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Enzymatic Lactone-Carbene C#H Insertion to Build Contiguous Chiral Centers Andrew Z

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Enzymatic Lactone-Carbene C#H Insertion to Build Contiguous Chiral Centers Andrew Z Subscriber access provided by Caltech Library Letter Enzymatic Lactone-Carbene C#H Insertion to Build Contiguous Chiral Centers Andrew Z. Zhou, Kai Chen, and Frances H. Arnold ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01349 • Publication Date (Web): 21 Apr 2020 Downloaded from pubs.acs.org on April 21, 2020 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. 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ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 8 ACS Catalysis 1 2 3 4 5 6 7 Enzymatic Lactone-Carbene C‒H Insertion to Build Contiguous 8 Chiral Centers 9 10 Andrew Z. Zhou, Kai Chen,* Frances H. Arnold* 11 12 a Division of Chemistry and Chemical Engineering 210-41, California Institute of Technology, Pasadena, CA 91125, USA. 13 KEYWORDS: Cytochrome P450, directed evolution, carbene transfer, C‒H functionalization, lactone 14 15 16 ABSTRACT: We report a biocatalytic platform of engineered cytochrome P411 enzymes (P450s with axial serine ligation) to carry 17 out efficient lactone-carbene insertion into primary and secondary α-amino C‒H bonds. Directed evolution of a P450 variant, P411- 18 C10, yielded a lineage of enzyme variants capable of forming chiral lactone derivatives with high catalytic efficiency (up to 4000 19 TTN) and in a stereo-divergent manner. For carbene insertion into secondary C‒H bonds, a single mutation was discovered to invert 20 the two contiguous chiral centers and lead to the opposite enantiomers of the same major diastereomers. This work demonstrates the 21 utility of engineered enzymes for asymmetric catalysis and highlights the remarkable tunability of these genetically-encoded 22 biocatalysts for accessing desired selectivities. 23 24 25 Direct functionalization of carbon‒hydrogen bonds represents a Rather than using the well-studied donor-acceptor carbenes, we 26 powerful and efficient strategy for installing new chemical focused on lactone-based carbenes, which are difficult to use 27 moieties in organic compounds.1 In particular, enantioselective with rhodium catalysts due to challenges with β-H elimination 28 C(sp3)‒H alkylation via carbene insertion into C‒H bonds and stereocontrol.14 Despite limited examples of C‒H insertion 29 provides a platform for C(sp3)‒C(sp3) bond formation to build with cyclic carbenes,15 we previously revealed that lactone- 30 diverse molecular skeletons and for late-stage modification of based carbenes can be transferred to different functionalities 31 complex molecules.2 Transition-metal catalysts based on with high efficiency and stereoselectivity using engineered 32 rhodium,3 iridium,4 cobalt,5 copper,6 and other metals7 have hemeprotein catalysts.16,17 Those studies demonstrated the 33 been shown to catalyze carbene insertion into C‒H bonds. In enzymes’ ability to stabilize the lactone-carbene intermediates, 34 most reported methods, carbenes bearing one electron-donating circumvent undesired β-H migration, and facilitate carbene aryl/alkenyl group and one electron-withdrawing group transfer with exquisite stereocontrol, thus laying the foundation 35 (‘donor-acceptor carbenes’) have been demonstrated to be for the current study. 36 superior for intermolecular C‒H insertions, with control over 37 reactivity and selectivity in these catalytic systems.8 Dirhodium We initiated this investigation of C‒H functionalization with α- 38 catalysts, for example, have achieved site-selective diazo-γ-lactone (LAD) and 4,N,N-trimethylaniline (1a) as 39 functionalization of various types of C‒H bonds through the substrates (Figure 2).18 The expected carbene-transfer reaction 40 manipulation of ligand scaffolds.9 Other carbenes, however, leads to the formation of a β-amino lactone product, 2a, through such as acceptor-only carbenes, are less explored for C‒H 41 carbene insertion into an α-amino C‒H bond with a chiral center insertion reactions;4b,6a,7c acceptor-only carbenes with an 42 generated at the α-position. Such β-amino lactone products are additional alkyl substituent at the α-position are even more 43 analogs of sesquiterpene-lactone amino derivatives, which challenging to use in these systems due to competitive β- 44 possess desirable pharmaceutical properties.19 Screening hydride migration upon the formation of the metallo-carbene 45 various hemeproteins, including P450 variants, P411s, and species.10 46 cytochromes c in the form of whole Escherichia coli (E. coli) 47 cell catalysts identified a P411 variant, P411-C10, capable of 48 Recently, we reported that a cytochrome P450, which uses an the desired C‒H insertion transformation (Figure 1). P411- 49 iron-heme cofactor for its native oxygenase activity, can be C10, a promiscuous enzyme for different carbene-transfer engineered to transfer carbene moieties to C‒H bonds using chemistries including internal cyclopropene formation,20 50 diazo compounds bearing a single electron-withdrawing catalyzed the C‒H insertion reaction using a cyclic carbene with 51 substituent (Figure 1).11,12 Engineered P450 enzymes modest efficiency (105 TTN) and stereoselectivity (47% ee). 52 substituted with serine as the heme-ligating residue (‘P411s’)13 53 were established as an efficient platform for stereoselective 54 C‒C bond assembly with a chiral center formed at the β- 55 position. We thus anticipated that the P411 enzymes could be 56 evolved further to adopt branched carbenes for C‒H insertion, 57 which would enable them to build a chiral center at α-position 58 or even contiguous chiral centers at both the α and β-positions. 59 60 ACS Paragon Plus Environment ACS Catalysis Page 2 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Figure 1. Enzymatic carbene insertion into C‒H bonds. 22 To enhance enzyme activity and selectivity by directed 23 Figure 2. Directed evolution of P411-C10 for lactone-carbene evolution, we targeted active-site residues for site-saturation insertion into α-amino C‒H bonds. Reactions were performed in 24 mutagenesis and screening (Figure 2). Loop residues in the quadruplicate under the following conditions: 10 mM 4,N,N- 25 enzyme’s active site were tested first, and beneficial mutations trimethyl aniline (1a), 10 mM LAD, E. coli harboring P411-C10 26 T327V and Q437L together increased total turnovers 9-fold. variants (OD600 = 15 to 60), D-glucose (25 mM), M9-N 27 However, enantioselectivity decreased to 40% ee after three buffer/EtOH (19:1), anaerobic, 24 h. Product formation was 28 rounds of evolution. As substrate 1a is symmetric, we quantified by high-performance liquid chromatography (HPLC), 29 hypothesized it might bind with different orientations relative TTNs were determined based on protein concentration, and to the carbene intermediate, which would lead to the diminished enantioselectivity was measured using chiral HPLC. The heme- 30 domain structure of P411-E10 variant, an enzyme previously 31 stereoselectivity. To address this, we next targeted amino acids previously shown to dramatically affect stereoselectivity in evolved for C‒H amination with high sequence identity to P411- 32 C10, (pdb: 5UCW) was used to guide site-saturation mutagenesis; either native or non-native functions of this P450, such as sites 33 mutation sites are highlighted. See Tables S1, S2 in SI for details. 87, 264, 268, and 328.13b-d,21 Screening a site-saturation library 34 at site 87 for increased enantioselectivity resulted in discovery 35 As different variants in the enzyme lineage (L1 to L10) showed of a proline mutation giving 56% ee, albeit with decreased TTN. different levels of activity or selectivity for the C‒H insertion 36 Residue 264 is the closest residue to the iron center, which may reaction, we selected representative variants (L6 to L10) with 37 also influence binding of substrate or the orientation of the which to evaluate the transformation of various N,N-dialkyl 38 carbene intermediate. The A264S mutation improved both aniline derivatives, as shown in Figure 3. Substituents on the 39 activity and enantioselectivity. Revisiting site 327 identified phenyl ring, including methyl, methoxyl or halide, are all 40 another proline mutation, which boosted the ee to 75%. The compatible with the biocatalytic system, giving TTNs ranging 41 three mutations A87P, A264S, and V327P may have improved from 410 to 2920. Variants L9 and L10 showed consistently 42 enantioselectivity by providing a more restricted binding mode opposite stereo-preference for diverse substrates (e.g., for 2d for substrate 1a in the enzyme.
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