Functionalizing glycine derivatives by direct C-C bond formation

Article abstract of DOI:10.1002/anie.200801367

(Chemical Equation Presented) Come on glycine: Two different types of glycine derivatives are α-functionalized using cross-dehydrogenative- coupling (CDC) reactions. The method allows the efficient attachment of a malonate or aromatic alkyne group on the α-position of the glycine derivatives under very mild conditions.

Full text of DOI:10.1002/anie.200801367

Angewandte
Chemie
DOI: 10.1002/anie.200801367
Synthetic Methods
À
Functionalizing Glycine Derivatives by Direct C C Bond Formation**
Liang Zhao and Chao-Jun Li*
With the recent advances in proteomics, there has been a
great interest in the study of properties and functions of
natural and non-natural (synthetic) amino acids.[1] By using
non-natural (synthetic) a-amino acids, the conformation and/
or stability of biologically active peptides can be modified.[2]
For example, by incorporating a-aminoisobutyric acid into
oligopeptides, the peptide backbone can be rigidified through
the formation of b-turns or a-helices.[3] In addition, the
demand for peptide-based structures is increasing rapidly for
drug discoveries.[4] Thus, general methods to synthesize non-
natural a-amino acids and/or to modify natural amino acids
rapidly are highly desirable. The direct a-functionalization of
natural peptides takes advantage of existing structure and
provides rapid access to diverse new peptides. The best-
known methods of a-functionalization of amino acid deriv-
atives or amides include: functionalization of a-carbanions
(preformed by deprotonation with a strong base),[5] radical
(a-bromination by N-bromosuccinimide[6a,b] or UV photolysis
in the presence of di-tert-butyl peroxide[6c]), Claisen rear-
rangements,[7] and a ruthenium-catalyzed a-oxygenation.[8]
for functionalizing peptido-amides through the direct reac-
À
À
tion at a-peptido C H bonds, to give new C C bonds in a
cross-dehydrogenative coupling (CDC) process (Scheme 1,
Path B).
To begin our study, with a view to peptide functionaliza-
tion, we decided to use the amino acid derivative N-
acetylglycine ethyl ester (1) to react with diethyl malonate
À
(2; see Table 1). However, we could not obtain any desired C
C bond formation product under the previously optimized
conditions for amines, that is, CuBr as catalyst and TBHP
(tBuOOH) as oxidant. When 2equivalents of Cu(OAc) 2 were
used, however, we obtained a small amount of the C–C
coupling product between N-acetylglycine ethyl ester (1) and
diethyl malonate (2; Table 1, entry 1). After extensive opti-
mizations, we identified di(2-pyridyl) ketone as the best
ligand for this reaction (Table 1, entry 5) affording consid-
erably higher yields than either 4,4’-dimethyl-2,2’-bipyridine
or 1,10-phenanthroline (Table 1, entries 2and 3). This high
reactivity is probably due to the fact that, in coordinating with
copper, di(2-pyridyl) ketone forms a six-membered ring
complex, which is more reactive than the five-membered
ring complexes formed with the other nitrogen ligands. In
addition, the presence of a catalytic amount of base is
beneficial to the reaction (Table 1, entries 6, 7, 8). After
further screening, 20 mol% of Cs2CO3 gave the best results
(Table 1, entry 8). A catalytic amount of Cu(OAc)2 under 1
atm O2 with or without Pd(OAc)2 gave only low yields of the
desired products (Table 1, entries 9 and 10). The use of
1.2equivalents of Cu(OAc) 2 furnished a lower yield; how-
ever, it demonstrated that Cu(OAc)2 served as a stoichio-
metric oxidant in the reaction (Table 1, entry 11).
À
À
However, direct C C bond formation by C H bond func-
tionalization of amino acid derivatives is unprecedented. We
À
and other groups have developed C C bond forming
À
reactions based on oxidative activation of the C H bond
adjacent to a tertiary nitrogen atom.[9] Although these results
À
provide new or alternative ways to construct different C C
À
bonds by the activation of C H bonds (Scheme 1, Path A),
they are not applicable to amino acid derivatives. Thus
selective oxidative functionalization of a-amino acid deriva-
tives is still rare.[10] Herein, we wish to report a novel method
The CDC method could be applied to a variety of
malonates as well as other glycine derivatives (Table 2). For
most functionalized products, decomposition occurred after
extended heating. To compare the relative reactivity, all the
reactions were also performed and stopped at 4 h. Diiso-
propyl or diethyl malonates furnished better yields (Table 2,
entries 1, 3, 5, and 7) than the corresponding dimethyl
malonate (Table 2, entries 2 and 8), indicating that a more
electron-rich malonate is beneficial to the reaction. Increased
steric hindrance in the carbon center decreased the reactivity
(Table 2, entries 4, 6, and 9). For the amino acid moiety, the
electronic effect was shown to be more significant than the
steric effect. The iPr- and Et-substituted esters furnished
higher yields (Table 2, entries 1 and 5) than the Me-substi-
tuted substrate (Table 2, entry 10). The effect of the substitu-
ent on the amide moiety was also studied. As shown in Table
2, when R1 was changed from Me (Table 2, entries 6 and 9)
and Et (Table 2, entries 11 and 14) to an iPr group (Table 2,
entries 12and 15), the yield decreased dramatically. Further-
more, when R1 was changed to a tBu group (Table 2,
entries 13 and 16), the reaction was completely shut down.
À
À
Scheme 1. Direct C C bond formation by C H bond functionalization
adjacent to a tertiary nitrogen atom (Path A) and in amino acid
derivatives (Path B). PG=Protecting group.
[*] L. Zhao, Prof. C.-J. Li
Department of Chemistry
McGill University
Montreal, QC H3A 2K6 (Canada)
Fax: (+1)514-398-3739
E-mail: cj.li@mcgill.ca
Homepage: http://cjli.mcgill.ca/
[**] This work was supported by the NSERC, CFI, and the Canada
Research Chair (Tier I) program (to C.-J.L.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801367.
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7075

Communications
Table 1: Optimization of reaction conditions.[a]
an imino intermediate (Scheme 2),
precedes copper(II)-catalyzed
a
Mannich-type reaction between
the imino ester and malonate to
afford the final coupling product.
The di(2-pyridyl) ketone serves as a
better ligand in this reaction prob-
ably owing to its electron-withdraw-
ing nature, which renders the CuII
center in the transition state more
Entry
Ligand
none
Base
Cu(OAc)2 [equiv]
Yield [%][b]
1
2
3
4
5
6
7
8
none
none
none
none
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.2
0.2
1.2
5
30
12
23
56
70
71
84
15
15
68
4,4’-dimethyl-2,2’’-bipyridine
1,10-phenanthroline
TMEDA
di(2-pyridyl) ketone
di(2-pyridyl) ketone
di(2-pyridyl) ketone
di(2-pyridyl) ketone
di(2-pyridyl) ketone
di(2-pyridyl) ketone
di(2-pyridyl) ketone
electronegative. As
a
result,
abstraction of the NH proton
occurs more easily. Cs2CO3 neutral-
izes the generated acetic acid and
helps the enolization of the malo-
nate.
none
NaOAc
KHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9[c]
10[d]
11
To extend the scope of the direct
À
functionalization of a-peptido C H
[a] Reaction conditions: 1 (0.125 mmol), 2 (0.25 mmol), 20 mol% ligand, 20 mol% base in toluene
(1 mL), 1508C, 8 h. [b] Yields were based on compound 1 and determined by NMR spectroscopy using
an internal standard. TMEDA=N,N,N’,N’-tetramethylethylenediamine. [c] 5 mol% Pd(OAc)2 was
added and run under 1 atm O2. [d] 5 mol% Pd(OAc)2 was added.
bonds, we found that, by switching
the protected amino acid derivative
from amide 1 to compound 7 (see
Table 3), a CDC reaction with
phenylacetylene could proceed
readily at room temperature using
the CuBr/TBHP system.[9p–v] This
enhanced reactivity could be attrib-
uted to the para-methoxyphenyl
(PMP) protecting group (the oxida-
tion potential of an amine is much
lower than that of an amide). The
success of this transformation is also
dependent on R1 being a substituted
amine moiety. If R1 was an OEt
group (Table 3, entry 10), the cou-
pling reaction did not occur at all at
room temperature. By switching R1
Table 2: Functionalization of 4 by CDC reactions with malonate 5.[a]
Entry
Reaction t [h]
R1
R2
R3
R4
6[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6
10
6
10
8
10
6
6
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
iPr
tBu
Et
iPr
tBu
iPr
iPr
iPr
iPr
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
H
H
H
Me
H
Me
H
H
Me
H
Me
Me
Me
Me
Me
Me
Et
Me
iPr
Et
6a
6b
6c
6d
6e
6 f
6g
6h
6i
82(73)
85(40)
80(62)
94(48)
84(72)
75(48)
73(63)
63(46)
75(32)
65(55)
75
Et
Me
iPr
Me
Et
to
a
phenyl group (Table 3,
10
6
entry 11), the reaction afforded a
complex unidentified mixture of
products, indicating that the pres-
ence of a substituted amine moiety
reduces the oxidation potential of
the substrate and stabilizes the
imine intermediate. Under the opti-
mized conditions, various substi-
tuted glycine derivatives could be
coupled with aromatic alkynes
(Table 3). Secondary (Table 3,
entries 1–4) and tertiary (Table 3,
entry 5) amides all reacted well.
Et
6j
10
10
10
10
10
10
Et
Et
6k
6l
53
NR
78
60
Et
6m
6n
6o
6p
Me
Me
Me
Et
Et
NR
[a] Reaction conditions: 4 (0.125 mmol), 5 (0.25 mmol), Cu(OAc)2 (0.25 mmol), Cs2CO3 (0.025 mmol),
di(2-pyridyl) ketone (0.025 mmol), toluene (1 mL). [b] For full experimental data, see the Supporting
Information. [c] Yields of isolated product are based on 4, and the yields after 4 h reaction are given in
parentheses. NR=No reaction.
Interestingly, it should be noted that a-amino acid derivatives
bearing a substituent on the a-position did not react under the
present conditions, possibly because of steric effects.
The mechanism of this novel transformation was explored
briefly. Adding a radical inhibitor BHT (2,6-di-tert-butyl-4-
methylphenol) did not have a significant influence on the
reaction, suggesting that the involvement of a free radical
intermediate is unlikely. We tentatively propose that coordi-
nation of nitrogen to CuII, followed by oxidation to generate
The aromatic alkyne counterparts, 4-ethynylbiphenyl
(Table 3, entry 6), 1-bromo-4-ethynylbenzene (Table 3,
entry 7), and 4-ethynyltoluene (Table 3, entry 8) all afforded
the corresponding products in decent yields. However,
2-methoxyphenylacetylene (Table 3, entry 9) proved less
reactive than the other substrates, indicating that the steric
hindrance on the alkyne retarded its reactivity.
Encouraged by this promising result, we tested this
method on a simple peptide 10 (Scheme 3). To our delight,
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the coupling reaction proceeded at 708C in dichloroethane
(DCE), affording the isolated coupling product 11 in 63%
yield. Compared with previous methods in functionalizing
glycine derivatives,[5,6] this method distinguished itself by
specifically introducing the alkynyl group at the protected
glycine terminus. In contrast, the carbanion- or radical-based
methods would not have any significant selectivity between
the two CH2 groups in peptide 10.
It should be noted that the existing methods to synthesize
b,g-alkynyl a-amino acid derivatives requires the coupling of
a-halo glycinates with alkynyltin reagents under refluxing
conditions,[11] alkynylmagnesium reagent at À788C,[12] or
transition-metal catalyzed alkynylation of a-imino esters.[13]
Pre-functionalizations of amino acid derivatives at the a-
position are essential in all cases. The CDC reaction described
above takes advantage of the existing structures and allows
the facile installation of the alkynyl group under very mild
conditions. Furthermore, this method is the first reported
CDC reaction on a secondary amine substrate.
Scheme 2. Proposed mechanism for the oxidative functionalization of
glycine derivatives with diethyl malonate.
Table 3: Functionalization of 7 by CDC reaction with alkyne 8.[a]
This methodology also provides a versatile method to
synthesize homophenylalanine derivatives (Scheme 4), which
are an important synthon in many important angiotensin-
converting enzyme inhibitors.[14] Hydrogenation of the alky-
nylation product 9a provided compound 9aa. Subsequent
cleavage of the PMP protecting group afforded the homo-
phenylalanine product 9ab.
Entry
R1
R2
9[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
NHMe
NHEt
NH(CH2)3CH3
NH(CH2)3Ph
1-pyrrolidinyl
NHMe
H
H
H
H
H
4-Ph
4-Br
4-Me
2-OMe
H
9a
9b
9c
9d
9e
9 f
9g
9h
9i
68(93)
55(73)
62(79)
76(93)
67(90)
72(86)
78(89)
60(81)
50(63)
NR
NHMe
NHMe
NHMe
OEt
10
11
NA
NA
Ph
H
ND
[a] Reaction conditions: 7 (0.30 mmol), 8 (0.90 mmol), TBHP (54 mL, 5–
6m in decane), CuBr (0.03 mmol), CH2Cl2 (0.5 mL). [b] For full
experimental data, see the Supporting Information [c] Yields of isolated
product are based on 7, and NMR yields, using an internal standard, are
given in parentheses. NA=Not applicable. NR=No reaction. ND=Not
determined.
Scheme 4. Synthesis of homophenylalanine derivative 9ab. TCCA=Tri-
chloroisocyanuric acid
In conclusion, we have developed a new way to function-
alize a-amino acid derivatives, which allows the efficient
installation of a malonate or a phenylethynyl group, using an
À
À
oxidative C H/C H coupling. Starting from commercially
inexpensive starting materials, a range of a-functionalized
amino acid derivatives can be readily obtained. Further
studies on expanding the scope of the substrates and on
enantioselective reactions are in progress.
Experimental Section
For full experimental and spectroscopic data, see the Supporting
Information.
6e (Table 2, entry 5): Cu(OAc)2 (45 mg, 0.25 mmol), di(2-pyridyl)
ketone (4.6 mg, 0.025 mmol), Cs2CO3 (8.2mg, 0.025 mmol), N-
Scheme 3. Functionalization of simple peptide 10 with ethynylbenzene.
Angew. Chem. Int. Ed. 2008, 47, 7075 –7078
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Communications
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Received: March 21, 2008
Published online: August 1, 2008
À
À
Keywords: amino acids · C C coupling · C H functionalization ·
cross-coupling · homogeneous catalysis
.
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