Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/123874
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Rearrangement-free hydroxylation of methylcubanes by a cytochrome P450: the case for dynamical coupling of C-H abstraction and rebound
Author: Sarkar, M.R.
Houston, S.D.
Savage, G.P.
Williams, C.M.
Krenske, E.H.
Bell, S.G.
De Voss, J.J.
Citation: Journal of the American Chemical Society, 2019; 141(50):19688-19699
Publisher: ACS Publications
Issue Date: 2019
ISSN: 0002-7863
1520-5126
Statement of
Responsibility: 
Md. Raihan Sarkar, Sevan D. Houston, G. Paul Savage, Craig M. Williams, Elizabeth H. Krenske, Stephen G. Bell and James J. De Voss
Abstract: The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s-1 at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C-H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cubane core ring-opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C-H abstraction and C-O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.
Rights: Copyright © 2019 American Chemical Society
RMID: 1000009998
DOI: 10.1021/jacs.9b08064
Grant ID: http://purl.org/au-research/grants/arc/FT140100355
http://purl.org/au-research/grants/arc/FT110100851
http://purl.org/au-research/grants/arc/DP180103047
Appears in Collections:Chemistry publications

Files in This Item:
File Description SizeFormat 
hdl_123874.pdfAccepted version864.13 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.