Biocatalytic Construction of Chiral Pyrrolidines and Indolines via Intramolecular C(sp<sup>3</sup>)–H Amination
Ziyang Qin, Shilong Gao, Yike Zou, Zhen Liu, James B. Wang, K. N. Houk, Frances H. Arnold
Abstract
High Resolution Image Download MS PowerPoint Slide Nature harnesses exquisite enzymatic cascades to construct N -heterocycles and further uses these building blocks to assemble the molecules of life. Here we report an enzymatic platform to construct important chiral N -heterocyclic products, pyrrolidines and indolines, via abiological intramolecular C(sp 3 )–H amination of organic azides. Directed evolution of cytochrome P411 (a P450 enzyme with serine as the heme-ligating residue) yielded variant P411-PYS-5149, capable of catalyzing the insertion of alkyl nitrene into C(sp 3 )–H bonds to build pyrrolidine derivatives with good enantioselectivity and catalytic efficiency. Further evolution of activity on aryl azide substrates yielded variant P411-INS-5151 that catalyzes intramolecular C(sp 3 )–H amination to afford chiral indolines. In addition, we show that these enzymatic aminations can be coupled with a P411-based carbene transferase or a tryptophan synthase to generate an α-amino lactone or a noncanonical amino acid, respectively, underscoring the power of new-to-nature biocatalysis in complexity-building chemical synthesis.