Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products

Abstract

International audienc

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

“…88 The letter n denotes the number of monomers in the monocyclic polymer. RGD β-lactam peptidomimetics that induce differential gene expression in human endothelial cells, 49 G-quadruplex ligands for anticancer therapeutics, 50 the excellent tumor uptake and pharmacokinetics of 64 Cu-labeled cyclic RGD peptide dimers with Gly and PEG linkers, 51 macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity, 52,53 proteasome inhibitors, 54 inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase, 55 macrocyclic lactams inspired on the skeleton of natural products with anticancer properties, 56 etc. Besides the considered biomedical applications, macrocyclic structures have found important applications in other fields such as chemical analysis 57,58 or nanotechnology.…”

The Synthesis of Macrocycles for Drug Discovery

“…This was due, in part, to the peptidomimetic nature of many of these structures, which often were targeted at protease enzyme inhibition, and thus lent themselves readily to macrolactamization for amide bond formation or macrolactonization for cyclic depsipeptide-like compounds. 7,8 Representative examples of these two general transformations are shown in Scheme 11.1 (BOP (benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, Castro's reagent), EDC (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide), DMAP (4-dimethylamino-pyridine)) for the matrix metalloproteinase (MMP) inhibitor template 2 9 and the renin inhibitor scaffold 4. 10 These approaches possess several advantages: (1) well-developed chemistry and procedures; (2) wide selection of readily available reagents;…”

“…Nonetheless, this chemical approach has been used to advantage to prepare both macrocyclic peptidomimetic and non-peptidic compounds, including renin inhibitors, [23][24][25][26][27] thrombin inhibitors (7, Figure 11.1, ring closure site and reagent used for cyclization indicated), 28,29 human immunodeficiency (HIV) protease inhibitors, 30,31 b-secretase (BACE-1) inhibitors, 32 TNF-a converting enzyme (TACE) inhibitors, 33 selective MMP-8 inhibitors, 34 protease inhibitors, 35 calpain inhibitors, 36 cholecystokinin (CCK)-B antagonists, 37 subtype selective somatostatin analogues, 38 growth factor receptor-bound protein 2 (Grb) Src homology 2 (SH2) domain inhibitors, 39 histone deacetylase (HDAC) inhibitors, 40 heat shock protein 90 (Hsp90) inhibitors, 41 PDZ domain ligands, 42 multicyclic mimics of protein loop structures, 43,44 and a wide variety of structures that target the G-quadruplex (8). [45][46][47] For this latter example, it was actually simultaneous double amide bond formation that created the ring.…”

2,4,6-Trichlorobenzoyl Chloride (Yamaguchi Reagent)

“…Yamaguchi and co-workers were the first to discover its use as esterifying reagent in 1979. 1 It is a light yellow colored liquid (bp 107-108 °C, ρ = 1.561 g/cm 3 ) 2 and a moisture-sensitive reagent. TCBC allows the regioselective synthesis of highly functionalized esters under mild reaction conditions.…”

“…The Yamaguchi esterification is one of the most preferred protocol for macrolactonizations as evident by more than 340 research papers published using this methodology. 3 Preparation TCBC was first prepared by Yamaguchi and co-workers from 2,4,6-trichloroaniline. 4 Seebach and colleagues reported a simple synthesis from 1,3,5-trichlorobenzene (Scheme 1).…”