Site-Selective Cu-Catalyzed Alkylation of Α-Amino Acids and Peptides toward the Assembly of Quaternary Centers

Article abstract of DOI:10.1002/cssc.201802216

The Cu^I-catalyzed selective α-alkylation of α-amino acid and peptide derivatives with 2-alkyl-1,3-dioxolanes is reported. This oxidative coupling is distinguished by its site-specificity, high diastereoselectivity, and chirality preservation and exhibits absolute chemoselectivity for N-aryl glycine motifs over other amino acid units. Collectively, the method allows for the assembly of challenging quaternary centers, as well as compounds derived from natural products of high structural complexity, which may provide ample opportunities for late-stage functionalization of peptides.

Full text of DOI:10.1002/cssc.201802216

Accepted Article
Title: Site-selective Cu-catalyzed Alkylation of α-Amino Acids and
Peptides toward the Assembly of Quaternary Centers
Authors: Arkaitz Correa and Marcos San Segundo
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ChemSusChem
10.1002/cssc.201802216
COMMUNICATION
Site-selective Cu-catalyzed Alkylation of α-Amino Acids and Pep-
tides toward the Assembly of Quaternary Centers
Marcos San Segundo and Arkaitz Correa*
Dedication ((optional))
Abstract: A novel Cu(I)-catalyzed selective α-alkylation of α-amino
acid and peptide derivatives with 2-alkyl-1,3-dioxolanes is reported.
This oxidative coupling is distinguished by its site-specificity, high
diastereoselectivity, chirality preservation and exhibits entire
chemoselectivity for N-aryl glycine motifs over other amino acid units.
Collectively, the method allows for the assembly of challenging
quaternary centers as well as compounds derived from natural
products of high structural complexity, which illustrates its ample
opportunities toward the late-stage functionalization of peptides.
number of U.S. Food and Drug Administration (FDA) approved
[7]
3
pharmaceuticals , the direct functionalization of α-C(sp )–H of cyclic
[8]
ethers represents a challenging task of prime synthetic importance.
In the last years, their powerful use as proelectrophiles in CDC
[8]
reactions has received a great deal of attention; as a result,
tetrahydrofuran (THF) and related ethers have been efficiently
coupled with a variety of nucleophiles (Scheme 1, route a). The
generally accepted mechanism involves a first hydrogen atom
abstraction step to produce α-carbon-centered radical I prone to
undergo a subsequent oxidation to the corresponding electrophilic
oxonium cation II via a SET step (Scheme 1, route b). In this respect,
we surmised that the reactivity of the transient alkyl radical species I
could be enhanced by starting from a tertiary alkyl ether, thus
α-Amino acids constitute the core backbone of peptides and proteins
and rank among the most widespread building-blocks in organic
[1]
synthesis and chemical biology. In fact, they are prevalent motifs in
a sheer number of drugs with a broad spectrum of biomedical
applications. Owing to the enhanced biological activities and often
improved pharmacokinetic properties exhibited by unnatural amino
acids and peptides derived thereof, the recent years have witnessed
an increased interest in the site-specific chemical modification of
favoring the formation of
a strongly stabilized tertiary radical
[9]
intermediate. The latter could be presumably triggered by a
kinetically competent electrophile instead of undergoing further
oxidation to species II. If successful, such a conceptually simple
strategy would result in the virtually unexplored formation of a
quaternary center. So far, the use of substituted ethers for the
construction of quaternary carbon centers have been overlooked in
organic synthesis and only scattered examples of oxidative func-
[2]
peptides. In this regard, transition-metal catalysis has recently
unlocked new paradigms for the site-selective C–H functionalization
of α-amino carbonyl compounds. Most of the latter relied on the
modification (arylation and alkynylation) of specific side chain C–H
bonds within cysteine, tryptophan or alanine containing-peptides via
3
tionalization of α-C(sp )–H of tertiary ethers with olefins have been
[10]
reported.
[3]
organometallic intermediates. Despite the recent advances realized,
the available C–H functionalization portfolio in these endeavors
mostly use expensive Pd catalysts and toxic halide-derived coupling
(a) Ethers as Chemical Feedstocks
H
Nu
partners.
A
distinct approach relies on metal-catalyzed cross-
Ox
SET
Nu
[4]
3
O
O
O
dehydrogenative couplings (CDCs) occurring between α-C(sp )–H
bonds of glycine derivatives and nucleophilic C–H coupling partners,
hence allowing the modification of the amino acid backbone in a
O
OxH
II
C(sp )-H bond low BDE
I
-
3
powerful proelectrophiles
rare examples of tertiary ethers
[
5]
more sustainable manner. However, this straightforward and atom-
economical technique is rarely applied to the challenging site-
selective modification of structurally complex peptide compounds. In
this light, we envisioned that the introduction of novel C–H
R
R
E
H
masked formyl synthons
nucleophilic alkyl radicals
quaternary centers
R
Ox
E
O
O
O
O
O
O
[6]
counterparts could increase its utility for the late-stage
OxH
III
functionalization of glycine-containing peptides, thus streamlining the
rapid assembly of high-value biomolecules featuring the use of less
explored earth-abundat metal catalysts.
(
b) This Work
O
H
O
N
H
Ar
N
O
H
Ar
H
N
Electrophile
Ar
Due to their chemical inertness as well as high prevalence in a high
+
Cu
R
O
R
O
O
H
O
R
O
O
Nucleophile
[
a]
M. San Segundo, Dr. A. Correa
Chemo- & diastereoselective alkylation
Late-stage peptide modification
Assembly of quaternary centers
University of the Basque Country (UPV/EHU)
Department of Organic Chemistry I
Joxe Mari Korta R&D Center, Avda. Tolosa 72, 20018 Donostia-San
Sebastián (Spain)
3
Dual -C(sp )-H activation
E-mail: arkaitz.correa@ehu.eus
Scheme 1. CDCs with ethers and α-amino acid derivatives.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
A particular class of oxygen heterocycles are 2-substituted-1,3-
dioxolanes, which represent inexpensive formyl equivalents and
offer an attractive avenue for the formal introduction of a carbonyl
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ChemSusChem
10.1002/cssc.201802216
COMMUNICATION
[
a]
group into an organic compound. However, their conversion into the
corresponding α,α-dioxy radicals III could be counterintuitive at first
sight due to: (a) the sterical hindrance of the group in C2 and (b) the
regioselectivity issues between C2 and C4 position of the dioxolane
Table 1. Cu-catalyzed alkylation of 1a with 2-methyl-1,3-dioxolane
O
Me
H
O
N
H
Cu(OAc) (5 mol %)
Ph
OEt
Me
N
O
O
+
Ph
OEt
[9]
TBHP(aq) (2.0 equiv)
DCE, 60 ºC
O
(
Scheme 1, route a). We anticipated that the judicious screening of
O
1
a
2a
3a
the reaction parameters together with the rational selection of the
C2-substituent could exploit the inherent stability of a transient
tertiary radical vs the secondary one. Accordingly, we envisioned
that the use of open-shell intermediates upon SET events could
unlock new reaction pathways not yet accomplished via polar-type
scenarios. Herein we report a practical Cu-catalyzed site-selective
alkylation of α-amino acids and peptides with 2-alkyl-1,3-dioxolanes
toward the assembly of new fully substituted carbon centers. This
method features the advantageous use of a cost-efficient Cu catalyst
along with an aqueous solution of tert-butyl hydroperoxide (TBHP) to
assist a challenging in situ dual activation of both C–H coupling
Ar, 16h
3a (%)[b]
79 (80)[c]
0
entry
change from standard conditions
none
without Cu(OAc)
1
2
3
4
5
6
without TBHP(aq)
TBHP(dec) instead of TBHP(aq)
O2 instead of TBHP(aq)
under air
0
65
0
6
8
7
8
9
without DCE
56
65
51
79
CuBr instead of Cu(OAc)
CuCl instead of Cu(OAc)
Cu(OAc)2 instead of Cu(OAc)
Cu(acac)2 instead of Cu(OAc)
Fe(OAc)2 instead of Cu(OAc)
1
0
11
69
1
1
1
2
3
4
traces
traces
traces
Co(OAc)2 instead of Cu(OAc)
Mn(OAc)2 instead of Cu(OAc)
[
11]
partners. Remarkably, our catalytic manifold is endowed with a
large scope, operational simplicity, reaction scalability, high
diastereoselectivity and preservation of the α-center chirality.
Accordingly, it clearly broadens the scope of CDCs to produce
molecular diversity from inexpensive biomass devoid of
prefunctionalization in a selective and rapid manner.
[a]
Reaction conditions: 1a (0.5 mmol), Cu(OAc) (5 mol %), TBHP(aq) (2.0
equiv), 2a (0.5 mL), DCE (1.0 mL) at 60 ºC for 16 h under Ar. [b] Yield of
isolated product after column chromatography. [c] Gram-scale reaction. TBHP
(
aq) = tBuOOH 70% in H O; TBHP (dec) = tBuOOH 5.0-6.0 M in decane.
2
Following our dual catalyst activation design principle, we selected
the alkylation of the benchmark amino ester 1a with commercially
available 2-methyl-1,3-dioxolane (2a) as the model reaction. After
With the optimized conditions in hand, we next investigated the
3
scope of the C(sp )–H alkylation protocol. With respect to the
oxygen heterocycle,
a wide variety of 2-alkyl substituted 1,3-
[12]
careful optimization, we found that the desired transformation was
feasible and α-alkylated glycinate 3a was obtained in 79% yield
when a combination of Cu(OAc) as catalyst, an aqueous solution of
TBHP as oxidant, and 1,2-dichloroethane as solvent was used
dioxolanes smoothly underwent the target oxidative coupling in
[13]
moderate to excellent yields.
Remarkably, dioxolanes bearing
3
alkenes (3d) or oxidizable C(sp )–H bonds in adjacent position to
[14]
benzylic positions (3b), ketones (3i), esters (3f,g), nitriles (3h) or
(
Table 1, entry 1). Importantly, undesired functionalization on the C4
even a pharmaceutically relevant heterocyclic motif such as pyra-
zole (3o) were perfectly accommodated and were chemoselectively
coupled by the C2 site of the dioxolane. Likewise, the alkylation was
tolerant of a vast array of differently substituted N-aryl glycine esters
site of the dioxolane was never observed, which evidenced that the
methyl group in C2 did not hamper the process and that electronic
factors dominated over the sterics on the corresponding hydrogen
atom abstraction step. As expected, control experiments verified the
crucial role of both copper catalyst and oxidant as not even traces of
with halides (3j,k), carboxylic acids (3l), esters (3o-q), ethers (3o-q),
[15]
amides (3m)
and even sensitive azobenzenes (3n) being
3
a were detected in their absence (entries 2 and 3, respectively).
amenable to this oxidative alkylation. Of remarkable importance are
Notably, an aqueous solution of TBHP was found superior than its
analogue in decane (entry 4), which constitutes a practical bonus in
3
o-q, where high chemoselectivity was achieved toward the
3
preferential activation of the dioxolane motif versus the C(sp )–H
terms of economics and sustainability; other oxidants such as O
2
[7]
bonds adjacent to other biologically relevant cyclic ethers such as
[
12]
(
entry 5) or related peroxides afforded substantially lower yields of
a. A variety of copper sources were tested (entries 8−11), and
Cu(OAc) and Cu(OAc) provided the higher yields. Likewise, the
performance of the process with other metal sources (entries 12-14)
oxetane (3o,p) and THF (3q). Not only glycine esters, but also other
α-amino carbonyl compounds including α-amino ketones (3t,u) and
amides (3v) could be selectively alkylated in moderate yields.
Importantly, the alkylation of N-phenylglycinonitrile was also
achieved; to the best of our knowledge, it represents the first
example of a CDC with an α-amino nitrile compound (3r,s), which
offers ample opportunities for further manipulation upon either
hydrolysis or reduction reactions. The structure of 3r was unambigu-
ously assigned by X-Ray analysis.
3
2
[12]
or at distinct temperatures did not improve the reaction outcome.
Importantly, the reaction was amenable to scale-up to gram
quantities in similar yields (entry 1) and even a low Cu-catalyst load-
[12]
ing (3 mol %) led to the formation of 3a in 75% yield.
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COMMUNICATION
3
[a,b]
Table 2. Cu-catalyzed C(sp )−H alkylation of α-amino carbonyl compounds
O
O
R3
H
N
H
N
R2
R2
Cu(OAc) (5 mol %)
R1
R1
+
R3
O
O
TBHP(aq) (2.0 equiv)
DCE, 60 ºC
O
O
1
or 4
2
Ar, 16h
3
a-v, 5a-k
-Amino Ester & Dioxolane Scope
H
N
H
H
N
H
N
H
N
H
N
CO Et
2
N
2
CO Et
CO Et
2
CO
Bn
2
Et
CO
2
Et
2
CO Et
Me
OBz
Me
Cy
O
O
O
O
O
O
O
O
O
O
O
O
Me
O
Me
3b, 90% (78%)[c]
3f
, 48%
3
a, 79% (80%)[c]
3c, 79%
3d, 67%
dr 1:1
3
e, 35%
H
H
N
H
N
H
N
H
N
N
CO Et
CO
2
Et
R
O
CO
Me
2
Et
CO
Et
2
2
Cl
CO
2
Et
R
Me
O
Cy
O
Ac
O
O
NC
O
N
H
NC
O
O
O
O
O
O
O
3i, 57%
3k, R = CF , 68%
3l, R = CO H, 52%
3m, 92%
3
g, R = OBz, 51%
h, R = CN, 53%[d]
3
3
j, 79%
dr 1:1
3
2
O
O
H
N
O
O
O
O
CO Et
2
Me
NH
Me
Me
NH
NH
N
O
CO Et
Ph
N
O
O
2
CO Et
2
O
O
2
CO Et
O
O
Me
3n, 49%
3o, 86%
N
N
Me
3
p, 84%
O
3q, 74%
O

-Amino Carbonyl Derivative Scope
O
H
O
O
H
H
N
H
N
H
N
N
CN
Bn
CN
Cy
N
Ph
Me
N
Ph
Bn
Me
O
O
O
O
O
O
O
O
O
O
3t, 53%[e]
Short Peptide Scope
3v, 52%
3r, 50%
X-ray of 3r
3s, 52%
, 38%[e]
3u
O
Me
O
Me
CN
O
O
H
H
N
H
N
H
N
N
N
CO Bn
2
N
2
CO Bn
N
CO Me
N
H
CO Me
O
H
2
2
H
O
O
H
O
Me
Me
O
O
O
O
CN
a, 85% (dr 1:1)[f,g]
5b, 72% (dr 1:1)[g]
5c, 72% (dr 1:1)[f,g]
from Ph-Gly-Ala-OBn
5d, 84% (dr 1:1)[f,g]
5
from Ph-Gly-Ala-OBn
from Ph-Gly-Val-OMe
from Ph-Gly-Val-OMe
O
O
H
O
CO Me
2
O
H
H
N
Me
O
N
N
N
N
N
2
CO Me
N
CO
2
Me
N
H
O
H
Me
O
H
O
Bn
MeO
NH
Me
O
O
O
O
O
2
CO Me
5g, 60% (dr 20:1[f,g]
from PMP-Gly-Pro-OMe
5h, 22% (dr 20:1)[g]
5f, 68% (dr 1:1)[g]
e, 71% (dr 1:1)[g]
5
from Ph-Gly-Pro-Leu-OMe
from Ph-Gly-Leu-OMe
from Ph-Gly-Leu-OMe
O
O
O
H
H
N
Me
N
CO Et
2
Me
NH
O
EtO
Me
C
N
O
N
CO
2
Me
2
N
N
H
H
Me
N
H
O
O
O
NH
O
O
O
O
CO
2
5
i, 48% (dr 20:1)[g]
from Ph-Gly-Pro-Phe-Val-OMe
5k, 75%
from EtO-Gly-Ph-Gly-OEt
5
j, 43% (dr 20:1)[g]
from Ph-Gly-Pro-Val-OMe
[
a]
[b]
[c]
As for Table 1, entry 1. Yield of isolated product after column chromatography, average of at least two independent runs. Reaction performed at gram-
[
d]
[e]
[f]
[g]
scale. Reaction performed at 80 ºC. Reaction performed with CuCl. HPLC analysis verified the retention of the native chirality of the substrate. dr value
calculated by H NMR.
1
.
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COMMUNICATION
We subsequently examined our oxidative alkylation in the more
complex setting of peptides, which are known to undergo oxidative
[
16]
fragmentations upon the formation of α-carbon radicals and hence
are often difficult to be selectively manipulated through oxidative
processes. Notably, dipeptides containing Val (5a,b), Ala (5c,d), Leu
(5e,f) and Pro (5g) units selectively underwent in good to high yields
the alkylation on the terminal Gly unit, directed by the neighboring N-
aryl group upon stabilization of the corresponding iminium-type
intermediate. As verified by HPLC analysis, the oxidative alkylation
[
12]
proceeded with preservation of the α-center chirality.
Whereas
dipeptides containing Val, Ala or Leu units afforded the correspond-
ing products as diastereomeric mixtures (dr 1:1), the presence of a
Pro residue resulted in a highly diastereoselective process (5g, dr
2
0:1). Although merely speculative, we hypothesized that owing to
the rigidity of the Pro backbone, the alkyl radical species could
attack the in situ formed iminium-type intermediate from its less
sterically encumbered face, thus delivering stereochemically en-
[
17]
riched derivatives. The robustness of our method was further
demonstrated by the site-selective functionalization of tri- and
tetrapeptides in moderate to reasonable yields. It is worth noting that
the presence of a Pro motif favored the alkylation to occur in a
diastereoselective fashion (dr 20:1) in all cases (5h-5j), which
underscores the high potential for Pro residues as key structural
elements at the late-stage functionalization in complex peptides
settings. Moreover, the oxidative alkylation exclusively occurred at
the terminal Gly unit and other amino acid residues possessing oxi-
dizable aliphatic chains with reactive secondary C–H bonds such as
[
a]
[b]
As for Table 1, entry 1.
Yield of isolated product after column
chromatography, average of at least two independent runs.
O
O
H
N
H
N
HCl (4N)
Ph
OEt
Me
Ph
OEt
dioxane, 60 ºC
3h
O
[3i]
O
Me
Leu (5h) and Val (5i,j) remained intact. Interestingly, the site-
selective alkylation of dipeptide 5k incorporating a phenyl unit as a
linker between the Gly residues reinforced the directing role of the N-
aryl moiety and verified that the process was not restricted to the
functionalization of the terminal N-aryl Gly unit. Collectively, the
small library of peptide-containing compounds rapidly assembled
illustrates the high value of our C–H alkylation process to streamline
the late-stage functionalization of complex molecules in a predictable
and efficient manner, which resembles to an enzyme-type reactivity
of utmost interest in the field of molecular recognition. Moreover,
O
7, 33%
3a
Scheme 2. Cleavage of the dioxolane moiety
In order to gain some insights into the reaction mechanism, we
carried out several control experiments. Firstly, we found that the
CDC of N-Ph-Gly-OEt 1a with dioxolane 2a was entirely inhibited in
the presence of radical traps such as TEMPO and BHT, which
[19]
indicated that a radical pathway may be operative. Secondly, other
N-substituted glycine derivatives including a tertiary amine remained
unreactive under the standard conditions (Scheme 3, path a), thus
highlighting the determinant role of the free-NH aryl group in the
reaction outcome. Thirdly, α-tertbutyldioxanyl intermediate 8 was
easily prepared in a gram-scale and provided the alkylated product
[
11]
unlike previous alkylation methods, our protocol allows for the
introduction of cyclic ethers of high structural complexity resulting in
heavily substituted peptide analogues containing heteroatom
residues.
3
a in 56% yield under the optimized conditions (Scheme 3, path c),
hence evidencing its possible key role as a competent reaction
intermediate within our catalytic cycle. Curiously, treatment of imine
In order to evaluate the compatibility of the reaction in structurally
more intricate contexts, several dioxolanes embedded in biologically
significant molecules and active pharmaceuticals were tested,
including those derived from fatty acids (palmitic, oleic and myristic
acid), ibuprofen or citronellal (a key ingredient for perfumes). The
use of the latter resulted in a selective alkylation to produce 6a-e in
moderate to excellent yields, which underscores the utility to
introduce add-value moieties into α-amino carbonyl compounds.
Although trivial at first sight, the cleavage of the introduced acetal
group was not as simple as expected, and it was accomplished upon
treatment with HCl, albeit the corresponding acetylated derivative 7
9
furnished the corresponding coupling product 3a in
a
comparatively lower 14% yield. On the basis of the above results
[
20]
and previous literature reports, a plausible reaction mechanism is
proposed in Scheme 3. The reaction would commence with the
[
20b,e]
Cu(I)-assisted cleavage of tBuOOH
radical species and a Cu(II) complex. The corresponding α-amino
carbonyl compound would next undergo hydrogen atom
to furnish alkyl radical
to produce tert-butoxy
a
[
21]
abstraction step by tBuO radical species
intermediate IV, which could be likely converted into the more stable
carbocation V through a SET event assisted by Cu(II) (route a).
Carbocation V could be further stabilized as the corresponding
iminium ion VI. Based on experimental evidence, the latter could be
reversibly trapped by a tert-butylperoxide anion to yield intermediate
[
18]
was obtained in low yields (Scheme 2).
3
Table 4. Cu-catalyzed C(sp )−H alkylation of glycine esters with
[
a,b]
dioxolanes derived from natural products and drugs
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ChemSusChem
10.1002/cssc.201802216
COMMUNICATION
[
12,22]
VII,
which would ultimately react with in situ generated α-dioxy
for technical and human support provided by SGIker of UPV/EHU
and European funding (ERDF and ESF). Cost-CHAOS action
radical VIII to produce the coupling product.
(
CA15106) is also acknowledged. M. Agirre is kindly acknowledged
3
by her support on HPLC analysis.
In summary, we have developed
functionalization reaction of α-amino carbonyl compounds and 2-
alkyl-1,3-dioxolanes. From fundamental point of view, this
a practical dual C(sp )−H
a
Keywords: sustainable C–H functionalization • quaternary
transformation represents a robust, yet unprecedented, means for
the selective oxidation of 2-susbtituted dioxolane derivatives toward
the challenging assembly of quaternary centers. Importantly, this Cu-
catalyzed oxidative alkylation constitutes a powerful, yet sustainable,
tool for building up structural diversity within a peptide framework
and providing access to novel α-amino acids beyond those found in
naturally occurring proteins. Important features of our strategy are
the low-price of the copper catalyst, the retention of the chiral
integrity of the existing stereocenters in peptide settings, the broad
functional group tolerance, the site-seletivity toward the
functionalization of N-aryl glycine unit and the high
diastereoselectivity induced by proline-containing peptides. As a
result, we anticipate that our Cu-catalyzed oxidative alkylation could
become a versatile platform technology of tremendous importance in
drug discovery and protein engineering.
center • copper catalysis • late-stage peptide modification • CDC
[1]
a) L. Pollegioni, S. Servi, Non-natural Amino Acids: Methods and
Protocols; Springer: New York, 2012; b) A. B. Hughes, Amino Acids,
Peptides and Proteins in Organic Chemistry; Wiley-VCH: Weinheim,
2011.
[
2]
For reviews, see: a) W. Wang, M. Lorion, J. Shah, A. R. Kapdi, L.
Ackermann, Angew. Chem. Int. Ed. 2018, 10.1002/anie.201806250; b)
X. Lu, S.-J. He, W.-M. Cheng, J. Shi, Chin. Chem. Lett. 2018, 29, 1001;
c) S. Mondal, S. Chowdhury, Adv. Synth. Catal. 2018, 360, 1884; d) L.
R. Malins, Curr. Opin. Chem. Biol. 2018, 46, 25; e) J. N. deGruyter, L.
R. Malins, P. S. Baran, Biochemistry 2017, 56, 3863; f) G. He, B. Wang,
W. A. Nack, G. Chen, Acc. Chem. Res. 2016, 49, 635; g) A. M. Metz, M.
C. Kozlowski, J. Org. Chem. 2015, 80, 1; h) K. Fosgerau, T. Hoffmann,
Drug. Discov. Today 2015, 20, 122; i) A. F. M. Noisier, M. A. Brimble,
Chem. Rev. 2014, 114, 8775.
[
3]
For selected recent examples, see: a) W. Wang, M. M. Lorion, O.
Martinazzoli, L. Ackermann, Angew. Chem. Int. Ed. 2018, 57, 10554;
Angew. Chem. 2018, 130, 10714; b) B. A. Vara, X. Li, S. Berritt, C: R:
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M. M. Lorion, C. Dong, L. Ackermann, Angew. Chem. Int. Ed. 2018, 57,
203; Angew. Chem. 2018, 130, 209; e) 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;
Angew. Chem. 2018, 130, 5960; f) N. Ichiishi, J. P. Caldwell, M. Lin, W.
Zhong, X. Zhu, E. Streckfuss, H.-Y. Kim, C. A. Parish, S. W. Krska,
Chem. Sci. 2018, 9, 4168; g) T. Liu, J. X. Qiao, M. A. Poss, J.-Q. Yu,
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Chem. 2017, 129, 320; i) T. J. Osberger, D. C. Rogness, J. T. Kohrt, A.
F. Stepan, M. C. White, Nature 2016, 537, 214.
Me
O
A
B
O
O
O
Cu
no reaction
FG
+
OEt
as above
FG = NHTs, NHBn,
NHAc, NMePh
2a
O
H
H
N
N
Cu
Ph
OEt
Ph
OEt
OOtBu
1
a
as above
8
, 71%
gram-scale
O
H
N
C
D
Ph
OEt
OOtBu
8
2a
Cu
3a, 56%
+
as above
O
N
Ph
OEt
3a (14%)
[4]
For selected reviews, see: a) H. Yi, G. Zhang, H. Wang, Z. Huang, J.
Wang, A. K. Singh, A. Lei, Chem. Rev. 2017, 117, 9016; b) L. Lv, Z. Li,
Top. Curr. Chem. 2016, 374, 225; c) S. A. Girard, T. Knauber, C.-J. Li,
Angew. Chem. Int. Ed. 2014, 53, 74; Angew. Chem. 2014, 126, 76.
a) M. S. San Segundo, A. Correa, Synthesis 2018, 50, 2853; b) T.
Brandhofer, O. García Mancheño, Eur. J. Org. Chem. 2018,
10.1002/ejoc.201800896.
Cu
2a
+
9
as above
Mechanism Proposal
O
tBuOH
CuI
[5]
[6]
O
O
H
H
N
CuII
R1
tBuO
H
R1
N
N
Ar
R1
V
Ar
Ar
SET
route a
route b
IV
Cu(OAc)(OOtBu)
or tBuOO
For selected reviews on the late-stage C−H functionalization, see: a) R.
R. Karimov, J. F. Hartwig, Angew. Chem. Int. Ed. 2018, 57, 4234;
Angew. Chem. 2018, 130, 4309; b) T. Cernak, K. D. Dykstra, S.
Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc. Rev. 2016, 45, 546; c)
J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369.
O
H
O
H
N
O
VI
H
N
Ar
R1
Ar
R1
N
R1
R2
Ar
O
O
R2
tBuOO
VII OOtBu
O
isolated
O
[
7]
M. D. Delost, D. T. Smith, B. J. Anderson, J. T. Njardarson, J. Med.
Chem. 2018, 10.1021/acs.jmedchem.8b00876.
VIII
O
O
[8]
For selected reviews, see: a) A. Batra, P. Singh, K. N. Singh, Eur. J.
Org. Chem. 2017, 3739; b) S.-r. Guo, P. S. Kumar, M. Yang, Adv.
Synth. Catal. 2017, 359, 2; c) M. K. Lakshman, P. K. Vuram, Chem. Sci.
tBuOH tBuO
R
2
Scheme 3. Control experiments and mechanism proposal
2
017, 8, 5845; d) S.-Y. Zhang, F.-M. Zhang, Y.-Q. Tu, Chem. Soc. Rev.
011, 40, 1937.
2
[
[
9]
a) N. W. A. Geraghty, A. Lally, Chem. Commun. 2006, 4300; b) A. B.
Shtarev, F. Tian, W. R. Dolbier Jr., B. E. Smart, J. Am. Chem. Soc.
Acknowledgements ((optional))
1999, 121, 7335; c) V. Malatesta, K. U. Ingold, J. Am. Chem. Soc. 1981,
103, 609.
We are grateful to MINECO (CTQ2016-78395-P) and Basque
Government (IT1033-16) for financial support. A. C. thanks MINECO
for a Ramón y Cajal research contract (RYC-2012-09873). We thank
10] a) Y. Lan, P. Fan, X.-W. Liu, F.-F. Meng, T. Ahmad, Y.-H. Hu, T.-P. Loh,
Chem. Commun. 2017, 53, 12353; b) A. SØlvhØj, A. Ahbulrg, R.
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ChemSusChem
10.1002/cssc.201802216
COMMUNICATION
H. Fang, J. Han, Y. Pan, Org. Lett. 2015, 17, 1160; d) P. Du, H. Li, Y.
Wang, J. Cheng, X. Wan, Org. Lett. 2014, 16, 6350.
corresponding tertiary alkyl radical but also resulted in a more stable
product.
[
11] For the CDC of glycine derivatives with secondary alkyl ethers, see: a)
M. San Segundo, I. Guerrero, A. Correa, Org. Lett. 2017, 19, 5288; b)
W.-T. Wei, R.-J. Song, J.-H. Li, Adv. Synth. Catal. 2014, 356, 1703.
12] For more details, see the Supporting Information.
[19] The performance of the process under an oxygen atmosphere resulted
in the formation of 3a in a comparatively lower 44% yield, which
supported the intermediacy of radical species. For the direct reaction of
[
[
2
O with a dioxolane-derived radical, see: H. Zeng, S. Yang, H. Li, D. Lu,
13] The acyclic acetaldehyde dimethyl acetal or related acyclic derivatives
remained unreactive under the optimized conditions, which revealed
the subtleties of our system. Likewise, the use of 2-aryl-1,3-dioxolanes
resulted in the obtention of complex mixtures of products. We
hypothesized that the trapping of a strongly stabilized radical, being
both tertiary and benzylic radical, might be slower than other side-
reactions such as homo-coupling or even water-assisted acetal opening
reactions: a) R. Mosca, M. Fagnoni, M. Mella, A. Albini, Tetrahedron
Y. Gong, J.-T. Zhu, J. Org. Chem. 2018, 83, 5256.
[20] a) H. Bartling, A. Eisenhofer, B. König, R. M. Gschwind, J. Am. Chem.
Soc. 2016, 138, 11860; b) E. Boess, L. M. Wolf, S. Malakar, M.
Salamone, M. Bietti, W. Thiel, M. Klussmann, ACS Catal. 2016, 6,
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1549; d) G.-J. Cheng, L.-J. Song, Y.-F. Yang, X. Zhang, O. Wiest, Y.-D.
Wu, ChemPlusChem 2013, 78, 943; e) E. Boess, C. Schmitz, M.
Klussmann, J. Am. Chem. Soc. 2012, 134, 5317; f) E. Boess, D.
Sureshkumar, A. Sud, C. Wirtz, C. FarHs, M. Klussmann, J. Am. Chem.
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2001, 57, 10319; b) S. V. Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster,
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14] X.-Q. Chu, D. Ge, Z.-L. Shen, T.-P. Loh, ACS Catal. 2018, 8, 258
15] For CDCs between amides and cyclic ethers, see: a) Q. Yue, Z. Xiao, Z.
Kuang, Z. Su, Q. Zhang, D. Li, Adv. Synth. Catal. 2018, 360, 1193; b) I.
Buslov, X. Hu, Adv. Synth. Catal. 2014, 356, 3325; c) L. Zhou, S. Tang,
X. Qi, C. Lin, K. Liu, C. Liu, Y. Lan, A. Lei, Org. Lett. 2014, 16, 3404.
16] R. T. Dean, S. Fu, R. Stocker, M. J. Davies, Biochem. J. 1997, 324, 1.
17] For a diastereoselective arylation within proline-based peptides, see: X.
Wu, D. Zhang, S. Zhou, F. Gao, H. Liu, Chem. Commun. 2015, 51,
[
[
[21] Cu(I)-catalyzed hydrogen abstraction reactions from the α-carbon of N-
aryl glycine derivatives are well established; see for example: a) H. Zhi,
S. P.-M. Ung, Y. Liu, L. Zhao, C.-J. Li, Adv. Synth. Catal. 2016, 358,
2553; b) J.-C. Wu, R.-J. Song, Z.-Q. Wang, X.-C. Huang, Y.-X. Xie, J.-
H. Li, Angew. Chem. Int. Ed. 2012, 51, 3453; Angew. Chem. 2012, 124,
3509; c) L. Zhao, O. Baslé, C.-J. Li, Proc. Natl. Acd. Sci. USA 2009,
106, 4106.
[
[
[22] At this stage, the formation of species VII by direct reaction of radical
species IV with in situ formed tBuOO radical species or
Cu(OAc)(OOtBu) cannot be entirely ruled out (Scheme 3, route b).
12571.
[
18] Such acetylated compound was unstable and rapidly decomposed. On
the other hand, all attempts to perform the direct CDC of aldehydes and
1a failed to provide the target acylation reaction, which reinforced the
notion that dioxolanes did not act as merely protecting groups in our
process and not only tamed the reactivity toward the formation of the
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ChemSusChem
10.1002/cssc.201802216
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Marcos San Segundo and Arkaitz
Correa*
O
O
R
H
H
N
H
R
N
O
Ar
+
Ar
Cu
Page No. – Page No.
H
O
O
O
3
8 examples
Site-selective Cu-catalyzed Alkylation
of α-Amino Acids and Peptides
toward the Assembly of Quaternary
Centers
(
up to 92% yield)
Chemo- & diastereoselective alkylation
Assembly of quaternary centers
Application to natural products
Late-stage peptide modification
Just Glycine! A novel Cu-catalyzed selective α-alkylation of α-amino acid and peptide derivatives with 2-alkyl-
,3-dioxolanes is reported. This oxidative coupling is distinguished by its site-specificity, high diastereoselectivity,
1
chirality preservation and exhibits entire chemoselectivity for N-aryl glycine motifs over other amino acid units.
The method allows for the sustainable assembly of challenging quaternary centers as well as compounds derived
from natural products of high structural complexity, which illustrates its ample opportunities toward the late-stage
radical functionalization of peptides.
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