This review summarizes the synthetic applications of hypervalent iodine(V) reagents: iodylbenzene, IBX (2-iodoxybenzoic acid), DMP (Dess-Martin periodinane) and pseudocyclic IBX analogs. Application of these reagents allows mild and highly selective oxidative transformations in a facile and environmentally friendly manner.
A pseudo‐benziodoxazine structure with intramolecular secondary I⋅⋅⋅O bonding, as shown by X‐ray analysis, is seen in a series of N‐(2‐iodylphenyl)acylamides prepared from 2‐iodoaniline (see scheme). These compounds contain a six‐membered pseudocyclic scaffold about an iodine(V) center and are able to oxidize either alcohols or sulfides, with the reactivity depending largely on the substitution pattern on the amide group adjacent to the iodyl moiety.
Incorporation of a methyl group onto a macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the macrocyclic structure, as demonstrated by NMR studies. We designed a conformational constraint favoring the desired atropisomer in which this methyl group interacts with the S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint was prepared and demonstrated by NMR to reside predominantly in the desired conformation. This modification improved potency 180-fold relative to the unsubstituted, racemic macrocycle and improved selectivity. An X-ray crystal structure of a closely related analogue in the FVIIa active site was obtained and matches the NMR and modeled conformations, confirming that this conformational constraint does indeed direct the methyl group into the S2 pocket as designed. The resulting rationally designed, conformationally stable template enables further optimization of these macrocyclic inhibitors.
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A simple three-step preparation of polymer-supported N-(2-iodyl-phenyl)-acylamide (NIPA resin) starting from 2-iodoaniline is described. The resin was obtained with good loading levels (0.7-0.8 mmol g(-1)) and has been successfully used for efficient oxidation of a diverse collection of alcohols. Thus, treating alcohols with 1.0 equiv of the resin in 1,2-dichloroethane under reflux for 30-60 min allowed rapid and in most cases complete conversion to the corresponding carbonyl compound.
Rare-earth metal(III) triflates are extremely mild, efficient and water-tolerable Lewis acid catalysts for a wide range of organic transformations. Rare-earth metal triflates retain activity even in the presence of multiple Lewis bases containing oxygen, nitrogen, sulfur and phosphorus atoms, and can be easily recovered and reused without any loss of catalytic activity. This review summarizes recent developments and highlights key applications of these unique Lewis acids in cycloaddition and cyclization reactions.
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.
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