Foundation Graduate Fellowship (2001–2005) and Postdoctoral Fellowship (2005–2007), the 2007 Friedrich‐Weygand Outstanding Graduate Research Award, University of Rochester’s Multidisciplinary Research Award (2011) and University Award (2016), and the 2014 Tetrahedron Young Investigator Award for Bioorganic and Medicinal Chemistry.

Graeme L. Fraser

Graeme L. Fraser has more than 20 years of industry experience in both management and technical positions. Previously, Graeme was V.P. of Drug Discovery at Tranzyme Pharma (Sherbrooke, Canada) where he led the discovery and preclinical development activities for a pipeline of GPCR‐small molecule programs. Earlier, he managed preclinical development activities at Viron Therapeutics Inc. (London, Canada) and led specific GPCR target validation activities at Astra Pain Control AB (Södertälje, Sweden, and Montreal, Canada). In total, he has directed research activities for three products currently in clinical development. Graeme received a Ph.D. from McGill University (Montreal, Canada) and is an author of over 50 publications and research abstracts, including 9 patents and 2 IND filings.

Jagan Gaddam

Jagan Gaddam was born in Telangana, India (1984). He was awarded a bachelor’s degree in life sciences from Osmania University, Hyderabad (2005) and a master’s degree in organic chemistry (2008) from Kakatiya University. He joined Professor Prabhat Arya’s research group in 2011 at Dr. Reddy’s Institute of Life Sciences of the University of Hyderabad for doctoral studies. His research interests are in the synthesis of natural product‐inspired macrocycles and in building natural product‐derived macrocyclic toolbox. His Ph.D. research is mainly focused on stereoselective synthesis of neopeltolide‐inspired macrocycles.

René Gagnon

René Gagnon earned his Ph.D. in Organic Chemistry in 1993 from University Laval (Québec). He then joined the team of Stanley M. Roberts at University of Exeter (United Kingdom) as a postdoctoral fellow working on enzymatic catalyze in organic synthesis. In 1995, at the Armand‐Frappier Institute, he was implicated in biosynthesis studies on taxol and related analogues. He moved in 1996 to Sherbrooke to be part of Prof. Pierre Deslongchamps team. In 1998, he was mandated to build the analytical group of a new promising drug discovery company called Neokimia (founded by Prof. Deslongchamps). He was appointed in 2003 as head manager of the analytical division of Tranzyme Pharma (resulting from the Tranzyme and Neokimia merger). Over the years, he was implicated in various fields related to drug discovery, such as chemical library analysis, drug substance and drug product analysis, pharmacokinetic and stability studies, and purification and formulation of chemical entities. From 2007 to 2011, he was an associate professor at the genetic biomedical department of the CHUS working on pediatric diseases. From 2011 to 2015, he managed the mass spectrometry facility at the Chemistry Department of the University of Sherbrooke, where, since 2015, he joined its steering committee and also became the manager of the teaching laboratories.

Fabrizio Giordanetto

Fabrizio Giordanetto graduated with first‐class honors in medicinal chemistry in 2000 from the University of Genova (Italy). He completed his Ph.D. in Computational Medicinal Chemistry in 2003 at the University of London (United Kingdom) while working for the chemistry unit of Pharmacia (Pfizer) in Nerviano (Italy). In 2004, he joined the Medicinal Chemistry Department of AstraZeneca in Mölndal (Sweden) where he grew professionally to the position of Principal Scientist and Preclinical Project Leader. Since 2013, he has been Director of Medicinal Chemistry for Taros GmbH, a research‐based SME in Dortmund (Germany), where he leads proprietary and third‐party medicinal chemistry activities. During his career, he worked on several drug discovery projects resulting in multiple clinical candidates spanning oncology and cardiovascular indications and has more than 80 peer‐reviewed publications, book chapters, and international patents.

Hamid R. Hoveyda

Hamid R. Hoveyda obtained his Ph.D. from the University of British Columbia (Vancouver, Canada) followed by a stint at Harvard University as an NSERC postdoctoral fellow. He began his industrial career at the Affymax Research Institute (CA, USA) working on applications of diversity‐oriented synthesis in drug discovery. In 2001, he joined Neokimia Inc. (Sherbrooke, Canada), which later became known as Tranzyme Pharma, where he contributed initially to the platform HTS library technology and was subsequently in charge of lead optimization efforts across several projects including the ghrelin project that culminated in two clinical candidates (ulimorelin, TZP‐102) as potential GI therapeutics. Since September 2007, he has led medicinal chemistry efforts on various GPCR targets at Euroscreen (Belgium) that has resulted, inter alia, in the discovery of ESN364 clinical candidate, an NK3R antagonist currently in phase IIa for the treatment of sex‐hormone disorders. His scientific contributions thus far have been captured in over 50 publications and patents.

Ted W. Johnson

During his undergraduate studies at the University of California, Irvine, as a Chemistry major, Ted performed research under the direction of Professor Harold Moore where he worked on the synthesis of quinone antitumor/antifungal agents, completing the synthesis of nanaomycin D and making progress toward the total synthesis of griseusin A. He received his B.S. degree in Chemistry in 1994. During his graduate studies at the University of California–Los Angeles with Professor Michael Jung, he completed the total synthesis of 7‐deoxy‐xestobergsterol A, xestobergsterol A, and several potent antihistamine unnatural analogues. He simultaneously carried out synthetic studies toward the synthesis of eleutherobin, a potent antitumor compound. He was awarded the Saul Winstein Fellowship, the Gregory Research Fellowship, and the Distinguished First‐Year Graduate Student Award. Ted received his Ph.D. in 1999. As an NIH postdoctoral fellow at Harvard University with Prof. E.J. Corey, Ted completed the total synthesis of putative pseudopteroxazole, a potent antituberculosis compound, showcasing an unprecedented diastereoselective intramolecular imidoquinone Diels–Alder reaction. During his studies and ongoing 15 years as a medicinal chemist at Pfizer in La Jolla, California, Ted published many high‐profile patents and publications. He won the American Chemical Society Young Investigator Award in 2011 and the Pfizer Global Medicinal Chemistry Award in 2013. Most notably, he was the co‐project leader of the ALK program and co‐designed lorlatinib, which is currently a kinase inhibitor in phase 2 clinical trials for the treatment of ALK positive non‐small cell lung cancer (NSCLC). Notably, lorlatinib was designed to be potent against drug resistant mutants of ALK and also penetrate the central nervous system, a major challenge in kinase inhibitor space. Ted continues to work at Pfizer, La Jolla, in the Oncology Department.

Quentin Kaas

Quentin Kaas obtained his Chemical Engineering degree in 2001 from the École Nationale Supérieure de chimie de Montpellier (ENSCM) and his Ph.D. degree in chemical biology in 2005 from the University of Montpellier II. He conducted 1 year of postdoctoral research in the Laboratory of Immunoinformatics of Professor Marie‐Paule Lefranc in Montpellier, studying antigen/receptor interactions. He was then awarded an Australian postdoctoral fellowship by the Australian Research Council to undertake 3 years of postdoctoral research on plant cyclic peptide structure–activity relationships in the laboratory of Professor David J. Craik at the Institute for Molecular Bioscience of the University of Queensland, Australia. He is currently working in that laboratory where he focuses on structural bioinformatics and computational modeling studies of toxins extracted from plants and animals. He has developed and currently maintains the only database specialized on sequences and structures of cone snail toxins, ConoServer (http://www.conoserver.orgMacrocyclesDavidCraikManuscript_revised.doc).

Mahender Khatravath

Mahender Khatravath was born in Telangana, India (1988). He received his B.Sc. degree from Osmania University in 2008 and M.Sc. degree with specialization in organic chemistry from M.N.R. P.G. College (affiliated to Osmania University) in 2010. He joined as a doctoral student at the Dr. Reddy’s Institute of Life Sciences, University of Hyderabad, under the supervision of Professor Prabhat Arya and obtained his Ph.D. in Chemistry (2016). Currently, he is working as a national postdoctoral fellow under the supervision of Dr. Srinivasa Reddy at the National Chemical Laboratory, Pune. His research focuses on stereoselective synthesis of substructures of eribulin and related macrocyclic compounds.

Saidulu Konda

Saidulu Konda was born in Telangana, India (1985). He received his B.Sc. degree from Osmania University in 2007 and M.Sc. degree with specialization in organic chemistry from M.N.R. P.G. College (affiliated to Osmania University) in 2010. He received his Ph.D. degree from Hyderabad Central University in 2016. Presently, he is working as an associate scientist at GVK Biosciences Private Limited, Hyderabad.

Jongrock Kong

Jongrock Kong obtained his bachelor’s degree from Sungkyunkwan University and master’s degree from Pohang University of Science and Technology (POSTECH) in the Republic of Korea. In 2002, he started his graduate studies with Professor Michael J. Krische at the University of Texas at Austin, where he studied hydrogen‐mediated reductive C–C bond formation. After the completion of his Ph.D. in 2007, he moved to Princeton University for a postdoctoral fellowship with Prof. David W. MacMillan and worked on enantioselective α‐arylation of aldehyde via organo‐SOMO catalysis. In 2009, he joined the Process Research Department at the Merck Research Laboratories in Rahway, NJ, where he has been focusing on the development of robust processes for drug candidates.

Justine L. Lam

Dr. Justine L. Lam is a senior principal scientist at Pfizer Worldwide Research and Development in the department of pharmacokinetics, dynamics and metabolism (San Diego, CA). She received her Ph.D. degree in pharmaceutical sciences and pharmacogenomics from the University of California in San Francisco, under the guidance of Professor Leslie Z. Benet. Since joining Pfizer in 2006, she provided DMPK strategies to projects in all stages of drug discovery and development.

As a member of AAPS and ISSX, Dr. Lam’s expertise and research interests are in the area of drug transporters and their impact on drug disposition, metabolism, and drug–drug interaction. Her most recent research is focusing on the drug transporters in the blood–brain barrier and their impact on brain penetration.

Eilidh Leitch

Eilidh Leitch is currently a third‐year Ph.D. student in the Tavassoli group at the University of Southampton, United Kingdom. Previously, Eilidh received her B.Sc. in Biochemistry and M.Sc. in Oncology, both at the University of Nottingham, United Kingdom. Eilidh then went on to work at Sygnature Discovery in Nottingham, within the bioscience department, providing assay development and routine screening as part of the integrated drug discovery model. Eilidh’s Ph.D. studies focus on the development, identification, and characterization of cyclic peptide inhibitors of a metabolic protein–protein interaction target through the utilization of SICLOPPS.

Mylène de Léséleuc

Mylène de Léséleuc was born in Hull, Québec, Canada, in 1989. In 2011, she received her B.Sc. in Chemistry from the University of Ottawa and pursued her graduate studies (Ph.D.) at the Université de Montréal under the supervision of Prof. Shawn K. Collins. She is currently a senior research scientist at OmegaChem in Laval, Québec.

Spiros Liras

Spiros Liras is the Vice President of Medicinal Chemistry and Head of the Cardiovascular, Metabolic, and Endocrine Diseases (CVMET) Medicinal Chemistry at Pfizer Worldwide Research and Development. Prior to joining CVMET, Spiros was Senior Director of Medicinal Chemistry in Neuroscience at Pfizer. In Neuroscience, Spiros was involved in research aiming to deliver treatments for addiction, depression, schizophrenia, cognition, and Alzheimer’s disease. Spiros joined Pfizer medicinal chemistry in 1994 after completing postdoctoral research in organic synthesis at the University of Texas, Austin. Spiros obtained a Ph.D. in organic chemistry in 1990 from Iowa State University.

Shingai Majuru

Shingai Majuru is the Executive Director of Oral Drug Product Development at Cempra, Inc., Chapel Hill, North Carolina. He has 20 years of experience in the pharmaceutical industry. His areas of expertise include formulation development, clinical supplies manufacture, technology transfer, process scale‐up, process validation, and drug delivery technology development. He earned a B. Pharm. (Hons) degree and a Masters in Medicine from Department of Pharmacy of the University of Zimbabwe. He is also a holder of an M.Sc. and Ph.D. in Pharmaceutics from the College of Pharmacy of the University of Iowa. Shingai obtained an M.B.A. from Ancell School of Business of Western Connecticut State University.

Naveen Kumar Mallurwar

Naveen Kumar Mallurwar was born in Telangana, India (1985). He obtained his bachelor’s degree in 2005 and master’s degree with specialization in organic chemistry in 2007 from Kakatiya University. He received his Ph.D. degree from the University of Hyderabad in 2016 under the supervision of Professor Prabhat Arya at Dr. Reddy’s Institute of Life Sciences of said university. His research interests are the synthesis of natural product‐derived hybrid macrocycles and natural product‐inspired macrocycles.

Eric Marsault

Eric Marsault obtained his Ph.D. at McGill University (Montreal, QC, Canada) in 1996 with the late Prof. George Just and then worked as a visiting scientist for Sanofi (Milan, Italy) prior to moving to Université de Sherbrooke (QC, Canada) as a postdoctoral fellow with Prof. Pierre Deslongchamps.

He joined Neokimia (which later became Tranzyme Pharma) in 2000, where he worked as a researcher, group leader, and then director of the medicinal chemistry department. During this time, he took an active role in maturing the first platform enabling high‐throughout parallel synthesis of macrocycles that delivered up to 40 000 macrocyclic peptidomimetics and became the core of the company. Based on these, several drug discovery programs were established, aimed primarily at GPCR targets, leading to the identification of several preclinical candidates, including clinical candidates ulimorelin and TZP‐102.

In 2009, he joined the Department of Pharmacology of Université de Sherbrooke as a professor, where he now focuses on the development of new molecules to validate emerging drug targets in the context of academic drug discovery, with a particular focus on peptidomimetics and macrocycles targeting GPCRs and transmembrane serine proteases for cardiovascular diseases, pain, and infectious diseases. He is coauthor of more than 50 publications and co‐inventor of more than 30 patents. Since 2013, he is also the chairman of the Institut de pharmacologie de Sherbrooke.

Alan M. Mathiowetz

Alan M. Mathiowetz is currently the Director of Computational Chemistry in the Cardiovascular, Metabolic, and Endocrine Diseases (CVMET) Medicinal Chemistry Department within Pfizer Worldwide Research and Development. Alan obtained a B.A. in Chemistry at Rice University and a Ph.D. from the California Institute of Technology in Pasadena, California. Alan has worked in a number of technology and therapeutic areas within Pfizer, with an emphasis on structure‐based design and virtual screening, in silico modeling and physical property analyses, and therapeutics targets for type II diabetes and obesity.

Prasenjit Mitra

Prasenjit Mitra researches on the regulation of cellular metabolism and energy homeostasis at the interface of diabetes and cancer. He has obtained his Ph.D. at the Indian Institute of Chemical Biology, Kolkata, India, and postdoctoral research at UMass Medical School, Worcester, MA, USA. Currently, he is working as a principal research scientist at the Dr. Reddy’s Institute of Life Sciences located in the University of Hyderabad campus.

Micjel Chávez Morejón

Micjel Chávez Morejón was born in Pinar del Río, Cuba, in 1985. He earned his Bachelor in Chemistry Science from the University of Havana in 2009, in the field of antimicrobial peptide mimetics. He received his Master of Science in Organic Chemistry in 2011 from the Faculty of Chemistry, University of Havana, on the topic of Multicomponent synthesis of polycationic peptidomimetic peptide–peptoid hybrids. In 2012, he joined the Ph.D. program of the Leibniz Institute of Plant Biochemistry, Halle (Saale), in collaboration with the Martin Luther University Halle‐Wittenberg, Germany, and University of Havana, Cuba. Under the supervision of Prof. Wessjohann and Prof. Rivera, he focused on the development of new multicomponent reaction strategies for the synthesis of cyclic lipopeptides, inspired by natural products.

Ricardo A. W. Neves Filho

Ricardo Antonio Wanderley Neves Filho was born in Recife/PE, Brazil, in 1984. He received his B.Sc. and M.Sc. degrees from the Federal University of Pernambuco (UFPE) in 2006 and 2008, respectively. In 2010, he moved to Germany and enrolled in the Ph.D. program in the Division of Organic Chemistry of the Martin Luther University Halle‐Wittenberg, while working at the Leibniz Institute of Plant Biochemistry under the supervision of Prof. Wessjohann. In 2015, he finished his Ph.D. research that focused on the development of reagents for multicomponent reactions and their applications in the synthesis of natural products.

Ashok D. Pehere

Ashok Pehere received his B.Sc. and M.Sc. (Organic Chemistry) at the University of Pune, India. He was a research chemist at Merck Pharmaceutical in Mumbai, India, in 2002–2008, then received his Ph.D. at the University of Adelaide, Australia, under the direction of Professor Andrew D. Abell. This was followed by postdoctoral research at the University of Minnesota, USA, under the direction of Professor Thomas R. Hoye and Professor Marc A. Hillmyer, working on Diels–Alder reactions of furans and polymer synthesis. Currently working at UT MD Anderson Cancer Center, his research interest is related primarily to the design, synthesis, and characterization of cyclic peptide and new macromolecular materials.

Dehua Pei

Dr. Dehua Pei obtained his bachelor’s degree in chemistry from Wuhan University, China, and Ph.D. in Organic Chemistry in 1991 from the University of California in Berkeley. After a postdoctoral fellowship at Harvard Medical School, he joined the faculty of Ohio State University in 1995 and is currently a professor of chemistry and biochemistry. His current research interests include the development of new combinatorial chemistry methods for macrocycle synthesis and screening, discovery of novel cyclic cell‐penetrating peptides, and integration of the aforementioned two areas to develop macrocyclic inhibitors against challenging drug targets, such as intracellular protein–protein interactions.

David Pereira

David Pereira received a B.S. in Biochemistry from Virginia Tech in 1981. He conducted research on pyrrolizidine and indole carbamates as potential antineoplastic agents at Virginia Commonwealth University and earned a Ph.D. in Medicinal Chemistry in 1985. From 1985 to 1988, he was a postdoctoral scientist in the laboratory of Professor Nelson Leonard at the University of Illinois. David has been a research scientist in the pharmaceutical industry for over 25 years and has held senior management positions at Cempra, Inc., since 2006.

Mark L. Peterson

Prior to co‐founding Cyclenium in December 2013, Dr. Peterson was the Vice President of IP and Operations at Tranzyme Pharma where he led the chemistry R&D efforts during the technology development stage of the company and the initiation of its GPCR drug discovery programs. He later focused on building and maintaining an extensive portfolio of over 120 patents and applications protecting Tranzyme’s pioneering technology and pharmaceutical product candidates. Previously with Monsanto and Advanced ChemTech, he has productively worked in a wide variety of research areas, including structure‐based design, solid phase organic chemistry, combinatorial libraries, synthesis automation, heterocycles, unnatural amino acids, peptides, and peptidomimetics. A native of Wisconsin, he received his Ph.D. in Organic Chemistry from Washington State University (asymmetric synthesis) and conducted postdoctoral research at the University of Minnesota (antiviral carbocyclic nucleosides) prior to starting his industrial career. He is author or coauthor of over 90 publications and abstracted presentations and three book chapters, as well as co‐inventor on over 25 patents.

Lovy Pradeep

Lovy Pradeep obtained her Ph.D. in Biochemistry/Biophysics in the field of protein folding and stability in 2004. She continued her academic research in protein folding and misfolding diseases at Baker Labs in Cornell University and later addressed the binding of small molecules to nicotinic acetylcholine receptors (nAChRs) using electrophysiology techniques, directed toward understanding Alzheimer’s disease. Lovy joined Cempra in 2013 and is the holder of RAC and PMP globally recognized certifications. She is currently the Senior CMC Program Manager and continues to work on several aspects of the various solithromycin dosage forms.

David A. Price

David A. Price currently holds the position of Senior Director of Medicinal Chemistry in the Cardiovascular, Metabolic, and Endocrine Diseases (CVMET) department within Pfizer Worldwide Research and Development. David obtained a B.Sc. (First‐Class Hons.) and Ph.D. from the University of Nottingham, United Kingdom, after which he carried out postdoctoral research at Colorado State University with Prof. Al Meyers. During his tenure with Pfizer, David has worked on projects to develop drugs for a wide variety of diseases including HIV/AIDS, hepatitis C, respiratory diseases, and, most recently, type II diabetes and obesity.

Alfredo R. Puentes

Alfredo R. Puentes was born in Pinar del Rio, Cuba, in 1983. He obtained his B.Sc. (summa cum laude) from the Faculty of Chemistry, University of Havana, Cuba. He obtained his master’s degree under the guidance of Prof. Wessjohann (Halle) and Prof. Rivera (Havana) in 2014. Currently, he is a Ph.D. student at the Department of Bioorganic Chemistry of Leibniz Institute of Plant Biochemistry (IPB) in Halle (Saale), Germany, in a cooperative study between Halle and Havana, studying new beta‐turn inducers with synthetic application in macrocyclization reactions.

Ziqing Qian

Dr. Ziqing Leo Qian obtained his Ph.D. in 2014 from the Ohio State University under the guidance of Dr. Dehua Pei. Currently, he is a postdoctoral researcher in the same group. His research interests include the development of cyclic cell‐penetrating peptides for drug delivery and cell‐permeable macrocycles as intracellular PPI inhibitors.

Michaël Raymond

Michaël Raymond was born in Rimouski, Québec, Canada, in 1989. In 2011, he received his B.Sc. in Chemistry from the University of Ottawa and is pursuing his graduate studies (Ph.D.) at the Université de Montréal under the supervision of Prof. Shawn K. Collins.

Thomas O. Ronson

Thomas O. Ronson was born and brought up in Bristol in the southwest of England. He completed his undergraduate studies at the University of Oxford in 2011, having carried out a Part II project in the group of Professor Jeremy Robertson. He then moved to the University of York to pursue a Ph.D. under the joint supervision of Professors Ian J. S. Fairlamb and Richard J. K. Taylor, working toward the total synthesis of unusual macrocyclic natural products using novel palladium catalysts. Following the completion of his Ph.D. studies in 2015, he moved to the University of Antwerp where he currently works as a postdoctoral researcher in the group of Professor Bert Maes.

Jeffrey Santandrea

Jeffrey Santandrea was born in Montréal, Québec, Canada, in 1990. In 2012, he received his B.Sc. in Chemistry from the Université de Montréal and is currently pursuing his graduate studies (Ph.D.) at the Université de Montréal under the supervision of Prof. Shawn K. Collins.

Stephen E. Schneider

Stephen E. Schneider was formally introduced to chemistry at the North Carolina School of Science and Math by Dr. Lawrence Knecht. He received his B.S. degree from the University of North Carolina at Chapel Hill, where he performed research for Professors Bruce Erickson and Alex Tropsha and was initiated into Alpha Chi Sigma. He earned a Ph.D. in Organic Chemistry from the University of Texas in Austin in 1999 under the supervision of Professor Eric V. Anslyn. Stephen began his career as a process chemist at Trimeris, Inc., and is currently Executive Director, Chemistry at Cempra, Inc.

R. Scott Lokey

R. Scott Lokey did undergraduate research in organometallic chemistry with Professor Nancy Mills at Trinity University and received his Ph.D. at the University of Texas, Austin, working under Professor Brent Iverson, where his research centered on the synthesis of molecules that fold into protein‐like shapes in water and bind to specific DNA sequences. He did postdoctoral research at Genentech, where he worked on the synthesis of bioactive cyclic peptides, and then at Harvard Medical School and the Institute of Chemistry and Cell Biology with Professors Timothy Mitchison and Marc Kirschner on chemical biology approaches to the study of the actin cytoskeleton. He joined the faculty of the Department of Chemistry and Biochemistry at UCSC in 2002, where his research group focuses on the relationship between molecular structure and drug‐like properties, especially cell permeability. Professor Lokey is also the director of the UCSC Chemical Screening Center, a high‐throughput screening facility dedicated to early‐stage lead discovery, especially against infectious agents and neglected disease targets. He lives in Santa Cruz where he and his family enjoy trips to the beach and hiking among the redwoods.

Silvia Stotani

Silvia Stotani graduated with first‐class honors in Medicinal Chemistry in 2012 from the University of Rome (Italy). While working as a quality control chemist for Baxter in Rieti (Italy), she started a second‐level master’s degree on the design and development of drugs at the University of Pavia (Italy). For her master’s project, she joined the Drug Design Department of Professor Dömling at the University of Groningen (the Netherlands), where she spent 5 months as a master’s student and the other 6 months as a research assistant. She is currently a Ph.D. student at Taros GmbH in Dortmund (Germany), for the European Marie Curie Integrate ETN project in antibacterial drug discovery.

Ali Tavassoli

Ali is a professor of chemical biology at the University of Southampton, United Kingdom. His team’s efforts are focused on the identification of cyclic peptide inhibitors of protein–protein interactions and their development for use as tools in cell biology and as the starting point for new therapeutics. Ali is currently the Chair of the Royal Society of Chemistry’s Chemical Biology and Bioorganic Group.

Nicholas K. Terrett

Nick Terrett is currently the Scientific Associate Vice President and European Chemistry Lead for Merck Sharp & Dohme GmbH based in Kriens, Switzerland. Prior to this role, he was the Chief Scientific Officer for Ensemble Therapeutics, a biotech company based in Cambridge, Massachusetts, USA. In this role, he focused on the discovery of novel macrocyclic molecules with affinity for significant oncology targets. Using a DNA‐encoded library synthesis platform, Ensemble has generated libraries of novel and drug‐like synthetic macrocycles that have been screened against enzymes and challenging protein–protein interaction disease targets. In addition to the discovery of the novel IAP antagonists described in Chapter 17, other successes with this technology approach have been the discovery of novel antagonists of the oncology targets IDO and USP9x and IL17 antagonists for treating inflammation. Before Ensemble, much of Nick’s career was at Pfizer both in the United Kingdom and the United States where, among other activities, he was lead chemist and inventor for the program that discovered sildenafil (marketed as Viagra™ and Revatio™). Nick has an M.A. and Ph.D. in Organic Chemistry from the University of Cambridge.

William P. Unsworth

William P. Unsworth completed his Ph.D. at the University of Oxford under the supervision of Prof. Jeremy Robertson before accepting an EPSRC‐funded postdoctoral post at the University of York to work with Prof. Richard J. K. Taylor. He then moved on to a Research Fellow position, also at the University of York, before starting his present post as a Leverhulme Trust Early Career Research Fellow. His research interests include diversity‐oriented synthesis, transition metal catalysis, dearomatizing spirocyclization reactions, and total synthesis. A major focus of his group currently is the development of versatile and scalable methods to assemble medium‐sized rings and macrocycles using ring expansion reactions.

Simon Vézina‐Dawod

Simon Vézina‐Dawod received his B.Sc. in Chemistry from Université Laval. After completing an M.Sc. in Pharmaceutical Sciences in 2014 at the same university, he joined the laboratory of Prof. Biron as a Ph.D. student in pharmaceutical sciences. He is currently working on the development of new peptoid synthesis methodologies and the design and synthesis of macrocyclic peptidomimetics. His research interests principally involve the design and synthesis of complex mono‐ and polycyclic peptides and the development of new approaches to prepare and screen combinatorial macrocycle libraries.

Francesca Vitali

Francesca Vitali received a B.S. in Chemistry from La Sapienza University in Rome, in 1999 under the supervision of Prof. Claudio Ercolani. She earned her Ph.D. in Bioorganic Chemistry from Prof. John Robinson’s group at the University of Zurich, working on the synthesis of peptide precursors and cytochrome P450 enzymes involved in the biosynthesis of the antibiotic vancomycin. She then joined the Swiss Federal Institute of Technology (ETH) in Zurich as a postdoctoral fellow associated with the research groups of Prof. Frederic Allain and Prof. Kurt Wüthrich and worked on the development of cell‐free expression methods for segmental isotope labeling of RNA‐binding proteins. In 2005, she joined Prof. Thomas Poulos’ group at the University of California, Irvine, to work on applying expressed protein ligation techniques for isotope labeling of redox enzymes. Since 2009, she has worked as a senior scientist in Prof. Fasan’s laboratory at the University of Rochester focusing on the development of novel chemobiosynthetic strategies for the synthesis of biologically active macrocyclic peptides.

Conan K. Wang

Conan K. Wang is currently a postdoctoral researcher at the Institute for Molecular Bioscience of the University of Queensland in Brisbane, Australia. Conan completed a Bachelor of Engineering at the University of New South Wales in Sydney and then a doctorate at the University of Queensland. He moved to the University of Science and Technology in Hong Kong on an NHMRC exchange fellowship before his return to Australia. His general research area is cyclic peptide drugs with specific interests on the application of NMR and X‐ray crystallography to guide the design of peptide drug leads. Lately, he has focused on improving the bioavailability of cyclic peptide drugs and exploring their potential in the treatment of neurological disorders. Conan has authored more than 30 papers on cyclic peptides and the use of biophysical techniques to characterize their structure and function.

Ludger A. Wessjohann

Professor Wessjohann studied chemistry in Hamburg (Germany), Southampton (United Kingdom), and Oslo (Norway, under the guidance of Prof. Skattebøl). He earned his doctorate in 1990 with Prof. de Meijere in Hamburg. After a short period as a lecturer in Brazil, he became a postdoctoral Feodor‐Lynen fellow of the Alexander von Humboldt foundation with Prof. Paul Wender at Stanford University (USA) to work on the total synthesis of Taxol®. After an assistant professorship in Munich (LMU, 1992–1998), he was appointed as the Chair of Bioorganic Chemistry at the Vrije Universiteit Amsterdam (NL) to work on organometallic chemistry and biocatalysis. Since 2001, he is the director of the Department of Bioorganic Chemistry at the Leibniz Institute of Plant Biochemistry (IPB) in Halle (Germany) and, in parallel, holds the Chair of Natural Product Chemistry of the Martin Luther University Halle‐Wittenberg. In 2010, he was appointed the Managing Director of the IPB (www.ipb‐halle.de).

Prof. Wessjohann focuses on the discovery, synthesis, and application of natural products and bioactive derivatives thereof. He was the first to look into the chemoinformatics of macrocycles and to study their efficient synthesis by multiple multicomponent reactions. He has over 300 publications and 25 patent applications and is co‐founder of five companies, the latest being Ontochem IT Solutions. He is a member of many boards and commissions including the Brazilian Academy of Science and received numerous scholarships, prices, and honors, for example, Microsoft IT Founders Award, honorary membership of the Argentinean Soc. of Synth. Org. Chem. and the 2016 Leibniz Drug of the Year award.

Sara Wu

Sara Wu received a B.S. in Applied Chemistry from the University of Science and Technology of China in 1988. Her Ph.D. in Medicinal Chemistry was from the University of Kansas in 1997 with research on enzyme inhibition kinetics and mechanisms with Professor John V. Schloss. She did her postdoctoral research on the pre‐formulation and degradation mechanisms of anticancer drug candidates with Professor Valentino J. Stella in the Pharmaceutical Chemistry department also at the University of Kansas from 1997 to 1998. Since October 1998, Sara has been working for various pharmaceutical companies on drug pre‐formulation and formulation development including Eisai, Wyeth, and, presently, Cempra, Inc. Sara is currently the Executive Director of Drug Product Development.

Shinji Yamazaki

Dr. Shinji Yamazaki is currently an associate research fellow in the Department of Pharmacokinetics, Dynamics, and Metabolism (PDM) at Pfizer Worldwide Research and Development (San Diego, CA). He received his Ph.D. degree in Pharmaceutical Science at Tokyo University of Pharmacy and Life Sciences (Tokyo, Japan) under the supervision of Professor Tadashi Watabe. Before joining Pfizer Worldwide Research and Development in 2003, he has over 15 years of international experience in pharmaceutical industry to provide leaderships in drug discovery and development.

Dr. Yamazaki is a scientific leader with a strong background in ADME/PK characterization of clinical candidate drugs in vitro and in vivo. His current research activities are devoted to the investigation of pharmacokinetic–pharmacodynamic modeling, translational pharmacology, in vitro‐to‐in vivo extrapolation of pharmacokinetics, physiologically based pharmacokinetic modeling, and so on. He serves on the editorial board of Drug, Metabolism, and Disposition and has authored and coauthored over 40 peer‐reviewed articles and book chapters in this field.

Andrei K. Yudin

Professor Andrei K. Yudin obtained his bachelor in science degree at Moscow State University and his Ph.D. degree at the University of Southern California under the direction of Professors G. K. Surya Prakash and George A. Olah. He subsequently took up a postdoctoral position in the laboratory of Professor K. Barry Sharpless at the Scripps Research Institute. In 1998, he started his independent career at the University of Toronto. He received early tenure, becoming an associate professor in 2002, and an early promotion to the rank of Full Professor in 2007.

Prof. Yudin is one of the pioneers in the design of new chemical transformations. Currently, the main focus of research in the Yudin group is to develop a bridge between basic chemistry research and drug discovery. In addition to significant fundamental discoveries, his lab is making tangible contributions to the chemical industry. In 2009, Sigma‐Aldrich used his method and created a wide range of reagents now known as the Yudin amino aldehydes. These powerful molecules are being used to solve some of the long‐standing problems of complex molecule synthesis. Prof. Yudin and his students have made molecules that effectively mimic secondary structures such as beta‐turns, beta‐sheets, and alpha‐helices in various contexts.

Among Professor Yudin’s awards are the CSC Award in Combinatorial Chemistry, the 2004 Amgen New Faculty Award, the 2010 CSC Merck‐Frosst Therapeutic Center Award, the 2010 Rutherford Medal of the Royal Society of Canada, the 2011 University of Toronto Inventor of the Year Award, and the 2015 Bernard Belleau Award in Medicinal Chemistry. Professor Yudin is a fellow of the Royal Society of Canada. He is currently the Editorial Board Chair of the Royal Society of Chemistry journal Organic & Biomolecular Chemistry.

Serge Zaretsky

Serge Zaretsky was born in Moscow, Russia, and grew up in Toronto, Canada. He received his B.Sc. in Biochemistry from McGill University (Montreal, Canada) in 2009. There, he performed research in the Tsantrizos group, the Moitessier group, and the Stone Pain Lab. He then joined the University of Toronto (Toronto, Canada) in order to pursue a Ph.D. in Organic Chemistry under the supervision of Prof. Andrei Yudin. His graduate research focused on mechanistic studies and the development of multicomponent peptide macrocyclization techniques. A major element of his studies was the application of cyclic peptides in the fields of chemical biology and medicinal chemistry. Since graduating in 2014, he went on to work in the field of process chemistry at Alphora Research Inc. (Toronto, Canada) and then at Bristol‐Myers Squibb (New Brunswick, New Jersey, USA), where he presently works in the Chemical & Synthetic Development department as a member of the reaction sciences group.

Part I

Challenges Specific to Macrocycles

1

Contemporary Macrocyclization Technologies

Serge Zaretsky and Andrei K. Yudin

Lash Miller Chemical Laboratories, University of Toronto, Toronto, Ontario, Canada

1.1 Introduction

In medicinal chemistry, macrocycles occupy the middle space between small organic molecules and proteins (Figure 1.1). By virtue of displaying the features of both small molecules and proteins, macrocycles have the potential to harness both the exquisite specificity of biological drugs and the synthetic tractability of small molecule drugs [1–3].

Figure 1.1 Macrocycles are at the intersection of small molecules and biological drugs chemical space.

Macrocycles encompass a tremendous variety of molecules. Barring the requirement of a suitably large ring size (conventionally over 12 atoms), the constituents of the ring can vary. Macrocycles can be based on primarily aliphatic backbones as exemplified by macrolides [1, 4] or on heteroatom‐based scaffolds as exemplified by macrocyclic polyethers [5]. No macrocycle discussion could be whole without mentioning the central role of cyclic peptides (see also Chapters 3, 4, and 9). Cyclic peptides are employed by nature and chemists in a variety of settings, and these molecules are particularly noteworthy for their modular assembly from amino acid building blocks [6–8]. The relative ease of synthesis, both chemical and biological, makes cyclic peptides highly sought‐after molecules in drug discovery [9].

Having a constrained backbone enables macrocycles to pre‐organize for effective binding to ligands and host molecules; however, the requirements for effective pre‐organization have to be considered; simply having a constrained molecule does not always ensure binding [10, 11]. Moreover, the manner in which binding elements of a macrocycle are presented in three dimensions can change dramatically with the macrocycle ring size. The overall effect is ring size‐dependent binding affinity and specificity between macrocycles and their hosts or guests [12–17].

In addition to binding affinity gains, macrocycles possess a number of pharmacokinetic advantages when compared with their linear counterparts. This aspect is particularly important for peptides as the linear forms often exhibit very poor cellular permeability and are proteolytically labile, and as a result linear peptidic drugs have to be injected or use advanced formulation techniques and cell‐penetration tags for efficacy [18, 19]. Cyclic peptides, on the other hand, can prearrange their peptidic backbone and amino acid side chains such that polar surface character is minimized and the formation of internal hydrogen bonds is facilitated (Figure 1.2) [20–22]. This area of research continues to be actively pursued with concentrated efforts on establishing a rationale for peptide modification toward improved cellular permeability with cyclic peptides [23–26]. An additional differentiation is that macrocycles can be more metabolically stable than their linear counterparts [9]. For example, cyclic peptides are not subject to exopeptidases and generally can resist endopeptidases [27, 28].

Figure 1.2 Lokey’s conformational hypothesis for passive membrane permeability of peptide macrocycles.

Perhaps the most significant and enabling feature of macrocyclic drugs with respect to small molecule therapeutics is their intricate three‐dimensional structure. Whereas conventional small molecule therapeutics favor achiral and aromatic (i.e., heterocyclic) substituents, macrocycles offer a robust framework that takes advantage of multiple sp³ centers to furnish large and unique binding surfaces [29]. Accordingly, macrocycles have been pinned as a privileged class of molecules to modulate protein–protein interactions, which is a difficult, yet growing, target space in drug design [2, 3, 9].

1.2 Challenges Inherent to the Synthesis of Macrocycles

The benefits of macrocycles are vast, especially when compared with their linear analogues, but there are some challenges inherent to their synthesis and isolation. The synthetic challenges are rooted in the conformational difficulties of tying the ends of a molecule together, irrespective of the nature of the cyclization chemistry (amide, ester, alkene formation, etc.).

In the case of smaller macrocycles (around 12 atoms), transannular strain significantly impacts the cyclization rate. This form of strain energy arises from the clash of backbone atom substituents, such as C─H groups in simple cycloalkanes or side‐chain atoms in more complex cycles, within the ring of the forming molecule. Seminal studies by Illuminati, Gali, and Mandolini have shown that ring‐closing transition state energies are elevated for ring sizes ranging between 7 and 13 atoms with 8–10 atom ring sizes being most affected [30]. In addition to transannular strain, additional detrimental factors to the kinetic rate arise from bond angle and length deformations and unfavorable eclipsed conformations, all of which are increasingly alleviated in larger rings (>12 atoms) [31, 32].

When considering ring closure kinetics, it is instructive to use effective molarity (EM), the ratio between the intramolecular and intermolecular rates, as a guide to reactivity [33]. The proximity of the two reactive ends in an intramolecular cyclization reaction greatly facilitates the coupling of the two partners versus the intermolecular case. Strain energy impacts the EM as outlined previously for ring sizes of 8–11 atoms, but as the strain energy diminishes with ring size for macrocycles, so too does the EM. For medium and large macrocycles, the main concern becomes the lack of a proximity effect, which, without forcing features (e.g., Thorpe–Ingold effect), makes the cyclization‐conducive conformation an entropically challenging one to reach [34].

In an effort to create a macrocyclization reaction, the effectiveness of the desired transformation has to be balanced with the cyclization ability. A fast cyclization reaction is required to limit side reactions, but if the cyclization‐conducive conformation is not readily attainable, then intermolecular reactivity can predominate. For example, the synthesis of cyclic peptides can be complex, and methodology is often not transferrable between sequences and ring sizes [35]. Conventional approaches for peptide cyclization often suffer from oligomerization side reactions unless performed at high dilution. The difficulty in cyclic peptide synthesis stems from the tendency for carboxylic acid activation chemistry to disfavor the cyclization‐conducive conformation by negating the peptide termini’s ion pair interaction (Scheme 1.1). The consequence is a highly sequence‐dependent equilibrium between conformation 2 and 3, which can affect the expected EM of the system and result in intermolecular reactivity. Research into methods that maintain the stabilizing zwitterionic interaction of peptide ends has recently emerged [36–39].

Scheme 1.1 Carboxylic acid activation disfavors the cyclization‐conducive conformation 3.

Schmidt and Langner’s work on sequence dependency in forming 15‐membered cyclic peptide rings clearly illustrates the challenges faced in this process [40]. Depending on the amide linkage that was formed in the ring‐closing reaction, the researchers noted a wide variability in reaction selectivity, with some cases even forming the cyclodimer as the predominant product (Figure 1.3). For a successful cyclization reaction, the linear substrate has to be carefully selected and the cyclization site considered, as the substrate‐dependent cyclization reaction can fail or simply result in isolation of cyclodimers [35, 41].

Figure 1.3 The site of retrosynthetic ring disconnection can greatly affect the yield and selectivity of the forward process.

In order to ensure sufficient selectivity for cyclic monomers, macrocyclization reactions are often performed at high dilution. By decreasing the concentration to the mM and μM range, bimolecular reactivity can be diminished such that the desired monomer cyclization takes place. However, at low concentrations, the desired chemistry also tends to be significantly slowed, and side reactions other than oligomerization may arise [42–45]. The necessity for low concentration may be afforded by working on solid phase, which ensures pseudo‐high dilution through physical separation of the reactive species (Section 1.5).

In carboxylate activation chemistry, there is a propensity for C‐terminal amino acid epimerization if the nucleophilic coupling is not kinetically competitive [46]. Epimerization results from amide O‐attack on the active ester to generate an oxazolone intermediate (Scheme 1.2a). In the presence of base, oxazolone 6 can be deprotonated to form 7, which is stabilized due to aromaticity, with subsequent reprotonation racemizing the amino acid stereocenter to give 8. For acyl halides (Scheme 1.2b), the highly activated nature of the functional group can invoke an alternate epimerization pathway through ketene formation as well as provoking hydrolysis [47]. While acyl azides pose less risks for epimerization, a side‐product pathway exists through the Curtius rearrangement (Scheme 1.2c) [46].

Scheme 1.2 Carboxylic acid side‐reaction pathways by way of oxazolone intermediate (a), ketene formation (b), and Curtius rearrangement of acyl azides (c).

In the synthesis of peptides, an additional side product may arise from diketopiperazine (DKP) formation. Under conditions where the