Macrolide Synthesis through Intramolecular Oxidative Cross-Coupling of Alkenes

Article abstract of DOI:10.1002/anie.201710601

A Rh^III-catalyzed intramolecular oxidative cross-coupling between double bonds for the synthesis of macrolides is described. Under the optimized reaction conditions, macrocycles containing a diene moiety can be formed in reasonable yields and with excellent chemo- and stereoselectivity. This method provides an efficient approach to synthesize macrocyclic compounds containing a 1,3-conjugated diene structure.

Full text of DOI:10.1002/anie.201710601

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Macrolide Synthesis via Intramolecular Oxidative Cross-Coupling
of Alkenes
Authors: Yunhe Xu, Bing Jiang, Meng Zhao, Shu-Sen Li, and Teck-
Peng Loh
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710601
Angew. Chem. 10.1002/ange.201710601
Link to VoR: http://dx.doi.org/10.1002/anie.201710601
http://dx.doi.org/10.1002/ange.201710601

10.1002/anie.201710601
Angewandte Chemie International Edition
COMMUNICATION
Macrolide Synthesis via Intramolecular Oxidative Cross-Coupling
of Alkenes
Bing Jiang, Meng Zhao, Shu-Sen Li, Yun-He Xu* and Teck-Peng Loh*[a]
Dedication ((optional))
ABSTRACT: A Rh(III)-catalyzed intramolecular oxidative cross-
coupling between double bonds for the synthesis of macrolides is
described. Under the optimized reaction conditions, the macrocycles
containing diene moiety could be formed in reasonable yields and
with excellent chemo- and stereoselectivities. This study provides an
efficient method to synthesize macrocyclic compounds containing a
1,3-conjugated diene structure.
organometallic reagents to connect different double bonds were
also reported (Scheme 1a and 1b).[8] Inspired by the recent
advances on the transition-metal catalyzed C-H bond direct
functionalization[9] especially the pioneering work reported by
Glorious on Rh-catalyzed oxidative cross-coupling reaction
9b]
between electron-deficient alkenes[9a,
and combined our
continuous interest in the alkene-alkene coupling reactions,[10]
we envisage that an intramolecular cross-coupling between two
different double bonds will provide an efficient method to access
this class of compounds. Herein, we would like to report a
Rh(III)-catalyzed macrocyclization reaction via intramolecular
oxidative cross-coupling between double bonds. The big-sized
ring macrocyclic products could be obtained in reasonable yields
via this strategy. This method is atom-economical and the
products obtained can be converted to other useful functional
compounds. In addition, this firstly reported an example on
intramolecular oxidative cross-coupling reaction between double
bonds.
Macrocycles are important class of compounds since they
are featured widely in many natural products and
pharmaceuticals.[1] Common strategies utilized to construct
these macrocyclic compounds are macrolactonizations,[2]
macroaldolizations,[3] and macrolactamizations[4]. Furthermore in
the past several decades, the transition-metal catalyzed cross-
coupling reactions to forge new C-C or C-X (X = heteroatom)
bond for the construction of large rings have also emerged as
powerful tools.[5] In recent years, the strategy of ring closing
metathesis (RCM) has also become a popular way to construct
large rings containing double bond albeit with difficulty in
controlling E/Z stereoselectivity.[6] There are also numerous
macrocyclic natural products such as Rifaximin, Viridenomycin,
and (-)-zampanclide etc. containing a conjugated diene moiety.[7]
However, methods to construct this type of macrocycles
have been rare. Except for the traditional strategies via step-by-
step synthesis of the conjugated double bonds respectively,
recently, few examples on the synthesis of such compounds via
Scheme 1. Synthesis of Macrocyclic Compounds Containing 1,3-Conjugated
Diene Moiety.
To evaluate the feasibility of the rhodium-catalyzed
intramolecular cross-coupling reaction between alkenes, we
chose the easily available 6-methacrylamidohexyl acrylate 1l for
the model reaction. Optimization of reaction conditions was
carried out by employing [RhCp*Cl2]2 as the catalyst, and the
results were summarized in Table 1. Pleasingly, the 14-
membered ring product 2l could be obtained in 8% yield and
with single Z,E-configuration in the presence of 5 mol%
[RhCp*Cl2]2 as catalyst, Cu(OAc)2·H 2O (2.0 equiv) as oxidant in
DCE (0.01 M) at 100 oC for stirring 24 h under argon atmosphere
(Table 1, entry 1). The Z,E-configuration of the product 2l was
determined by 1H-1H COSY NMR spectrum analysis, which
indicated the amide group possibly acting as a directing group
role in the C(sp2)-C(sp2) bond formation step. Thus different
solvents, reaction temperatures and oxidants were examined in
sequence. And it was found that the desired product could be
obtained in 42% yield in acetone. It is worthwhile to note that a
cross-coupling dimer product with 28-membered ring structure
transition-metal-catalyzed
coupling
reactions
using
[a]
Prof. Dr. Y. H. Xu, Prof. Dr. T. P. Loh
Hefei National Laboratory for Physical Sciences at the Microscale
iChEM (Collaborative Innovation Center of Chemistry for Energy
Materials),
University of Science and Technology of China
Hefei, Anhui 230026, China
E-mail: xyh0709@ustc.edu.cn, teckpeng@ustc.edu.cn
Prof. Dr. T. P. Loh
Institute of Advanced Synthesis, Jiangsu National Synergetic
Innovation Center for Advanced Materials, Nanjing Tech University,
Nanjing, Jiangsu, China, 210009
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637616
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.201710601
Angewandte Chemie International Edition
COMMUNICATION
was also generated along with the formation of the 14-
membered normal macrocyclic product 2l in 25% yield (Table 1,
entry 8) at high concentration (0.2 M). Following, some additives
and other rhodium catalysts were proved no significant effect on
improving the product’s yield (Table 1, entries 9-13). Therefore,
a cationic rhodium species was expected to be more reactive to
catalyze this coupling reaction. Thus, 20 mol% sodium
(triisopropylsilyl)oxy)methyl or benzyl group all reacted well and
furnished the corresponding products in moderate to good yields
(2p-2r). Current annulation method, allowed to access even
larger or smaller rings by tethering a longer or shorter linker
between acrylate and acrylamide fragments (2s-2x/2x’). It is
worth noting that apart from the formation of product 2x in 22%
yield with a Z/E-configuration, another 12-memberd macrocyclic
product 2x’ with a Z/Z-configuration could also be isolated in 24%
yield when the acrylamide-enoate 1x was applied in this reaction.
Moreover, in contrast to the previous result,10b the substrate 1u
with N-phenyl acrylamide moiety also showed good reactivity,
and the desired 14-membered ring product 2u was obtained in
51% yield. Further studies showed that current catalytic protocol
was not only limited to α-substituted substrates, but also was
compatible to α,β-disubstituted acrylamide derivatives. However,
these substrates only exhibited low reactivity along with low
conversion. The acrylamide embedded with a cyclopentenyl and
a cyclohexenyl moiety afforded the desired bicyclic compounds
in 40% and 39% yields, respectively (2y-2z). Low yields of the
products 2aa and 2ab were observed when α-phenyl-β-phenyl-
and α-methyl-β-aryl-substituted acrylamides were subjected to
this reaction. Unfortunately, the unsubstituted substrate 1ad
could not give any desired product under the optimized reaction
conditions even though prolonging the reaction time.
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
(NaBARF)
as
additive was introduced, as a result the desired product could be
obtained in 52% yield (Table 1, entry 18). Finally, the desired
product 2l could be isolated in 69% yield via increasing the
loadings of NaBARF (40 mol%) and Cu(OAc)2·H 2O (2.5
equivalents) (Table 1, entry 19-20). Control experiments
indicated that all the components in the catalytic system were
necessary in this reaction to afford the desired product 2l in a
good yield.
Table 1. [RhCp*Cl2]2 Catalyzed Macrocyclization of 1l.
Table 2. Substrate Scope for the Intramolecular Cross-Coupling Reactiona
a Reaction was run under the following reaction conditions: 0.15 mmol 1,
5
mol % [RhCp*Cl2]2, 0.375 mmol Cu(OAc)2·H 2O and 0.05 mmol NaBARF in 15
mL acetone at 100 oC for 24 h under air atmosphere. Yield in parentheses was
isolated yield. NaBARF: Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
b
c
Yield was determined by 1H NMR using mesitylene as internal standard.
d
e
Ag2CO3 (2.0 equiv) was used. 2.5 mol% [RhCp*Cl2]2 was used. under air
atmosphere. f Under oxygen atmosphere. g Reaction was run for 48 h. 5 mol%
h
Rh(CH3CN)3Cp*(SbF6)2 was used. i Cu(OAc)2·H 2O (2.5 equiv) was used.
a
Reaction was run under the following reaction conditions: 0.15 mmol 1,
5
mol % [RhCp*Cl2]2, 0.375 mmol Cu(OAc)2·H2O and 0.05 mmol NaBARF in 15
mL acetone at 100 oC for 24 h under air atmosphere. NaBARF: Sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. Yield in parentheses was
isolated yield.
After determining the optimized reaction conditions, further
investigation on the substrate scope and limitation of current
intramolecular oxidative cross-coupling was performed. Firstly,
we turned our attention to examine the substituents tolerated on
the acrylamide part. It was observed that the desired 14-
membered macrocycles were obtained in moderate to high
yields when the substrate with an aryl substituent at α-position.
Both electron-donating and electron-withdrawing functional
groups were well tolerated on the phenyl ring. The
corresponding products were isolated in 44-74% yields. The
structure of 2a with a Z/E configuration of the diene moiety was
determined by X-ray crystallography diffraction analysis (CCDC
numbers: 1574636). Furthermore, the substrates with aliphatic
substituents at α-position of acrylamide were tested for this
macrocyclization reaction (2l-2o). It was found that the
substrates bearing no matter a carbon chain, ethoxymethyl,
To explore the synthetic utility of current protocol,
derivatization reactions of macrocycle 2a were investigated
(Scheme 2). Treatment of 2a with DBU in acetonitrile afforded
the bicyclic compound 3a in 73% yield via intramolecular
Michael addition and dehydrogenation processes.[11] In contrast
to this result, if 2a was treated with Cs2CO3, more stable Michael
addition product 3b could be obtained in 74% yield.[12] In addition,
the 1,4-hydrosilylation of acrylate fragment product 3e was
obtained in 96% yield under the NHC-Cu-OtBu catalytic
system.[13]
A similar chemoselective 1,4-Michael addition
reaction happened when nitromethane was used as nucleophile
under basic condition.[14] And the desired product 3f was isolated
This article is protected by copyright. All rights reserved.

10.1002/anie.201710601
Angewandte Chemie International Edition
COMMUNICATION
in 74% yield. In addition, a highly stereoselective reductive
product 3c with E-configuration was obtained in an excellent
yield by using the bis(pinacolato)diboron reagent and copper
catalyst. This result was attributed to a 1,6-conjugated boryl
addition and a sequential allylic boronate reduction processes.
Furthermore, hydrogenation reaction of 2a catalyzed by Pd/C
led to the product 3d in a high yield.
Table 3. Substrate Scope for the Intramolecular Cross-Coupling Reactiona
Scheme 3. Isotopically Labelled Experiments for KIE Studies.
Therefore, a plausible mechanism to account for the Rh(III)-
catalyzed macrocyclization was proposed on the basis of our
experimental results and precedent literatures (Scheme 4).[15]
Anion exchange of [RhCp*Cl2]2 with NaBARF and Cu(OAc)2·H 2O
afforded the reactive species A, which selectively activates the
Z-olefinic C-H bond of acrylamide derivative 1 to form an
vinylrhodium(III) species B. Subsequent intramolecular
coordination and migratory insertion of acrylate form accordingly
intermediate C and D, which undergoes β-hydride elimination to
provide the macrocycle and concomitantly release a Rh (III)
hydride species. Reductive elimination followed by reoxidation of
[Rh(I)] to [Rh(III)] by Cu(OAc)2·H 2O would release the active
catalyst for next catalytic cycle.
a Reaction was run under the following reaction conditions: 0.15 mmol 1,
5
mol % [RhCp*Cl2]2, 0.375 mmol Cu(OAc)2·H2O and 0.05 mmol NaBARF in 15
mL acetone at 100 oC for 24 h under air atmosphere. Yield in parentheses was
isolated yield. NaBARF: Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
Scheme 4. Proposed Reaction Mechanism.
In summary, we have accomplished the first intramolecular
Rh(III)-catalyzed oxidative cross-coupling reaction between
double bonds. This work provides a rapid and atom-economical
synthetic pathway to form macrolide compounds with a Z/E-
configuration diene moiety. This work is also featured by its high
chemoselectivity and stereoselectivity, good functional groups
compatibility and versatile utility of the diene fragment in further
derivation reactions. And the in-depth application studies of this
intramolecular oxidative cross-coupling reaction in organic
synthesis will be implemented in our laboratory.
Scheme 2. Derivatization of the Cross-Coupling Macrocycle Product.
Finally, to gain some preliminary understanding of the
mechanism, the isotopically labeled experiment of acrylamide 4a
was carried out. A remarkable Z-selective olefinic H/D exchange
was detected with addition of D2O, which implicated a reversible
cyclometalation process (Scheme 3, eq. 1). Furthermore, a
kinetic isotope effect (KIE) value (kH/kD = 5) was observed in the
competitive cross-coupling reactions of 1a and 1a-d2, suggesting
the alkenyl C-H bond activation was the possible rate-
determining step (Scheme 3, eq. 2).
Acknowledgements ((optional))
We gratefully acknowledge the funding support of the
National Natural Science Foundation of China (21372210,
21672198), the State Key Program of National Natural Science
Foundation of China (21432009), the State Key Laboratory of
Elemento-organic Chemistry Nankai University (201620) and the
This article is protected by copyright. All rights reserved.

10.1002/anie.201710601
Angewandte Chemie International Edition
COMMUNICATION
Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38, 3242. (d) T. W. Lyons,
M. S. Sanford, Chem. Rev. 2010, 110, 1147. (e) D. A. Colby, R. G. Bergman,
J. A. Ellman, Chem. Rev. 2010, 110, 624. (f) T. Newhouse, P. S. Baran,
Angew. Chem., Int. Ed. 2011, 50, 3362. (g) L. Ackermann, Chem. Rev. 2011,
111, 1315. (h) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011,
40, 1885. (i) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012,
112, 5879. (j) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem., Int. Ed.
2012, 51, 8960. (k) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem.
Res. 2012, 45, 788. (l) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius,
Angew. Chem., Int. Ed. 2012, 51, 10236. (m) L. Yang, H. Huang, Chem. Rev.
2015, 115, 3468. (n) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang,
Org. Chem. Front. 2015, 2, 1107. (o) Y. Park, Y. Kim, S. Chang, Chem. Rev.
2017, 117, 9247. (p) Z. Dong, Z. Ren, S. J. Thompson, Y. Xu, G. Dong, Chem.
Rev. 2017, 117, 9333.
Collaborative Innovation Center of Chemistry for Energy
Materials (2011-iChEM) for financial support.
Keywords: Rhodium • C-H activation • macrocyclization • cross-
coupling
[1] (a) C. Olano, C. Méndez, J. A. Salas, Mar. Drugs 2009, 7, 210. (b) A. M. S.
Mayer, A. D. Rodríguez, R. G. S. Berlinck, M. T. Hamann, Biochim. Biophys.
Acta, Gen. Subj. 2009, 1790, 283. (c) J. J. Coleman, S. Ghosh, I. Okoli, E.
Mylonakis, PLoS One 2011, 6 (1−9), e25321. (d) C. M. Madsen, M. H.
Clausen, Eur. J. Org. Chem. 2011, 2011, 3107. (e) X. Yu, and D. Sun,
Molecules 2013, 18, 6230. (f) D. Jelić, R. Antolović, antibiotics 2016, 5, 29. (g)
M. Peres de Carvalho, H. Weich, W.-R. Abraham, Curr. Med. Chem. 2016, 23,
23.
[2] Review: (a) A. Parenty, X. Moreau, J.-M.Campagne, Chem. Rev. 2006, 106,
911. (b) A. Parenty, X. Moreau, G. Niel, J. M. Campagne, Chem. Rev. 2013,
113, PR1.
[10] (a) Y.-H. Xu, J. Lu, T.-P. Loh, J. Am. Chem. Soc. 2009, 131, 1372. (b) J.
Zhang, T.-P. Loh, Chem. Commun. 2012, 48, 11232. (c) Z.-K. Wen, Y.-H. Xu,
T.-P. Loh, Chem. Sci. 2013, 4, 4520. (d) X.-H. Hu, J. Zhang, X.-F. Yang, Y.-H.
Xu, T.-P. Loh, J. Am. Chem. Soc. 2015, 137, 3169. (e) X.-H. Hu, X.-F. Yang,
T.-P. Loh, Angew. Chem., Int. Ed. 2015, 54, 15535.
[3] See for example: (a) C. M. Hayward, D. Yohannes, S. J. Danishefsky, J.
Am. Chem. Soc. 1993, 115, 9345. (b) A. Balog, D. Meng, T. Kamenecka, P.
Bertinato, D. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem., Int. Ed.
Engl. 1996, 35, 2801. (c) D. Meng, P. Bertinato, A. Balog, D.-S. Su, T.
Kamenecka, E. J. Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119,
10073. (d) D.-S. Su, D. Meng, P. Bertinato, A. Balog, E. J. Sorensen, S. J.
Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B.Horwitz, Angew. Chem., Int.
Ed. Engl. 1997, 36, 757–759. (e) R. R. Knowles, J. Carpenter, S. B. Blakey, A.
Kayano, I. K. Mangion, C. J. Sinz, D. W. C. MacMillan, Chem. Sci. 2011, 2,
308. (f) L. A. Wessjohann, G. O. Scheid, U. Eichelberger, S. Umbreen, J. Org.
Chem. 2013, 78, 10588.
[11] (a) C.-E. Yeom, Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63, 904. (b) L.
Li, Y.-L. Zhao, Q. Wang, T. Lin, Q. Liu, Org. Lett. 2015, 17, 370.
[12] D. Heine, T. Bretschneider, S. Sundaram, C. Hertweck, Angew. Chem.,
Int. Ed. 2014, 53, 11645.
[13] (a) K. Lee, A. R. Zhugralin, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131,
7253. (b) K. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 2898. (c) K.
Lee, H. Wu, F. Haeffner, A. H. Hoveyda, Organometallics 2012, 31, 7823. (d)
V. Pace, J. P. Rae, D. Procter, J. Org. Lett. 2014, 16, 476. (e) T. Kitanosono, L.
Zhu, C. Liu, P. Xu, S. Kobayashi, J. Am. Chem. Soc. 2015, 137, 15422.
[14] F. Felluga, G. Pitacco, E. Valentin, C. D. Venneri, Tetrahedron:
Asymmetry 2008, 19, 945.
[4] See for example: (a) D. A. Evans, S. J. Miller, M. D. Ennis, P. L. Ornstein, J.
Org. Chem. 1992, 57, 1067. (b) D. A. Evans, S. J. Miller, M. D. Ennis, J. Org.
Chem. 1993, 58, 471. (c) K. Ishihara, Y. Kuroki, N. Hanaki, S. Ohara, H.
Yamamoto, J. Am. Chem. Soc. 1996, 118, 1569. (d) S. Wen, G. Packham, A.
Ganesan, J. Org. Chem. 2008, 73, 9353. (e) Z. J. Song, D. M. Tellers, M.
Journet, J. T. Kuethe, D. Lieberman, G. Humphrey, F. Zhang, Z. Peng, M. S.
Waters, D. Zewge, A. Nolting, D. Zhao, R. A. Reamer, P. G. K. M. Dormer,
Belyk, I. W. Davies, P. N. Devine, D. M. Tschaen, J. Org. Chem. 2011, 76,
7804.
[15] (a) S. H. Park, J. Y. Kim, S. Chang, Org. Lett. 2011, 13, 2372. (b) N. K.
Mishra, J. Park, S. Sharma, S. Han, M. Kim, Y. Shin, J. Jang, J. H. Kwak, Y. H.
Jung, I. S. Kim, Chem. Commun. 2014, 50, 2350. (c) R. Feng, W. Yu, K. Wang,
Z. Liu, Y. Zhang, Adv. Synth. Catal. 2014, 356, 1501. (d) J. Park, S. Han, M.
Jeon, N. K. Mishra, S. Y. Lee, J. S. Lee, I. S. Kim, J. Org. Chem. 2016, 81,
11353. (e) S. E. Korkis, D. J. Burns, H. W. Lam, J. Am. Chem. Soc. 2016, 138,
12252. (f) F. Li, C. Yu, J. Zhang, G. Zhong, Org. Biomol. Chem. 2017, 15,
1236. (g) H.-J. Xu, Y. Lu, M. E. Farmer, H.-W. Wang, D. Zhao, Y.-S. Kang, W.-
Y. Sun, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139, 2200.
[5] See for example: (a) R. Lépine, J. Zhu, Org. Lett. 2005, 7, 2981. (b) H.
Uchiro, R. Kato, Y. Arai, M. Hasegawa, Y. Kobayakawa, Org. Lett. 2011, 13,
6268. (c) R. Yamasaki, A. Shieto, S. Saito, J. Org. Chem. 2011, 76, 10299. (d)
V. Velvadapu, T. Paul, B. Wagh, I. Glassford, C. DeBrosse, R. B. Andrade, J.
Org. Chem. 2011, 76, 7516. (e) C. W. Zapf, J. D. Bloom, J. L. McBean, R. G.
Dushin, J. M. Golas, H. Liu, J. Lucas, F. Boschelli, E. Vogan, J. I. Levin,
Bioorg. Med. Chem. Lett. 2011, 21, 3627. (f) M. Dieckmann, M. Kretschmer, P.
Li, S. Rudolph, D. Herkommer, D. Menche, Angew. Chem., Int. Ed. 2012, 51,
5667. (g) M. Dieckmann, S. Rudolph, S. Dreisigacker, D. Menche, J. Org.
Chem. 2012, 77, 10782. (h) L. Shen, C. J. Simmons, D. Sun, Tetrahedron Lett.
2012, 53, 4173. (i) W. P. Unsworth, K. A. Gallagher, M. Jean, J. P. Schmidt, L.
J. Diorazio, R. J. Taylor, K. Org. Lett. 2013, 15, 262. (j) T. O. Ronson, R. J. K.
Taylor, I. J. S. Fairlamb, Tetrahedron 2015, 71, 989.
[6] (a) A. Gradillas, J. Pérez-Castells, Angew. Chem., Int. Ed. 2006, 45, 6086.
(b) S. Monfette, D. E. Fogg, Chem. Rev. 2009, 109, 3783. (c) Y. Zhao, B. Gao,
C. Ni, J. Hu, Org. Lett. 2012, 14, 6080. (b) P. Jakubec, D. M. Cockfield, D. J.
Dixon, J. Am. Chem. Soc. 2009, 131, 16632. (d) C. J. White, A. K. Yudin, Nat.
Chem. 2011, 3, 509. (e) M. Yu, C. Wang, A. F. Kyle, P. Jakubec, D. J. Dixon,
R. R. Schrock, A. H. Hoveyda, Nature 2011, 479, 88. (f) V. M. Marx, M. B.
Herbert, B. K. Keitz, R. H. Grubbs, J. Am. Chem. Soc. 2013, 135, 94. (g) H.
Zhang, E. C. Yu, S. Torker, R. R. Schrock, A. H. Hoveyda, J. Am. Chem. Soc.
2014, 136, 16493.
[7] (a) D. J. Newman, G. M. Cragg, In Macrocycles in Drug Discovery; Levin,
J., Ed.; The Royal Society of Chemistry: Cambridge, U.K., 2015; Vol. 40, pp
1−36. (b) D. M. Ramsey, R. R. A. Kitson, J. I. Levin, C. J. Moody, S. R.
McAlpine, In Macrocycles in Drug Discovery. Levin, J., Ed.; The Royal Society
of Chemistry: Cambridge, U.K., 2015; Vol. 40, pp 37−77.
[8] (a) M. A. Duncton, C. Pattenden, J. Chem. Soc., Perkin Trans. 1 1999,
1235. (b) P. Li, J. Li, F. Arikan, W. Ahlbrecht, M. Dieckmann, D. Menche, J.
Am. Chem. Soc. 2009, 131, 11678. (c) S. E. Denmark, J. M. Muhuhi, J. Am.
Chem. Soc. 2010, 132, 11768.
[9] (a) T. Besset, N. Kuhl, F. W. Patureau, F. Glorius, Chem. Eur. J. 2011, 17,
7167. (b) M. Boultadakis-Arapinis, M. N. Hopkinson, F. Glorius, Org. Lett.
2014, 16, 1630. and selective review papers, see: (c) R. Giri, B.- F. Shi, K. M.
This article is protected by copyright. All rights reserved.

10.1002/anie.201710601
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Bing Jiang, Meng Zhao, Shu-Sen Li,
Yun-He Xu* and Teck-Peng Loh*
Page No. – Page No.
Macrolide Synthesis via Intramolecular
Oxidative Cross-Coupling of Alkenes
Palladium-catalyzed vinyl C-H functionalization with diaryliodonium was promoted
by the irradiation of visible light. Under darkness the C-H activation step is the rate
determining step, and kinetic isotope effect (KIE) is around 3.6. With the aid of
visible light, the C-H activation step was significantly accelerated and KIE was
This article is protected by copyright. All rights reserved.