Asymmetric recognition and sequential ring opening of 2-substituted-N- nosylaziridines with (DHQD)2AQN and TMSNu

Article abstract of DOI:10.1039/b821650a

A new method for asymmetric ring opening of terminal aziridines using a chiral amine, (DHQD)₂AQN, is described; the reaction is based on the asymmetric recognition of aziridines using (DHQD)₂AQN and on sequential ring opening using T

Full text of DOI:10.1039/b821650a

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Asymmetric recognition and sequential ring opening of
2-substituted-N-nosylaziridines with (DHQD)2AQN and TMSNu†
Satoshi Minakata,* Yuta Murakami, Masamitsu Satake, Ikumasa Hidaka, Yuriko Okada and Mitsuo Komatsu
Received 2nd December 2008, Accepted 15th December 2008
First published as an Advance Article on the web 7th January 2009
DOI: 10.1039/b821650a
A new method for asymmetric ring opening of terminal
aziridines using a chiral amine, (DHQD)2AQN, is described;
the reaction is based on the asymmetric recognition of
aziridines using (DHQD)2AQN and on sequential ring open-
ing using TMSNu.
the reaction of N-(o-nitrobenzenesulfonyl)-2-benzylaziridine (1a)
with (DHQD)2AQN7 was examined and the results are shown in
Fig. 1 (left). Interestingly, the consumption of aziridine induced
an increase in enantio-purity, indicating that (S)-aziridine was
selectively captured by (DHQD)2AQN. Fig. 1 (right). This profile
represents the time courses of theoretical yields of (R)-1a and (S)-
1a calculated from the results in Fig. 1 (left). It is easy to see that
the chiral amine reacted faster with (S)-1a than with (R)-1a.
Aziridines are very useful building blocks for the synthesis of
biologically active compounds and functional materials.1 The
ring opening of aziridines, involving induction of chirality, leads
directly to the synthesis of valuable intermediates. The asymmetric
ring opening of aziridines has been investigated mainly with meso-
aziridines.2 Although the highly enantioselective desymmetriza-
tion of aziridines has been elegantly achieved by several groups, the
substituents of the resulting amino group are logically restricted.3
Thus far, there has been only one example of an alternative to
the asymmetric ring opening of aziridines, which is based on
the palladium-catalyzed kinetic resolution of racemic terminal
aziridines.4 However, this reaction has been limited to the use
of a phenyl group-substituted aziridine, and the enantioselectivity
is unsatisfactory. This novel method of ring opening of aziridines,
developed using TMSNu (Nu: CN, N3, Br, I) catalyzed by a simple
tertiary amine,5 would serve as the kinetic resolution of racemic
terminal aziridines using chiral tertiary amines. In particular, the
ring opening products using TMSCN are a precursor to chiral
b-amino acids.6 While the preliminary experiment unexpectedly
gave an optically active aziridine, the pathway of the reaction was
found to be different from our proposed mechanism5 based on
the activation of TMSNu with a chiral amine (vide infra). From
this background, we herein report on the asymmetric recognition
and sequential ring opening of terminal N-nosylaziridines using
TMSNu and a chiral amine.
Since the reaction of 2-benzyl-N-tosylaziridine with TMSCN
in the presence of (DHQD)2PHAL7 (20 mol%) did not give
good selectivity (ring opening product: 6% ee, aziridine: 2%
ee) to increase the reactivity of aziridine, the change to an
o-nosyl group from p-tosyl on the nitrogen of the aziridine
improved the enantioselectivity (ring opening product: 25% ee,
aziridine: 33% ee). However, the absolute configuration of the
major products (the ring opening product and the remaining
aziridine) was the same (R), indicating that the chiral amine
recognized (captured) (S)-aziridine, and the remaining aziridine
was partially opened with TMSCN in the presence of the
amine. In order to confirm the phenomenon, the time course of
Fig. 1 Time course of the reaction of 1a with (DHQD)2AQN (left) and
time courses of the theoretical yield of 1a (right).
This recognition ability of (S)-1a with (DHQD)2AQN was
applied to the sequential ring opening of the remaining (R)-
1a (Scheme 1). Aziridine 1a was treated with (DHQD)2AQN
in acetonitrile at room temperature for 75 min., and then three
equivalents of TMSCN were added to the mixture, giving the
regioselective ring opening product with cyanide in a 76% yield
with 75% ee. The chemical yield was based on the consumption
of a half-amount of the starting aziridine. The reaction time of
the first step should be very important for yield and selectivity,
and a time of 75 min. was found to be the best among several
investigations.
Department of Applied Chemistry, Graduate School of Engineering, Osaka
University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan. E-mail:
minakta@chem.eng.osaka-u.ac.jp; Fax: +81 6-6879-7402
† Electronic supplementary information (ESI) available: Synthetic proce-
dures and experimental data for the products. See DOI: 10.1039/b821650a
Scheme 1 Asymmetric recognition of 1a with (DHQD)2AQN and its ring
opening with TMSCN.
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Table 1 Asymmetric ring opening of arylmethylated N-nosylaziridines with TMSCN
Entry
1
Ar
Time (min)
75
Yielda (%)
70
eeb (%)
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
87
2
3
4
5
90
75
68
62
72
68
80
81
86
82
60
120
6
7
1g
1h
105
90
2g
2h
78
72
75
95
a Isolated yield based on consumption of half the amount of aziridine 1. b Determined by chiral HPLC.
As described in the introduction, the ring opening products
of terminal aziridines with TMSCN are versatile precursors
of chiral b-amino acids and b-lactams. Among them, b-homo
phenylalanine is currently of great interest for m-type opioid
receptor affinity.8 The demand for this type of b-amino acid
prompted us to investigate the enantioselective ring opening of
arylmethylated aziridines, which are readily prepared from the
aziridination of allyl arenes using our method.9 The asymmetric
recognition and sequential ring opening of arylmethylated N-
nosylaziridines with TMSCN was examined in Table 1.
The reaction time for the recognition of electron-sufficient,
aromatic-substituted aziridines tended to be rather longer than
that of electron-deficient ones. The ring opening reactions pro-
ceeded with good to excellent enantioselectivity. In particular,
thiophenylmethylaziridine 1h ring-opened efficiently to afford a
precursor of a unique b-amino acid. Consequently, this is the first
example of the asymmetric ring opening of terminal aziridines
with TMSCN.
In addition to TMSCN, TMSN3 and TMSI were applicable to
the ring opening reaction, as reported in our previous work.5 Thus,
these TMSNu were employed in the ring opening of 1h to give the
corresponding products in good enantioselectivity (Scheme 2).
In addition to arylmethyl-substituted terminal aziridines, n-
hexyl-substituted aziridine was also applicable to the ring opening
reaction. Although the selectivity of the reaction was rather
low compared with that of arylmethylated aziridines, chiral ring
opening products with cyanide, azide and iodide were obtained
with moderate enantioselectivity.10
Scheme 2 Asymmetric ring opening of 1h with TMSNu.
On the other hand, adducts of 1 with (DHQD)2AQN were
separated from the mixtures of the reactions shown in Scheme 1
and Table 1 using flash column chromatography on silica gel
(eluent: MeOH/diethylamine = 50/50). The FAB mass spectrum
of aziridine 1a trapped by (DHQD)2AQN shows peaks at 1175
and 1493, which are attributed to peaks of a mixture of 1:1
and 2:1 adducts of 1a and (DHQD)2AQN. The analysis of the
1H NMR spectra of the adducts was very difficult because so
many signals were observed, but the signal of the a-hydrogen
of the quinoline moiety did not shift compared with that of
(DHQD)2AQN. Moreover, the polarity of the adduct was very
high. From these results, the structure of the adducts would be
salts that are formed by the ring opening of 1a with a tertiary
amine (nitrogen of quinuclidine) of (DHQD)2AQN.10
Much effort was devoted to the liberation of the enantio-
enriched aziridine unit from the adducts. For example, although
the adduct of 1a with (DHQD)2AQN was treated with TMSCN
(5 equiv) in acetonitrile at refluxing temperature for 24 h, the
reaction did not proceed at all. Consequently, the nosyl group was
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deprotected using Fukuyama’s method11 followed by a reaction
with phenyl isocyanate to give a chiral cyclic urea (Scheme 3). The
starting adduct, which was recovered from the reaction shown in
Scheme 1, was used for this reaction.
2 (a) Z. D. Zhang and R. Scheffold, Helv. Chim. Acta, 1993, 76, 2602;
(b) M. Hayashi, K. Ono, H. Hoshimi and N. Oguni, J. Chem. Soc.,
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Shibasaki, J. Am. Chem. Soc., 2005, 127, 11252; (c) I. Fujimori,
T. Mita, K. Maki, M. Shiro, A. Sato, S. Furusho, M. Kanai and
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4 W.-H. Leung, W.-L. Mak, E. Y. Y. Chan, T. C. H. Lam, W.-S. Lee, H.-L.
Kwong and L.-L. Yeung, Synlett, 2002, 1688.
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2005, 7, 3509.
Scheme 3 Transformation of the adduct of 1a to (DHQD)2AQN.
6 (a) S. Abele and D. Seebach, Eur. J. Org. Chem., 2000, 1; (b) F. Fu¨lo¨p,
Chem. Rev., 2001, 101, 2181; (c) M. Liu and M. P. Sibi, Tetrahedron,
2002, 58, 7991.
7 S. G. Hentges and K. B. Sharpless, J. Am. Chem. Soc., 1980,
102, 4263 (DHQD)2PHAL is a good chiral source for asymmet-
ric silylcyanation of ketones. See: S.-K. Tian, R. Hong and L.
Deng, J. Am. Chem. Soc., 2003, 125, 9900. However, (DHQD)2AQN
was better than (DHQD)2PHAL for the present asymmetric
induction.
8 L. Longobardo, D. Melck, R. Siciliano, A. Santini, V. D. Marzo and
G. Cammarota, Bioorg. Med. Chem. Lett., 2000, 10, 1185.
9 (a) T. Ando, D. Kano, S. Minakata, I. Ryu and M. Komatsu,
Tetrahedron, 1998, 54, 13485; (b) S. Minakata, D. Kano, Y. Oderaotoshi
and M. Komatsu, Angew. Chem., 2004, 116, 81; S. Minakata, D. Kano,
Y. Oderaotoshi and M. Komatsu, Angew. Chem., Int. Ed., 2004, 43,
79.
In summary, this paper describes the asymmetric ring opening
of aziridines based on chiral recognition and sequential ring
opening. Although good methods have been in use for the
asymmetric ring opening of meso-aziridines thus far, this is the
first example presenting high selectivity for the ring opening of
terminal aziridines, and this method contributes to the supply of
a new series of chiral b-amino acids.
Notes and references
1 (a) J. B. Sweeny, Chem. Soc. Rev., 2002, 31, 247; (b) D. Tanner, Angew.
Chem., 1994, 106, 625; D. Tanner, Angew. Chem., Int. Ed. Engl., 1994,
33, 599; (c) A. Padwa, W. H. Pearson, B. N. Lian, S. C. Bergmeier,
in Comprehensive Heterocyclic Chemistry II, Vol. 1A (Eds.: A. R.
Katritzky, C. W. Rees and E. F. Scriven), Pergamon, Oxford, 1996,
pp. 1-60; (d) A. Padwa, A. D. Woolhouse, InComprehensive Heterocyclic
Chemistry Vol. 7 (Ed.: W. Lwowski), Pergamon, Oxford, 1984.
10 See Supporting Information for details†.
11 W. Kurosawa, T. Kan and T. Fukuyama, Org. Synth., 2004, 10, 482.
The deprotected product was not isolated and the resulting mixture
was treated with the isocyanate.
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 641–643 | 643
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