P450-Catalyzed Intramolecular sp³ C–H Amination with Arylsulfonyl Azide Substrates

Abstract

The direct amination of aliphatic C—H bonds represents a most valuable transformation in organic chemistry. While a number of transition metal-based catalysts have been developed and investigated for this purpose, the possibility to execute this transformation with biological catalysts has remained largely unexplored. Here, we report that cytochrome P450 enzymes can serve as efficient catalysts for mediating intramolecular benzylic C—H amination reactions in a variety of arylsulfonyl azide compouds. Under optimized conditions, the P450 catalysts were found to support up to 390 total turnovers leading to the formation of the desired sultam products with excellent regioselectivity. In addition, the chiral environment provided by the enzyme active site allowed for the reaction to proceed in a stereo- and enantioselective manner. The C—H amination activity, substrate profile, and enantio/stereoselectivity of these catalysts could be modulated by utilizing enzyme variants with engineered active sites.

Iron Catalysis in Organic Synthesis

“…935 The group of Fasan relied on the mutant P450 BM3 FL# 62 as catalyst for this transformation. 936 In contrast to a suggestion by Arnold, they could prove that cysteineÀheme ligated P450 enzymes can also be effective catalysts in this system.…”

Intramolecular C(sp3)H amination of arylsulfonyl azides with engineered and artificial myoglobin-based catalysts

“…19 In particular, these studies evidenced the direct involvement of the P450-embedded heme cofactor, in the reduced, ferrous form, for mediating these reactions. Based on these initial experimental data, a mechanism for these transformations was proposed which invokes the formation of an imido-iron(IV)(ppIX) species (ppIX = protoporphyrin IX) followed by metal-nitrenoid insertion into the benzylic C—H to give the corresponding benzosultam product.…”

The nature of chemical innovation: new enzymes by evolution

“…In choosing our first reaction targets we were inspired by early work of Breslow and Gellman, with iron-tetraphenyl porphyrin complexes (Breslow & Gellman, 1983), and then Dawson and coworkers (Svastits et al 1985), who reported that rabbit liver P450 enzymes catalyze low levels (<5 total turnovers, TTN) of intramolecular nitrene transfer to make benzosultams when provided with iminoiodinane nitrene precursors. As far as we can tell, no one followed up on Dawson's observations until we (McIntosh et al 2013) and Rudi Fasan (Singh et al 2014) showed that cytochrome P450 BM3 catalyzes low levels of intramolecular C-H amination to yield the same benzosultams from the more atom-efficient azide-based nitrene precursors (Fig. 1, reaction 5).…”