Enantioselective synthesis of arylglycine derivatives by direct C-H oxidative cross-coupling

Article abstract of DOI:10.1039/c4cc07361d

A new method for the synthesis of chiral α-amino acid derivatives by enantioselective C-H arylation of N-aryl glycine esters with aryl boric acids in the presence of a chiral Pd(ii)-catalyst has been developed. This work successfully integrates the direct C-H oxidation with asymmetric arylation and exhibits excellent enantioselectivity. This journal is

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Enantioselective synthesis of arylglycine derivatives
by direct C–H oxidative cross-coupling†
Cite this:DOI: 10.1039/c4cc07361d
Xiao-Hong Wei,a Gang-Wei Wanga and Shang-Dong Yang*ab
Received 18th September 2014,
Accepted 14th October 2014
DOI: 10.1039/c4cc07361d
www.rsc.org/chemcomm
A new method for the synthesis of chiral a-amino acid derivatives by
Over the past few decades, various high efficiency and versatile
enantioselective C–H arylation of N-aryl glycine esters with aryl boric protocols for C–H activation have been demonstrated,10 especially
acids in the presence of a chiral Pd(II)-catalyst has been developed. This the building of C–C and C–heteroatom bonds directly from two
work successfully integrates the direct C–H oxidation with asymmetric simple C–H bonds or C–H and carbon nucleophiles has emerged as
arylation and exhibits excellent enantioselectivity.
a highly valuable strategy for C–C bond formation and has been
studied extensively because of its great ecological and high atom
Chiral a-amino acids are useful compounds of great interest economy.11 However desirable realization of stereo-, and enantio-
and frequently constitute the cores of peptides, proteins, and selective Csp3–C bond formation by direct C–H oxidative remains a
pharmaceutical agents.1 These amino acids have also been challenging task.12 For the synthesis of chiral a-amino acid deriva-
used in organic chemistry to synthesize natural products or tives, very few examples have been reported to date. Recently, Wang
as chiral auxiliaries, catalysts, or catalyst ligands.2 Therefore, and coworkers disclosed a significant method of chiral Lewis acid
the discovery of general methodology that can produce chiral controlled asymmetric C–H oxidative cross-coupling to synthesize
a-amino acid derivatives in high yield and with useful levels of chiral alkyl a-amino acid derivatives (A, Scheme 1).13 Another novel
enantioselectivity is of considerable importance.3 Up to now, strategy of palladium-catalyzed C–H functionalization of chiral
relatively straightforward catalytic asymmetric approaches to chiral a-amino acids also provides an effective pathway (B, Scheme 1).14
a-amino acid derivatives mainly include the asymmetric Strecker
reaction,4 direct amination reaction involving metal-carbenes,5
and transition metal-catalyzed asymmetric hydrogenation of
a-enamides6 or imino esters.7 Furthermore, transition metal-
mediated asymmetric addition of various nucleophiles to
a-imino esters8 also provides for the development of concise
and attractive routes to synthesize optically active a-amino acid
derivatives. Recently, the use of asymmetric alkylation of benzo-
phenone Schiff base glycine esters with phase-transfer catalysts
(PTCs)9 has established direct approaches to such compounds
and has shown impressive progress. Despite tremendous signifi-
cant achievements in this field, the development of more efficient
and practical methods for convenient construction of various
chiral a-amino acids remains a difficult but potentially rewarding
challenge given the great demand for these compounds.
a State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China. E-mail: yangshd@lzu.edu.cn;
Fax: +86-931-8912859; Tel: +86-931-8912859
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1005709. For ESI
Scheme 1 Various strategies for the synthesis of chiral a-amino acid
derivatives.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc07361d
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Table 1 Scope of synthesis of various chiral a-amino acid estersa
Entry
Product
Yieldb
eec
Entry
Product
Yieldb
24%
eec
2m
92% (S)
2a
2b
2c
2d
R1 = Et
69%
60%
31%
63%
90% (S)
91% (S)
96% (S)
88% (S)
R1 = Me
R1 = t-Bu
R1 = Bn
2n
2o
77%
67%
66% (S)
86% (S)
2e
2f
58%
40%
52%
81%
85%
81%
91% (S)
96% (S)
92% (S)
87% (S)
85% (S)
87% (S)
2p
78%
66% (S)
2g
2h
2i
2q
2r
2s
2t
2u
2v
2w
2x
R = CF3
R = COCH3
R = CO2Et
R = Ph
R = F
R = Cl
R = Br
R = I
20%
26%
24%
70%
62%
66%
69%
71%
94% (S)
93% (S)
94% (S)
90% (S)
87% (S)
90% (S)
90% (S)
94% (S)
2y
78%
74% (S)
2j
2z
68%
41%
95% (S)
66% (S)
2k
60%
53%
92% (S)
90% (S)
2aa
2l
Reaction conditions: 1a (0.3 mmol), boronic acid (1.2 equiv.), Pd(OAc)2 (0.1 equiv.), L8 (0.1 equiv.), T+BF4ꢀ (1.1 equiv.), DCE (2.5 mL) 60 1C under
a
b
c
Ar, 16 h. Yield of the isolated product. The enantiomeric excess was determined by chiral HPLC.
However, these two strategies are subject to substrates and only
have been applied to synthesize chiral alkyl a-amino acid
derivatives. The synthesis of chiral aryl a-amino acid deriva-
tives by direct C–H arylation has not been reported. In this
communication, we describe a novel strategy and approach: a
highly efficient route to chiral arylglycine derivatives via the
enantioselective cross-coupling of aryl boric acids to N-aryl
glycine esters in the presence of a chiral Pd(II)-catalyst that
successfully integrates direct C–H oxidation with asymmetric
arylation (C, Scheme 1).
In an initial study, we chose para-methoxyphenyl-(PMP)-protected
glycine ester 1a and para-methyphenyl boric acid as model substrates
to identify suitable reaction conditions (Table S1, see ESI†). We first
selected achiral 2,2-bipyridine as a ligand and 10 mol% Pd(OAc)2 as
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a catalyst to screen different oxidants; to our delight the desired
product of racemic 2a was obtained in 32% yield by using the
2,2,6,6-tetramethylpiperidine-1-oxoammonium tetra-fluoroborate
(T+BF4ꢀ) as an oxidant at 60 1C. Subsequently, diverse solvent
screening showed that 1,2-dichlorethane (DCE) is the best choice;
the yield of 2a improved to 70% (see ESI† for details). Based on
these results, the enantioselective C–H oxidative cross-coupling
between para-methoxyphenyl-(PMP)-protected glycine ester 1a and
para-methyphenyl boric acid was carried out in the presence of
10 mol% Pd(OAc)2 with various chiral ligands in DCE at 60 1C
(Table S1, entries 1–9, ESI†). As expected, the best result was
obtained by employing L8 as a ligand: chiral a-amino acid ester
of 2a was obtained in 69% yield and 90% ee (Table S1, entry 8,
ESI†). We fixed the chiral ligand as L8 and evaluated some solvents
again. Results indicated that DCE is still the best choice (Table S1,
entries 9–15, ESI†). We also examined other palladium catalysts
such as PdCl2, Pd(TFA)2, Pd(PPh3)2Cl2, and Pd(CH3CN)2(OTs)2;
results indicate that Pd(TFA)2 and Pd(CH3CN)2(OTs)2 could prompt
the reaction with lower yields and ee values (Table S1, entries 16–19,
ESI†). Finally, the reaction temperature evaluation indicated that 60 1C
is still the best (Table S1, entries 20 and 21, ESI†). Thus, the optimal
reaction conditions were obtained by using Pd(OAc)2 (10 mol%) as the
catalyst, (4S,40S)-4,40-diisopropyl-2,20-bis(2-oxazoline) of L8 (10 mol%)
Scheme 2 Enantioselective a-arylated peptides by direct C–H oxidation.
enantioselective direct C–H oxidative cross-coupling reaction and
afford products in good yields with moderate-to-good ee values
(Table 1, entries 2y–2z). Of particular note is the heterocycle boric
acid, which was also compatible for the reaction; the chiral
a-thiophene amino acid ester 2aa was obtained in 41% yield and
66% ee (Table 1, entry 2aa). The relative and absolute configuration
of 2z has been confirmed unequivocally to be (S)-2z by X-ray
diffraction analysis (Fig. S1; see the ESI† for the details). Those
of other adducts were deduced on the basis of this result.
In addition to the demonstration of the broad applicability
of this catalytic system, we carried out enantioselective direct
C–H oxidative cross-coupling of peptides under standard reac-
tion conditions. Corresponding chiral a-arylated peptides were
obtained in good yield with moderate ee values (3b and 4b,
Scheme 2). We believe that after appropriate optimization of
the catalytic system, yields and ee values of the product will
increase accordingly. These results indicate that enantio-
selective direct C–H oxidative cross-coupling reaction provides
the best pattern of modification of peptides and proteins.
as a ligand, 1.1 equiv. T+BF4 as the oxidant in 2.5 mL of DCE for
ꢀ
0.3 mmol 1a with 1.2 equiv. Of para-methyphenyl boric acid at 60 1C
under an argon atmosphere.
To demonstrate the generality of this enantioselective direct
C–H oxidation cross-coupling reaction, various substituted sub-
strates were investigated under optimized conditions (Table 1). We
first surveyed N-para-methoxylphenyl protected various glycine
esters (Table 1, entries 2a–2d). Although the tert-butyl glycine ester
gave the 96% ee value, the yield of 2c was only 31%. Thus, we
selected the glycine ethyl ester to react with para-methylphenyl
boric acid. Investigation of different N-aryl groups revealed that the
corresponding products of chiral a-amino acid esters were obtained
in moderate to good yields with 85–96% ee values (Table 1, entries
2e–2j). 2h was obtained in a good yield of 81% and a relatively high
87% ee, respectively, so we also examined the reaction of the
N-meta-bromophenyl glycine ethyl ester with some boric acids with
the hope of finding the best pattern for the synthesis of chiral
a-amino acid esters (Table 1, entries 2k–2m). Indeed, the products
were obtained in excellent ee values, but yields were moderate. After
summarizing these results, we selected the N-para-bromophenyl
glycine ethyl ester as the substrate to further evaluate different
arylboric acids. The steric effect was first examined using the
ortho-, meta- and para-methoxyl phenylboric acids, but results
demonstrate its insignificance (Table 1, entries 2n–2p). However,
the electronic effect in this transformation was very notable; the
strong electron-deficient groups such as p-CF3, p-COCH3, and
p-CO2Et phenylboric acids afforded desired products in relatively
low yields, but ee values were excellent (Table 1, entries 2q–2s).
If phenyl and halogen are the para-position substituted groups,
the corresponding products of chiral a-amino acid esters are
obtained in moderate-to-good yields with 87–94% ee (Table 1,
entries 2t–2x). Furthermore, the benzo [1,3]dioxol-5-ylboronic
acid and naphthalen-2-ylboronic acid could also undergo the
Scheme 3 A plausible mechanistic pathway of Pd(II)-catalyzed enantio-
selective C–H oxidative cross-coupling.
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pioneering reports,15 we propose a plausible mechanistic pathway
outlined in Scheme 3. Pd(OAc)2 first coordinates with the ligand of
(4S,40S)-4,40-diisopropyl-2,20-bis(2-oxazoline) to form the activated
chiral palladium catalyst 1A, which reacts with aryl boric acid by
transmetallation to produce the arylpalladium intermediate 1B.
This active species subsequently attacks the a-imino ester, which
was produced by the oxidation of the N-aryl glycine ester, because
of the coordination mode of the nitrogen atom of the imine to the
palladium center, the aryl group preferred to add to imines from
the rear face in a highly selective manner to afford the added
product 1D, which then yielded the product of (S)-2a upon disso-
ciation, and the active palladium catalyst was regenerated and
entered the next catalytic cycle synchronously.
In conclusion, we have developed a novel pattern for the
synthesis of a series of chiral a-amino acid derivatives by
palladium-catalyzed enantioselective direct C–H oxidation and
arylation reaction. This method also holds significant promise
for a potential pathway of enantioselective Csp3–C bond
formation by direct C–H oxidative cross-coupling.
We are grateful to the NSFC (No. 21272100), FRFCU (lzujbky-
2013-ct02), PCSIRT (IRT1138), and Program for New Century
Excellent Talents in University (NCET-11-0215 and lzujbky-
2013-k07) for financial support.
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