Iterative Arylation of Amino Acids and Aliphatic Amines via δ-C(sp3)?H Activation: Experimental and Computational Exploration

Article abstract of DOI:10.1002/anie.201900479

Directed C?H functionalization has been realized as a complementary tool to the traditional approaches for a straightforward access of non-proteinogenic amino acids; albeit such a process is restricted mostly up to the γ-position. In the present work, we demonstrate the diverse (hetero)arylation of amino acids and analogous aliphatic amines selectively at the remote δ-position by tuning the reactivity controlled by ligands. An organopalladium δ-C(sp³)?H activated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction with computational studies shed light on the difference in the mechanistic picture depending on the substrate structure.

Full text of DOI:10.1002/anie.201900479

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Iterative Arylation of Amino Acids and Aliphatic Amines via
δ-C(sp3)−H Activation: Experimental and Computational
Exploration
Authors: Debabrata Maiti, Robert S. Paton, Srimanta Guin, Pravas
Dolui, Xinglong Zhang, Satyadip Paul, Vikas Kumar Singh,
Sukumar Pradhan, Hediyala B. Chandrashekar, and Anjana
S. S.
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900479
Angew. Chem. 10.1002/ange.201900479
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Iterative Arylation of Amino Acids and Aliphatic Amines via -
C(sp3)H Activation: Experimental and Computational Exploration
Srimanta Guin,§,† Pravas Dolui,§,† Xinglong Zhang,‡ Satyadip Paul,† Vikas Kumar Singh,† Sukumar
Pradhan,† Hediyala B. Chandrashekar,† Anjana S. S.,† Robert S. Paton,*,‡ and Debabrata Maiti*,†
ABSTRACT: Directed CH functionalization has been realized as a
complementary tool to the traditional approaches for
guided by the Curtin-Hammett principle have been recently
developed.[8a,8b] Some examples exist of intra- or intermolecular
δ-C(sp3)−H functionalizations of certain conformationally biased
substrates.[7m,8c,8d] In the present work we demonstrate how
tuning of ligands play
(hetero)arylation of amino acids and structurally analogous
aliphatic amines (Scheme 1).
a
straightforward access of non-proteinogenic amino acids; albeit such
a process is restricted mostly up to the -position. In the present
work, we demonstrate the diversification [(hetero)arylation] of amino
acids and analogous aliphatic amines selectively at the remote -
position by tuning the reactivity controlled by ligands. An
organopalladium -C(sp3)H activated intermediate has been
isolated and crystallographically characterized. Mechanistic
investigations carried out experimentally in conjunction with
computational studies shed light on the difference in the mechanistic
picture depending on the substrate structure.
a
crucial role in the δ-C(sp3)−H
α-Amino acids (αAAs) are privileged moieties in both
biological and chemical synthesis.[1] From
a
biosynthetic
perspective, construction of the primary sequence in proteins
uses small set of proteinogenic αAAs. In contrast,
a
nonproteinogenic AAs are being vastly utilized for the production
of secondary metabolites.[2] The routes to avail these
nonproteinogenic αAAs units in Nature are via enzymatic C−H
functionalization of common proteinogenic αAAs.[3] Since the
unnatural amino acids in peptide linkages often display superior
bioactivity over their parent structures, engineering a protocol to
decorate amino acids is a key research area in proteomics and
drug discovery.[4] As
a complementary tool to enzymatic
catalysis, transition metal mediated C−H bond functionalization,
could enable similar diversification of αAAs.[5] Over the years,
this realization has been materialized to produce functionalized
αAAs via α-, - and ɣ-C(sp3)H activation. While the α-
functionalization of αAAs occurs mostly through single electron
transfer or α-oxidation processes, the derivatizations at the
primary or secondary - and ɣ-C(sp3)H positions leverage the
coordination of the metal species from the directing group (DG)
through favorable formation of cyclometallated intermediate
(Scheme 1).[5,6] Generalization of this approach demands
significant advancements by expanding the activation process
beyond ɣ-C(sp3)H position engaging a series of αAAs and
analogous amines.[7]
Scheme 1. Directed C(sp3)–H functionalization of -amino acids
To commence with the functionalization process at the
remote δ-position of ethyl ester of leucine (1a), the effects of
pyridine and pyridone based ligands were probed initially.[7a,9] 4-
Benzyloxy-2(1H)-pyridone (L14) was the only promising ligand
from the series of ligands tested.[10] Other reaction parameters
were optimized using L14 as the ligand and it was observed that
the use of Pd(OPiv)2 (10 mol%), Ag2CO3 (3 equiv) and
CF3COONa (2 equiv) in tert-butyl methyl ether (TBME) solvent
provided a significant enhancement in the product yield.[10]
Finally, the influences of different directing groups were
investigated and picolinic acid (PG1) turned out to be the best
amongst the directing groups. These observations were further
supported by computational studies (see ESI2 Section II.5).[10,11]
Reaching out to the unattended distal position of amines,
in particular of αAAs [such as δ-C(sp3)H of leucine] assisted by
a
directing group has to surpass certain hurdles. The
intermediacy of a larger metallacycle (six-membered or more) is
the pre-requisite for such remote activation, that is difficult to
attain because of unfavorable thermodynamic parameters.[7m,8]
Some elegant approaches on unusual δ-selectivity of isoleucine,
Leucine, homoleucine and structurally analogous amine
derivatives were compatible as substrates under the present
reaction conditions providing good yields of the δ-arylated
products (1-8, Scheme 2). Despite the presence of two
inequivalent δ-C(sp3)H positions in case of 8, arylation
occurred selectively at the primary methyl CH over the
secondary methylene CH. This was traced computationally to
the unfavourable steric clashes between 휀-methyl group and the
heterocyclic ring of the directing group and the distal methyl
group on α-carbon (see ESI2, Section IV). We next proceeded to
examine the feasibility of this transformation with alicyclic
amines that have multiple competitive sites of reaction. In all
these cases highly δ-selective mono-arylated products were
obtained, keeping other accessible δ- and ɣ-sites intact (see
[†] S. Guin, P. Dolui, S. Paul, V. K. Singh, S. Pradhan, H. B.
Chandrashekar, Anjana S. S., and Prof. Dr. D. Maiti*
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400076, India
E-mail: dmaiti@chem.iitb.ac.in
[‡] X. Zhang, and Prof. Dr. R. S. Paton*
Department of Chemistry, Chemistry Research Laboratory, University
of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
E-mail: rpaton@colostate.edu
[§] These authors contributed equally to this work.
ESI2, Section IV). Gratifyingly,
a
high degree of
diastereoselectivity was observed in the products when the L-
isomer of leucine derivative was subjected to the present
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.XXXXXXXX.
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transformation (13-14). The observed diastereoselectivity was
further supported by DFT studies (ESI2 Figure S21).
nature (62-86). Notably, even the heterocycle could be
accommodated into the aliphatic amine at the third arylation
stage (70).
Scheme 2. -Mono-arylation of aliphatic amines
Protected 2,4,4-trimethylpentan-2-amine (2a) under the
same conditions proceeded with substantially higher conversion,
albeit with an appreciable formation of undesired multiple
arylated products. Lowering of aryl iodide equivalence and
temperature along with the use of pyridine as ligand (L1) was
able to out-compete the di-arylated product formation to a
considerable extent maintaining an optimal balance between
yield and mono-selectivity.[10] The revised condition was then
employed for δ-arylation of 2,4,4-trimethylpentane-2-amine (2a)
with an array of electronically diverse aryl iodides. The X-ray
crystallographic structures of 16 and 24 unambiguously
establish the formation of δ-selective arylated products.
Gratifyingly, a range of aryl iodides derived from different
naturally occurring products and drugs (31-43) could be
effectively utilized (Scheme 3). The utility of the transformation
was further showcased by introducing ferrocene moiety (44).
In order to materialize heteroarylation, the ligand effect
was re-investigated with 1-hydroxy isoquinoline (L12) turning out
to be the best for this transformation.[10] The heteroarylation
process was amenable to a variety of N, O, S heterocycles (45-
55) (Scheme 4). It was intriguing to find that fluorogenic
BODIPYs[12,13] could also be introduced at the δ-position of
aliphatic amines (56-60) including the bioactive ones such as 3-
pinanamine (60) (Scheme 5). The inclusion of pyridine and
quinoline based ligands for reactions with a BODIPY pendant
aryl iodide resulted in poor yields of the desired product,
presumably due to competitive binding of the ligand to the boron
center in BODIPY by fluoride substitution. Hence, these
reactions were carried out under ligand-free conditions.
Scheme 3. Scope of aryl iodides
After the mono-arylation, the vacant -sites were utilized
for iterative tri-functionalization (Scheme 6). To achieve the
sequential arylation process, mono- and di-arylation was
initiated at 90 C keeping the third methyl group intact. However,
when attempting the third arylation at the same temperature, the
reaction failed completely with no traces of the tri-arylated
product. Slight modification in the reaction conditions by
increasing the reaction temperature to 130 C afforded the δ-
hetero triarylated product (61). This strategy was then employed
for triarylation with other aryl iodides of different electronic
The synthetic utility of the present transformation was
elaborated by utilizing the δ-arylated products for the synthesis
of tetrahydronaphthalene (Scheme 7A). The practicality was
further demostrated by scaling up the arylation reaction up to
gram level that afforded an acceptable yield of the product 15
(Scheme 7B). The directing group removal was achievable
under mild conditions by converting the amide 4 to its Fmoc
derivative (89, Scheme 7C).[8b]
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Scheme 6. Iterative (hetero)arylation of aliphatic amines
Scheme 4. Scope of heteroaryl iodides
Scheme 7. Synthetic applications of -arylation protocol
intermediate that cycled through Pd(II)/Pd(IV) manifold.[14]
Although the mononuclear picture provides
understanding of the reaction mechanism (ESI2 Section II.1),
consideration of potentially polynuclear Pd-catalyst is
a
basic
a
necessary.[15] Without any ligand, the lowest reaction barrier was
41.4 kcal mol-1 (Figure 1A), which was rather high due to
enthalpic loss of the interactions between paddlewheel bridging
ligands and Pd–Pd metal centres[16] when the trinuclear complex
dissociated (Figure S5C path I). C–H activation via trinuclear
complex (ts-A, Figure S5B) was also uncompetitive.[15a] Pyridine
ligands coordinated to Pd metal, whose favourable interactions
compensated for this enthalpic loss of trinuclear complex
dissociation (Figure 1B); the exergonic formation of Pd(TFA)2L2
favored the dissociation.[14] The overall energy barrier decreased
to 30.5 kcal mol-1, making the reaction faster than without
pyridine. Although pyridine did not directly participate in OA or
RE from computational studies (ESI2 Section II.1), it was
essential in breaking up the trinuclear complex to access the
mononuclear pathway since oxidative addition (OA) and
reductive elimination (RE) were both catalyzed by mononuclear
palladium catalyst, since Pd(II) metal is tetra-coordinating and a
vacant coordination site on the metal is needed for the incoming
aryl iodide. Pyridine ligand further coordinated to the end
product of first arylation, giving a rather stabilized complex int-8’,
making a second arylation thermally much less accessible
(activation barrier of 50.1 kcal mol-1, ESI2 Section II.5).
Scheme 5. BODIPY labelling of -C(sp3)H bonds of amines
To obtain a mechanistic picture, we embarked on the
synthesis of the organopalladium complex that might be involved
in this transformation. The ligand (pyridine) bound [5,6]-fused
cyclopalladated intermediate (Int A) was successfully isolated
and characterized by different spectroscopic methods and X-ray
crystallography.[10] Different control experiments carried out
indicate Int A is a catalytically and kinetically viable precatalyst
complying with the present transformation.[10] Reversibility
experiments on a series of amine substrates in conjunction with
the kinetics and order determination studies reveal an important
correlation between substrate structure and mechanistic
operation: those having a quaternary ɣ-center exhibit reversibility
and no primary KIE while those without quaternary ɣ-center
display irreversibility and CH activation is more likely to be the
r.d.s. in these cases.[10]
DFT investigations found that the reaction occurred with
base-/ligand-assisted C–H activation, giving cyclopalladated
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Figure 1. Mechanistic and computational data for δ-C(sp3)H arylation of substrate 2a
.
The absence of Thorpe-Ingold
effect in substrate 3a (as compared
to substrate 2a) renders the CMD
r.d.s step more difficult. This was
further demonstrated by isodesmic
reactions[18] for the formation of
pyridine-coordinated C–H activated
complex for 2a and 3a (ESI2
Section III.5) where the formation of
C–H activated complex for 3a was
1.2 kcal mol-1 higher than for 2a
(measured by 훥훥H between these
two reactions). Using pyridine in
addition to a separate TFA ion as a
base was not as good in positioning
the C–H bond for activation; ligand
L14 could coordinate to Pd-metal
while carrying out the CMD step,
giving more organised TS structure
that would not be possible with
separated
pyridine
and
trifluoroacetate (Figure S18) (see
ESI2 for details).
In summary, we have developed a
Figure 2. Computed Gibbs free energy profile for first arylation of
protocol
to
avail
the
non-
substrate 3a. Blue pathway: with pyridone ligand L14; green
pathway: with L14 and silver carbonate; black pathway: without L14
or silver carbonate. Bond distances in optimized structures are
quoted in Å
proteinogenic (hetero)arylated leucine and analogous amines
via palladium catalyzed remote δ-C(sp3)H activation. The
ligands were found to have pronounced effect in tuning the
reactivity depending on the nature of substrates. The multi-
faceted aspects of this transformation have been illustrated
through: (i) the diastereoselective synthesis of δ-arylated
leucine; (ii) incorporation of diverse natural products and drugs
in amines; (iii) BODIPY labelling of bioactive amines and (iv)
sequential (hetero)arylation. A six-membered organopalladium
δ-C(sp3)H activated complex was isolated and found to be
catalytically competent suggesting its intermediacy in this
transformation. The experimental evidences and in-silico studies
shed light on the substrate dependent mechanistic difference.
This explains the excellent mono- over di-arylation selectivity in
the presence of pyridine. Overall, C–H activation was found not
to be the r.d.s., consistent with KIE studies and that OA was the
overall r.d.s. (see ESI2 for details).
A study on substrate 3a gave similar findings as for
substrate 2a, with the r.d.s. being the OA step (black path,
Figure 2). The inclusion of silver carbonate, in a fashion similar
to the heterodimeric Pd–Ag catalytic species considered for C–H
activation step by Houk and Schaefer,[17] lowered the activation
barriers of OA/RE steps such that the C–H activation step
became the r.d.s. (green path, Figure 2). The cooperative
pyridone/silver carbonate binding lowered the high activation
barrier for OA such that C–H activation became the overall r.d.s.,
corroborating experimental findings. Pyridone ligand L14 was
crucial in giving highly organised TSs with favourable
interactions which would not be possible with pyridine ligand L1.
Acknowledgements
This activity was supported by research grant from SERB, India.
Fellowships from NPDF (File No. PDF/2015/000127) (S.G.),
UGC India (P.D. and C.H.B.), CSIR, India (S.P.) and funding
from A*STAR Singapore (X.Z.) are gratefully acknowledged. X.Z.
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6, 146; h) J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S.
Sanford, Nature 2016, 531, 220; i) Y. Wu, Y.-Q. Chen, T. Liu,
M. D. Eastgate, J.-Q. Yu, J. Am. Chem. Soc. 2016, 138,
14554; j) Y. Xu, M. C. Young, C. Wang, D. M. Magness, G.
Dong, Angew. Chem. Int. Ed. 2016, 55, 9084; k) Y. Liu, H.
Ge, Nat. Chem. 2017, 9, 26; l) A. Yada, W. Liao, Y. Sato, M.
Murakami, Angew. Chem. Int. Ed. 2017, 56, 1073; For - and
-C(sp3)H arylation: m) Y.-Q. Chen, Z. Wang, Y. Wu, S. R.
Wisniewski, J. X. Qiao, W. R. Ewing, M. D. Eastgate, J.-Q.
Yu, J. Am. Chem. Soc. 2018, 140, 17884.
For publications on -CH functionalization of amines, see:
a) J. W. Xu, Z. Z. Zhang, W. H. Rao, B.-F. Shi, J. Am. Chem.
Soc. 2016, 138, 10750; b) B. B. Zhan, Y. Li, J. W. Xu, X. L.
Nie, J. Fan, L. Jin, B.-F. Shi, Angew. Chem. Int. Ed. 2018, 57,
5858; c) E. T. Nadres, O. Daugulis, J. Am. Chem. Soc. 2012,
134, 7; d) W. Cui, S. Chen, J.-Q. Wu, X. Zhao, W. Hu, H.
Wang, Org. Lett. 2014, 16, 4288.
R.-Y. Zhu, Z.-Q. Li, H. S. Park, C. H. Senanayake, J.-Q. Yu,
J. Am. Chem. Soc. 2018, 140, 3564.
See supporting information for detailed description.
a) M. L. O’Duill, R. Matsuura, Y. Wang, J. L. Turnbull, J. A.
Gurak, D. W. Gao, G. Lu, P. Liu, K. M. Engle, J. Am. Chem.
Soc. 2017, 139, 15576. b) M. Liu, P. Yang, M. K.
Karunananda, Y. Wang, P. Liu, K. M. Engle, J. Am. Chem.
Soc. 2018, 140, 5805.
and R.S.P. acknowledge the EPSRC Centre for Doctoral
Training in Theory and Modelling in Chemical Sciences
(EP/L015722/1) and the use of Dirac cluster at Oxford.
Keywords: δ-arylation • natural product incorporation• BODIPY
labelling • iterative arylation • mechanistic and DFT studies
REFERENCES
[1]
V. A. Soloshonok, K. Izawa, Eds. Asymmetric Synthesis and
Application of α-Amino acids; American Chemical Society:
Washington DC, 2009; Vol. 1009.
[8]
[9]
[2]
[3]
[4]
[5]
A. Ambrogelly, S. Palioura, D. Söll, Nat. Chem. Biol. 2007, 3,
29.
J. C. Lewis, P. S. Coelho, F. H. Arnold, Chem. Soc. Rev.
2011, 40, 2003.
K. Fosgerau, T. Hoffmann, Drug Discov. Today 2015, 20,
122.
a) A. F. M. Noisier, M. A. Brimble, Chem. Rev. 2014, 114,
8775; b) G. He, B. Wang, W. A. Nack, G. Chen, Acc. Chem.
Res. 2016, 49, 635; c) W. Wang, M. M. Lorion, J. Shah, A.
Kapdi, L. Ackermann, Angew. Chem. Int. Ed. 2018, 57,
14700.
[10]
[11]
[6]
For selected publications, see: a) T. J. Osberger, D. C.
Rogness, J. T. Kohrt, A. F. Stepan, M. C. White, Nature 2016,
537, 214; b) L. Zhao, O. Baslé, C. J. Li, Proc. Natl. Acad. Sci.
USA 2009, 106, 4106; c) B. V. S. Reddy, L. R. Reddy, E. J.
Corey, Org. Lett. 2006, 8, 3391; d) Y. Ano, M. Tobisu, N.
Chatani, J. Am. Chem. Soc. 2011, 133, 12984; e) L. D. Tran,
O. Daugulis, Angew. Chem. Int. Ed. 2012, 51, 5188; f) S. Y.
Zhang, Q. Li, G. He, W. A. Nack, G. Chen, J. Am. Chem.
Soc. 2013, 135, 12135; g) M. Fan, D. Ma, Angew. Chem. Int.
Ed. 2013, 52, 12152; h) G. He, S.-Y. Zhang, W. A. Nack, Q.
Li, G. Chen, Angew. Chem. Int. Ed. 2013, 52, 11124; i) J. He,
S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A.
Homs, J.-Q. Yu, Science 2014, 343, 1216; j) L. S. Zhang, G.
Chen, X. Wang, Q. Y. Guo, X. S. Zhang, F. Pan, K. Chen, Z.
J. Shi, Angew. Chem. Int. Ed. 2014, 53, 3899; k) W. Gong, G.
Zhang, T. Liu, R. Giri, J.-Q. Yu, J. Am. Chem. Soc. 2014,
136, 16940; l) S. Li, G. Chen, C.-G. Feng, W. Gong, J.-Q. Yu,
J. Am. Chem. Soc. 2014, 136, 5267; m) G. He, S.-Y. Zhang,
W. A. Nack, R. Pearson, J. Rabb-Lynch, G. Chen, Org. Lett.
2014, 16, 6488; n) Q. Zhang, X. S. Yin, K. Chen, S. Q.
Zhang, B.-F. Shi, J. Am. Chem. Soc. 2015, 137, 8219; o) G.
Liao, X. S. Yin, K. Chen, Q. Zhang, S. Q. Zhang, B.-F. Shi,
Nat. Commun. 2016, 7, 1290; p) S. Li, R.-Y. Zhu, K.-J. Jiao,
J.-Q. Yu, Angew. Chem. Int. Ed. 2016, 55, 4317; q) A. Deb,
S. Singh, K, Seth, S. Pimparkar, B. Bhaskararao, S. Guin, R.
B. Sunoj, D. Maiti, ACS Catal. 2017, 7, 8171; r) N.
Thrimurtulu, S. Khan, S. Maity, C. M. R. Volla, D. Maiti,
Chem. Commun. 2017, 53, 12457; s) A. Dey, S. Pimparkar,
A. Deb, S. Guin, D. Maiti, Adv. Synth. Catal. 2017, 359,
1301; t) M. Bauer, W. Wang, M. M. Lorion, C. Dong, L.
Ackermann, Angew. Chem. Int. Ed. 2018, 57, 203; u) S. Guin,
A. Deb, P. Dolui, S. Chakraborty, V. K. Singh, D. Maiti, ACS
Catal. 2018, 8, 2664; v) X. Zhang, G. Lu, M. Sun, M.
Mahankali, Y. Ma, M. Zhang, W. Hua, Y. Hu, Q. Wang, J.
Chen, G. He, X. Qi, W. Shen, P. Liu, G. Chen, Nat. Chem.
2018, 10, 540; w) W. Wang, M. M. Lorion, O. Martinazzoli, L.
Ackermann, Angew. Chem. Int. Ed. 2018, 57, 10554.
For selected reviews and publications on -CH
functionalization of amines, see: a) J. He, M. Wasa, K. S. L.
Chan, Q. Shao, J.-Q. Yu, Chem. Rev. 2017, 117 , 8754; b) G.
Rouquet, N. Chatani, Angew. Chem. Int. Ed. 2013, 52,
11726; c) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am.
Chem. Soc. 2005, 127, 13154; d) G. He, G. Chen, Angew.
Chem. Int. Ed. 2011, 50, 5192; e) G. He, Y. Zhao, S. Zhang,
C. Lu, G. Chen, J. Am. Chem. Soc. 2012, 134, 3; f) S.-Y.
Zhang, G. He, Y. Zhao, K. Wright, W. A. Nack, G. Chen, J.
Am. Chem. Soc. 2012, 134, 7313; g) K. S. L. Chan, M. Wasa,
L. Chu, B. N. Laforteza, M. Miura, J.-Q. Yu, Nat. Chem. 2014,
[12]
[13]
a) S. Bose, A. H. Ngo, L. H. Do, J. Am. Chem. Soc. 2017,
139, 8792; b) A. Vázquez-Romero, N. Kielland,; M. J.
Arévalo, S. Preciado, R. J. Mellanby, Y. Feng, R. Lavilla, M.
Vendrell, J. Am. Chem. Soc. 2013, 135, 16018.
a) L. J. Patalag, L. P. Ho, P. G. Jones, D. B. Werz, J. Am.
Chem. Soc. 2017, 139, 15104; b) L. J. Patalag, P. G. Jones,
D. B. Werz, Angew. Chem. Int. Ed. 2016, 55, 13340.
Y. Dang, S. Qu, J. W. Nelson, H. D. Pham, Z.-X. Wang, X.
Wang, J. Am. Chem. Soc. 2015, 137, 2006.
a) R. Giri, Y. Lan, P. Liu, K. N. Houk, J.-Q. Yu, J. Am. Chem.
Soc. 2012, 134, 14118. b) J. Vana, J. Lang, M. Soltesova, J.
Hanusek, A. Ruzicka, M. Sedlak, J. Roithova, Dalton Trans.
2017, 46, 16269. c) J. Vana, J. Hanusek, M. Sedlak, Dalton
Trans. 2018, 47, 1378.
[14]
[15]
[16] B. E. Haines, J. F. Berry, J.-Q. Yu, D. G. Musaev, ACS Catal.
2016, 6, 829.
[17]
a) Y. F. Yang, G. J. Cheng, P. Liu, D. Leow, T. Y. Sun, P.
Chen, X. Zhang, J.-Q. Yu, Y. D. Wu, K. N. Houk, J. Am.
Chem. Soc. 2014, 136, 344. b) M. Anand, R. B. Sunoj, H. F.
Schaefer, J. Am. Chem. Soc. 2014, 136, 5535.
a) Wheeler, S. E.; Houk, K. N.; Schleyer, P. V. R.; Allen, W.
D. J. Am. Chem. Soc. 2009,131, 2547. b) Wheeler, S. E.
WIREs Comput. Mol. Sci. 2012, 2, 204–220.
[18]
[7]
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10.1002/anie.201900479
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A Pd catalyzed protocol
to avail the non-
proteinogenic
S. Guin, P. Dolui, X.
Zhang, S. Paul, V. K.
Singh, S. Pradhan, H.
(hetero)arylated leucine
and analogous amines
via remote δ-C(sp3)H
activation is developed.
B.
Chandrashekar,
Anjana, S. S., Prof. Dr.
R. S. Paton* and Prof.
Dr. D. Maiti*
The
multi-faceted
Page No. – Page No.
aspects
of
this
transformation
have
Iterative Arylation of
Amino Acids and
Aliphatic Amines via
-C(sp3)H
been illustrated through:
(i)
the
diastereoselective
synthesis of δ-arylated
leucine; (ii)
Activation:
Experimental and
Computational
Exploration
incorporation of diverse
natural products and
drugs in amines; (iii)
BODIPY labelling of
bioactive amines and
(iv)
sequential
(hetero)arylation.
This article is protected by copyright. All rights reserved.