Enantioselective aza-darzens reaction catalyzed by a chiral phosphoric acid

Article abstract of DOI:10.1021/ol900674t

Aza-Darzens reaction of ethyl diazoacetate with aldimines, derived from phenyl glyoxal, furnished cis-aziridine carboxylates with excellent enantioselectivities by means of a chiral phosphoric acid.

Full text of DOI:10.1021/ol900674t

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2445-2447
Enantioselective Aza-Darzens Reaction
Catalyzed by A Chiral Phosphoric Acid
Takahiko Akiyama,* Tohru Suzuki, and Keiji Mori
Department of Chemistry, Gakushuin UniVersity, 1-5-1 Mejiro, Toshima-ku,
Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received April 1, 2009
ABSTRACT
Aza-Darzens reaction of ethyl diazoacetate with aldimines, derived from phenyl glyoxal, furnished cis-aziridine carboxylates with excellent
enantioselectivities by means of a chiral phosphoric acid.
Chiral aziridines are versatile intermediates for the prepara-
tion of optically active amines, which are employed as chiral
building blocks, intermediates, auxiliaries, and ligands.1 The
structure is also found in antitumor and antibiotic compounds
such as mitomycin and mitiromycin.2 Most of the methods
for the preparation of the chiral aziridines rely on starting
from chiral compounds.3 The development of a catalyzed
reaction is highly desired. Reactions involving asymmetric
nitrogen transfer reactions to alkene by means of transition-
metal catalysts4 as well as organocatalysts5 have been
extensively explored. The aza-Darzens reaction of R-diaz-
oacetate with aldimine is a useful method for the preparation
of aziridine carboxylates.6 Wulff and co-workers developed
a chiral Lewis acid catalyst.7,8 Quite recently, Maruoka and
co-workers reported that a chiral dicarboxylic acid also
proved to be an efficient catalyst for the aza-Darzens
reaction.9
Recently, chiral phosphoric acids have emerged as efficient
green chiral catalysts.10-12 As part of our ongoing program
on the development of chiral Brønsted acid catalyzed
reactions, we have investigated the reaction of aldimine with
R-diazoacetate catalyzed by a chiral phosphoric acid (Figure
1). Terada and co-workers already have reported the chiral
Figure 1. Chiral phosphoric acid catalysts.
phosphoric acid catalyzed alkylation reaction of R-diazoac-
etate with aldimines bearing an N-acyl moiety (Scheme 1,
(1) Sweeney, J. B. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006; p 117.
(2) Fu¨rmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2001, 649–659.
(3) For recent examples, see: (a) Forbeck, E. M.; Evans, C. D.; Gilleran,
J. A.; Li, P.; Joullie´, M. M. J. Am. Chem. Soc. 2007, 129, 14463–14469.
(b) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Simal, C. Org. Lett. 2008, 10,
4457–4460. (c) Luisi, R.; Capriati, V.; Cunto, P. D.; Florio, S.; Mansueto,
R. Org. Lett. 2007, 9, 3295–3298. (d) Musio, B.; Clarkson, G. J.; Shipman,
M.; Florio, S.; Luisi, R. Org. Lett. 2009, 11, 325–328.
(4) For the transition-metal-catalyzed addition of nitrenes to olefins,
see: (a) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39,
194–206. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328–5329. (c) Hansen, K. B.;
Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 1995, 34, 676–
678.
10.1021/ol900674t CCC: $40.75
Published on Web 04/27/2009
 2009 American Chemical Society

Scheme 1
.
Aza-Darzens Reaction versus Addition Reaction
Table 2. Effect of Solventa
entry
solvent
Et2O
CH2Cl2
CH3CN
mesitylene
benzene
toluene
3ab (yield, %)
3ac (ee, %)
1
69
72
71
76
64
78
72
89
87
81
87
89
90
94
2b
3b
4b
5
path b).13 We wish to report herein chiral phosphoric acid
catalyzed aza-Darzens reaction leading to aziridines (Scheme
1, path a).
6
7
toluene (-30 °C)
a 2.0 equiv of ethyl diazoacetate was employed. b Yield of isolated
product. c Enantiomeric excess was determined by chiral HPLC analysis.
At the outset, aza-Darzens reaction of an aldimine 2,
derived from phenylglyoxal and p-anisidine, with R-diaz-
oacetate was examined using phosphoric acid 1.14 Treatment
of 2 with ethyl diazoacetate in the presence of 10 mol % of
phosphoric acid 1 in toluene at 0 °C furnished cis-aziridine
3 accompanied by 4.15 The effects of the 3,3′-substituents
were studied, and the results are shown in Table 1. The
Interestingly, although 1d, bearing triphenylsilyl groups, was
not effective (entry 4), use of 1e having a tris(p-tert-
butylphenyl)silyl group proved to be highly effective (entry
5), and the corresponding aziridine 3 was obtained in 90%
ee. It was found that the introduction of a bulky substituent
to the terminal position on the phenyl group significantly
improved the enantioselectivity. Recently, both Yamamoto16
and List17 demonstrated the beneficial effect of introducing
a bulky group to the terminal position of the 3,3′-positions.
We then studied the effect of solvent in the presence of 5
mol % of 1e, and the results are shown in Table 2. Aromatic
Table 1. Effect of the 3,3′-Substituents of Chiral Phosphoric
Acid 1a
(9) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008,
130, 14380–14382.
(10) For reviews on Brønsted acid catalysis, see: (a) Akiyama, T.; Itoh,
J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999–1010. (b) Akiyama, T.
Chem. ReV. 2007, 107, 5744–5758. (c) Connon, S. J. Angew. Chem., Int.
Ed. 2006, 45, 3909–3912. (d) Terada, M. Chem. Commun. 2008, 4097–
4112, and references cited therein.
entry
X
3b (yield, %) 3c (ee, %) 4b (yield, %)
1
2
3
4
5
4-NO2C6H4
9-anthryl
2,4,6-(i-Pr)3C6H2
SiPh3
69
63
53
80
81
-17
-64
-88
-22
90
13
18
34
20
17
(11) For our reports, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Int. Ed. 2004, 43, 1566–1568. (b) Akiyama, T.; Morita,
H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583–2585. (c) Akiyama, T.;
Saitoh, Y.; Morita, H.; Fuchibe, K. AdV. Synth. Catal. 2005, 347, 1523–
1526. (d) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348,
999–1010. (e) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc.
2006, 128, 13070–13071. (f) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita,
H.; Fuchibe, K. Synlett 2006, 141–143. (g) Yamanaka, M.; Itoh, J.; Fuchibe,
K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756–6764. (h) Akiyama,
T.; Honma, Y.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2008, 350, 399–
402. (i) Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis 2008, 1319–1322. (l)
Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016–
4018.
Si(4-(t-Bu)C6H4)3
a 2.0 equiv of ethyl diazoacetate was employed. b Yield of isolated
product. c Enantiomeric excess was determined by chiral HPLC analysis.
enantioselectivities were determined by chiral HPLC analy-
sis. TRIP (1c) exhibited high enantioselectivity (entry 3).
(5) (a) Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem., Int.
Ed. 2006, 45, 8005–8008. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios,
R.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 778–781. (c) Pesciaioli,
F.; Vincentiis, F. D.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti,
A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703–8706.
(6) For Lewis acid catalysis, see: (a) Casarrubios, L.; Pe´rez, J. A.;
Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358–8359. (b)
Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612–1613.
(7) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099–
5100. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39,
4518–4521. (c) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007,
129, 7185–7194. (d) Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff,
W. D. Chem.sEur. J. 2008, 14, 3785–3803.
(12) For selected examples, see: (a) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356–5357. (b) Nakashima, D.; Yamamoto, H. J. Am.
Chem. Soc. 2006, 128, 9626–9627. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86. (d) Wanner,
M. J.; Haas, R. N. S. v. d.; Cuba, K. R. d.; Maarseveen, J. H. v.; Hiemstra,
H. Angew. Chem., Int. Ed. 2007, 46, 7485–7487. (e) Rowland, E. B.;
Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007,
129, 12084–12085. (f) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am.
Chem. Soc. 2008, 130, 5652–5653. (g) Wang, X.; Reisinger, C. M.; List,
B. J. Am. Chem. Soc. 2008, 130, 6070–6071. (h) Xu, S.; Wang, Z.; Zhang,
X.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, 2840–2843. (i)
Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem., Int.
Ed. 2008, 47, 5661–5665. (j) Rueping, M.; Antonchick, A. P. Angew. Chem.,
Int. Ed. 2008, 47, 5836–5838. (k) Rueping, M.; Antonchick, A. P.; Sugiono,
E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908–910. (l) Schrader,
W.; Handayani, P. P.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2009, 48,
1463–1466. (m) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2009, 131, 3430–3431.
(8) For asymmetric aziridination with chiral sulfur ylides, see: (a)
Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J.
Org. Chem. 1996, 61, 8368–8369. (b) Aggarwal, V. K.; Alonso, E.; Fang,
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40, 1433–1436.
2446
Org. Lett., Vol. 11, No. 11, 2009

solvents gave better results, and among the solvents exam-
ined, toluene exhibited the highest enantioselectivity at 0 °C
(90% ee, entry 6). Lowering the temperature to -30 °C
improved the ee to 94% without reducing the chemical yield
(entry 7).
Cleavage of the PMP protecting group on the nitrogen of
3a was effected by means of CAN to give the corresponding
aziridine 6 in 93% yield (Scheme 2). On exposure of 3a to
Next, the three-component reaction starting from phenylg-
lyoxal monohydrate, p-anisidine, and diazo acetate was
examined. Treatment of phenylglyoxal monohydrate and
p-anisidine in the presence of 2.5 mol % of 1e and MgSO4
in toluene at room temperature for 1 h, followed by the
addition of R-diazoacetate at -30 °C for 1 day gave rise to
aziridines 3a exclusively as the cis isomer18 in 95% yield
with 97% ee (entry 1). The three-component reaction gave
better results than the reaction of aldimine with diazoacetate
in terms of both chemical yield and enantioselectivity. It
should be noted that the use of 1 mol % of 1e as a catalyst
gave aziridine in 84% yield with 96% ee (entry 2). The
results with other phenylglyoxal derivatives are shown in
Table 3. A range of aldimines derived from phenyl glyoxal
Scheme 2. Transformation of Aziridine 3a
NaBH4, reduction of the ketone proceeded to give an alcohol
7 with high diastereoselectivity (>98:<2), whose relative
stereochemistry was determined by X-ray analysis of its
p-bromobenzoate 8.19
Table 3. Results of the Aza-Darzens Reactiona
Terada’s group employed aldimines with the N-acyl moiety
for the formation of the alkylation product.13 In that study,
the electron density of the nitrogen atom was decreased by
the presence of the electron-withdrawing group on the
nitrogen, and therefore, nucleophilic addition was suppressed.
In our case, the PMP group on nitrogen increased the
nucleophilicity, and aziridination was promoted.
entry
Ar
3b (yield, %)
3c (ee, %)
1
2
3
4
5
6
7
8
Ph (3a)
95
84
93
100
100
91
94
98
96
100
100
97
96
93
94
94
97
92
95
94
96
92
Ph (3a)d
In summary, chiral phosphoric acid catalyzed aza-Darzens
reaction of in situ generated aldimine with diazo acetate
proceeded smoothly to furnish aziridines with excellent
chemical yields and enantioselectivities.
4-BrC6H4 (3b)
4-ClC6H4 (3c)
4-FC6H4 (3d)
4-CF3C6H4 (3e)
4-MeC6H4 (3f)
4-MeOC6H4 (3g)
4-biphenyl (3h)
1-naphthyl (3i)
2-thienyl (3j)
Acknowledgment. This work was partially supported by
a Grant-in Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformations of Carbon Resources”
(Grant No. 19020062) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
9
10
11
a 2.0 equiv of ethyl diazoacetate was employed. b Yield of isolated
product. c Enantiomeric excess was determined by chiral HPLC analysis.
d 1.0 mol % of 1e was employed.
Note Added after ASAP Publication. A corrected
Supporting Information file was posted on May 6, 2009.
derivatives underwent the aza-Darzens reaction to furnish
corresponding aziridines with excellent ee’s. The absolute
stereochemistry of an aziridine 3b, derived from 5b (Ar )
p-BrC6H4), was unambiguously determined to be (2R,3S) by
X-ray analysis, and those of the other aziridines were
surmised by the analogy.19
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR and HPLC
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL900674T
(13) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005,
127, 9360–9361.
(18) Aziridines were obtained exclusively as the cis isomer, and the
trans isomer was not observed by 400 MHz 1H NMR in all cases
examined.
(14) An aldimine derived from benzaldehyde and p-anisidine did not
give the corresponding aziridine.
(15) R-Diazo compounds were decomposed during the purification by
(19) Crystallographic data for the structures of 3b and 8 reported in
this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC-719446 and CCDC-
722770. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (+44) 1223-
336-033; e-mail: deposit@ccdc.cam.ac.uk).
thin-layer chromatography to afford 4.
(16) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed.
2008, 47, 2411–2413.
(17) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int. Ed.
2008, 47, 5079–5081.
Org. Lett., Vol. 11, No. 11, 2009
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