Copper-Catalyzed Synthesis of γ-Amino Acids Featuring Quaternary Stereocenters

Article abstract of DOI:10.1002/anie.201709511

The first general asymmetric synthesis of γ,γ-disubstituted γ-amino acids by copper-catalyzed ring opening of nonstrained lactones with amines is reported. This approach features ample scope, operational simplicity, and wide functional-group diversity. The catalytic process allows access to a series of highly functionalized enantioenriched γ-amino acids featuring quaternary stereocenters with excellent enantiomeric ratios of up to 98:2 and excellent yields of up to 98 %.

Full text of DOI:10.1002/anie.201709511

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Accepted Article
Title: Copper-Catalyzed Synthesis of gamma-Amino Acids Featuring
Quaternary Stereocenters
Authors: Arjan Willem Kleij, Jose Enrique Gómez, Silvia Gaspa, and
Wusheng Guo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709511
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10.1002/anie.201709511
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Synthesis of -Amino Acids Featuring
Quaternary Stereocenters
José Enrique Gómez,[a] Wusheng Guo,*[a] Silvia Gaspa,[a] and Arjan W. Kleij*[a][b]
Abstract: The first general asymmetric synthesis of -disubstituted
-amino acids via Cu-catalyzed ring opening of non-strained lactones
with amines is reported. This approach features ample scope,
operational simplicity and wide functional group diversity. The
catalytic process allows to access a series of highly functionalized
enantioenriched -amino acids featuring quaternary stereocenters
with excellent enantiomeric ratios up to 98:2 and excellent yields up
to 98%.
amino acids would be feasible through a Cu-allenylidene
mediated ring opening of non-strained five-membered lactones
(Scheme 1b).
Significant efforts have been devoted towards the synthesis of -
amino acids due to their important applications in pharmaceutical
industry and peptide chemistry.[1-4] Various biologically active -
amino acids are used as drugs including 4-methylpregabalin,
vigabatrin, baclofen and -aminobutyric acid (GABA).[3] The -
amino acid scaffolds are also frequently encountered in
biologically active short peptides such as pepstatin, hapalosin and
dolastatins.[4] Recently, oligomers constructed from -amino acid
synthons have demonstrated great potential in material science
as these protein-like foldamers display interesting functional
properties; specifically, the stereodefined -amino acid monomers
are highly essential to control the folding patterns.[5] Although
appreciable progress has been noted in the synthesis of -amino
acids (mostly analogues or precursors), the enantioselective
synthesis of ,-disubstituted amino acids featuring a quaternary
stereocenter is still quite challenging and underdeveloped.[6] Thus,
designing new catalytic methods toward the synthesis of these
challenging chiral scaffolds will prospectively reinforce their use
in pharmaceutical development and peptide chemistry.
Scheme 1. Transition metal-catalyzed ring opening of five-membered lactones
with nucleophiles.
To test our working hypothesis, the reaction of lactone A and
aniline was selected as a model reaction (Table 1). The Trost
ligand L1 using THF as solvent at rt was probed first and
promisingly, the desired amino acid 1 could be isolated in 47%
yield with 60:40 er (entry 1). Decreasing the reaction temperature
to 0ºC resulted in higher enantioselectivity though low conversion
(<15%, entries 2‒3). Changing the solvent to MeOH at 0oC led to
quantitative product formation with a lower er value (entries 3-7,
entries 3 vs 6). The utilization of a mixed solvent MeOH/THF (1:3)
gave promising result with 40% yield and 87:13 er (entries 8‒10).
The Cu-catalyst precursor and type of base also showed
significant effect towards the reaction outcome (entries 9 vs 10,
see also Tables S1 and S2 in the supporting information (SI)). We
were pleased to find that the use of Pybox ligand L6 resulted in
quantitative yield of product 1 and excellent enantioselectivity
(entries 11‒16). Lowering the reaction temperature, concentration
and catalyst loading had positive effects (entries 17-22). Notably,
the reaction could be performed open to air without any special
precautions, requiring only 3 mol% of Cu (entry 23: 94% yield and
97:3 er) which is a significant advantage compared to other Cu-
catalyzed reactions generally requiring 10 mol% of metal
loading.[9]
Despite the highly stable nature of non-strained five-
membered lactones,[7] the Pd-catalyzed nucleophilic ring opening
of vinyl-lactones toward the (amino) acid formation has been
achieved
(Scheme
1a).[8]
Furthermore,
Cu-catalyzed
transformation of propargylic compounds via Cu-allenylidene
intermediates has been extensively studied in synthetic
chemistry; this protocol enables the installation of synthetically
versatile alkyne functionality.[9] Inspired by the Pd-catalyzed
carboxylic acid formation from vinyl-lactones[8] (Scheme 1a) and
also our own work on challenging amine synthesis,[10,11] we
envisaged that the asymmetric synthesis of ,-disubstituted -
With the optimized reaction conditions in hand (Table 1, entry
23), the scope in lactone substrates was first investigated (Figure
1). The catalytic system proved to be efficient in the conversion of
lactones with electron-withdrawing (2, 3, 5 and 7) or -donating
groups (4, 7, 9 and 10) present in the aryl-substituents and gave
rise to the amino acids generally with er values higher than 95:5.
The presence of meta-substituted aryl substituents in the lactones
(7 and 9) allowed the formation of -amino acids with high
[a]
[b]
J. E. Gómez, Dr. W. Guo, S. Gaspa, Prof. Dr. A. W. Kleij, Institute of
Chemical Research of Catalonia (ICIQ), the Barcelona Institute of
Science and Technology, Av. Països Catalans 16, 43007 -
Tarragona, Spain
E-mail: wguo@iciq.es; akleij@iciq.es
Prof. Dr. A. W. Kleij
Catalan Institute of Research and Advanced Studies (ICREA), Pg.
Lluís Companys 23, 08010 Barcelona, Spain
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201709511
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COMMUNICATION
Table 1: Selected screening data for the formation of chiral ,-disubstituted -
amino acid 1.[a]
Entry
1
L
Solvent
THF
T [oC]
25
Yield[b]
47
er[c]
L1
60:40
2
3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
L6
L6
THF
10
0
15
10
46
20
96
50
96
54
40
38
88
98
98
98
98
98
98
98
98
98
97
94
73:27
77.5:22.5
69:31
THF
4
Acetone
0
5
Et2O
0
62.5:37.5
60.5:39.5
68:32
6
MeOH
0
7
iPrOH
0
8
MeOH/THF (1:1)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
MeOH/THF (1:3)
0
77:23
9
0
80.5:19.5
87:13
10
0
11
0
60:40
Figure 1. Scope in lactones (0.2 mmol scale). Reaction performed under the
optimized conditions (Table 1, entry 23). The er values were determined by
UPC2. [a] Cu(ACN)4(OTf) (5 mol%), L6 (6 mol%). [b]Cu(ACN)4(OTf) (10 mol%),
L6 (11 mol%), solvent (200 L). [c] 0ºC. [d] Performed at rt; lactam 11 was
isolated instead of the amino acid (SI for details).
12
0
74:26
13
0
73:27
14
0
56:44
15
0
90:10
16
0
61.5:38.5
91.5:8.5
92:8
enantioselectivity and isolated yield, while the ortho-Me-
substituted lactone is less reactive (10). The presence of a bulky
naphthyl group did not reduce the efficiency of the catalysis (8).
Substitution at the -position (R1) of the lactone is possible as
exemplified by the successful isolation of compound 11. The
lactones bearing a cyclohexyl or methyl group proved to be
unproductive, not even at higher reaction temperatures of up to
50ºC and higher catalyst loading up to 10 mol% (12 and 13),
suggesting an significant electronic effect within this catalytic
process.
17[d]
18[d]
19[d]
20[d,e]
21[d,f]
22[d,f,g]
23[d,f,h]
-5
-10
-20
-20
-20
-20
-20
93:7
94:6
95:5
96:4
97:3
Various amine nucleophiles were then examined (Figure 2).
The use of aryl amines bearing electron-donating groups afforded
the -amino acids in both high yield and enantioselectivity (14‒17,
26). In contrast, the aryl amines equipped with strongly electron-
withdrawing substituents such as nitro, ester and trifluoromethyl,
gave rise to only trace amount of product under the optimized
conditions; performing these reactions at higher reaction
temperature (products 22‒24), however, significantly improved
the reaction outcome. The incorporation of a heterocycle in the
final product proved to be feasible (25) which is of interest in
pharmaceutical development.[12] The installation of boro- and
halogen-functionality (18 and 20) is potentially useful for the
application of these -amino acid products in Suzuki-coupling
reactions. The presence of meta- or ortho-substituents in the aryl
amine (15, 16, 23, 24 and 26) is tolerated towards efficient amino
acid formation. The reactions with morpholine and propargylic
amine at ‒20ºC for 24 h displayed low conversions (<5%), while
reasonable reactivity was observed at 0ºC though with lower
enantio-discrimination or none (28 and 29).
[a] Reaction conditions unless otherwise noted: lactone A (0.2 mmol),
aniline (0.30 mmol, 1.5 equiv), solvent (200 L), iPr2NEt (0.24 mmol, 1.2
equiv), Cu catalyst precursor (10 mol%; entries 1-9 using Cu(OTf)2,
entries 10-23 using Cu(ACN)4(OTf)), L (11 mol%). [b] Isolated yield. [c]
Determined by UPC2. [d] Aniline (0.22 mmol). [e] Solvent (400 L). [f]
Solvent (600 L). [g] Cu(ACN)4(OTf) (5 mol%), L6 (6 mol%). [h]
Cu(ACN)4(OTf) (3 mol%), L6 (4 mol%), 24 h.
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10.1002/anie.201709511
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COMMUNICATION
Based on previous mechanistic investigations on related
chemistry[9e-f,9h-i,16] and our experimental observations, a plausible
mechanism is proposed in Scheme 2. First, the Cu-complex
activates the alkyne group of lactone B generating a Cu-acetylide
i
species C in the presence of Pr2NEt. Then, isomerization of C
leads to a zwitterionic species D, which is in dynamic equilibrium
with Dʹ providing resonance stabilization. Considering the
thermodynamically stable nature of five-membered lactone,[7] the
back conversion of intermediate D into starting material B through
intermediate C is likely dominant over the nucleophilic attack of
the amine;[8c-e] thus, a hydrogen bond assisted amine attack may
be involved (D to E) enabling the formation of the Cu-bound
product E.[17] Hereafter, the amino acid product is obtained upon
a proton-transfer process with regeneration of the catalyst and
ligand. The asymmetric induction may be rationalized by a well-
established bimetallic model[9e-f,9i,16,18] in which the amine attacks
on the Si-face of the Cu-allenylidene intermediate is favored thus
resulting in the (R)-amino acid as major product.
Figure 2. Scope in amine partners (0.2 mmol scale). Reaction performed under
the optimized conditions (Table 1, entry 23); er values determined by UPC2. [a]
Cu(ACN)4(OTf) (5 mol%), L6 (6 mol%). [b] Cu(ACN)4(OTf) (10 mol%), L6 (11
mol%). [c] 0ºC. [d] Solvent (200 L). [e] Lactam 25 was isolated instead of the
amino acid, see SI for details. [f] The er value was determined by using a chiral
shift reagent, see SI for details.
The pendant alkyne functional group in these amino acid
scaffolds (products 1‒29) creates potential for in vivo bio-
orthogonal reactions through click chemistry.[13] These amino
acids could be easily converted into various valuable
enantioenriched products (Figure 3) such as lactams 30 and 31,
pyrrolidine 32 and triazole 33. Notably, chiral lactams are very
important building blocks in pharmaceutical development (also
see products 11 and 25).[14] The absolute configuration of the
amino acid product (R) was deduced from X-ray diffraction
analysis of lactam 30 (inset in Figure 3).[15]
Scheme 2. Plausible mechanism for the formation of the -amino acid product
from lactone B.
In conclusion, we herein present the first general approach
toward the asymmetric synthesis of ,-disubstituted -amino
acids through Cu-catalyzed ring opening of non-strained lactones
with amine nucleophiles. The protocol features ample reaction
scope, wide functional group tolerance and high asymmetric
induction with typical er values >95:5. The resultant amino acids
can be easily converted into other important building blocks as
exemplified by the synthesis of chiral lactams 30 and 31, and
pyrrolidine 32. Importantly, this procedure is user-friendly (no
special precautions required) and thus marks a great step forward
in the challenging synthesis of chiral -amino acids featuring
quaternary stereocenters.
Figure 3. Synthetic conversions of chiral amino acid 1. Reaction conditions: (i)
KOH, DMSO, rt, 1 h; then MeI, rt, 1 h. (ii) Lindlar catalyst (2 mol%), H2 (balloon),
EtOAc, rt, 30 min. (iii) LiAlH4 (5 equiv), AlCl3 (2 equiv), THF, 0ºC‒rt, 2 h. (iv)
CuTC (10 mol%), BnN3 (1.2 equiv), toluene, rt, 1 h. See SI for details.
Acknowledgements
We thank the CERCA Program/Generalitat de Catalunya, ICREA,
the Spanish MINECO (CTQ-2014-60419-R, Severo Ochoa
Excellence Accreditation SEV-2013-0319, and Severo Ochoa/FPI
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10.1002/anie.201709511
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COMMUNICATION
[7]
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acknowledged for the UPC2 analyses. E. C. Escudero-Adán and
Dr. E. Martin are acknowledged for the X-ray analysis of lactam
30.
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Keywords: amino acids • asymmetric synthesis • copper •
lactam • lactone
[9]
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[18] A non-linear relationship was observed upon using L6 (having different
ee values) and the corresponding enantioenriched amino acid product 1,
suggesting the involvement of a dinuclear copper complex as a key
reactive species, see also Refs. [9e,9f] and supporting information for
details.
[6]
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Entry for the Table of Contents:
COMMUNICATION
Amino acid: The first general
José Enrique Gómez, Wusheng Guo,* Silvia
Gaspa and Arjan W. Kleij*
asymmetric synthesis
of
-
disubstituted -amino acids through
Cu-catalyzed ring opening of non-
strained lactones by amines is
reported. This catalytic system
allows the synthesis of a series of
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highly
enriched -amino acids featuring
quaternary stereocenters with
excellent enantiomeric ratios up to
98:2 and yields of up to 98%.
functionalized
enantio-
Copper-Catalyzed Synthesis of -Amino
Acids Featuring Quaternary Stereocenters
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