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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