Enantiocontrolled synthesis of β-branched α-amino acids by using CuI-catalyzed 1,4-addition of glycine imines to β-substituted gem-diactivated olefins

Article abstract of DOI:10.1002/chem.201100374

Branching out! The catalytic asymmetric conjugate addition of glycinate Schiff bases to β-substituted gem-diactivated Michael acceptors under proton transfer conditions gives a variety of β-branched α-amino acids (see scheme; Dpm=diphenylmethylene, EWG=electron-withdrawing group) with excellent levels of diastereo- (typically syn/anti >90:10) and enantiocontrol (90-99 % ee). Copyright

Full text of DOI:10.1002/chem.201100374

DOI: 10.1002/chem.201100374
Enantiocontrolled Synthesis of b-Branched a-Amino Acids by Using
CuI-Catalyzed 1,4-Addition of Glycine Imines to b-Substituted
gem-Diactivated Olefins
Jorge Hernꢀndez-Toribio, Ramꢁn Gꢁmez Arrayꢀs,* and Juan C. Carretero*[a]
Peptide-based therapies are emerging at an increasingly
rapid pace because peptides offer lower toxicity, show
higher specificity, and demonstrate fewer toxicology issues
compared with small molecule drugs.[1] Modification of
these therapeutics with non-natural amino acids of desired
structural complexity is instrumental to identify target-spe-
cific peptides. Enantiopure b-branched a-amino acids[2] are
highly valuable because the incorporation of the b-substitu-
ent generally imposes severe conformational restraints, thus
allowing the de novo design of peptidic entities with a pre-
determined three-dimensional structure.[3] Because glutamic
acid is the main excitatory amino acid in the central nervous
system, its derivatives have attracted great interest as essen-
tial components of peptides, as well as potential signal medi-
ators of neurotransmission.[4]
The catalytic asymmetric alkylation of Schiff bases of gly-
cine esters is one of the most reliable and straightforward
synthetic routes to optically active a-amino acid deriva-
tives.[5] In particular, the asymmetric conjugate addition of
glycinate imines to a,b-unsaturated carbonyl compounds[6]
(mainly acrylates) is a highly versatile reaction to afford op-
tically active glutamic acid derivatives. However, in contrast
to the number of examples able to provide enantioenriched
a-amino acid derivatives, the application of this methodolo-
gy to the synthesis of b-substituted a-amino acids has
proven frustratingly elusive. In addition to the difficulty of
controlling both diastereo- and enantioselectivity in the two
new contiguous stereogenic centers, a major obstacle is the
much lower reactivity of b-substituted a,b-unsaturated car-
bonyl compounds (e.g., crotonates) compared to simple
acrylates. The use of strong bases to overcome this limita-
tion has been reported to be detrimental to enantiocon-
trol.[6a]
dent for the catalytic asymmetric 1,4-addition of glycine de-
rivatives to b-substituted acrylic acid derivatives.[6b,7] High
yields and high levels of diastereo- and enantiocontrol were
attained with b-alkyl-substituted substrates by using calcium
complexes of chiral deprotonated bisoxazoline (Box) ligands
as catalysts. In spite of these excellent results, there is room
for innovation, especially with regard to the substrate scope
of the electrophile component. For instance, the potential of
this reaction has not been applied so far to Michael-type ac-
ceptors with aromatic substituents at the b-position (i.e., cin-
namates), even though the resulting products would offer
unique opportunities for further functionalization.[8] We dis-
close herein a catalytic enantioselective and diastereoselec-
tive method for the synthesis of b-branched a-amino acids
(up to 99% enantiomeric excess (ee) and 99:1 diastereo-
meric ratio (d.r.)), due to the use of the more reactive gem-
diactivated olefins such as alkylidene malonates.
On the basis of our previous results, which report highly
enantioselective [3+2] cycloaddition[9] and direct Mannich
reaction,[10] the optimization studies focused on testing CuI
or AgI complexes of the Fesulphos ligand (1) in the model
reaction of methyl glycinate benzophenone imine 2 with di-
ethyl 2-benzylidenemalonate (3a) in the presence of several
bases and solvents[11] at room temperature (Table 1). The
first attempts were rather disappointing; a catalytic amount
of Et3N failed to afford the desired Michael adduct after
12 h (Table 1, entries 1 and 2). A very low conversion was
observed with excess (2 equiv) of a stronger base such as
Na2CO3 (Table 1, entries 3 and 4). Gratifyingly, the more
soluble K2CO3 (2 equiv) induced complete conversion with
excellent levels of reactivity and stereocontrol in the case of
using the CuI–Fesulphos couple (syn/anti=93:7, 96% ee,
Table 1, entry 5), yet lower values with the AgI–Fesulphos
complex (Table 1, entry 6). The use of K3PO4 resulted in
lower reactivity than with K2CO3 and provided unpractical
levels of stereocontrol (Table 1, entry 7).[12] These results
suggested that the ionization ability of the base in the reac-
tion medium could play a critical role in the catalytic gener-
ation of the carbon nucleophile through proton transfer. In
accordance with this hypothesis, a substoichiometric amount
(20 mol%) of Cs2CO3, a base that ionizes more readily in
THF than K2CO3,[13] effectively promoted the reaction in 4 h
at room temperature, affording the product syn-4a in high
yield (85%) and excellent diastereo- (syn/anti=96:4) and
enantioselectivity (95% ee, Table 1, entry 8).[13,14]
In a seminal work, the group of Kobayashi recently de-
scribed, to our knowledge, the only existing general prece-
[a] J. Hernꢀndez-Toribio, Dr. R. Gꢁmez Arrayꢀs,
Prof. Dr. J. C. Carretero
Departamento de Quꢂmica Orgꢀnica
Universidad Autꢁnoma de Madrid (UAM)
Facultad de Ciencias, Cantoblanco
28049 Madrid (Spain)
Fax : (+34)91-497-3966
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100374.
6334
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Chem. Eur. J. 2011, 17, 6334 – 6337

COMMUNICATION
Table 1. Optimization of the reaction conditions.
Table 2. Substrate scope of arylidene malonates.[a]
Entry [M][a] Base
[(x) mol%]
t
Yield
syn/anti[c] ee
[%][d]
Entry
R
3
T
t
4
Yield syn/anti[c] ee
[%][b] [%][d]
[h] [%][b]
[8C] [h]
1
CuI
AgI
CuI
AgI
CuI
AgI
CuI
CuI
CuI
CuI
CuI
Et3N (20)
12
12
12
12
5
5
12
4
<5
<5
–
–
–
–
–
–
–
–
1
2
3
4
5
6
7
8
9
Ph
3a RT
4
6
6
6
8
6
6
6
6
4a 85
4b 73
4c 74
4d 81
4e 53
4 f 74
4g 79
4h 70
4i 77
96:4
97:3
97:3
96:4
92:8
96:4
98:2
97:3
96:4
95
96
96
97
90
93
96
93
97
2
Et3N (20)
4-BrC6H4
4-CF3C6H4
4-OMeC6H4
2,5-(OMe)2C6H3 3e
2-MeC6H4
2-BrC6H4
3b
3c
3d
0
0
0
0
0
3
4
5
6
7
8
9
Na2CO3 (200)
Na2CO3 (200)
K2CO3 (200)
K2CO3 (200)
K3PO4 (200)
Cs2CO3 (20)
NBu4OBz (20)
<15
<15
100 (82) 93:7
90 (68)
80 (45)
100 (85) 96:4
70
85 (71)
100 (72) 95:5
96
76
60
95
–
87:13
88:12
3 f
3g RT
3h
3i
2-Naphthyl
1-Naphthyl
0
0
12
82:18
93:7
10
11
N
95
96
[a] Conditions:
2 (0.1 mmol), [CuACHTNUTGNRUEGN(CH3CN)4]PF6 (0.005 mmol), (R)-1
4
(0.005 mmol), Cs2CO3 (0.020 mmol), 3 (0.11 mmol) and THF (1 mL).
[b] Isolated product yield. [c] Determined by NMR spectroscopy (inte-
gration of the CO2Me signal of each diastereomer) and/or HPLC. [d] De-
termined by chiral stationary phase HPLC analysis (syn-4).
ACHTUNGTRENNUNG
[a] CuI =[Cu(CH3CN)4]PF6; AgI =AgOAc. [b] Conversion yield obtained
from NMR data; the yield of the isolated product is given in parenthesis.
[c] Determined by 1H NMR spectroscopy (integration of the CO2Me
signal of each diastereomer) and/or HPLC. [d] Determined by chiral sta-
tionary phase HPLC analysis.
Organic ionic bases,[13] composed of ammonium cations
and basic anions, also allowed the model reaction to be per-
formed in good conversions with 20 mol% of base (Table 1,
entries 9–11). However, only the Et4NHCO3 (Table 1,
entry 11) led to comparable levels of reactivity (72% yield
in 4 h) as well as diastereo- (syn/anti=95:5) and enantiose-
lectivity (96% ee) to those previously attained with Cs2CO3.
Nevertheless, the combination of [CuACHTUNGTRNEUNG(CH3CN)4]PF6/(R)-1
Scheme 1. Products from substrates 3j–3m containing challenging hetero-
aryl substituents; the reaction conditions were similar to those shown in
Table 2 (see also the representative procedure in the Experimental Sec-
tion).
(5 mol%)[14] and Cs2CO3 (20 mol%) was chosen as optimal
because a cleaner reaction was observed, leading to a better
product yield.[15]
The substrate scope and limitations of this method were
next examined. As shown in Table 2, a wide range of aryl-
idene malonates with either electron-donating or electron-
withdrawing substituents at the ortho-, meta-, or para posi-
tion of the aromatic ring (substrates 3a–3i) reacted with 2
to afford the expected products 4a–4i with excellent dia-
stereo- (syn/anti=92:8–97:3) and enantioselectivities
(ꢀ90% ee).[16] Even the encumbered and highly electron-
rich substrate 3e, with two methoxy substituents at both
ortho- and meta positions, proved to be highly reactive
(Table 2, entry 5).
The method was also tolerant to the incorporation of a
variety of heteroaromatic substituents (Scheme 1), including
challenging substrates with basic pyridyl groups, such as 3l
and 3m, to give products 4l and 4m. This result is especially
remarkable given that copper-based catalysts frequently fail
with substrates containing pyridyl substituents (and related
groups) likely due to tight binding of the substrate with the
catalyst.
selectivity (Scheme 2). Both the relative and absolute con-
figuration of the Michael adducts syn-4 were unequivocally
established by single crystal X-ray diffraction analysis of the
sulfur-containing derivative syn-4j.[16,17]
Encouraged by the high degree of stereochemical fidelity
shown by this catalyst system, we sought to explore other
gem-diactivated olefins. In this regard, bisACTHNUGRTENUNG(sulfonyl) ethyl-
enes offer an attractive alternative to b-alkyl a-amino acid
derivatives, provided that the sulfonyl groups can potentially
be easily removed from the resulting Michael adducts. As
depicted in Table 3, the reaction of 2 with electronically and
sterically varied 2-aryl-substituted 1,1-bisACTHNUTRGNE(NUG sulfonyl) ethylenes
Alkylidene malonates 3n and 3o also participated suc-
cessfully in the reaction, to give the corresponding b-alkyl-
substituted a-amino esters 4n and 4o with excellent asym-
metric induction (96–98% ee), albeit with a lower diastereo-
Scheme 2. Conjugate addition of alkylidene malonates.
Chem. Eur. J. 2011, 17, 6334 – 6337
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J. C. Carretero, R. Gꢁmez Arrayꢀs, and J. Hernꢀndez-Toribio
Table 3. b-Substituted 1,1-bisACHTUNGTRNEUNG
(sulfonyl)ethylenes as electrophiles.[a]
Entry Ar
5
T
t
6
Yield syn/anti[c] ee
[%][b] [%][d]
[8C] [h]
1
2
3
4
5
Ph
4-FC6H4
5a À20 12 6a 73
5b À20 12 6b 74
99:1
95:5
95:5
99:1
98:2
97
95
95
94
95
4-OMeC6H4 5c À40 16 6c 65
2-Naphthyl
2-Furyl
5d À40 24 6d 81
5e À20 12 6e 79
[a] Conditions:
2 (0.1 mmol), [CuACHTUTGNENRNUG
(0.005 mmol), Cs2CO3 (0.02 mmol),
5
[b] Isolated product yield. [c] Determined by NMR spectroscopy (inte-
gration of the CO2Me signal of each diastereomer) and/or HPLC analy-
sis. [d] Determined by chiral stationary phase HPLC analysis (syn-6).
5a–5e under the optimized reaction conditions proceeded
very efficiently, leading to the desired adducts 6a–6e in
good yields (65–81%), excellent syn-diastereoselectivity
(syn/anti ꢀ95:5), and asymmetric induction (ꢀ94% ee).[16]
The absolute and relative configuration of syn-6a was un-
equivocally established by X-ray diffraction analysis.[18]
The versatility of the b-branched a-amino acid derivatives
as valuable chiral building blocks was demonstrated in the
transformations shown in Scheme 3. b-Substituted glutamic
acid derivatives 4 were easily converted into densely func-
tionalized pyroglutamic acid derivatives 7 in good yields
upon imine hydrolysis under mild acidic conditions; subse-
quent spontaneous cyclization of the free amine afforded
the corresponding g-lactam (Scheme 3a). Remarkably, very
high stereocontrol was observed in the new stereogenic
center generated at C-a (d.r. 95:5–98:2).[19] As shown in
Scheme 3b, this procedure is also amenable to pyroglutamic
acid derivatives with the two ester groups orthogonally pro-
tected. The conjugate addition of the benzyl glycinate Schiff
base 8 to the arylidenemalonate 3d led to the b-(4-methoxy-
phenyl) a-amino acid derivative 4p with excellent levels of
diastereo- (syn/anti=95:5) and enantiocontrol (98% ee),
which was subsequently converted to the pyroglutamic die-
ster 7p upon acid-promoted cyclization. Selective benzylic
ester deprotection was easily performed under typical hy-
drogenolysis conditions, affording the free carboxylic acid 9,
which is suitable for direct use in peptide synthesis.
Scheme 3. Synthetic transformations of the products; AIBN=azobisiso-
butyronitrile.
ductive desulfonylation (Mg, MeOH) of the a-amino acid
derivative syn-6a led to the corresponding b-methylphenyl-
alanine derivative 11 in 62% yield.
In summary, an efficient asymmetric protocol for the CuI-
catalyzed conjugate addition of glycinate imines to b-substi-
tuted a,b-unsaturated gem-diactivated olefins under catalyt-
ic Brønsted base conditions has been developed. Glutamic,
pyroglutamic, and other b-branched a-amino acid deriva-
tives were readily obtained with high levels of both syn-dia-
stereoselectivity and enantiocontrol (90–99% ee), especially
those with a b-aromatic substituent. The use of CuI–Fesul-
phos complexes as Lewis acid catalysts proved to be crucial
for achieving homogeneously high values of diastereo- and
enantioselectivity. Further studies towards expanding the
scope at the Michael acceptor and developing synthetic ap-
plications are ongoing in our laboratory.
The ortho-bromo-substituted derivative 4g offered an al-
ternative cyclization strategy based on the intramolecular
free radical-mediated aryl amination.[20] The aryl radical,
À
generated from homolysis of the C Br bond, undergoes cyc-
lization to the nitrogen of the imine moiety to give the opti-
cally active 2,3-disubstituted indoline 10 in a protected form
(N-benzhydryl group, Scheme 3c). This methodology may
find useful applications in enantioselective natural product
synthesis, given the wide abundance of the indoline sub-
structure in a variety of bioactive alkaloids.[20b] On the other
hand, sulfonylated amino acid derivatives 6 also allow op-
portunities for further derivatization (Scheme 3d). The re-
Experimental Section
Representative procedure: The reaction of N-(diphenylmethylene)glycine
methyl ester (2) with diethyl 2-benzylidenemalonate (3a) to afford
(2R,3S) 1,1-diethyl 3-methyl 3-(diphenylmethyleneamino)-2-phenylpro-
pane-1,1,3-tricarboxylate (syn-4a) was performed as follows: To a round-
6336
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Chem. Eur. J. 2011, 17, 6334 – 6337

Enantiocontrolled Synthesis of b-Branched a-Amino Acids
bottom flask containing a solution of Fesulphos ligand (R)-1 (2.3 mg,
COMMUNICATION
[9] a) S. Cabrera, R. Gꢁmez Arrayꢀs, J. C. Carretero, J. Am. Chem. Soc.
2005, 127, 16394; b) S. Cabrera, R. Gꢁmez Arrayꢀs, B. Martꢂn-
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[11] CH2Cl2 gave slightly poorer results than THF, whereas no reaction
was observed in toluene or CH3CN (see the Supporting Informa-
tion).
0.005 mmol) and [CuACHTUNGTRENNUNG(CH3CN)4]PF6 (1.9 mg, 0.005 mmol) in THF
(0.5 mL), under nitrogen atmosphere at room temperature, were succes-
sively added a solution of 2 (25.3 mg, 0.1 mmol) in THF (0.5 mL),
Cs2CO3 (6.5 mg, 0.02 mmol) and a solution of 3a (27.3 mg, 0.11 mmol) in
THF (0.5 mL). The mixture was stirred at room temperature for 4 h,
then filtered through celite, and the filtrate was then concentrated to dry-
ness. The residue was analyzed by 1H NMR spectroscopy to determine
the diastereomeric ratio (syn/anti=96:4) and then purified by flash chro-
matography (n-hexane/EtOAc 4:1) to afford syn-4a as a colourless oil;
yield: 42.6 mg (85%, syn/anti=96:4). See the Supporting Information for
spectroscopic data.
[12] The use of a very strong base such as KtBuO (2 equiv) resulted in
complete conversion after 4 h at RT, although with poor diastereose-
lectivity (syn/anti=76:24) and no asymmetric induction.
Acknowledgements
This work was supported by the Ministerio de Ciencia e Innovaciꢁn
(MICINN, CTQ2009–07791) and the Consejerꢂa de Educaciꢁn de la Co-
munidad de Madrid (programme AVANCAT, S2009/PPQ-1634). J.H.T.
thanks the MICINN for a predoctoral fellowship.
[13] Electric conductivities of various inorganic and organic bases, direct-
ly related to their ionization ability, has been measured in organic
solvents to explain their different performance in metal-catalyzed
cross-coupling reactions: C.-T. Yang, Y. Fu, Y.-B. Huang, J. Yi, Q.-X.
Guo, L. Liu, Angew. Chem. 2009, 121, 7534; Angew. Chem. Int. Ed.
2009, 48, 7398. Cs2CO3 shows slightly higher conductivity in THF
than K2CO3 or Na2CO3 or Na3PO4.
Keywords: amino acids · asymmetric catalysis · conjugate
addition · copper · glycinate imines
[14] Lowering the Fesulphos–CuI loading from 5 mol% to 2.5 mol%
(0.5 mmol scale) led to a slower reaction (12 h, RT) but still good
yield (71%), as well as good diastereo- (syn/anti=94:6) and enan-
tiocontrol (91% ee).
[1] P. M. Watt, Nat. Biotechnol. 2006, 24, 177.
[15] Screening of a number of other metal–chiral ligand combinations
led to much poorer reactivity and/or diastero- and enantiocontrol,
whereas tuning the steric and electronic properties of the glycinate
pronucleophile by modification of the ester and imine moieties did
not improve the results obtained with substrate 2 (see the Support-
ing Information for these studies). For the beneficial effect of alter-
ing the steric or electronic properties of the glycinate component in
the reactivity and stereoselectivity, see: a) M. M. Salter, J. Kobaya-
shi, Y. Shimizu, S. Kobayashi, Org. Lett. 2006, 8, 3533; b) S. Kobaya-
shi, R. Yazaki, K. Seki, Y. Yamashita, Angew. Chem. 2008, 120,
5695; Angew. Chem. Int. Ed. 2008, 47, 5613. See also referen-
ce [10b].
[16] The absolute configuration of the Michael adducts syn-4 and syn-6
can be rationalized assuming the participation of a well defined Fes-
ulphos–CuI-enolate complex as active nucleophile catalysts (see the
Supporting Information for a tentative stereochemical model). For
computational studies on this type of intermediate, see ref. [9b].
[17] CCDC-794978 (unit cell parameters: space group P212121: a=
10.4954(3), b=13.5389(4), c=18.2447(5) ꢇ) contains the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[18] CCDC-794979 (unit cell parameters: space group P212121: a=
9.9427(3), b=16.9270(4), c=18.6029(5) ꢇ) contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[19] The stereochemistry of the products of type 7 was established by
NMR spectroscopy and by correlation with a known derivative (see
the Supporting Information).
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Received: February 2, 2011
Published online: April 27, 2011
Chem. Eur. J. 2011, 17, 6334 – 6337
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6337