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Epimerization of Tertiary Carbon Centers via Reversible Radical Cleavage of Unactivated C(sp3)-H Bonds Yaxin Wang, Xiafei Hu, Cristian A. Morales-Rivera, GuoXing Li, Xin Huang, Gang He, Peng Liu, and Gong Chen J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05753 • Publication Date (Web): 08 Jul 2018 Downloaded from http://pubs.acs.org on July 8, 2018
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Journal of the American Chemical Society
Epimerization of Tertiary Carbon Centers via Reversible Radical Cleavage of Unactivated C(sp3)-H Bonds Yaxin Wang,1# Xiafei Hu,1# Cristian A. Morales-Rivera,3 Guo-Xing Li,1 Xin Huang,1 Gang He,1,2* Peng Liu,3* and Gong Chen1,2,4* 1
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China 3 Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States 2
4
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
ABSTRACT: Reversible cleavage of C(sp3)-H bonds can enable racemization or epimerization, offering a valuable tool to edit the stereochemistry of organic compounds. While epimerization reactions operating via cleavage of acidic C(sp3)-H bonds, such as the Ca-H of carbonyl compounds, have been widely used in organic synthesis and enzyme-catalyzed biosynthesis, epimerization of tertiary carbons bearing a nonacidic C(sp3)-H bond is much more challenging with few practical methods available. Herein, we report the first synthetically useful protocol for the epimerization of tertiary carbons via reversible radical cleavage of unactivated C(sp3)-H bonds with hypervalent iodine reagent benziodoxole azide and H2O under mild conditions. These reactions exhibit excellent reactivity and selectivity for unactivated 3o C-H bonds of various cycloalkanes and offer a powerful strategy for editing the stereochemical configurations of carbon scaffolds intractable to conventional methods. Mechanistic study suggests that the unique ability of N3• to serve as a catalytic H atom shuttle is critical to reversibly break and reform 3o C-H bond with high efficiency and selectivity.
INTRODUCTION
A) Epimerization via cleavage of acidic C(sp3)-H bond R1 R
3 H Methods for the selective functionalization of alkyl C-H bonds O R1 O(H) R3 R R2 have been greatly advanced over the past few decades, offering 1 R3 R2 O H streamlined strategies for the synthesis and modification of complex enolization molecules.1-4 A wide range of reactions have been developed to transB) Epimerization of Ile residue in peptide by radical SAM peptide epimerase form C(sp3)-H bonds into different functional groups.5-9 However, NH 2 N reactions featuring reversible cleavage of unactivated C(sp3)-H N N bonds have received much less attention. Racemization or epimeriN 3 zation via reversible cleavage of C(sp )-H bonds might offer an inH-S O CH 2 5'-dA HO valuable tool for editing the stereochemistry of organic compounds. H H HO 5'-dA Cys Additionally, exchanging C(sp3)-H bonds with C-deuterium bonds N N N H H H may provide valuable deuterated compounds for biomedical appliO O O [4Fe-4S] D-allo-Ile L-Ile SAM cations.10,11 Epimerization reactions of tertiary Ca of carbonyl compounds via cleavage of their acidic C(sp3)-H bonds have been rouC) Epimerization strategy via radical cleavage of nonacidic 3o C−H bond tinely used in the synthesis of complex molecules, and in catalytic A-H D A D-H process such as dynamic kinetic resolution (Scheme 1A). Similar H R1 R1 R3 R2 R3 enolization mechanisms have also been widely used by enzyme epiR1 R R 3 2 12 R2 H merases for the biosynthesis of natural products. Compared with A : H acceptor D-H : H donor acidic C(sp3)-H bonds, epimerization of tertiary carbons bearing non-acidic C(sp3)-H bonds is much more challenging. Interestingly, D) This work: selective epimerization of nonacidic 3o C−H of cyclic alkanes recent biochemical studies have shown that [4Fe-4S]-cluster radical R S-adenosyl-L-methionine (SAM) epimerases invert the stereocenO R H O ters of amino acid or sugar units through radical-mediated pathI N H R 3 ways.13, 14 For example, an epimerase selectively converts an L-Ile 1 (2-3 equiv) unactivated efficient; selective; amino acid residue of a peptide to D-allo-Ile via abstraction of CaEtOAc(or PhCl) / H 2O simple to operate; 3o C-H BIN 3 1 35-50 oC compatible with H by a 5’-deoxyadenosyl radical (5’-dA•) and quenching of the carcomplex substrate a catalytic N3 bon radical intermediate by a thiol group of an enzyme cysteine resH atom shuttle 13 3 idue (Scheme 1B). Radical-mediated C(sp )-H cleavage reactions Scheme 1. Epimerization of tertiary carbon via reversible cleavage could potentially provide a unique solution to epimerize traditionof tertiary C-H bonds. ally “unepimerizable” tertiary carbon centers in organic synthesis. ACS Paragon Plus Environment
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To achieve such transformations with useful efficiency, the sequence of H abstraction by a suitable radical H atom acceptor (A•) and quenching of the tertiary C-radical by suitable H atom donor (D-H) must be developed (Scheme 1C). Herein, we report an efficient and synthetically useful protocol for epimerizing tertiary carbons via radical cleavage of non-acidic 3o C(sp3)-H bonds with hypervalent iodine reagent benziodoxole azide and H2O under mild conditions (Scheme 1D).
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H
H
N3
H Ara
H 2-trans
2-cis
H 3
entry
Reagents (equiv), reaction time, temp
Solvents
2-trans (2-cis) %
3%
1
1 (2), BzOOBz (0.1), 24 h, 80 oC
2
1 (2), Fe(OAc)2 (0.1), PyBOX (0.1), 24 h,
DCE
