Asymmetric aza-mannich addition of oxazolones to N-tosyl aldimines: Synthesis of chiral α-disubstituted α,β-diamino acids

Article abstract of DOI:10.1021/ol902916s

(Figure Presented) An organocatalytic enantioselective addition of oxazolones to N-tosyl aldimines has been developed. The process Is promoted by a readily prepared cinchona alkaloid ligand and affords a series of valuable α,β-diamino acid derivatives with excellent enantioselectivities (up to 97% ee) and diastereoselectivities (up to >30:1 dr). The adducts can be transformed Into the corresponding protected chiral α-disubstituted α,β-diamino acids by a one-pot hydrolyzed reaction smoothly.

Full text of DOI:10.1021/ol902916s

ORGANIC
LETTERS
2010
Vol. 12, No. 4
876-879
Asymmetric Aza-Mannich Addition of
Oxazolones to N-Tosyl Aldimines:
Synthesis of Chiral r-Disubstituted
r,ꢀ-Diamino Acids
Xiaodong Liu, Leijiao Deng, Xianxing Jiang, Wenjin Yan, Chunliang Liu, and
Rui Wang*
State Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and
Molecular Biology, Key Laboratory of Preclinical Study for New Drugs of Gansu
ProVince, Lanzhou UniVersity, Lanzhou 730000, China
wangrui@lzu.edu.cn
Received December 21, 2009
ABSTRACT
An organocatalytic enantioselective addition of oxazolones to N-tosyl aldimines has been developed. The process is promoted by a readily
prepared cinchona alkaloid ligand and affords a series of valuable r-disubstituted r,ꢀ-diamino acid derivatives with excellent enantioselectivities
(up to 97% ee) and diastereoselectivities (up to >30:1 dr). The adducts can be transformed into the corresponding protected chiral r-disubstituted
r,ꢀ-diamino acids by a one-pot hydrolyzed reaction smoothly.
Chiral R-disubstituted R,ꢀ-diamino acids are known as the
key structural components in many biological active com-
pounds.1 Such molecules can, for instance, serve as building
blocks for the synthesis of chiral auxiliaries and pharma-
ceuticals.2 Moreover, they can also be incorporated into the
peptides to impart conformational stability and display
antibiotic activity.3 Therefore, the synthesis of R-disubstituted
R,ꢀ-diamino acids in an optically pure form has gained
considerable interest and has become a significant and
challenging work for organic chemists. In 2008, on the basis
of several different catalytic routes for the R,ꢀ-diamino acid
synthesis,4 a metal catalytic approach for the preparation of
R-disubstituted R,ꢀ-diamino acids was developed by the
Shibasaki group.5 Since then, a handful of protocols have
been described in the literature by several groups.6 In the
past decade, due to its operational and economic advantages,
asymmetric organocatalysis has been proven to be a powerful
tool for the synthesis of optically pure compounds.7 There-
fore, it is significant to develop organocatalytic approaches
for the synthesis of R-disubstituted R,ꢀ-diamino acids.
Because of the easy availability and the well-documented
power, the cinchona alkaloids and their derivatives have
become efficient bifunctional organocatalysts in various
asymmetric reactions.8 Recently, in our own work, a sodium
demethylquinine salt derived from the cinchona alkaloid has
been successfully applied to the Michael reaction between
(1) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.; Flores, A. Chem.
ReV. 2005, 105, 3167.
(2) (a) Lucet, D.; LeGall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580. (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517.
(3) (a) Kan, T.; Kawamoto, Y.; Asakawa, T.; Furuta, T.; Fukuyama, T.
Org. Lett. 2008, 10, 168. (b) Takahashi, A.; Naganawa, H.; Ikeda, D.;
Okami, Y. Tetrahedron. 1991, 47, 3621.
10.1021/ol902916s  2010 American Chemical Society
Published on Web 01/20/2010

the trisubstituted carbanion and the nitroalkenes.9 We decided
to investigate this initial observation further and to apply
aza-Mannich reaction in the presence of a chiral cinchona
alkaloid ligand 1a (20 mmol %) in toluene at room
temperature. We found that the reaction proceeded efficiently
to afford the adduct 4b in a good diastereomeric ratio of
11:1 but with the moderate enantioselectivity (Table 1, entry
1). Switching solvents to tetrahydrofuran or acetonitrile
(entries 2 and 3) had a negative influence on the enantiose-
lectivities, whereas the use of benzene or tetrachloromethane
(entries 4 and 5) gave better results. Gratifyingly, when the
ethyl ether was used as the solvent, the adduct was smoothly
obtained with an excellent ee value of 96% and a further
improved 17:1 diastereomeric ratio (entry 6). Under the same
conditions, the impact of ligand frameworks was examined.
The disadvantage of the free OH group in the catalyst
structure was verified by the lower enantioselectivity of the
reaction catalyzed by 1b (entry 7). Less efficiency was also
observed in terms of enantioselectivities for the analogues
1c and 1d (entries 8 and 9). Furthermore, the similar
diastereomeric ratio and enantioselectivity were obtained with
the low reaction temperature of 10 °C (entry 10).
Scheme 1. Cinchona Alkaloid Derived Ligands Explored for the
Synthesis of Optically Active R-Disubstituted R,ꢀ-Diamino Acids
the cinchona alkaloid ligands 1a-d to the Mannich addition
of racemic oxazolones to N-tosyl aldimines (Scheme 1).
An additional impetus for this work was that, although
the oxazolones were important masked amino acid frag-
ments10 and have been employed to synthesize R-substituted
R,ꢀ-diamino acids by Jørgensen and Ooi successively,11 the
use of these aza species for the synthesis of amino acid
derivatives was still scarce. To the best of our knowledge,
using N-tosyl aldimines as electrophile reagents in this field
has not been thoroughly explored.
Table 1. Representative Screening Results for the Reaction of
Oxazolone 2a and N-Tosyl Imine 3ba
cat.
(20 mmol %)
In our exploratory study, we decided to choose N-tosyl
imine 3b and oxazolone 2a as substrates for the proposed
entry
temp.
rt
rt
rt
rt
rt
rt
rt
solvent
drb
ee [%]c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
Tol
11:1
10:1
7:1
11:1
14:1
17:1
19:1
20:1
17:1
17:1
71
52
65
86
92
96
91
80
52
91
(4) (a) Cutting, G. A.; Stainforth, N. E.; John, M. P.; Kociok-Ko¨hn, G.;
Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10632. (b) Singh, A.; Yoder,
R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466. (c)
Kiss, L.; Mangelinckx, S.; Sillanpa¨a¨, R.; Fu¨lo¨p, F.; De Kimpe, N. J. Org.
Chem. 2007, 72, 7199. (d) Shibuguchi, T.; Mihara, H.; Kuramochi, A.;
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Soc. 2008, 130, 2170.
THF
MeCN
C6H6
CCl4
Et2O
Et2O
Et2O
Et2O
Et2O
rt
rt
9
10d
-10 °C
a Experimental conditions unless otherwise stated: a mixture of 2a (0.2
mmol), 2b (0.1 mmol), and catalyst (20 mmol %) in the corresponding
solvent (1 mL) was stirred at room temperature for 8-12 h, and full
conversion was observed in all the cases. b Determined by 1H NMR
spectroscopic analysis. c The enantiomeric excess was determined by HPLC
analysis on a Chiralcel column. d Reaction time: 16 h.
With the optimized conditions established, the scope of
N-tosyl aldimines and oxazolones in the presence of 20 mmol
% catalyst 1a was explored (Table 2). Overall, all of the
reactions proceeded smoothly to furnish the corresponding
R-disubstituted R,ꢀ-diamino acid derivatives 4 in good yields
and excellent diastereo- and enantioselectivities. For the
reactions with the oxazolone 2a, a wide range of substituents
could be present at the aryl position on the N-tosyl imine 2.
All of the aryl-substituted substrates with either electron-
rich or electron-deficient at different sites had limited effect
on the results of the diastereo- and enantioselectivity of the
(6) (a) Arraya´s, R. G.; Carretero, J. C. Chem. Soc. ReV. 2009, 38, 1940.
(b) Herna´ndez-Toribio, J.; Arraya´s, R. G.; Carretero, J. C. J. Am. Chem.
Soc. 2008, 130, 16150. (c) Singh, A.; Johnston, J. N. J. Am. Chem. Soc.
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Deng, J.-G.; Chen, Y.-C. Chem.sEur. J. 2008, 14, 8094.
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see: (a) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138. (b) Dondoni, A.; Massi, A. Angew. Chem., Int.
Ed. 2008, 47, 4638. (c) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int.
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Science 2006, 313, 1584. (h) List, B. Chem. Commun. 2006, 819. (i) Seayad,
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Angew. Chem., Int. Ed. 2004, 43, 5138.
Org. Lett., Vol. 12, No. 4, 2010
877

reaction. A series of aza-Mannich adducts were obtained in
excellent diastereomeric ratios and ee values (entries 1, 2,
and 4-9). Good results were also gained by using an N-tosyl
imine with a bulky naphthyl substituent group as a substrate
(entry 10). In addition, different substituents on the CdN
bond of the oxazolone were also tested. The outstanding
diastereo- and enantioselectivity were observed for the
oxazolone with the para-chlorophenyl group at this position
(entry 12). Other oxazolones with a different alkyl substituent
at the R1 position could also be smoothly applied as substrates
in this reaction (entries 13-15). For example, an ee value
of as high as 97% with an excellent diastereomeric ratio of
20:1 was attained when the imine 3d and oxazolone 2d were
used in entry 13.12
Under the optimized conditions, the opposite enantiomer
of product 4b could also be favorably obtained by carrying
out the reaction with the opposite configuration quinidine
derivative 1e in excellent diastereoselectivity and good
enantioselectivity (entry 3).
The constitution and absolute configuration of the product
4g were determined by using X-ray crystallography (Figure
1) as well as by NMR spectroscopic studies.13
Table 2. Asymmetric Synthesis of R-Disubstituted R,ꢀ-Diamino
Acid Derivativesa
entry
1
R1/R2, 2
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/Ph
2a
iPr/o-F-Ph
2b
iPr/p-Cl-Ph o-Cl-Ph
2c
iBu/Ph
2d
R3, 3
Ph
3a
p-Me-Ph
3b
p-Me-Ph
3b
o-MeO-Ph
3c
o-F-Ph
3d
o-Cl-Ph
3e
p-Cl-Ph
3f
p-Br-Ph
3g
p-NO2-Ph
3h
2-naphth
3i
yield [%]b
drc
ee [%]d
94
92
4a
80
4b
85
4b
80
4c
93
4d
89
4e
75
4f
70
4g
49
4h
84
4i
94
4j
82
4k
78
4l
90
4m
76
4n
15:1
2
3
17:1
23:1
30:1
26:1
30:1
19:1
17:1
24:1
9:1
96
-80e
93
4
5
92
6
95
7
93
The synthetic versatility of the aza-Mannich adducts in
this reaction was illustrated by a further transformation.
Optically active R-disubstituted R,ꢀ-diamino acids 5 were
8
92f
84
9
(8) For reviews on chiral cinchona alkaloid catalysts, see: (a) Connon,
S. J. Chem. Commun. 2008, 2499. (b) Marcelli, T.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496. (c) Tian, S.-K.; Chen,
Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004,
37, 621. (d) Chen, Y. G.; McDaid, P.; Deng, L. Chem. ReV 2003, 103,
2965. For selected examples of chiral cinchona alkaloid catalysis, see: (e)
Liu, Y.; Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L. J. Am. Chem.
Soc. 2009, 131, 41. (f) Dodda, R.; Goldman, J. J.; Mandal, T.; Zhao, C.-
G.; Broker, G. A.; Tiekink, E. R. T. AdV. Synth. Catal 2008, 350, 537. (g)
Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Liu, X. J.; Deng, L. J. Am.
Chem. Soc. 2008, 130, 2422. (h) Liu, T.-Y.; Cui, H.-L.; Chai, Q.; Long, J.;
Li, B. J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem. Commun. 2007, 2228.
(i) Comer, E.; Rohan, E.; Deng, L., Jr.; Porco, J. A. Org. Lett. 2007, 9,
2123. (j) Wang, Y.; Li, H. M.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng,
L J. Am. Chem. Soc. 2007, 129, 6364. (k) Wang, B. M.; Wu, F. H.; Wang,
Y.; Liu, X. F.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (l) Wang, J.;
Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc.
2006, 128, 12652. (m) Li, H. M.; Wang, Y.-Q.; Deng, L. Org. Lett. 2006,
8, 4063. (n) Wu, F. H.; Hong, R.; Khan, J. H.; Liu, X. F.; Deng, L. Angew.
Chem., Int. Ed 2006, 45, 4301. (o) Wang, Y.; Liu, X. F.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 3928. (p) Li, H. M.; Wang, B. M.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 732. (q) Liu, X. F.; Li, H. M.; Deng, L. Org. Lett.
2005, 7, 167. (r) Li, H. M.; Wang, Y.; Tang, L.; Wu, F. H.; Liu, X. F.;
Guo, C. Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed 2005, 44,
105. (s) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004,
126, 8120. (t) Li, H. M.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906. (u) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
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2009, 21, 600. (b) Chen, F.; Shao, C.; Wang, Y.; Gong, P.; Zhang, D. Y.;
Zhang, B. Z.; Wang, R. Tetrahedron Lett. 2007, 48, 8456.
10g
11
12
13
14
15
93
p-Me-Ph
3b
3:1
86
>30:1
20:1
25:1
22:1
93
3e
o-F-Ph
3d
o-Cl-Ph
3e
o-Br-Ph
97
iBu/Ph
2d
iBu/Ph
90
93
2d
3j
a Experimental conditions unless otherwise stated: a mixture of 2a (0.2
mmol), 2b (0.1 mmol), and 1a (20 mmol %) in the ethyl ether (1 mL) was
stirred at room temperature for 8-12 h, and full conversion was observed
in all the cases. b Yield of diastereoisomeric mixture isolated by silica-gel
column chromatography. c Determined by 1H NMR spectroscopic analysis.
d The enantiomeric excess was determined by HPLC analysis on a Chiralcel
column. e The quinidine derived catalyst 1e was used. f The absolute
configuration of 4g was determined by X-ray crystal-structure analysis. The
absolute configurations of the other products were assigned by analogy.
g The reaction was carried out with 20 mmol % 1b under 0 °C for 16 h.
(10) (a) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36,
1432. (b) Trost, B. M.; Jakel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125,
4438. (c) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256. (d)
Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727. (e) Ruble,
J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532.
(11) (a) Uraguchi, D.; Koshimoto, K; Ooi, T. Chem. Commun. 2010,
46, 300. (b) Alema´n, J.; Milelli, A.; Cabrera, S.; Reyes, E.; Jørgensen, K. A.
Chem.sEur. J. 2008, 14, 10958. (c) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am.
Chem. Soc. 2008, 130, 14088. (d) Cabrera, S.; Reyes, E.; Alema´n, J.; Milelli,
A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 12031.
(12) Under the optimized conditions, the alkyl-substituted isobutyl
N-tosyl imine showed no reactivity toward oxazolone 2a.
(13) CCDC 755504 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/da-
a_request/cif.
Figure 1. X-ray structure of compound 4g.
Org. Lett., Vol. 12, No. 4, 2010
878

amino acids with excellent yields (entries 1 and 2). When
the R2 was a phenyl substituent group, the Ts- and Bz-
diprotected R-disubstituted R,ꢀ-diamino acids were obtained.
Table 3. Hydrolyzed to the Corresponding Protected
R-Disubstituted R,ꢀ-Diamino Acidsa
In summary, a simple cinchona alkaloid catalyzed aza-
Mannich addition of N-tosyl aldimines with oxazolones has
been accomplished. It was proven that this was an efficient
way to synthesize R-disubstituted R,ꢀ-diamino acid derivates
with good yields and excellent diastereo- (up to >30:1) and
enantioselectivities (up to 97%). The high enantiopure
R-disubstituted R,ꢀ-diamino acids can be gained from the
adducts just by a one-pot hydrolyzed reaction.
entry
substrates
R1/R2
R3
yield [%]
1
2
4ab
4gb
iPr/Ph
iPr/Ph
Ph
p-Br-Ph
92 (5a)c
95 (5b)c
a The reaction was carried out with 4 (0.3 mmol) and concd HCl (0.6
mmol) in 1.0 mL of MeCN as solvent. b The major diastereoisomer of 4
was isolated and used in this reaction. c A single diastereoisomer was
obtained.
Acknowledgment. We gratefully acknowledge financial
support from NSFC (20525206, 90813012, and 20932003)
andtheNationalS&TMajorProjectofChina(2009ZX09503-
017).
obtained by using the protocol developed by Trost et al
(Table 3).14 Both of the adducts 4a and aryl-substituted 4g
could react efficiently to afford the corresponding protected
Supporting Information Available: Experimental details,
characterization data for the products, and crystal structure
data of adduct 4g in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) (a) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727.
(b) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256. (c) Trost,
B. M.; Jakel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438.
OL902916S
Org. Lett., Vol. 12, No. 4, 2010
879