Regio- and Stereoselective Halogenation by an Iron(II)- and 2-Oxoglutarate-Dependent Halogenase in the Biosynthesis
Philip M Palacios1, Xiaoyun Li2, Simahudeen Bathir Jaber Sathik Rifayee3
1Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States.
Abstract:
Iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) enzymes have garnered strong research interest in past decades due to their ability to catalyze regio- and stereoselective C-H functionalization via a single reactive intermediate, the oxyferryl species. In addition to the hydroxylation reaction that is commonly observed, other reaction outcomes have also been discovered in Fe/2OG enzymes. Among them, halogenation has attracted much research effort with the goal of revealing the molecular determinants to favor halogenation over hydroxylation; however, a full mechanistic picture is still missing. In this study, by investigating a recently identified Fe/2OG halogenase, AdeV, from the biosynthetic pathway of Adechlorin, we show, via biochemical, kinetics, and spectroscopic characterizations, that two oxyferryl intermediates are formed during the AdeV reaction in a sequential manner, which interconvert but only one shows kinetic competency to enable C-H activation and leads to the conversion of 2'-deoxyadenosine monophosphate (2'-dAMP) and 2',3'-dideoxyadenosine monophosphate (ddAMP) to 2'-Cl-dAMP and 2'-Cl-ddAMP, respectively. By applying chemical synthesis and product characterization by detailed NMR analysis, the stereochemical assignment of the AdeV-catalyzed reaction is resolved, whereof the C-H bond cleavage and the C-Cl bond formation occur in a suprafacial manner. Using the experimental observations as a guide, the computational studies reveal that the kinetically competent oxyferryl intermediate structurally exhibits an offline configuration. However, this offline oxyferryl intermediate requires a structural conversion to a metastable inline configuration to perform a regio- and stereospecific C-H activation via a σ reaction channel. The subsequent conversion back to the offline configuration in the hydroxy-ferric state facilitates the final C-Cl bond formation.
More Related Videos
09:54Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes
Published on: September 12, 2018
08:43Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives
Published on: January 19, 2016
Related Concept Videos
02:17Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule
The hydrohalogenation of an unsymmetrical alkene can yield two haloalkane products, depending on which vinylic carbon takes up the halogen. However, one product usually predominates, where hydrogen adds to the vinylic carbon bearing the...
00:51Base-Promoted α-Halogenation of Aldehydes and Ketones
01:13Electrophilic Aromatic Substitution: Fluorination and Iodination of Benzene
01:21Acid-Catalyzed α-Halogenation of Aldehydes and Ketones
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –OH group. Consequently, the double bond attacks an electrophilic halogen to form a...
02:46Halogenation of Alkenes
Consider the bromination of cyclopentene. Molecular bromine is polarized in the proximity of the π electrons of cyclopentene. An electrophilic bromine atom adds across the double bond, forming a cyclic bromonium ion intermediate.
02:36Regioselectivity and Stereochemistry of Hydroboration
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.