Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Maraviroc (UK-427

No abstract

Introduction 1.1 Insect Pest Management 1.2 The Neem Tree, Azadirachta indica A. Juss (Meliaceae) 1.3 Azadirachtin Biosynthesis 1.4 Azadirachtins and Related Compounds 1.5 The Biological Effects of Azadirachtin I .6 Discovery and Structure Determination 2.1 Hydroxyl Group Reactivity 2.2 Hydrogenation 2.3 Reactions of the C-22-C-23 Enol Ether 2.4 Saponification Reactions 2.5 Functional Group Chemistry of Azadirachtol 2.6 Oxidation Reactions 2.7 Functional Group Chemistry of 7-Ketoazadirachtins 2.8 Retro-aldol Reaction Studies 2.9 Skeletal Rearrangements 2 Natural Product Modification 3 The Synthesis of Azadirachtin-derived Di hydrofuranacetal Components 3.1 The Shibasaki Route to Azadirachtin 3.2 The Synthesis of Racemic Hydrofuranacetals Related to Azadirachtin 3.3 The Preparation of an Enantiomerically Pure Hydrofuranylacetal Intermediate 3.4 The Preparation of Prototype Coupling Fragments 3.5 The Preparation of Enantiomerically Pure Insect Antifeedants Based on Azadirachtin 4 Decalin Synthesis 4.1 Other Approaches to Azadirachtin 4.2 Early Approaches to a Decalin Fragment 4.3 A Remote Oxidation Approach 4.4 An Angular Hydroxymethylation Approach 4.5 An Intact Hydroxymethylene Residue Approach 4.6 Factors Influencing Intramolecular Diels-Alder 4.7 A Silicon Directed IMDA Approach 4.8 The Dimethyl(pheny1)silyl Group as a Stereocontrol 4.9 Elaboration of an A-Ring Syn-1,3-diol for Total Cyclization Element for Intramolecular Diels-Alder Reactions Synthesis Studies 4.10 Tetrahydrofuran Annulation 5 Structure-Activity Relationships 6 Conclusions 7 References NATURAL PRODUCT REPORTS, 1993-S. V. LEY, A. A. DENHOLM AND A. WOOD 113 0 (23) Nakanishi's azadirachtin (24) Kubo's deacetylazadirachtinol(25) prieurianin bond joining two halves. This conclusion drawn on the basis of an upfield shift in the 13C NMR resonance of C-13 with respect to that of azadirachtin was truly serendipitous given the now known homology between the two compounds. The single C-8 4 -1 4 bond joining two 'halves' accounts well for the temperature dependent NMR behaviour of azadirachtin, an observation which was not pursued until after an unequivocal structure was available for azadirachtin. The implication of this type of behaviour on the structure of a similarly arranged compound prieurianin (25)52 was known in 1975 and if the analogy with azadirachtin had been noticed at this time it may have profoundly influenced Nakanishi's original deductions. Frenzied activity, initiated in 1985 by the publication of the first reappraised azadirachtin structure (26),53 was culminated later in that year with the unequivocal assignment of azadirachtin through single crystal X-ray analysis.54 The structure suggested by Ley and c o -w ~r k e r s ~~ in early 1985 represented a significant advance in showing the presence of a C-8 angular methyl group and a C-9-C-10 annulated tetrahydrofuranacetal moiety. This revised structure was based on 2D-NOESY and ID NOE difference spectroscopy which revealed the presence of H-1 -H-19 and H-2-H-I9 interactions thus placing th...

A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and tetrahydrofuran analogues, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further reduction in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metabolism, relative to its 2-substituted isomer. The slower rates of metabolism with 3-substituted cyclic ethers most likely originate from reductions in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacology studies with a representative oxetane indicate that the series is generally capable of lowering Aβ in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.