Pentanidium-catalyzed enantioselective phase-transfer conjugate addition reactions

Article abstract of DOI:10.1021/ja1098353

A new chiral entity, pentanidium, has been shown to be an excellent chiral phase-transfer catalyst. The enantioselective Michael addition reactions of tert-butyl glycinate-benzophenone Schiff base with various α,β- unsaturated acceptors provide adducts with high enantioselectivities. A successful gram-scale experiment at a low catalyst loading of 0.05 mol % indicates the potential for practical applications of this methodology. Phosphoglycine ester analogues can also be utilized as the Michael donor, affording enantioenriched α-aminophosphonic acid derivatives and phosphonic analogues of (S)-proline.

Full text of DOI:10.1021/ja1098353

COMMUNICATION
pubs.acs.org/JACS
Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate
Addition Reactions
Ting Ma,† Xiao Fu,† Choon Wee Kee,† Lili Zong,† Yuanhang Pan,† Kuo-Wei Huang,‡ and
Choon-Hong Tan*,†
†Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
‡KAUST Catalysis Center and Division of Chemicals and Life Sciences & Engineering, 4700 King Abdullah University of Science and
Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
S Supporting Information
b
ABSTRACT: A new chiral entity, pentanidium, has been
shown to be an excellent chiral phase-transfer catalyst. The
enantioselective Michael addition reactions of tert-butyl
glycinate-benzophenone Schiff base with various R,β-un-
saturated acceptors provide adducts with high enantioselec-
tivities. A successful gram-scale experiment at a low catalyst
loading of 0.05 mol % indicates the potential for practical
Figure 1. Various chiral pentanidium salts.
applications of this methodology. Phosphoglycine ester
analogues can also be utilized as the Michael donor, afford-
ing enantioenriched R-aminophosphonic acid derivatives
and phosphonic analogues of (S)-proline.
directions). Thus, it is much more difficult to control the con-
figurational ion pair consisting of the catalyst and the substrate.
Besides Coulomb forces, other interactions, such as H-bonding7a
or π interactions,7b are thus required to fix the ion pair more
rigidly, so the electrophile can approach only from a fixed direc-
tion, leading to high stereoselectivity.
We have developed bicyclic guanidines as chiral Brønsted base
catalysts for enantioselective reactions over the past several
years.9 As an extension of this work, we began a program to dev-
elop novel structures that are more basic than guanidines. We
naively developed pentanidine, a structure containing five nitro-
gen atoms in conjugation, with the hypothesis that this may
render it more basic than guanidine. Serendipitously, we found
that its alkylated salt, pentanidium, is an excellent phase-transfer
catalyst.10 Herein we describe a novel C2-symmetric chiral
pentanidium (Figure 1) and its successful application to catalytic
enantioselective Michael addition of tert-butyl glycinate-benzo-
phenone Schiff base to various R,β-unsaturated acceptors, such
as vinyl ketones, acrylates, and chalcones.
The synthesis of pentanidium chloride 1a required five steps
starting from commercially available (S,S)-diphenyldiami-
noethane and other commonly available and inexpensive re-
agents (Scheme 1). The structure of the chiral pentanidium salt
was confirmed by single-crystal X-ray diffraction analysis (see the
Supporting Information). The preparation protocol required
flash chromatography only once and a single recrystallization at
the end of the synthesis.
Michael addition of tert-butyl glycinate-benzophenone Schiff
base (2) has been evaluated previously by several groups under
either phase-transfer or homogeneous conditions.3c,3d,4b,4c,11 As
a preliminary study, phase-transfer Michael addition of Schiff
base 2 to ethyl vinyl ketone (3a) was catalyzed using pentanidium
symmetric phase-transfer catalysis has been recognized as a
A
convenient and powerful methodology in organic chemistry.1
The unique advantages of this synthetic approach include simple
procedures, mild conditions, suitability for large-scale reactions, ease
of catalyst recovery, and a safe and environmentally benign char-
acter. In the 1980s, chiral phase-transfer catalysts (PTCs) were
mainly derived from Cinchona alkaloids.1,2 Following the success of
the “first- and second-generation catalysts”,1,2 the “third-generation
catalyst” containing an N-anthracenylmethyl group was reported by
Lygo and Corey independently.3 In 1999, Maruoka4 designed an N-
spiro chiral ammonium salt that showed excellent catalytic activity
toward a wide variety of phase-transfer reactions. Various PTCs
based on other designs have been developed, such as C2-symmetric
chiral pentacyclic guanidine,5 two-center tartrate,6 and C3-sym-
metric amine.7a It is still highly desirable to add to this list a catalyst
that is highly efficient and also highly amenable to modification so
that it is easy to accommodate substrates for a wide range of asym-
metric reactions. The ability to work in nonchlorinated solvents is
also important.
Despite the success of many chiral PTCs, almost all of them
are sp3-quaternized ammonium salts. The design and synthesis of
sp2-quaternized ammonium salts as PTCs is rare, with only one
existing example.8 The nitrogen of an sp3-quaternized ammo-
nium salt has an imaginary tetrahedron composed of four carbon
atoms. Three faces of this tetrahedron are efficiently blocked by
steric groups, leaving one face sufficiently open to allow close
contact between the enolate of the substrate and the ammonium
cation.1c,3a,4a However, sp2-quaternized ammonium is freely
accessible from two opposite directions (i.e., the “p orbital”
Received: November 12, 2010
Published: February 11, 2011
r
2011 American Chemical Society
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|

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COMMUNICATION
Scheme 1. Preparation of Pentanidium Chloride 1aa
Table 2. Michael Addition of Schiff Base 2 to Vinyl Ketones
and Acrylatesa
a Conditions: (a) Triphosgene, Et3N, CH2Cl2; (b) MeI, NaH, THF,
80% yield for two steps; (c) (COCl)2, toluene, reflux 24 h, >99% yield;
(d) NH3, MeCN, sealed tube, reflux overnight, 99% yield; (e) Et3N,
imidazoline salt, MeCN, recrystallization, 48% yield.
entry
3 [R]
4
time(h)
yield(%)b
ee (%)c
1
2
3a [Et]
4a
4b
4c
4d
4e
4f
4
3
92
86
97
50
71
80
77
75
93
91
93
88
97
96
93
91
3b [Me]
3c [nBu]
3d [Ph]
3
1
Table 1. Michael Addition between Schiff Base 2 and Ethyl
4
1
Vinyl Ketonea
5
3e [OEt]
3f [OBn]
3f [OBn]
3f [OBn]
6
6
4
7d
8e
4f
6
4f
12
a Reactions were performed by using 2 (0.06 mmol) and 3 (0.12 mmol)
in 0.6 mL of mesitylene for the indicated time. b Yield of isolated product.
c Determined by HPLC analysis using Chiralcel OD-H and Chiralpak
AD-H columns. d 0.1 mol % catalyst was used. e 0.03 mol % catalyst was
used.
entry
catalyst
temp/°C
solvent
Et2O
yield (%)b
ee (%)c
1
2
1a
1a
1a
1a
1b
1c
1d
1e
1f
r.t.
r.t.
r.t.
0
81
80
84
89
83
87
75
72
90
88
85
81
<5
83
86
76
85
80
57
<5
89
93
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
mesitylene
mesitylene
3
Table 3. Michael Addition of Schiff Base 2 to 5a
4
5
0
6
0
7
0
8
0
9
0
10
11d
1a
0
entry
R1, R2
Ph, Ph
product time (h) yield (%)b ee (%)c
1a
-20
a Reactions were performed by using 2 (0.02 mmol) and 3a (0.04 mmol)
in 0.2 mL of solvent for 2 h. b Yield of isolated product. c Determined by
HPLC analysis using a Chiralcel OD-H column. The absolute config-
uration was determined to be R.11c d Reaction time was 4 h.
1
2
6a
6b
6c
6d
6e
6f
12
12
24
21
18
15
15
10
12
36
12
12
18
11
12
12
16
24
98
91
93
88
89
98
96
91
93
89
90
91
83
80
95
92
71
89
92
92
90
91
90
92
92
94
94
85
92
91
87
91
90
90
87
92
Ph, 1-naphthyl
Ph, 2-naphthyl
Ph, 4-PhC6H4
Ph, 4-FC6H4
3
4
5
1a. With 2 mol % of the catalyst (S,S)-1a and 50% KOH(aq) as
the base, the reaction was complete in 5 min, affording adduct 4a
with 45% ee. After evaluation of several bases, the solid base
Cs2CO3 (5 equiv) was found to provide the best enantioselec-
tivity (83%; Table 1, entry 3). Diethyl ether (entry 1) afforded an
ee value comparable to that of toluene, and dichloromethane
(entry 2) led to almost racemic product. Decreasing the reaction
temperature to 0 °C increased the ee value slightly (entry 4).
Chiral pentanidiums 1b-1f were also tested under these reac-
tion conditions. Unfortunately, they did not improve the results
further (entries 5-9). When mesitylene was used as the solvent
and the reaction temperature decreased to -20 °C, the ee value
improved to 93% (entries 10 and 11).
With the optimal reaction conditions established, we studied
the phase-transfer Michael addition of 2 with various vinyl
ketones and acrylates (Table 2). Both alkyl vinyl ketones 3a-c
and phenyl vinyl ketone 3d gave excellent ee values (entries 1-
4). The low yield of adduct 4d (entry 4) might be due to double
addition.3d Acrylates 3e and 3f also provided good yields and
excellent enantioselectivities (entries 5-8). Remarkably, the
catalyst loading could be lowered to 0.03 mol % without
significantly affecting the enantioselectivity (entry 8).
6
Ph, 4-ClC6H4
Ph, 4-BrC6H4
Ph, 4-NO2C6H4
Ph, 2-ClC6H4
7
6g
6h
6i
8
9
10
11
12
13
14
15
16
17
18d
Ph, 4-MeOC6H4 6j
4-ClC6H4, Ph
6k
6l
4-NO2C6H4, Ph
4-MeOC6H4, Ph 6m
2-naphthyl, Ph
2-fural, Ph
6n
6o
6p
6q
6f
2-thiophenyl, Ph
Me, Ph
Ph, 4-ClC6H4
a Reactions were performed by using 2 (0.06 mmol) and 5 (0.072 mmol)
in 0.6 mL of mesitylene for the indicated time. b Yield of isolated product.
c Determined by HPLC analysis using a Chiralcel OD-H column. Only
one diastereomer was observed, and the absolute configuration was
verified by single-crystal X-ray diffraction of 7. d 2 (0.1 mmol), 5f (0.12
mmol), and 2.5 equiv of Cs2CO3 were used with a catalyst loading of
0.05 mol %.
The same conditions were successfully applied to chalcones and
led to adducts 6a-q with excellent yields, enantioselectivities, and
diastereoselectivities (Table 3) regardless of the steric or electro-
nic properties of the aromatic rings on the chalcones. All of the
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COMMUNICATION
Scheme 2. Synthesis of Enantiopure Pyrrolidine Derivatives
In summary, a new chiral entity, pentanidium, has been
developed as an excellent chiral phase-transfer catalyst. Michael
addition reactions of tert-butyl glycinate-benzophenone Schiff
base with various R,β-unsaturated acceptors, such as vinyl
ketones, acrylates, and chalcones, have been shown to provide
adducts with high ee values. A successful gram-scale experiment
at a low catalyst loading of 0.05 mol % indicates the potential for
practical applications of this methodology. Adducts can be easily
transformed to enantiopure pyrrolidines or R-aminophosphonic
acid derivatives and phosphonic analogues of proline.
Scheme 3. Gram-Scale Experiment with Low Catalyst
Loading
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
spectroscopic data, and crystallographic data (CIF). This ma-
terial is available free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Scheme 4. Michael Reaction between 9 and Benzyl Acrylate
Corresponding Author
chmtanch@nus.edu.sg
’ ACKNOWLEDGMENT
This work was supported by a research grant (R-143-000-342-
112) and a scholarship (to M.T.) from NUS.
’ REFERENCES
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electron-donating groups took a longer time for the reaction to
reach completion (entries 10 and 13). It was also revealed that a
low catalyst loading of 0.05 mol % was sufficient to provide
excellent enantioselectivity (entry 18), albeit longer reaction
time of 24 h was required.
The usefulness of adducts 6a-q was clearly demonstrated
through a simple and efficient synthesis of substituted pyrroli-
dines (Scheme 2). In the presence of citric acid, deprotection of
the amino group of 6f was followed by cyclization through imine
formation, affording 7. Reduction with NaBH4 provided pyrro-
lidine 8 in good yield with no loss of enantioselectivity.12 This
methodology provides an efficient entry to enantiopure substi-
tuted pyrrolidines that cannot be prepared through [3 þ 2]
cycloaddition reactions.13 Electron-rich alkenes usually do not
undergo [3 þ 2] cycloaddition reactions with glycinate imines.
Considering the low catalyst loading (Table 2, entry 8; Table 3,
entry 18), chiral pentanidium could be a highly efficient chiral
PTC for practical asymmetric synthesis. To exploit the potential
catalytic ability of chiral pentanidium 1a, we scaled up the
reaction in the presence of 0.05 mol % 1a (Scheme 3). Excellent
enantioselectivity was maintained with good yield.
In addition to Schiff base 2, benzophenone imines of phos-
phoglycine ester 9 could also be utilized as donors in a related
Michael addition reaction (Scheme 4). R-Aminophosphonic acid
can easily be obtained through a one-step modification of adduct
10.14 R-Aminophosphonic acids and their phosphonate esters
are transition-state analogues of amino acids.15 A number of
potent inhibitors of enzymes have been prepared from these
amino acid mimics. Furthermore, 10 can also be transformed to
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method of preparation exists.16 A single recrystallization of 11
improved the ee value to 96%, as indicated using N-Cbz-12.
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