Macrocycles occupy a unique segment of chemical space. In the past decade, their chemical diversity expanded significantly, supported by advances in bioinformatics and synthetic methodology. As a consequence, this structural type has now been successfully tested on most biological target classes. The goal of this article is to put into perspective the current applications, opportunities, and challenges associated with synthetic macrocycles in drug discovery. Historically, macrocyclic drug candidates have originated primarily from two sources. The first, natural products, provided unique drugs such as erythromycin, rapamycin, vancomycin, cyclosporin, and epothilone. Excellent reviews are dedicated to this class and how it inspired further synthetic and medicinal chemistry efforts; thus, it will not be covered here. From a molecular evolution standpoint, the medicinal chemistry of macrocyclic natural products usually involved direct use as a therapeutic agent or functionalization of the natural product scaffold by hemisynthesis. It parallels significant advances in the total synthesis of macrocyclic natural products during the past 2 decades. The second traditional source of macrocycles stems from peptides, some of which are natural products and, hence, also belong to the first category. Macrocyclization was recognized early in peptide chemistry as an efficient way to restrict peptide conformation, reduce polarity, increase proteolytic stability, and consequently improve druggability. Chemists accessed macrocyclic peptides with different geometries (head to tail, side chain to side chain, head to side chain), including the incorporation of nonpeptidic groups. Compelling examples of macrocyclic scaffolding of peptides include the works on somatostatins, melanocortins, and integrins, among others. Macrocyclic peptides generated several drugs from synthetic or natural sources, including octreotide, cyclosporine, eptifibatide, and caspofungin. Purely peptidic, depsipeptidic, and peptoid macrocycles will also not be covered in this article; the reader is instead referred to previous reviews. It is well understood that the boundary between synthetic macrocycles and the above categories is not always clear-cut; as a result, examples presented in the following sections could occasionally belong to one of these categories. In these cases, they were selected owing to their relevance to the perspective. Macrocycles are defined herein as molecules containing at least one large ring composed of 12 or more atoms. On the basis of standard molecular descriptors, macrocycles as a class are at the outskirts of the window generally considered optimal for good PK-ADME properties using these criteria. Indeed, their molecular weights tend to be on the higher end (often in the 500-900 g 3mol -1 range), their numbers of H-bond donors and acceptors, as well as their polar surface area (PSA), tend to be on the far side of the accepted druglike spectrum. For an equal number of heavy atoms, macrocycles inherently possess a lower number of rotatable bonds than their acyclic analogues, a beneficial feature for oral bioavailability (in the following, “acyclic” will be used in the sense of “nonmacrocyclic”). As a result, macrocycles are more conformationally restricted than their acyclic analogues, which potentially can impart higher target binding and selectivity and improved oral bioavailability (in this assessment, endocyclic bonds are considered to be nonrotatable, which is only an approximation; see ref 18). For a systematic chemoinformatic analysis of biologically active macrocycles, the reader is referred to the recent review of Brandt et al. Topologically, macrocycles have the unique ability to span large surface areas while remaining conformationally restricted compared to acyclic molecules of equivalent molecular weight. This characteristic makes them especially suited for targets displaying shallow surfaces, which can prove to be quite challenging for acyclic small molecules. Medicinal chemistry relies strategically on robust synthetic methods capable of producing an acceptable chemical diversity to adequately interrogate the chemical space of a biological target. Macrocycles are often (and rightly so) perceived as difficult to synthesize and hence deterred many medicinal chemists because of the lack of versatile synthetic platforms. The macrocyclization step is regularly plagued by low yields and often requires high dilution conditions to counterbalance entropic loss. In other words, the reduction in entropy responsible for beneficial conformational restrictions to the final molecule comes at a price during synthesis: what goes around comes around. Accordingly, the first part of this article is dedicated to the drug discovery aspects ofmacrocycles and highlights salient features of their medicinal chemistry. This section is organized by target class, a choice aimed at providing the reader an appreciation of the structural diversity generated for each class. To give the reader an appreciation of the tools available to construct macrocyclic scaffolds, the site and method of the pivotal macrocyclization step are indicated in the figures. Readers are referred to the source articles for further details. In the second part, the technologies and synthetic approaches that already have demonstrated utility or possess a high potential for macrocycle-based

Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery

The recent advent of transition-metal mediated CH activation is revolutionizing the synthetic field and gradually infusing a “CH activation mind-set” in both students and practitioners of organic synthesis. As a powerful testament of this emerging synthetic tool, applications of CH activation in the context of total synthesis of complex natural products are beginning to blossom. Herein, recently completed total syntheses showcasing creative and ingenious incorporation of CH activation as a strategic manoeuver are compared with their “non-CH activation” counterparts, illuminating a new paradigm in strategic synthetic design.

C-H activation: a complementary tool in the total synthesis of complex natural products.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

Enzyme-mediated oxidations for the chemist

The selective, direct hydrogenation of amides to the corresponding alcohols and amines with cleavage of the C-N bond was discovered. The expected products of C-O cleavage are not formed (except as traces in the case of anilides). The reaction proceeds under mild pressure and neutral, homogeneous conditions using a dearomatized, bipyridyl-based PNN Ru(II) pincer complex as a catalyst. The postulated mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroaromatic pincer core and does not involve hydrolytic cleavage of the amide. The simplicity, generality, and efficiency of this environmentally benign process make it attractive for the direct transformations of amides to alcohols and amines in good to excellent yields.

Direct Hydrogenation of Amides to Alcohols and Amines under Mild Conditions

10. Patented Literature 2616 10.1. Esterification 2616 10.2. Ether Formation 2619 10.2.1. Etherification without Cyclization 2619 10.2.2. Etherification with Cyclization 2624 10.3. N-Alkylation 2625 10.4. Other Reactions 2627 11. Summary and Outlook 2628 12. Note Added in Proof 2628 13. Abbreviations Used in This Review 2629 14. Acknowledgments 2629 15. Supporting Information Available 2630 16. References 2630

Mitsunobu and Related Reactions: Advances and Applications

Direct synthesis of α-substituted phosphonates

Chlorination of α-hydroxyphosphonate anthracen-9-yl(5,5-dimethyl-2-oxo-2λ 5 -1,3,2-dioxaphosphinan-2-yl)methanol ( 11) using thionyl chloride unexpectedly yields 10-(5,5-dimethyl-2-oxo-2λ 5 -1,3,2-dioxaphosphinan-2-ylmethylene)anthracen-9(10 H)-one ( 13), 2-(10-chloroanthracen-9-ylmethyl)-5,5-dimethyl-2λ 5 -1,3,2-dioxaphosphinan-2-one ( 14), and 10-(5,5-dimethyl-2-oxo-2λ 5 -1,3,2-dioxaphosphinan-2-ylmethylene)-9,10-dihydroanthracen-9-ol ( 15) in addition to 2-[anthracen-9-yl(chloro)methyl]-5,5-dimethyl-2λ 5 -1,3,2-dioxaphosphinan-2-one ( 12). The reaction of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinane ( 5) with 9-anthraldehyde leads to 2-chloro-1,1-dimethylethyl hydrogen 10-(5,5-dimethyl-2-oxo-2λ 5 -1,3,2-dioxaphosphinan-2-ylmethylene)-4a,9,9a,10-tetrahydroanthracen-9-ylphosphonate ( 20) in addition to 12. Bromination of 11 with phosphorus tribromide affords the 10-bromoanthracen-9-yl product, 2-(10-bromoanthracen-9-ylmethyl)-5,5-dimethyl-2λ 5 -1,3,2-dioxaphosphinan-2-one ( 22). Reaction of 12 with 4-chloro- or 4-nitrobenzaldehyde in the presence of sodium hydride affords the products, 9-(2-arylvinyl)anthracenes 23 and 24 in an uncommon Horner-Wadsworth-Emmons-type reaction. Compound 22 underwent the normal Horner-Wadsworth-Emmons reaction with benzaldehydes or ferrocenecarbaldehyde to afford disubstituted alkenes. One of these alkenes, ( E)-9-bromo-10-[2-(4-bromophenyl)vinyl]anthracene ( 26), undergoes Sonogashira coupling with terminal alkynes to afford the conjugated alkynes ( E)-9-bromo-10-[2-(4-ethynylphenyl)vinyl]anthracenes 30- 32 in moderate yields. X-ray crystal structures of 12- 15, 20, 23 and ( E)-9-bromo-10-[2-(4-methoxyphenyl)vinyl]anthracene ( 27) have been determined.

New Anthracenyl-Substituted Phosphonates: Synthesis and Utility

The α-substituted phosphonates (OCH 2 CMe 2 CH 2 O)P(O)CH(X)(Ar) [X=Cl, OMe, NMe 2 and OSiMe 3 ], useful precursors for Horner–Wadsworth–Emmons reactions, are readily prepared by treating (OCH 2 CMe 2 CH 2 O)PX with an aromatic aldehyde. In the reaction of (OCH 2 CMe 2 CH 2 O)PCl with furfuraldehyde and cinnamaldehyde, the 5-chlorofurfurylphosphonate (OCH 2 CMe 2 CH 2 O)P(O)CH 2 (5-Cl-C 4 H 2 O) and the γ-chlorophosphonate (OCH 2 CMe 2 CH 2 O)P(O)CHCH-CH(Cl)Ph, respectively, are formed in good yields.

K. Praveen Kumar

Papers

Mitsunobu and Related Reactions: Advances and Applications

Mitsunobu and Related Reactions: Advances and Applications

Direct synthesis of α-substituted phosphonates

New Anthracenyl-Substituted Phosphonates: Synthesis and Utility

Direct Synthesis of α-Substituted Phosphonates.