A powerful synergistic effect for highly efficient diastereo- and enantioselective phase-transfer catalyzed conjugate additions

Article abstract of DOI:10.1039/c0cc04321d

An efficient, catalytic, diastereo- and enantioselective conjugate addition of N-(diphenylmethylene)glycine tert-butyl ester to β-aryl substituted enones was realized in the presence of 1 mol% of newly desired dinuclear N-spiro-ammonium salts, affording f

Full text of DOI:10.1039/c0cc04321d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A powerful synergistic effect for highly efficient diastereo- and
enantioselective phase-transfer catalyzed conjugate additionsw
Ming-Qing Hua, Lian Wang, Han-Feng Cui, Jing Nie, Xiao-Ling Zhang and Jun-An Ma*
Received 9th October 2010, Accepted 2nd November 2010
DOI: 10.1039/c0cc04321d
An efficient, catalytic, diastereo- and enantioselective conjugate
addition of N-(diphenylmethylene)glycine tert-butyl ester to
b-aryl substituted enones was realized in the presence of
1 mol% of newly desired dinuclear N-spiro-ammonium salts,
affording functionalized a-amino acid derivatives in 57–98%
yields with high diastereoselectivity (up to 99 : 1 dr) and
enantioselectivity (up to 96.5 : 3.5 er).
Fig. 1 Designing principle for synergistic asymmetric bifunctional
Catalytic asymmetric carbon–carbon bond forming reactions
using glycine imine esters as nucleophiles have been intensively
studied and have evolved into a powerful tool for the synthesis
of various natural and non-natural amino acids following the
seminal work of O’Donnell.1 Among them, catalytic asymmetric
conjugate addition of glycine imine esters to a,b-unsaturated
carbonyl compounds provides expedient access to useful multi-
functional chiral building blocks.2 Despite recent impressive
progress in organo- and metal-catalyzed asymmetric
1,4-additions of glycine imine esters to many a,b-unsaturated
carbonyl compounds,3,4 the use of b-aryl substituted
a,b-unsaturated carbonyl compounds as the Michael acceptors
of glycine imine esters is extremely rare. DBU and achiral phase-
transfer catalyst promoted conjugate addition of glycine imines
to cinnamate derivatives have been recently reported (eqn (1)).5
However, to date there are no successful examples of direct
catalytic asymmetric conjugate additions of glycine imines to
b-aryl substituted Michael acceptors. This is probably due to the
fact that such as a reaction would be kinetically slow as it
involves two bulky reactants to give an adduct possessing vicinal
tertiary centers, and simultaneous control of diastereo- and
enantioselectivity could be extremely challenging. Attempts to
use several well documented and highly reactive phase-transfer
catalysts such as 11b and 21c were unsuccessful in the reaction of
N-(diphenylmethylene)glycine tert-butyl ester to chalcone and
low ee’s and/or yields were observed.6
phase-transfer catalysis of conjugate addition by dinuclear chiral
N-spiro-ammonium salts.
We surmised that a simultaneous, ideally synergetic, activation
of both the nucleophile and the electrophile is necessary for this
particularly challenging reaction. Therefore, a chiral dinuclear
phase-transfer catalyst containing two quaternary ammonium
units could provide a potential solution.7 As depicted in Fig. 1,
one quaternary ammonium moiety in the dinuclear phase-
transfer catalyst stabilizes the anionic enolate nucleophile, while
the second ammonium unit, if judiciously annexed by means of a
flexible linker, would simultaneously activate the chalcone via
electrostatic interaction with its carbonyl group. It is further
anticipated that the chiral bifunctional catalyst would facilitate
the reaction in a synergistic manner by bringing the two reaction
partners in close proximity and coaxing them into favorable
orientations. In this communication, we establish that chiral
Department of Chemistry, Tianjin University, Tianjin 300072, China.
E-mail: majun_an68@tju.edu.cn; Fax: +86 22 27403475;
Tel: +86 22 27402903
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 742621. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc04321d
Scheme 1 Dinuclear N-spiro-ammonium salts 6 as chiral catalysts for
the conjugate addition of 3 to b-aryl substituted enones 4.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1631–1633 1631

View Article Online
Table 1 Conjugate addition of 3 to chalcone 4a catalyzed by 6
The synthetic versatility of the resulting adducts 5 was demon-
strated by their conversion to a number of enantiomerically
enriched proline and indoline-2-carboxylic acid derivatives
possessing multiple stereocenters.
Entry
PTC
T/1C
Solvent
Yielda (%)
Drb
Erc
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6f
6f
6f
6f
6f
6f
6f
6f
6f
10
10
10
10
10
10
10
10
10
10
10
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
98
98
98
95
96
98
96
90
93
98
98
72
98
98
98
97 : 3
97 : 3
97 : 3
97 : 3
97 : 3
96 : 4
96 : 4
96 : 4
98 : 2
97 : 3
98 : 2
98 : 2
97 : 3
97 : 3
95 : 5
69 : 31
90 : 10
85 : 15
86 : 14
84 : 16
94 : 6
70 : 30
79 : 21
91 : 9
86 : 14
95 : 5
91 : 9
95.5 : 4.5
96.5 : 3.5
95 : 5
Our quest for a new catalytic system suitable for asymmetric
addition of 3 to 4 began with the examination of our previously
reported dinuclear N-spiro-ammonium salts such as 7a and 7b8
in the addition of N-(diphenylmethylene)glycine tert-butyl
ester 3 to chalcone 4a. The reaction proceeded well with both
catalysts to afford the desired product 5a in excellent yield and
diastereoselectivity (up to 98%, 98 : 2 dr), but with only
moderate enantioselectivities (o75 : 25 er). This finding does
indeed represent a significant improvement as Maruoka’s
mono-quaternary ammonium salts such as 2a and 2b gave
very low yield and/or poor stereoselectivity (supra infra),6 and
we believe that the bifunctional nature of 7 must be responsible
for the enhancement in reaction rate as well as in providing
good control of diastereoselectivity. This quickly directed us
to the screening of catalysts 6a–f whose aryl groups at the
3,30-positions of the chiral binaphthyl scaffold are amenable
for further modifications with bulky aryl groups with the
anticipation that this specific modification would bring about
an improvement in enantioselectivity. To our delight, this
modification does lead to the improvement in
enantioselectivity (Table 1, entries 1–6), with 1 mol% of
catalyst 6f giving the best performance in terms of both
the diastereoselectivity and the enantioselectivity (96 : 4 dr,
94 : 6 er, entry 6). A mono-cationic analog of 6f derived from
piperidine, the quaternary ammonium salt 8, was found to
perform poorly in nearly all aspects (52% yield, 80 : 20 dr, and
9
Et2O
10
11
12d
13e
14f
15f
Benzene
Xylene
Xylene
Xylene
Xylene
Xylene
25
30
40
a
b
Isolated yield. Enantiomeric excess was determined by chiral HPLC
c
analysis. Determined by NMR for crude product. Reaction time: 96 h.
e
d
f
Reaction time: 24 h. Reaction time: 12 h.
BINOL-derived N-spiro-ammonium structures can be engineered
into powerful bifunctional catalysts which synergistically
stabilize/activate both the nucleophile and the electrophile for
highly efficient, diastereo- and enantioselective conjugate addition
of a glycine imine ester to b-aryl substituted enones. Specifically,
we have found that modification on the 3,30-positions of the
chiral binaphthyl skeleton with a phenyl group that further bears
two substituents at its own 3,5-positions is a prerequisite for high
stereoselectivity in the conjugate addition of 3 to 4 (Scheme 1) and
the dimeric architecture of the quaternary ammonium salts 6 is
necessary to maintain high reactivity for the addition reaction.
Table 2 Conjugated addition of glycine ester 3 to enones 4 with 6f
a Isolated yield. b Enantiomeric excess was determined by NMR or HPLC analysis. c Determined by NMR for crude product. d At ꢀ15 1C. e The
reaction was run with 10 g of 4j. f In the presence of 1 mol% of the recovered catalyst 6f.
c
1632 Chem. Commun., 2011, 47, 1631–1633
This journal is The Royal Society of Chemistry 2011

View Article Online
73 : 27 er) for the addition of 3 to 4a, corroborating the notion that
peripheral modification of the binaphthyl units alone is not enough
and the linker-based conjoining of two quaternary centers are
necessary in order to achieve synergistic dual activation of the
reactants. Subsequent optimization on the reaction conditions
(entries 7–15) led to the discovery that the best results were
obtained when xylene was used as the solvent and the reactions
run at 30 1C (98% yield, 97 : 3 dr, 96.5 : 3.5 er, entry 14).
addition, free radical-mediated aryl amination5 of 5j gave indoline-
2-carboxylic acid derivative 17 without any erosion of its
enantiopurity. These promising results indicate that the present
protocol provides a reliable and rapid approach for the synthesis of
chiral proline and indoline-2-carboxylic acid derivatives.
In summary, we have developed an efficient diastereo- and
enantioselective conjugate addition of N-(diphenylmethylene)
glycine tert-butyl ester to chalcones and their analogs. In the
presence of catalytic amount of dinuclear N-spiro-ammonium salt
6f (1 mol%), the reaction proceeded smoothly for a broad variety
of b-aryl substituted enones. Moreover, mild reaction conditions
and applicability for large-scale preparations make compound 6f
a practical catalyst for the synthesis of highly functionalized
a-amino acid derivatives. Further mechanistic investigation and
extension of the reaction scope are underway in our laboratory.
This work was supported financially by NSFC (No.
20772091 and 20972110).
A series of b-aryl substituted enones were examined in the
diastereo- and enantioselective conjugate additions of glycine
imine ester 3 using 6f as the catalyst under the optimized
conditions (Table 2). Catalyst 6f exhibited a remarkably broad
substrate scope, and the corresponding products (5a–t) were
obtained in excellent isolated yields (91–98%) with high
diastereoselectivities (93 : 7–99 : 1 dr) and enantioselectivities
(91 : 9–96.5 : 3.5 er) (entries 1–21). It is noteworthy that 6f
performed well not only with substituted chalcones (entries
1–12, 18–20), similarly high stereoselection was also observed
for substrates derived from heteroaromatic aldehydes and/or
ketones (entries 13–17). Application of this reaction to
the diastereo- and enantioselective disymmetrization of
1,5-diphenyl-1,4-pentadien-3-one also proved successful (entry
21). In addition, enones with an aliphatic ketone group also gave
high stereoselection albeit with diminished yields (entries 22 and
23). To test the feasibility of potential large scale application of
this asymmetric process, the reaction of 2-bromochalcone was
repeated at a 10 g scale and product 5j was isolated in 92% yield,
98 : 2 dr and 95 : 5 er (entry 24). The chiral organocatalyst can be
readily recycled with one simple regenerating process (see ESIw),
and the recovered catalyst could be reused without an
appreciable loss of reactivity and stereoselectivity (entry 25).
Adducts 5 are versatile synthetic intermediates and can be readily
transformed into highly functionalized a-amino acid derivatives
that are otherwise difficult to access. For example, the hydrolysis of
the adducts 5a, 5j, 5v and 5w, followed by intramolecular reductive
amination, gave 3,5-disubstituted D-proline derivatives (9–15).
Further transformation of 12 furnished the crystalline derivative
16 whose absolute stereochemistry was determined to be (2R,3S,5S)
from single-crystal X-ray structural analysis (Scheme 2) (ESIw). In
Notes and references
1 Selected reviews: (a) M. J. O’Donnell, Acc. Chem. Res., 2004, 37,
506; (b) B. Lygo and B. I. Andrews, Acc. Chem. Res., 2004, 37, 518;
(c) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107, 5656.
2 Selected reviews: (a) T. Ooi and K. Maruoka, Angew. Chem., Int.
Ed., 2007, 46, 4222; (b) C. Najera and J. M. Sansano, Chem. Rev.,
2007, 107, 4584.
3 For asymmetric organocatalysis, see: (a) E. J. Corey, M. C. Noe and
F. Xu, Tetrahedron Lett., 1998, 39, 5347; (b) T. Ishikawa, Y. Araki,
T. Kumamoto, H. Seki, K. Fukuda and T. Isobe, Chem. Commun.,
2001, 245; (c) M. J. O’Donnell, F. Delgado, E. Dominguez, J. de Blas
and W. L. Scott, Tetrahedron: Asymmetry, 2001, 12, 821; (d) S. Arai,
R. Tsuji and A. Nishida, Tetrahedron Lett., 2002, 43, 9535;
(e) T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sekine, T. Ohshima
and M. Shibasaki, Tetrahedron Lett., 2002, 43, 9539; (f) T. Akiyama,
M. Hara, K. Fuchibe, S. Sakamoto and K. Yamaguchi, Chem.
Commun., 2003, 1734; (g) S. Arai, K. Tokumaru and T. Aoyama,
Chem. Pharm. Bull., 2004, 52, 646; (h) B. Lygo, B. Allbutt and E. H.
M. Kirton, Tetrahedron Lett., 2005, 46, 4461; (i) Y.-J. Lee, J. Lee,
M.-J. Kim, B.-S. Jeong, J.-H. Lee, T.-S. Kim, J. Lee, J.-M. Ku,
S.-s. Jew and H.-g. Park, Org. Lett., 2005, 7, 3207; (j) T. Shibuguchi,
H. Mihara, A. Kuramochi, S. Sakuraba, T. Ohshima and
M. Shibasaki, Angew. Chem., Int. Ed., 2006, 45, 4635;
(k) L. Bernardi, J. Lopez-Cantarero, B. Niess and K. A. Jørgensen,
J. Am. Chem. Soc., 2007, 129, 5772; (l) A. Ryoda, N. Yajima, T. Haga,
T. Kumamoto, W. Nakanishi, M. Kawahata, K. Yamaguchi and
T. Ishikawa, J. Org. Chem., 2008, 73, 133; (m) P. Elsner, L. Bernardi,
G. D. Salla, J. Overgaard and K. A. Jørgensen, J. Am. Chem. Soc.,
2008, 130, 4897; (n) T. Kano, T. Kumano and K. Maruoka, Org. Lett.,
2009, 11, 2023; (o) Y.-G. Wang, T. Kumano, T. Kano and
K. Maruoka, Org. Lett., 2009, 11, 2027.
4 Asymmetric metal-complex-catalysis, see: (a) S. Saito, T. Tsubogo and
S. Kobayashi, J. Am. Chem. Soc., 2007, 129, 5364; (b)T.Tsubogo,S.Saito,
K. Seki, Y. Yamashita and S. Kobayashi, J. Am. Chem. Soc., 2008, 130,
13321; (c) C.-G. Chen, X.-L. Hou and L. Pu, Org. Lett., 2009, 11, 2073.
5 (a) T. K. Ellis, H. Ueki and V. A. Soloshonok, Tetrahedron Lett.,
2005, 46, 941; (b) A. Chandra, R. Viswanathan and J. N. Johnston,
Org. Lett., 2007, 9, 5027; (c) Viswanathan, C. R. Smith,
E. N. Prabhakaran and J. N. Johnston, J. Org. Chem., 2008, 73, 3040.
6 Some results for the addition of N-(diphenylmethylene)glycine tert-butyl
ester 3 to chalcone 4a at 25 1C for 48 h to give the adduct 5a: 98% yield,
95 : 5 dr, o5% ee (with 1a); 97% yield, 95 : 5 dr, 8% ee (with 1b); 35%
yield, 84 : 16 dr, 36% ee (with 2a); 30% yield, 87 : 13 dr, 51% ee (with 2b).
7 For selected reviews on asymmetric dual activation, see:
(a) M. Shibasaki, M. Kanai, S. Matsunaga and N. Kumagai, Acc.
Chem. Res., 2009, 42, 1117; (b) D. H. Paull, C. J. Abraham,
M. T. Scerba, E. Alden-Danforth and T. Lectka, Acc. Chem. Res.,
2008, 41, 655; (c) J.-A. Ma and D. Cahard, Angew. Chem., Int. Ed.,
2004, 43, 4566.
8 M.-Q. Hua, H.-F. Cui, L. Wang, J. Nie and J.-A. Ma, Angew.
Chem., Int. Ed., 2010, 49, 2772.
Scheme 2 Synthetic transformations of the adducts 5.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1631–1633 1633

View Article Online