Dynamic kinetic resolution of azlactones catalyzed by chiral Bronsted acids

Article abstract of DOI:10.1021/ol102736t

Chiral Bronsted acids have been shown for the first time to catalyze the dynamic kinetic resolution of azlactones. 3,3'-Bis-(9-anthryl)-BINOL phosphoric acid 3c is particularly effective in the case of 4-aryl-substituted substrates, producing 85-92% ee's.

Full text of DOI:10.1021/ol102736t

ORGANIC
LETTERS
2011
Vol. 13, No. 3
356-358
Dynamic Kinetic Resolution of
Azlactones Catalyzed by Chiral
Brønsted Acids
Guojian Lu and Vladimir B. Birman*
Department of Chemistry, Washington UniVersity, Campus Box 1134, One Brookings
DriVe, St. Louis, Missouri 63130, United States
birman@wustl.edu
Received November 11, 2010
ABSTRACT
Chiral Brønsted acids have been shown for the first time to catalyze the dynamic kinetic resolution of azlactones. 3,3′-Bis-(9-anthryl)-BINOL
phosphoric acid 3c is particularly effective in the case of 4-aryl-substituted substrates, producing 85-92% ee’s.
Chiral Brønsted acid catalysis has been successfully applied to a
variety of enantioselective transformations.1 To the best of our
knowledge, however, it has never been used to promote asymmetric
acylation reactions. Here, we report the first example of such a
transformation: enantioselective alcoholysis of azlactones resulting
in their Dynamic Kinetic Resolution (DKR).2
In the course of our recent studies on this reaction5f using
enantioselective acyl transfer catalyst BTM (benzotetrami-
sole),6 we became aware of the importance of adding benzoic
acid as a cocatalyst, as was first noted by Fu et al.5b We
surmised that the presence of this proton source was
necessary to activate the substrate toward the nucleophilic
attack by BTM (see Figure 1, Path A, wherein Nu* ) BTM,
AH ) PhCO2H).7 No appreciable reaction was observed
when benzoic acid was used by itself, in the absence of BTM.
We hypothesized, however, that a strong chiral Brønsted acid
(A*H; see Figure 1, Path B) might be able to activate
azlactones enough to promote their direct alcoholysis without
the intermediacy of a nucleophilic catalyst.
To date, the DKR of azlactones (()-13 has been achieved
using enzymatic,4 Lewis acid,5a Lewis base,5b,f and bifunc-
tional catalysis.5d,e
(1) For reviews, see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth.
Catal. 2006, 348, 999. (b) Akiyama, T. Chem. ReV. 2007, 107, 5744. (c)
Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (d) Yu, X.;
Wang, W. Chem.sAsian J. 2008, 3, 516. (e) Kampen, D.; Reisinger, C. M.;
List, B. Top. Curr. Chem. 2010, 291, 395. (f) Terada, M. Synthesis 2010,
1929.
To test this mechanistically different alternative method,
we reacted 2,5-diphenylazlactone (()-1a with benzyl alcohol
in the presence of (R)-BINOL phosphoric acid 3a (pKa )
1.14).8 The reaction proceeded smoothly to give the expected
ester 2a, albeit in essentially racemic form (2% ee). Encour-
aged by this result, we undertook a survey of several 3,3′-
(2) For a recent review of dynamic kinetic resolution, see: Pelissier, H.
Tetrahedron 2008, 64, 1563.
(3) For a review of azlactone chemistry, see: Fisk, J. S.; Mosey, R. A.;
Tepe, J. J. Chem. Soc. ReV. 2007, 36, 1432.
(4) For enzymatic methods, see: Brown, S. A.; Parker, M.-C.; Turner,
N. J. Tetrahedron: Asymmetry 2000, 11, 1687, and references cited therein.
(5) Nonenzymatic methods: (a) Gottwald, K.; Seebach, D. Tetrahedron
1999, 55, 723. (b) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63,
3154. (c) Xie, L.; Hua, W.; Chan, A. S. C.; Leung, Y.-C. Tetrahedron:
Asymmetry 1999, 10, 4715. (d) Berkessel, A.; Cleeman, F.; Mukherjee, S.;
Mu¨ller, T. N.; Lex, J. Angew. Chem. Int. Ed. 2005, 44, 807. (e) Peschiulli,
A.; Quigley, C.; Tallon, S.; Gun’ko, Y. K.; Connon, S. J. J. Org. Chem. 2008,
73, 6409. (f) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892.
(6) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351.
(7) Activation of the azlactone carbonyl via double hydrogen bonding
has been utilized in the bifunctional catalyst design (ref 5d and e).
(8) Calculated value available through SciFinder.
10.1021/ol102736t  2011 American Chemical Society
Published on Web 12/22/2010

Table 2. Variation of the C2-Substituent and Solvent
entry
Ar
Phenyl
4-Cl-C6H4
4-OMe-C6H4
3,5-(OMe)2C6H3
3,5-(OMe)2C6H3
3,5-(OMe)2C6H3
3,5-(OMe)2C6H3
3,5-(OMe)2C6H3
3,5-(OMe)2C6H3
solvent
% conv(NMR)
% ee
1
2
3
4
5
6
7
8
9
CDCl3
CDCl3
CDCl3
CDCl3
CD2Cl2
C6D6
PhMe-d8
THF
EtOAc
91
84
91
72
68
59
63
35
32
63
61
66
77
74
54
56
ND
ND
Figure 1. Two modes of catalysis in alcoholysis of azlactones
employing Brønsted acids.
disubstituted derivatives of BINOL phosphoric acid (Table
1). 3,3′-Bis-(9-anthryl) analogue 3c gave the highest enan-
nol and 1-pyrenylmethanol were selected as optimal (entries
10 and 12). It should be noted, however, that acceptable
levels of enantioselectivity could also be achieved with
nonbenzylic primary alcohols of comparable steric bulk
(entries 3 and 4).
Table 1. Catalyst Screening
Table 3. Variation of the Alcohol
entry
R
% conv(NMR)
% ee
1
2
3
4
5
6
7
8
H (3a)
Phenyl (3b)
9-Anthryl (3c)
9-Phenanthryl (3d)
3,5-(CF3)2C6H3 (3e)
SiPh3 (3f)
2,4,6-(i-Pr)3C6H2 (3g)
10-Ph-anthryl (3h)
60
96
91
71
65
32
39
67
2
9
entry
R2OH
% conv(NMR)
% ee
63
34
25
48
34
25
1
2
3
4
5
6
7
8
MeOH
76
53
80
82
71
72
95
86
65
90
94
100
68
71
78
81
75
77
81
76
78
91
86
90
i-PrOH
i-PrCH2OH
t-BuCH2OH
CH2)CHCH2OH
PhCH2OH
4-Br-C6H4CH2OH
4-OMe-C6H4CH2OH
C6F5CH2OH
1-Naphthyl-CH2OH
2-Naphthyl-CH2OH
1-Pyrenyl-CH2OH
tioselectivity among common catalysts examined and thus
was selected for further studies (Table 1, entry 3 vs entries
2 and 4-7). An attempt to improve its performance by
further elaboration of its 9-anthryl substituents proved to be
counterproductive (entry 8).
9
10
11
12
Variation of the C2-aryl group on the substrate was
explored next. Para-substituents were found to have only a
small effect on the enantioselectivity (Table 2, entries 1-3).
On the other hand, the 3,5-dimethoxyphenyl group (entry
4) led to a substantial improvement.9 A survey of solvents
(entries 4-9) indicated that chloroform initially chosen to
facilitate NMR studies was, in fact, optimal.
In the course of the studies described above, we observed
that the activity of catalyst 3c prepared in our laboratory
according to literature protocols10 varied considerably from
one batch to the next. Re-examination of recent literature
reports indicated that BINOL phosphoric acids, after con-
ventional purification by chromatography, should be washed
with hydrochloric acid, presumably to remove metal cations
Next, we examined the effect of the of alcohol’s structure
on enantioselectivity (Table 3). Ultimately, 1-naphthylmetha-
(9) It is noteworthy that the 3,5-dimethoxyphenyl group also proved to
be optimal in a recent study of an enantioselective aldol-like reaction of
azlactones catalyzed by BINOL-phosphoric acids: Terada, M.; Tanaka, H.;
Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430.
(10) (a) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis,
W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121,
8251. (b) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566.
Org. Lett., Vol. 13, No. 3, 2011
357

absorbed from silica gel.11 Indeed, treatment of freshly
purified catalyst 3c with 4 M HCl led to a remarkable
Table 4. Variation of C4-Substituenta
entry
R1
time (h)
% yield
% ee
1b
2c
3d
4
5
6
7
8
9
10
11
12b
13f
14
15f
Phenyl
Phenyl
Phenyl
48
6
90
89
87
88
86
82
88
86
86
86
88
88
85
84
83
91
89
89
85
88
92
91
89
91
85
-8e
39
59
50
29
20
12
12
12
24
24
24
12
12
48
12
12
12
4-ClC6H4
4-MeOC6H4
3-MeOC6H4
2-ClC6H4
2-MeOC6H4
1-Naphthyl
2-Naphthyl
Methyl
Methyl
Methyl
Isopropyl
Isopropyl
Figure 2. Influence of acid treatment on catalyst’s activity.
a General conditions: 0.1 mmol of substrate, 0.11 mmol of 1-naphthyl-
methanol, 0.005 mmol of acid-washed catalyst 3c, 50 mg of Na2SO4, 1
mL of CDCl3, rt, unless specified otherwise. b Untreated catalyst 3c was
used. c Stopped at 95% conversion. d Carried out at -20 °C. e (S)-Enantiomer
was major in this case. f Carried out using acid-washed catalyst 3g.
increase in its activity (Figure 2). The enantioselectivity was
not affected significantly by the acid treatment (Table 4,
entries 1 and 2). Lowering the reaction temperature to -20
°C did not lead to any improvement (entry 3). Lower catalyst
loadings of the acid-washed catalyst, down to 1 mol %, were
still effective and also produced essentially the same ee
values ((1%)12 (Figure 2). However, for the sake of
consistency and experimental convenience, a 5 mol %
loading continued to be used for the rest of this study.
Having thus optimized the basic parameters of the new
DKR protocol, we applied it to a series of representative
substrates. Substituted 4-aryl-azlactones gave rise to the
corresponding R-arylglycine derivatives in 86-93% ee and
81-90% yields (Table 4, entries 4-10). Ortho-substitution
on the C4 aryl group of the substrates led to some decrease
in the reaction rate (entries 7-9). In contrast, 4-alkyl-
substituted substrates produced only modest ee’s (entries
11-15). Intriguingly, the DKR of 4-methyl-azlactone re-
sulted in opposite enantioselectivities depending on whether
acid-washed or untreated catalyst 3c was used (entries 11
and 12), which may reflect competition between Brønsted
acid and Lewis acid modes of catalysis.11c Furthermore,
catalyst 3g proved to be more enantioselective than 3c in
the case of this substrate, under otherwise identical conditions
(entry 13).
In conclusion, we have developed a new method for the
DKR of azlactones. It is especially suited for the C4-aryl-
substituted substrates, thus complementing most previously
available enzymatic4 and nonenzymatic5 protocols. In con-
trast to our previously disclosed BTM-catalyzed protocol,5f
it works well for substrates bearing ortho-substituted aryl
groups at C4. It is also noteworthy that our study demon-
strates for the first time the utility of Brønsted acid catalysis
in asymmetric acylation reactions. Further exploration of its
potential is currently under investigation.
Acknowledgment. We thank the National Science Foun-
dation for partial financial support of this study (CHE
1012979).
Supporting Information Available: Experimental pro-
cedures and NMR spectra. These materials are available free
of charge via the Internet at http://pubs.acs.org.
(11) (a) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K. Angew. Chem.,
Int. Ed. 2008, 47, 2840. (b) Cheon, C.-H.; Yamamoto, H. J. Am. Chem.
Soc. 2008, 130, 9246. (c) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara,
K. Angew. Chem., Int. Ed. 2010, 49, 3823.
(12) See Supporting Information.
OL102736T
358
Org. Lett., Vol. 13, No. 3, 2011