To fully exploit the inherent and enduring potential of natural products for fundamental cell biology and drug lead discovery, synthetic methods for functionalizing unique sites are highly desirable. Here we describe a strategy for the derivatization of natural products at ‘unfunctionalized’ positions via Rh(II)-catalyzed amination enabling simultaneous structure-activity relationship (SAR) studies and arming (alkynylation) of natural products. Employing Du Bois C–H amination, allylic and benzylic C–H bonds underwent amination and olefins underwent aziridination. With tertiary amine-containing natural products, amidines were produced via C–H amination/oxidation and unusual N-aminations provided hydrazine sulfamate inner salts. The alkynylated derivatives are readied for subsequent conjugation to access cellular probes for mechanism of action studies. Both chemo- and site-selectivity was studied by application to a diverse set of natural products including the marine-derived anticancer diterpene, eupalmerin acetate (EPA). Quantitative proteome profiling with an alkynyl EPA derivative obtained by site-selective, allylic C–H amination led to identification of several protein targets in HL-60 cells, including several known to be associated with cancer proliferation, suggestive of a polypharmacological mode of action for EPA.

Iodination of arene-containing natural products employing N-iodosuccinimide catalyzed by In(OTf)(3) at ambient temperature is reported as a versatile and mild method for natural product derivatization amenable to small scale. This process facilitates natural product derivatization of arene moieties for SAR studies, homo- and heterodimerization of natural products, and also conjugation with reporters such as biotin via subsequent metal-mediated coupling reactions.

Mild Arming and Derivatization of Natural Products via an In(OTf) 3 -Catalyzed Arene Iodination. -A variety of aromatic compounds is easily converted to the corresponding iodides using the mild reaction with NIS and In(OTf)3 as a catalyst. β-Estradiol (VIII) is easily iodinated and the functionalization of the product is demonstrated [cf. (XI), (XIII)]. Anti-inflammatory agent resveratrol (XIV) does not require any catalyst (to be continued). -(ZHOU, C.-Y.; LI, J.; PEDDIBHOTLA, S.; ROMO*, D.; Org. Lett. 12 (2010) 9, 2104-2107, DOI:10.1021/ol100587j ; Dep. Chem., Tex. A&M Univ., College Station, TX 77842, USA; Eng.) -R. Steudel

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AgOTf is an effective catalyst for intermolecular allylation of aromatic and heteroaromatic compounds with allylic alcohols affording allylated arenes in up to 99% yields. Heterogeneous allylation of arenes catalyzed by Ag 3 PW 12 O 40 gave comparable product yields to those obtained by AgOTf. Ag 3 PW 12 O 40 could be reused five times with slightly decreased activity.