Late Stage Azidation of Complex Molecules

Abstract

Selective functionalization of complex scaffolds is a promising approach to alter the pharmacological profiles of natural products and their derivatives. We report the site-selective azidation of benzylic and aliphatic C–H bonds in complex molecules catalyzed by the combination of Fe(OAc)2 and a PyBox ligand. The same system also catalyzes the trifluoromethyl azidation of olefins to form derivatives of natural products containing both fluorine atoms and azides. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Azides obtained by functionalization of C–H and C=C bonds were converted to the corresponding amines, amides, and triazoles, thus providing a wide variety of nitrogen-containing complex molecules.

Transition‐Metal‐Catalyzed Selective Functionalization of C(sp3)−H Bonds in Natural Products

“…Chemie ligand L1 is the catalyst (Figure 11). [35,36] This reaction proceeds with excellent regioselectivity,f avoring azidation at electron-rich, tertiary C À Hb onds.F or example,a zidation of betulinic acid derivative 29 a,w hich contains an electronwithdrawing alkoxycarbonyl group,did not give any azidation product, but as tructurally similar betulin derivative 30 a, which contains al ess electron-withdrawing acetoxymethyl group at the position of the ester,g ave azide 30 b in good yield.…”

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…However, madecassic acid derivative 412 contains an electron-rich trisubstituted alkene and indeed, azidation is observed to occur at the allylic, secondary C–H bond to yield 413a (the allylic, tertiary C–H bond is presumably deactivated by its proximity to the ester) (Figure 60). 275 As a note, 16% of diene side product 413b is observed, which the authors suggest arises from oxidation of the incipient allylic secondary radical to a carbocation, followed by elimination. However, upon oxidizing gibberellic acid derivative 414a , which contains a 1,1-disubstituted olefin and a 1,2-disubstituted alkene, diazidiation of the terminal olefin is observed.…”

“…275 In this case, trimethylsilyl azide (TMSN 3 ) and Togni’s reagent ( 415 ) were used and indeed, selective formation of products was observed. In all cases, the products contained trifluoromethyl groups at the less substituted position and azides at the most substituted site.…”

“…274,275 The authors discovered that PyBox ligand 385 was capable of facilitating selective C–H azidation in high yields on numerous model substrates (Figure 59). On small molecule substrates, the authors observed many similar trends to those observed for iron-catalyzed C–H oxidations as shown above.…”

“…275 Nucleophilic displacement of the C3–OH with MeSO 2 Cl and NaN 3 revealed product 421 . A two-step hydroboration/azidation of 420 could access the anti-Markovnikov product 422 .…”