A facile Cu(I)/BINAP-catalyzed asymmetric approach to functionalized pyroglutamate derivatives bearing a unique quaternary stereogenic center

Article abstract of DOI:10.1021/ol202326j

A direct and facile access to enantioenriched pyroglutamate derivatives bearing a unique quaternary stereogenic center has been developed via Cu(I)/BINAP-catalyzed tandem Michael addition-elimination of α-substituted aldimino esters with Morita-Baylis-Hil

Full text of DOI:10.1021/ol202326j

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5600–5603
A Facile Cu(I)/BINAP-Catalyzed
Asymmetric Approach to Functionalized
Pyroglutamate Derivatives Bearing a
Unique Quaternary Stereogenic Center
Huai-Long Teng,† Fei-Long Luo,† Hai-Yan Tao,† and Chun-Jiang Wang*,†,‡
College of Chemistry and Molecular Sciences, Wuhan University, 430072, China, and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Shanghai, 230012, China
cjwang@whu.edu.cn
Received August 27, 2011
ABSTRACT
A direct and facile access to enantioenriched pyroglutamate derivatives bearing a unique quaternary stereogenic center has been developed via
Cu(I)/BINAP-catalyzed tandem Michael additionꢀelimination of R-substituted aldimino esters with MoritaꢀBaylisꢀHillman (MBH) carbonates
followed by a deprotection/lactamization protocol, which performs well over a broad scope of substrates and provides biologically active
pyroglutamate derivatives in good yields and excellent enantioselectivities.
Optically active nonproteinogenic R,R-disubstituted R-
amino acids and derivatives1 have played a special role in
the design of peptides with enhanced properties due to the
unique stereochemically stable quaternary carbon center.2
When incorporated into peptides, R,R-disubstituted R-
amino acids confer increased stability under physiological
conditions and stabilize secondary structure motifs, which
eventually afford useful information for the elucidation of
an enzymatic mechanism.2 Pyroglutamates bearing a un-
ique quaternary stereogenic center, as a particular class of
nonproteinogenic R,R-disubstituted R-amino acid deriva-
tives, are prevalent scaffolds that serve as the core struc-
tures of natural alkaloids and bioactive molecules.3 For
example, oxazolomycin A and lactacystin were isolated
from the fermentation broth of Streptomyces sp,4 and
† Wuhan University.
‡ State Key Laboratory of Organometallic Chemistry.
(1) For recent reviews, see: (a) Soloshonok, V. A.; Sorochinsky, A. E.
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5, 406. (c) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127.
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r
10.1021/ol202326j
Published on Web 09/22/2011
2011 American Chemical Society

salinosporamide A was isolated from a marine actinomy-
cete Salinispora tropica5(Figure 1). These optically active
pyroglutamates bearing a quaternary stereogenic center
exhibit a broad array of important biological and poten-
tially valuable pharmaceutical properties, which have
inspired organic chemists to pursue efficient synthetic
methods for those compounds in recent years.6
Scheme 1. Tandem MA-Elimination/Deprotection/Lactamiza-
tion (3 Steps) for the Construction of Functionalized Pyroglu-
tamates Bearing a Unique Quaternary Stereogenic Center
available and cost-efficient imino ester derived from alde-
hyde and glycine ester, which demonstrates the R-proton
of the in situ generated R-substituted aldimino ester is still
acidic enough to be deprotonated, enabling the subsequent
second alkylation,9,10 we envisioned that the enantioen-
riched pyroglutamate derivatives bearing a quaternary
stereogenic center11 could be achieved through employing
R-substituted R-amino acids derived aldimino esters as the
nucleophile and MoritaꢀBaylisꢀHillman carbonates12 as
the Michael acceptors in the presence of an appropriate
chiral catalyst and base. Herein, we present the first
asymmetric synthesis of pyroglutamates containing a
unique quaternary stereogenic center via Cu(I)/(S)-BI-
NAP-catalyzed tandem Michael additionꢀelimination of
the R-substituted aldimino esters with MBH carbonates
followed by deprotection/lactamization.
In view of the above-mentioned literature work and
hypothesis, we initially examined the reactivity of MBH
carbonate 1a0 with (()-phenylalanine-derived aldimino
ester 2a in the presence of 10 mol % of the AgOAc/PPh3
complex as the catalyst and 2 equiv of K2CO3 as the base
in DCM at rt. To our delight, the tandem Michael addi-
tionꢀelimination reaction proceeded smoothly to afford
Figure 1. Representatives of biologically active pyroglutamates
bearing a quaternary stereogenic center.
Although there are elegant and creative strategies to-
ward the construction of a pyroglutamate architecture,6
the directly catalytic asymmetric approach to access opti-
cally pure pyroglutamate bearing a quaternary stereogenic
center has met with little success.7 To the best of our know-
ledge, only one noncatalytic and nonasymmetric example
has been reported for the synthesis of pyroglutamate
derivatives containing a quaternary stereogenic center via
stoichiometric LiHMDS-mediated tandem Michael addi-
tionꢀelimination of R-substituted aldimino esters with
MoritaꢀBaylisꢀHillman (MBH) carbonates followed by
a deprotection/lactamization protocol8(Scheme 1). There-
fore, the development of a catalytic asymmetricmethod for
the facile synthesis of enantioenriched pyroglutamate de-
rivatives bearing a unique quaternary stereogenic center is
in great demand.
Inspired by Maruoka’s excellent work on the efficient
synthesis of enantioenriched R,R-disubstituted R-amino
acids via PTC-catalyzed double alkylation of the easily
(9) (a) Ooi, T.; Taketuchi, M.; Kameda, M.; Maruoka, K. J. Am. Soc.
Chem. 2000, 122, 5228. (a) Ooi, T.; Arimura, Y.; Hiraiwa, Y.; Yuan, L.;
Kano, T.; Inoue, T.; Matsmoto, J.; Maruoka, K. Tetrahedron: Asym-
metry 2006, 17, 603. (b) O’Donnell, M. J; Wu, S. Tetrahedron: Asym-
metry 1992, 3, 591. (c) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron
Lett. 1999, 40, 8671.
(10) For recent representative excellent reviews on asymmetric
PTC, see: (a) Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007,
1487. (b) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222.
(c) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656. (d) O’Donnell,
M. J. Acc. Chem. Res. 2004, 37, 506. (e) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518.
(5) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355.
(6) For reviews, see: (a) Moore, B. S.; Guilder, T. A. M. Angew.
Chem., Int. Ed. 2010, 49, 9346. (b) Shibasaki, M.; Kanai, M.; Fukuda, N.
Chem.;Asian J. 2007, 2, 20. (c) Masse, C. E.; Morgan, A. J.; Adams, J.;
Panek, J. S. Eur. J. Org. Chem. 2000, 2513. For recent examples, see:
(d) Onyango, E. O.; Tsurunoto, J.; Imai, N.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Angew. Chem., Int. Ed. 2007, 46, 6703. (e) Bulger, P. G.;
Moloney, M. G.; Trippier, P. C. Org. Biomol. Chem. 2003, 1, 3726.
(f) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2000, 2, 1987. (g) Yamada,
T.; Sakaguchi, K.; Shinada, T.; Ohfune, Y.; Soloshonok, V. A. Tetrahe-
dron: Asymmetry 2008, 19, 2789. (h) Goswami, L. N.; Srivastava, S.;
Panday, S. K.; Dikshit, D. K. Tetrahedron Lett. 2001, 42, 7891.
(7) For the synthesis of glutamates or pyroglutamate derivatives
containing a tertiary stereogenic center, see: (a) Ramachandran, P. V.;
Madhi, S.; Bland-Berry, L.; Reddy, M. V. R.; O’Donnell, M. J. J. Am.
Chem. Soc. 2005, 127, 13450. (b) Chen, C.-G..; Hou, X.-L.; Pu, L. Org.
Lett. 2009, 11, 2703.
(11) For recent reviews, see: (a) Quaternary Stereocenters: Challenges
and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-
VCH: Weinheim, 2005. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(12) For recent reviews, see: (a) Wei, Y.; Shi, M. Acc. Chem. Res.
2010, 43, 1005. (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem.
Rev. 2010, 110, 5447. (c) Declerck, V.; Martinez, J.; Lamaty, F. Chem.
Rev. 2007, 109, 1. (d) Ciganek, E. In Organic Reactions; Paquette, L. A.,
Ed.; Wiley: New York, 1997; Vol. 51, pp 201ꢀ350.
(13) It seems that the first step proceeds by way of tandem Michael
additionꢀelimination due to no reaction occurring when the aldimino
ester 2a reacted with CHdCHCH2OAc under the same reaction
conditions.
(8) Tekkam, S.; Alam, M. A.; Jonnalagadda, S. C.; Mereddy, V. R.
Chem. Commun. 2011, 47, 3219.
Org. Lett., Vol. 13, No. 20, 2011
5601

the instable intermediate 4-benzylidene glutamic acid
derivative 3a,8,13 and no reaction occurred without the
AgOAc/PPh3 complex (Scheme 2). Cleavage of the imino-
protecting group of 3a under acidic conditions followed by
efficient lactamization delivered (E)-4-benzylidene pyro-
glutamate 3aa in 58% yield with a >10:1 diastereomeric
ratio favoring the E diastereomer, which indicated that
R-substituted aldimino esters could be applied as efficient
nucleophiles for the catalytic asymmetric construction of
pyroglutamate derivatives bearing a quaternary stereo-
genic carbon center.11
The effect of the leaving group of carbonate 1 was also
investigated. Replacing the acetoxyl group with the bulky
tert-butoxycarbonyloxyl group gave rise to higher enan-
tioselectivity without loss of reactivity (entries 4 and 11).
Cu(OTf)2 could also be used in this transformation albeit
with a little lower ee (entry 12). Reducing the reaction
temperature from rt to 0 °C led to complete reaction with
96% ee (entry 13). The catalyst loading was successfully
reduced to 5 mol %, with comparable results achieved with
an extended reaction time (entry 14).
Table 1. Screening Studies for Asymmetric Construction of
Funtionalized Pyroglutamate Derivatives Bearing a Quaternary
Stereogenic Centera
Scheme 2. AgOAc/PPh3-Catalyzed Tandem MA-Elimination/
Deprotection/Lactamization (Overall 3 Steps)
t
yield ee
entry
L
[M]
1
base
solvent (°C) (%)b (%)c
Encouraged by this promising result, different metal
salts and commercially available chiral ligands were sub-
sequently examined to establish optimal reaction condi-
tions, and the representative results are summarized in
Table 1. Combined with Monophos, both AgOAc and
Cu(CH3CN)4BF4 salts successfully promote the tandem
Michael additionꢀelimination of 2a with MBH carbonate
1a0, and (E)-pyroglutamate 3aa was achieved in 11%
and 29% ee, respectively, with an excellent E/Z ratio
through the subsequent deprotection/lactamization proto-
col (entries 1 and 2). A further survey of ligands revealed
that the bisphosphine ligand was more efficient than the
monophosphine ligand and the enantioselectivity was
greatly affected by the substituted groups on the P-atom
and the chiral backbone of the chiral ligands. With Cu-
(MeCN)4BF4 as the metal precursor, BINAP gave the best
results in terms of the reaction rate and enantioselectivity
among the tested bisphosphine ligands (entries 3 and 4). A
little lower enantioselectivity was observed when the phe-
nyl group on the P-atom of BINAP was replaced by the
bulky p-tolyl group (L3) (entry 5). The enantioselectivity
and catalytic ability decreased remarkably when the axial
binaphthyl backbone of bisphosphine ligand was replaced
by the axial biphenyl backbone ligand (L4 and L5) (entries
6 and 7). The bulkier and electron-donating biphenyl
ligand (R)-DTBM-segphos (L6) was totally inactive
(entry 8). Highly electron-donating P-chiral trialkyl phos-
phine ligand TangPhos (L7) was also tested in this trans-
formation affording the desired product with 68% ee
(entry 9). The solvent study revealed CH2Cl2 was the best
in terms of the yield and enantioselectivity. Further exam-
ination of the base disclosed that a high yield could be
obtained with Cs2CO3 while organic bases such as Et3N or
DBU were not suitable for this reaction (entry 10).
1
L1 AgOAc
L1 CuBF4
L2 AgOAc
L2 CuBF4
L3 CuBF4
L4 CuBF4
L5 CuBF4
L6 CuBF4
L7 CuBF4
L2 CuBF4
L2 CuBF4
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
1a0 K2CO3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
43
58
75
78
69
73
74
ꢀ
11
29
66
90
87
79
78
ꢀ
2
3
4
5
6
7
8
9
30
75
78
75
72
55
68
90
92
88
96
94
10
11
12
1a0 Cs2CO3 DCM
1a Cs2CO3 DCM
L2 Cu(OTf)2 1a Cs2CO3 DCM
13d L2 CuBF4
14e
L2 CuBF4
1a Cs2CO3 DCM
1a Cs2CO3 DCM
0
a Tandem Michael additionꢀelimination reactions (the first step)
were carried out with 0.3 mmol of 2a and 0.36 mmol of 1 in 2 mL of sol-
vent for 20 h. CuBF4 = Cu(CH3CN)4BF4. b Isolated yield of the overall
three steps. c Determined by chiral HPLC analysis. d In 36 h. e 5 mol %
catalyst loading, 48 h.
The scope and generality of this catalytic system with
regard to MBH carbonates and R-substituted aldimino
esters were investigated under the optimized experimental
conditions. As shown in Table 2, a series of representative
MBH carbonates derived from aromatic aldehydes, which
5602
Org. Lett., Vol. 13, No. 20, 2011

(entries 10 and 11). Notably, the MBH carbonates 1lꢀ1n
from aliphatic cyclohexanecarbaldehyde, propionalde-
hyde, and paraformaldehyde also worked well in this
sequential transformation, and the corresponding products
could be obtained in remarkably high enantioselectivity
and acceptable yields although a little lower E/Z ratio14
was noticed for 3la and 3ma (entries 12ꢀ14). To further
expand the synthetic utility of this transformation for the
construction of pyroglutamates bearing a unique quatern-
ary stereogenic center, the aldimino ester derived from
other R-substituted amino acids has also been examined.
Under the optimal reaction conditions, an acceptable yield
and excellent enantioselectivity were uniformly observed
for the aldimino esters derived from (()-phenylalanine
and (()-leucine (Table 2, entries 15 and 19), which bear a
branchedsubstituent at theR-position of the corresponding
aldimino esters. A lower reactivity by (()-2-phenylglycine
derived aldimino ester 2c was likely due to the unfavored
steric hindrance of the phenyl group at the R-position (entry
16). Yet, ∼80% ee was achieved for the aldimino esters
derived from (()-2-aminopentanoic (entry 17) and (()-2-
amino-hexanoic acid (entry 18) bearing a linear substituent
at the R-position, indicating that to some extent the steric
congestion around the nucleophilic attack position of the
aldimino ester was beneficial to the enhancement of asym-
metric induction. (()-Leucine tert-butyl ester and pheny-
lalanine benzyl ester derived aldimino ester also worked
well in this tandem reaction providing the desired products
in 99% and 95% ee, respectively (entries 19 and 20). For-
tunately, all the products are solid and enantioenriched
compounds can be easily obtained by simple recrystalliza-
tion of the crude products (entries 17 and 18).
Table 2. Substrates Scope for Asymmetric Construction of
Funtionalized Pyroglutamate Derivatives Bearing a Quaternary
Stereogenic Centera
2
entry
R1
Ph (1a)
R2
R3 prod yield (%)b ee (%)c,d
1
Bn 2a Me 3aa
72
58
65
73
67
75
65
63
67
71
65
46
50
62
58
40
63
56
65
65
96
2
p-MeO-Ph (1b) Bn 2a Me 3ba
m-MeO-Ph (1c) Bn 2a Me 3ca
93
3
94
4
o-Cl-Ph (1d)
m-Cl-Ph (1e)
p-Cl-Ph (1f)
p-F-Ph (1g)
p-Br-Ph (1h)
Bn 2a Me 3da
Bn 2a Me 3ea
Bn 2a Me 3fa
Bn 2a Me 3ga
Bn 2a Me 3ha
94
5
93
6
94
7
94
8
94
9
2-Naphthyl (1i) Bn 2a Me 3ia
91
10
11
2-thienyl (1j)
2-furyl (1k)
Bn 2a Me 3ja
Bn 2a Me 3ka
Bn 2a Me 3la
Bn 2a Me 3ma
Bn 2a Me 3na
iBu 2b Me 3ab
Ph 2c Me 3ac
Pr 2d Me 3ad
Bu 2e Me 3ae
iBu 2f tBu 3af
Bn 2g Bn 3ag
94
94
12e Cy (1l)
13f Et (1m)
94
95
14
15
16
17
18
19
20
H (1n)
93
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
97
89
77(99)
82(99)
99
95
In conclusion, we have successfully developed the first
catalytic asymmetric method for the rapid construction of
pyroglutamate derivatives bearing a unique quaternary
stereogenic center via Cu(I)/(S)-BINAP-catalyzed tandem
Michael additionꢀelimination of R-substituted aldimino
esters with MoritaꢀBaylisꢀHillman carbonates followed
by a simple deprotection/lactamization protocol. This cat-
alytic system performs well over a broad scope of sub-
strates and provides biologically active pyroglutamates in
good yields and excellent enantioselectivities. The ready
availability of the starting materials and the great impor-
tance of the enantioenriched products make the current
methodology particularly interesting in synthetic chemis-
try. Further investigations of the substrate scope and the
limitation of this methodology are ongoing.
a Tandem MA-elimination reaction (the first step) was carried out
with 0.3 mmol of 2 and 0.36 mmol of 1 in 2 mL of DCM. b Isolated yield
for the overall three steps. c Determined by HPLC analysis. The number
in bracket is the ee after recrystallization. d The configuration of 3ha was
determined to be S according to the X-ray analysis (see Supporting
Information for more details). e 10:1 E/Z ratio. f 6:1 E/Z ratio.
bear electron-rich (Table 2, entries 2 and 3), -neutral (entries 1
and9), or-deficientgroups(entries4ꢀ8) on the phenyl ring,
reacted smoothly with N-benzylidene-phenylalanine methyl
ester 2a followed by subsequent deprotection/lactamiza-
tion to afford the desired E-glutamates (3aa-3ia) in good
yields (58ꢀ72% for overall 3 steps) and excellent selectiv-
ities (91ꢀ96% ee, >19:1 dr) (entries 1ꢀ9). It appears that
the position and the electronic property of the substituents
on the aromatic rings have very limited effect on the
enantioselectivities. Sterically hindered ortho-chloro sub-
stituted MBH carbonates 1d work well in this transforma-
tion producing 3da with 73% yield and 94% ee (entry 4). It
is noteworthy that MBH carbonates 1j and 1k derivedfrom
hetero 2-furyl and 2-thienyl aldehyde were tolerated in this
transformation leading to (E)-3ja and (E)-3ka with 94% ee
Acknowledgment. This work is supported by the NSFC
(20972117), NCET-10-0649, IRT1030, 973 Program
(2011CB808600), and the Fundamental Research Funds
for the Central Universities.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(14) All these compounds could be readily purified by column
chromatography to afford the pure (E)-pyroglutamates.
Org. Lett., Vol. 13, No. 20, 2011
5603