A general phosphoric acid-catalyzed desymmetrization of meso-aziridines with silylated selenium nucleophiles

Article abstract of DOI:10.1039/c1ob05837a

The first example of meso-aziridine desymmetrization with selenium nucleophiles is reported. The reaction, promoted by VAPOL-hydrogen phosphate using (phenylseleno)trimethylsilane as the nucleophile, proves to be very general and highly enantioselective (84-99% ee).

Full text of DOI:10.1039/c1ob05837a

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A general phosphoric acid-catalyzed desymmetrization of meso-aziridines
with silylated selenium nucleophiles†
Matilde Senatore,a Alessandra Lattanzi,a Stefano Santoro,b Claudio Santib and Giorgio Della Sala*a
Received 26th May 2011, Accepted 12th July 2011
DOI: 10.1039/c1ob05837a
The first example of meso-aziridine desymmetrization with
selenium nucleophiles is reported. The reaction, pro-
moted by VAPOL-hydrogen phosphate using (phenylse-
leno)trimethylsilane as the nucleophile, proves to be very
general and highly enantioselective (84–99% ee).
nucleophiles,17,18 surprisingly no example has been reported with
selenium nucleophiles. Recently we reported a highly enantios-
elective desymmetrization of meso-N-acylaziridines 2 with the
readily available enantiopure VAPOL-derived phosphoric acid 119
as the catalyst and (phenylthio)trimethylsilane as the nucleophile
(Scheme 1).18 The presence of 2,3-dinitrobenzoyl as the activating
group proved to furnish the best enantioselectivities in this process.
A plausible catalytic cycle, analogous to that reported previously
for the desymmetrization with trimethylsilyl azide catalysed by
1,16e is presented in Scheme 1.
Chiral enantiopure b-aminoselenium compounds play a very
significant role in organic chemistry thanks to their biological
activity and reactivity. A broad range of medicinal properties
has recently been established.1 Although selenocysteine and its
derivatives are in a position of prominence as building blocks
for the synthesis of selenoproteins and as biologically active
compounds,2 interesting properties were also shown by different
chiral b-aminoselenides.3 These compounds, in non-racemic form,
were successfully employed as chiral ligands, especially in associ-
ation with late transition metal catalysts.4 In addition, the unique
reactivity of organoselenium compounds, compared to their sulfur
analogues, makes them highly versatile intermediates for organic
synthesis.5 In particular, chiral non-racemic b-aminoselenium
compounds, have been converted stereospecifically into enantioen-
riched aziridines,6–8 oxazolines,8,9 thiazolines,10 saturated amine
derivatives,9 allylic amine derivatives,11and pyrrolidines.12
The most straightforward method for the synthesis of enan-
tioenriched 1,2-disubstituted b-aminoselenides, with two adjacent
stereogenic carbons, is based on the chiral pool.4,7,11,13 However, in
spite of the great relevance of these products, to our knowledge
only one example of an asymmetric catalytic method has been
reported to date.14
The catalytic desymmetrization of meso-aziridines with different
nucleophiles is a highly convenient method for the synthesis
of enantioenriched b-functionalized amine derivatives, owing
to the use of a small amount of catalyst and the simultane-
ous formation of two adjacent stereocenters with the desired
relative configuration. Although many highly enantioselective
processes of desymmetrization of activated meso-aziridines have
been described,15,16 and some of them are based on sulfur
Scheme 1 Desymmetrization of meso-aziridines 2 with silylated sulfur
nucleophiles and a plausible mechanism.
The excellent results achieved in the desymmetrization of
aziridines with thiosilanes prompted us to investigate the anal-
ogous process featuring a selenosilane as nucleophile. Initially
we opted for the air- and moisture-stable selenosilane 4a.20 In
general, in the reaction of 4a with aziridine 2a catalysed by (R)-
1, good conversions were accomplished only after a very long
reaction time, but the enantioselectivity level was encouraging.
After an extensive screening of solvents we observed an unexpected
behaviour. In fact, unlike the related process with sulfur nucle-
ophiles, some aromatic solvents led to better enantioselectivies
than halogenated ones (Table 1). In toluene, in particular, full
aDipartimento di Chimica e Biologia, Universita` degli Studi di Salerno, Via
Ponte Don Melillo, 84084 Fisciano (SA), Italy. E-mail: gdsala@unisa.it;
Fax: (+)39 089 969603; Tel: (+)39 089 969554
bDipartimento di Chimica e Tecnologia del Farmaco, Universita` degli Studi
di Perugia, Via del Liceo, 06100 Perugia, Italy
† Electronic supplementary information (ESI) available: Experimental
details, characterization data and copies of 1H NMR and 13C NMR spectra
for all the unknown compounds. See DOI: 10.1039/c1ob05837a
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Table 1 Effect of solvent in the desymmetrization of aziridine 2a with
nucleophile 4aa
the less hindered (phenylseleno)trimethylsilane (4b) in place of
(phenylseleno)t-butyldimethylsilane (4a). As expected, the open-
ing of aziridine 2a, at 20 ◦C in toluene, was almost complete after 5
h, affording 3a with 92% yield and 64% ee. In 1,1,1-trichloroethane
after 7 h, 3a was obtained with 78% yield and 49% ee. Differently
from the previous reported analogous desymmetrization with
(phenylthio)trimethylsilane,18 the reaction appeared to slow down
severely after some hours. This different behaviour could be
ascribed to the lability of the actual nucleophile, PhSeH (5), that
was formed in small amount in the induction step of the catalytic
cycle (see Scheme 1). Accordingly, a modified protocol based on
the use of the mixture 4b/5 as the nucleophile was developed
(method A, Table 3). Under the latter conditions the reaction
of 2a turned out to be very fast, giving 3a in high yield (93%)
and enantioselectivity (92% ee) after 30 min. The ee was further
improved at 0 ◦C (entry 1, Table 3). When the same reaction
was ten-fold scaled up, the ee was increased up to 99%. It is
worth noting that the presence of a silylated nucleophile resulted
to be essential. In fact, unlike the desymmetrization with thiols
studied by Antilla and coworkers,17c the reaction of aziridine 2a
with PhSeH (6) catalysed by (R)-1, afforded 3a with only 45% ee
and 93% yield, after 2 h at room temperature in toluene.
Entry
Solvent
Time/days
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
ClCH2CH2Cl
CHCl3
CCl3CH3
benzene
PhCl
o-xylene
toluene
4
1
4
5
4
4
4
68
41
50
74
65
72
96
50
40
49
36
56
79
85
a Reaction performed at 0.08 mmol scale using 2a (1 equiv.), 4a (1.5 equiv.)
and 1 (0.10 equiv.) in solvent (0.1 M concentration). b Isolated yields.
c Determined by chiral HPLC.
Table 2 Scope of the desymmetrization of aziridines 2 with 4aa
A good reactivity and excellent enantioselectivity was observed
at 0 ◦C also for cyclic aziridines 2b–d (95–98% ee, entries 2–4). The
acyclic aziridines 2e,f and the seven-membered aziridine 2g turned
out to be less reactive and required the reaction to be performed at
20 ◦C. However, while the acyclic products 3e,f were obtained
in good yields (entries 5 and 6), a double amount of catalyst
and nucleophile was needed in order to obtain an acceptable
yield (method B, entry 7). Method A gave an unsatisfactory
enantioselectivity only with aromatic aziridine 2h (66% ee at 0
◦C). In that case, reverse molar ratio between nucleophile and
substrate proved to be advantageous (method C, entries 8 and 9).
The absolute configuration of product 3a was determined by
transformation into the known aminoalcohol hydrochloride 7
in two steps (Scheme 2). The almost enantiopure material was
subjected to typical conditions of cyclization9,21 affording cis-
oxazoline 6, which was then hydrolysed affording 7. The positive
[a]D measured for 7 allowed us to attribute the (1S,2R) config-
uration, by comparison with literature data,22 and consequently,
the (1R,2R) configuration to 3a. This assignment is in agreement
with the configuration previously established for the products of
desymmetrization with Me3SiSPh and with Me3SiN3 catalyzed by
phosphoric acid (R)-1.
Entry
1
2
Time/days
4
Yield (%)b
96
ee (%)c
85
2
3
4
5
7
7
63
46
38
61
99
82
37
85
4
12
a Reaction performed at 0.08 mmol scale using 2 (1 equiv.), 4a (1.5 equiv.)
and 1 (0.10 equiv.) in toluene (0.1 M concentration). b Isolated yields.
c Determined by chiral HPLC.
conversion was achieved at room temperature after 4 days, and
the b-aminoselenide 3a was obtained in 85% ee (entry 7).
The above reaction conditions were applied to different 3,5-
dinitrobenzoyl aziridines 2 (Table 2). However, although in most
cases the enantioselectivities varied from good to excellent, partial
conversions were obtained even after several days. The five
membered product 3d was obtained in both disappointing yield
and ee (entry 4).
Scheme 2 Determination of the absolute configuration of 3a.
We attributed the poor reactivity of 4a, to the steric hindrance
of the TBS group. With this in view, we submitted the substrate
2a to the same reaction conditions (see Tables 1 and 2), using
In conclusion, we have developed the first method for the enan-
tioselective synthesis of b-aminoselenides based on asymmetric
catalysis, specifically on the desymmetrization of meso-aziridines.
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Table 3 Scope of the desymmetrization of aziridines 2 with the 4b/5
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Entry
1
2
T/◦C Time/h Yield (%)b ee (%)c
0
1
94
73
74
90
72
66
46
97 (99)d
2
3
4
5
6
7e
0
6
95
0
8
98
0
2
96
20
20
20
3
92
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84
30
96
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8f
9f
20
0
7
6
97
46
72
84
a Except where otherwise specified, reaction performed at 0.08 mmol scale
using method A: 2a (1 equiv.), 4b (0.5 equiv.), 5 (1 equiv.) and 1 (0.10 equiv.)
in toluene (0.1 M concentration). b Isolated yields. c Determined by chiral
HPLC. d Reaction performed at 0.8 mmol scale. e Method B was used: 2a
(1 equiv.), 4b (1 equiv.), 5 (2 equiv.) and 1 (0.20 equiv.) in toluene (0.1 M
concentration). f Method C was used: 2a (1.5 equiv.), 4b (0.5 equiv.), 5 (0.5
equiv.) and 1 (0.10 equiv.) in toluene (0.1 M concentration).
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The process proved to be general in scope and highly enantioselec-
tive. The procedure employs a readily available enantiopure phos-
phoric acid as the catalyst and (phenylseleno)trimethylsilane as the
nucleophile. This approach allows us to obtain b-aminoselenium
compounds that are hardly accessible from the chiral pool and
can be easily elaborated, through known chemistry, to a number
of enantioenriched products. Mechanistic investigations into this
process are currently underway by our group and will be reported
in the due course.
Acknowledgements
We are grateful to M.I.U.R., National Projects PRIN2007 and
Consorzio CINMPIS for financial support. Our thanks to Mrs.
Elisabetta Rongoni for valuable experimental work.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6205–6207 | 6207
©