Cyclopropanations of Olefin-Containing Natural Products for Simultaneous Arming and Structure Activity Studies

Abstract

Cyclopropanations of alkene-containing natural products that proceed under mild conditions are reported for simultaneous arming and structure-activity relationship studies. An alkynyl diazo ester under Rh(II) catalysis is employed for cyclopropanations of electron-rich olefins while an alkynyl sulfonium ylide is used for electron-poor olefins. This approach enables simultaneous natural product derivatization for SAR studies and arming (i.e. via alkyne attachment) for subsequent conjugation with reporter tags (e.g. biotin, fluorophores, photoaffinity labels) for mechanism of action studies including cellular target identification and proteome profiling experiments.

Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate

“…15 These functionalization methods are dependent on the presence of native functional groups and are thus limited in terms of positional diversity. In addition, existing functional groups in natural products are often essential for maintaining biological activity.…”

“…In considering natural product derivatization via C–H amination, several issues were considered including the fact that inter molecular C–H amination is significantly more challenging than intra molecular processes, 15 high chemo- and site (chemosite) 12 selectivity is required for natural products which often bear multiple functional groups, and finally the requirement of microscale reaction conditions (≤ 1 mg) since natural products are often available in limited quantities. Mechanistic studies suggest that Rh-catalyzed C–H amination processes proceed through a concerted asynchronous transition state involving a rhodium nitrene reactant and follows the reactivity trend of 3° > α-amino > α-ethereal ≥ benzylic > 2° ≫ 1° C–H bonds.…”

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…287 This technique allows for the rapid evaluation of the effects of derivatization on pharmacological activity and the incorporation of bioprobes for binding affinity studies. Towards this end, one technique they examined was the site-selective cyclopropanation of natural products.…”

Chemo- and site-selective derivatizations of natural products enabling biological studies

“…In order to exploit olefins as possible sites for simultaneous SAR/arming of alkene-containing natural products, Romo and co-workers developed alkynyl-bearing diazo reagents 19 and 20 for mild cyclopropanations of both electron-rich and electron-poor olefins, respectively (Scheme 4). 32 Electron-rich, alkene-containing natural products were found to undergo chemo- and site-selective cyclopropanation reactions with TMS-alkynyl diazo ester 19 . The TMS-alkyne derivative was required to avoid competing inter- and intramolecular cyclopropenations with the alkynyl group.…”

“…32 Using optimized reaction conditions (Scheme 12), 63 the forskolin derivative 23 underwent desilylation and conjugation to biotin azide 55 to deliver conjugate 58 in 76% yield. Furthermore, the authors successfully applied the cyclopropanation/conjugation sequence on microscale to the synthesis of a bexarotene-biotin conjugate 60 .…”