Kinetic resolution of 2-oxazolidinones via catalytic, enantioselective N-acylation

Article abstract of DOI:10.1021/ja061560m

Kinetic resolution of racemic 2-oxazolidinones via catalytic, enantioselective N-acylation has been achieved for the first time and with outstanding selectivities. Copyright

Full text of DOI:10.1021/ja061560m

Published on Web 04/29/2006
Kinetic Resolution of 2-Oxazolidinones via Catalytic, Enantioselective
N-Acylation
Vladimir B. Birman,* Hui Jiang, Ximin Li, Lei Guo, and Eric W. Uffman
Department of Chemistry, Washington UniVersity, One Brookings DriVe, St. Louis, Missouri 63130
Received March 6, 2006; E-mail: birman@wustl.edu
Kinetic resolution (KR)1 of racemic alcohols2 and amines3 via
enzyme-catalyzed enantioselective acyl transfer is well-known.
Many nonenzymatic catalysts, which have been developed over the
past decade, allow catalytic, enantioselective O-acylation of alco-
hols.4 In contrast, there is to date only one report describing the
analogous N-acylation of amines.5 To the best of our knowledge,
catalytic, enantioselective N-acylation of another common class of
nitrogen nucleophilesschiral secondary amidesshas not been
achieved previously using either enzymes or synthetic catalysts.
Unlike amines, which can often be resolved via crystallization of
their diastereomeric salts with chiral acids, amides are not basic
enough to form stable salts. The development of enantioselective
acylation of racemic amides would thus provide a convenient means
of achieving their resolution.6 In this communication, we report
the first successful examples of this process.
Figure 1. Ring-fused imidazoline catalysts.
We were encouraged by reports on achiral DMAP-catalyzed
N-acylation of 4-substituted oxazolidinones with carboxylic acid
anhydrides.7 In addition, various amides, both cyclic and acyclic,
are known to be acylated with Boc2O in the presence of DMAP.8
Thus, we decided to employ our recently developed DHIP-based
enantioselective acylation catalyst 19a,c to test the feasibility of the
asymmetric version of this reaction (Figure 1). Since our earlier
experimental observations in KR of benzylic alcohols indicated the
importance of π-π and cation-π interactions in the chiral
recognition of benzylic alcohols, we chose 4-phenyl-2-oxazolidi-
none 4a as the starting point of our study (Figure 2).
Figure 2. Oxazolidinone substrates.
Scheme 1
In the first, proof-of-principle experiment, substrate 4a was
acylated with propionic anhydride in the presence of CF3-PIP (1),
under conditions analogous to those previously employed for
benzylic alcohol substrates. After 24 h, the conversion reached 39%,
and the selectivity factor10 was determined to be 7.8. As anticipated
on the basis of our model, the S-enantiomer of the substrate
(configurationally analogous to R-alcohols) was acylated prefer-
entially (Scheme 1).
The second-generation catalyst, Cl-PIQ (2), developed at that
time in our laboratory,9b proved to be more effective than 1 and
thus was selected for further optimization studies. Lower concentra-
tions were chosen to provide a standard set of conditions for all
oxazolidinone substrates 4-6, many of which have only limited
solubilities. The selectivity was improved when isobutyric anhydride
was substituted for propionic, whereas other anhydrides tested were
far less successful (Table 1, entries 1-5). tert-Amyl alcohol11
performed better than chloroform as a reaction media, and both
were considerably superior to other solvents screened (cf. entries
3 and 6-10).
4a (entry 14). The importance of π-interactions was confirmed
by the absence of any appreciable reaction with the isopropyl-
substituted oxazolidinone 4f even at room temperature (entry 15).
gem-Dimethyl substituted substrates 5a-c reacted with much higher
selectivities than their unsubstituted counterparts 4a-c (entries 16-
18 vs 6, 11, 12), whereas in the case of the heteroaryl substrates
the differences in selectivity were not significant (entries 19, 20 vs
13, 14). In the case of 5a, increased catalyst loading was needed
to achieve respectable reaction rates. Both cis- and trans-4,5-
diphenyl-2-oxazolidinones (6a and b, entries 21, 22) were resolved
with selectivities and rates comparable to those of substrate 4a. It
should be noted that the limited solubility of some of the
oxazolidinones (4c, 5b, c and 6a) in tert-amyl alcohol prevented
reliable selectivity measurements.12 Substrate 6c was practically
insoluble in this solvent, which rendered its resolution inefficient
(s < 2).
In a parallel development in our laboratory, catalyst 3 was
synthesized and shown to possess markedly higher enantioselectivity
than 2 in the KR of benzylic alcohols.9d Naturally, these findings
prompted us to test the new catalyst in the KR of 2-oxazolidinones.
The results far surpassed our expectations. Acylation of substrates
4a-e and 6a, b catalyzed by BTM (Table 2, entries 1-7) proceeded
The influence of the substrate structure was investigated next.
As expected, replacement of the phenyl group with 1- or 2-naphthyl
led to increased selectivities (entries 11, 12). Comparable results
were obtained with the 2-furyl analogue 4d (entry 13), while the
thiophene derivative 4e was resolved with lower selectivity than
9
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J. AM. CHEM. SOC. 2006, 128, 6536-6537
10.1021/ja061560m CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. KR of 2-Oxazolidinones Using Cl-PIQ (2)a
In conclusion, we have achieved for the first time kinetic
resolution of chiral 2-oxazolidinones via catalytic, highly enantio-
selective N-acylation. Besides providing a convenient route to these
compounds in enantiopure form, these findings pave the way for
further exploration of enantioselective N-acylation of other classes
of chiral secondary amides. Studies in this direction are currently
underway in our laboratory.
entry
substrate
R
′
solvent
time (h)
% conv
s
1
2
3
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
6a
6b
Me
Et
i-Pr
CHCl3
3
3.5
24
24
24
19
24
24
24
24
17
19
17
15
16
21.5
10
10
28
19
24
15
43
45
42
16
<3
44
17
25
12
7
46
44
50
47
0
43
40
49
50
49
43
48
1.3
10
17
CHCl3
CHCl3
CHCl3
4
Ph
-5.5
ND
24
5b
t-BuO CHCl3
6
7
8
9
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
EtMe2COH
THF
MeCN
EtOAc
12
3
8
9
38
44
25
16
Acknowledgment. We thank NIGMS (R01 GM072682) and
Washington University for financial support. Mass spectrometry
was provided by the Wash. U. Mass Spectrometry Resource, an
NIH Research Resource (Grant No. P41RR0954).
10b,c
11
12c
13
14
15b
16d
17c
18e
19
20
21c
22
PhMe
EtMe2COH
EtMe2COH
EtMe2COH
EtMe2COH
CDCl3
EtMe2COH
EtMe2COH
EtMe2COH
EtMe2COH
EtMe2COH
EtMe2COH
EtMe2COH
Supporting Information Available: Experimental procedures and
NMR spectra. These materials are available free of charge via the
Internet at http://pubs.acs.org.
ND
55
1.1 × 102
References
70
28
18
26
(1) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(2) Enzymatic enantioselective acylation of alcohols: (a) Sih, C. J.; Wu, S.-
H. Top. Stereochem. 1989, 19, 63. (b) Klibanov, A. M. Acc. Chem. Res.
1990, 23, 114. (c) Schoffers, E.; Golebiowski, A.; Johnson, C. R.
Tetrahedron 1996, 52, 3769.
(3) Enzymatic enantioselective acylation of amines: van Rantwijk, F.;
Sheldon, R. A. Tetrahedron 2004, 60, 501.
19
a Unless specified otherwise, the following conditions were used: 0.2
M substrate, 0.75 equiv (R′CO)2O, 0.75 equiv i-Pr2NEt, 4 mol % (R)-2,
0 °C. b RT. c Incompletely dissolved substrate at 0.2 M. d 8 mol % (R)-2
was used. e Incompletely dissolved substrate at 0.1 M.
(4) For recent reviews, see: (a) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
2005, 44, 3974. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138. (c) Jarvo, E. R.; Miller, S. J. Asymmetric Acylation. In
ComprehensiVe Asymmetric Catalysis, Supplement 1; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Heidelberg,
2004; Chapter 43. (d) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. ReV. 2003, 103, 2985.
Table 2. KR of 2-oxazolidinones Using BTM (3)
a
a
entry
substrate
eeSM
eeP
time (h)
%conva
sa
(5) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234.
1b
4a
4b
4c
4d
4e
6a
6b
6c
5a
4a
5a
5b
5c
5d
5e
54.1
71.6
87.6
70.5
96.0
71.7
72.3
96.2
17.0
89.6
48.4
80.4
56.6
70.5
98.7
98.3
99.1
97.8
95.7
98.2
98.5
91.8
93.2
98.3
96.4
99.1
99.1
98.2
95.2
97.4
8.5
21
14
8.5
6
36
42
47
42
49
43
44
51
15
48
33
45
37
43
50
2.0 × 102
4.5 × 102
2.6 × 102
(6) Resolution of chiral oxazolidinones has been achieved by (a) chromato-
graphic separation of their diastereomeric N-acyl derivatives: Ishizuka,
T.; Kimura, K.; Ishibuchi, S.; Kunieda, T. Chem. Lett. 1992, 991; and (b)
enantioselective deacylation of N-acyl-oxazolidinones via catalytic, asym-
metric borane reduction: Hashimoto, N.; Ishizuka, T.; Kunieda, T.
Tetrahedron Lett. 1998, 39, 6317.
2b
3b
4b
96
5b
4.3 × 102
6b
6
6
3.0 × 102
(7) (a) Kano, S.; Yokomatsu, T.; Shibuya, S. Heterocycles 1990, 31, 1711.
(b) Ager, D. J.; Allen, D. R.; Schaad, D. R. Synthesis 1996, 1283.
(8) (a) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424. (b) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1985,
24, 510. (c) Hansen, M. M.; Harkness, A. R.; Coffey, D. S.; Bordwell, F.
G.; Zhao, Y. Tetrahedron Lett. 1995, 36, 8949.
(9) (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am.
Chem. Soc. 2004, 126, 12226. (b) Birman, V. B.; Jiang, H. Org. Lett.
2005, 7, 3445. (c) Birman, V. B.; Li, X.; Jiang, H.; Uffman, E. W.
Tetrahedron 2006, 62, 285. (d) Birman, V. B.; Li, X. Org. Lett. 2006, 8,
1351.
(10) Selectivity factor is defined as s ) k(fast-reacting enantiomer)/k(slow-
reacting enantiomer). Both % conversion and selectivity factor are
calculated from ee’s of the product and the recovered starting material.1
Average values of duplicate runs are given for the % ee, % C and s.
(11) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794.
(12) Gradual dissolution of a racemic substrate in the course of KR will lead
to a lower apparent selectivity compared with that in a homogeneous
reaction.
(13) Hamersak, Z.; Ljubovic, E.; Mercep, M.; Mesic, M.; Sunjic, V. Synthesis
2001, 1989. In the original synthetic route, (-)-cytoxazone 6d was
obtained by KR of its racemate via enzymatic O-acylation with s ) 39.
(14) Isolation, structure elucidation, and biological activity: (a) Kakeya, H.;
Morishita, M.; Kobinata, K.; Osono, M.; Ishizuka, M.; Osada, H. J.
Antibiot. 1998, 51, 1126. (b) Kakeya, H.; Morishita, M.; Koshino, H.;
Morita, T.-i.; Kobayashi, K.; Osada, H. J. Org. Chem. 1999, 64, 1052.
For a list of leading references to synthesis of 6d, see: (c) Kim, J. D.;
Kim, I. S.; Jin, C. H.; Zee, O. P.; Jung, Y. H. Org. Lett. 2005, 7, 4025.
(15) (a) KR of 0.814 g of (()-5c with Cl-PIQ produced 40% isolated yield of
the N-acylated product with 92.1% ee, 48% recovered SM with 75.6%
ee (CHPLC ) 45%, s ) 56) and 79% recovered catalyst. (b) KR of 1.00 g
of (()-4e with BTM gave 51% isolated yield of the product with 96.7%
ee, 48% recovered SM with 99.4% ee (CHPLC ) 51%, s ) 3.5 × 102) and
60% recovered catalyst. (c) KR of 0.753 g of (()-6c with BTM gave
48% isolated yield of the product with 91.3% ee, 44% recovered SM
with 97.3% ee (CHPLC ) 52%, s ) 94) and 62% recovered catalyst. See
experimental details in Supporting Information.
7b
50
8b
5.75
8.5
5
12
7
8.5
7
6.5
1.1 × 102
1.3 × 102
1.7 × 102
3.4 × 102
5.2 × 102
2.0 × 102
9b
10c
11c
12c
13c
14c
15c
88
3.9 × 102
a Averages of duplicate runs. b General conditions: 0.2 M substrate, 0.75
equiv (i-PrCO)2O, 0.75 equiv i-Pr2NEt, 4 mol % (R)-3, Na2SO4, CHCl3, rt.
c General conditions: 0.2 M substrate, 1.5 equiv (i-PrCO)2O, 0.75 equiv
i-Pr2NEt, 8 mol % (R)-3, Na2SO4, CHCl3, rt.
at room temperature in chloroform with selectiVity factors 2.5 to
27(!) times higher than those obtained with 2.13
We were finally able to resolve substrate 6c with high enantio-
selectivity, taking advantage of its improved solubility under these
conditions (entry 8). This compound has previously served as an
intermediate in a concise racemic synthesis13 of cytoxazone (6d),
a naturally occurring oxazolidinone possessing cytokine modulating
activity.14 BTM-catalyzed KR of gem-dimethyl substituted sub-
strates, 5a-e, proceeded more slowly than that of their unsubstituted
counterparts 4a-e (cf., e.g., entries 1 and 9). In most of these cases,
high conversions were obtained on a convenient time scale by
doubling the catalyst and the anhydride loadings (entries 10-15).
Efficacy of both Cl-PIQ and BTM catalysts on preparative scale
was confirmed experimentally.15
JA061560M
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J. AM. CHEM. SOC. VOL. 128, NO. 20, 2006 6537