Desymmetrization of meso-N-acylaziridines with benzenethiols promoted by α,α-Diaryl-L-prolinols

Article abstract of DOI:10.1002/ejoc.200900095

α,α-Diaryl-L-prolinols were disclosed to promote the desymmetrization of meso-N-acylaziridines with benzenethiols to afford the products in good yields and moderate enantioselectivities (up to 61% ee), which can be greatly improved to >90% ee after a sing

Full text of DOI:10.1002/ejoc.200900095

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900095
Desymmetrization of meso-N-Acylaziridines with Benzenethiols Promoted by
α,α-Diaryl- -prolinols
L
Alessandra Lattanzi*[a] and Giorgio Della Sala[a]
Keywords: Desymmetrization / Aziridines / Organocatalysis / Amino alcohols / Asymmetric catalysis
α,α-Diaryl-
L
-prolinols were disclosed to promote the desym-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
metrization of meso-N-acylaziridines with benzenethiols to
afford the products in good yields and moderate enantio-
selectivities (up to 61% ee), which can be greatly improved
to Ͼ90% ee after a single recrystallization.
Introduction
based promoters proved to catalyze the opening of N-sulfon-
ylaziridines with thiols achieving moderate levels of asym-
metric induction.[10] Notably, the desymmetrization of N-
acylaziridines with TMSN3 catalyzed by chiral phosphoric
acids afforded the products in high enantioselectivity.[11]
Very recently, 1,3-dicarbonyl compounds were employed as
nucleophiles in the highly diastereo- and enantioselective
opening of N-tosyl-protected aziridines under phase-trans-
fer catalysis.[12] Thus, the development of catalytic systems
for the desymmetrization of meso-aziridines, which are of
general scope with respect to structure of aziridine, nitrogen
protective group and nature of the nucleophile, turns out to
be problematic. Indeed, it seems that catalytic ad hoc sys-
tems can be synthetically useful for the desymmetrization
of specific aziridines.
Recently, we disclosed that α,α-diaryl--prolinols pro-
mote asymmetric Michael additions, such as the epoxid-
ation of α,β-enones,[13] the β-peroxidation of nitroalkenes[14]
and the malonate ester addition to nitroalkenes[15] with high
to moderate levels of enantioselectivity. We proposed a dual
mode of activation of the nucleophile and the electrophile
provided by the amine and the hydroxy groups of these or-
ganocatalysts, respectively. We were intrigued to check the
effectiveness of α,α-diaryl--prolinols as promoters in a
mechanistically different process such as the ring opening
of meso-aziridines with thiols (Figure 1).
The elaboration of novel methodologies relying on the
use of chiral organocatalysts is an area of intensive investi-
gation in organic synthesis.[1] The simplicity of the reaction
conditions as well as the accessibility to a great variety of
organic compounds, to use as the promoters, constitute the
most attracting features of the organocatalysis methodolo-
gies. Simultaneous generation of two contiguous chiral
centres in a molecule is a powerful process, which serves to
estabilish a high degree of functionalization. Ring opening
of small heterocyclic compounds, like optically pure epox-
ides and aziridines, represents one of the possible routes to
achieve such a goal in an enantioselective manner.[2] In this
regard, although being rather challenging to differentiate
two enantiotopic centres, the opening of meso compounds
is an appealing process thanks to the use of achiral starting
materials. Several methologies have been reported for the
desymmetrization of meso-epoxides with various nucleo-
philes by either using metal-catalyzed asymmetric systems[3]
or enzymes,[4] but, quite surprisingly, the enantioselective
ring opening of meso-aziridines has received much less at-
tention. The first examples of asymmetric metal-catalyzed
desymmetrization of aziridines with carbon and heteroatom
nucleophiles were reported by Oguni,[5] Müller[6] and Ja-
cobsen.[7] Recently, highly enantioselective desymmetri-
zation of N-acylaziridines has been developed by Shibasaki[8]
employing TMSCN and TMSN3 with chiral Gd or Y com-
plexes and by Kobayashi treating N-arylaziridines with ani-
lines as nucleophiles in the presence of Nb-BINOL com-
plexes.[9] In the field of organocatalysis, cinchona alkaloid
We reasoned that the amine group would deprotonate
the thiol, thus generating the reactive nucleophile, while the
aziridine might be activated and preferentially orientated by
hydrogen bonding between the catalyst OH group and an
appropriate protecting group on the nitrogen atom (e.g. the
carbonyl oxygen atom in case of an N-acylaziridine). This
simultaneous activation of the reacting partners provided
by the chiral promoter would likely result in an enantiose-
lective desymmetrization process.
[a] Dipartimento di Chimica, Università di Salerno,
Via Ponte don Melillo, 84084 Fisciano, Italy
Fax: +39-089-969603
E-mail: lattanzi@unisa.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 1845–1848
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1845

A. Lattanzi, G. Della Sala
SHORT COMMUNICATION
Table 1. Desymmetrization of meso-aziridine 1a with thiophenol
(2a) promoted by compounds 3.[a]
Entry
3
Solvent
T
[°C]
t
[h]
Yield of 4a ee of 4a
[%][b]
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[d]
3a
3a
3a
3a
3a
toluene
p-xylene
m-xylene
hexane
25
25
25
25
25
24
22
16
22
21
22
23
24
24
22
24
21
24
48
72
73
30
65
67
34
17
48
66
55
67
61
69
33
88
Ͻ5
87
88
84
62
40
25
43
9
Figure 1. Proposed bifunctional mode of action of α,α-diaryl--
prolinol as promoter for the desymmetrization of meso-N-acyl-
aziridines.
CH2Cl2
3a ClCH2CH2Cl 25
47
42
49
52
52
53
–6
18
n.d.
51
50
47
51
3a
3b
3c
3d
3e
3f
3g
3d
3d
3d
3d
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
m-xylene
CHCl3
25
25
25
25
25
25
25
–6
–6
4
Results and Discussion
Initially, we studied the desymmetrization of model N-
acylaziridine 1a with thiophenol (2a) using 20 mol-% load-
ing of commercially available α,α-diphenyl--prolinol (3a)
[Equation (1)].
25
[a] Reaction performed at 0.2 mmol scale of 1a, 1.1 equiv. of 2a,
20 mol-% of 3 at c = 0.2 . [b] Yields after flash chromatography.
[c] Determined by chiral HPLC analysis. Absolute configuration
(1R,2R) was determined by comparison with the optical rotation
reported in the literature. [d] Using 10 mol-% of 3d.
(1)
Table 1 illustrates the results of the optimization process.
To our delight, compound 3a was able to catalyze the ring
opening of N-acylaziridine 1a when carrying out the reac-
tion at room temperature in toluene as the solvent (En-
try 1). The trans product 4a was isolated in good yield and
40% ee. The absolute configuration of 4a was estabilished
to be (1R,2R) by comparison of the optical rotation re-
ported in the literature.[5b] Different aromatic and haloge-
nated solvents were then checked, and a slight improvement
of the enantioselectivity was realized when chloroform was
used (Entry 7).
Figure 2. Catalysts tested in the model desymmetrization process.
The efficiency of various α,α-diaryl--prolinols in CHCl3
at room temperature was then examined (Figure 2). Substi-
tution on the phenyl rings in organocatalysts 3b–3d did not
affect the level of asymmetric induction (Entries 8–10), al-
though a better conversion was achieved when alkyl-substi-
tuted promoters were employed (Entries 8 and 10). The re-
action performed with the O-methylated compound 3e con-
firmed the key role played by the free OH group in the
catalysis (Entry 11).
Indeed, the conversion decreased, and an unselective de-
symmetrization process occurred. -Prolinol proved to be
highly active, although the reaction proceeded with poor
stereocontrol (Entry 12). Finally, -proline was found com-
pletely inactive (Entry 13). Reactions performed at lower
temperatures and in different solvents, using the most active
compound 3d, unexpectedly afforded the product with
slightly decreased ee (Entries 14–16). Catalyst 3d could be
Figure 3. ee vs. molarity for the reaction of 1a with 2a catalyzed
by 20 mol-% of 3d at room temperature in CHCl3.
An almost constant level of the enantioselectivity was
successfully employed at 10 mol-% loading (Entry 17). observed for the reactions carried out from 0.4 to 0.02 
Some experiments were then carried out at different molar concentration. This indicates that the organocatalyst does
concentrations by using catalyst 3d to see the effect on the not give rise to autoaggregation phenomena, which is in
enantioselectivity (Figure 3).
agreement with linear effects[16] previously observed in the
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Eur. J. Org. Chem. 2009, 1845–1848

Desymmetrization of meso-N-Acylaziridines
epoxidation of α,β-enones promoted by 3a with tert-butyl Table 3. Desymmetrization of aziridine 1d with benzenethiols 2
promoted by 3a in CHCl3 at 25 °C.[a]
hydroperoxide,[13a] thus suggesting that a single molecule of
the catalyst should be involved in the ring-opening process.
Aziridines are versatile electrophiles, whose reactivity can
be finely tuned by proper modification of the nitrogen pro-
tecting group. Hence, a variety of aziridines were treated
with thiol 2a under the optimized conditions employing cat-
alysts 3a and 3d (Table 2). As expected, two nitro groups
on the phenyl ring activated the aziridine 1b, and, after few
hours, the product was formed in satisfactory yield, but in
racemic form (Entry 1). The unsubstituted less reactive azir-
idine 1c furnished the product in 54% ee (Entry 2). When
using catalyst 3d as the promoter, a significant improvement
in the yield and slightly better ee were observed (Entry 3).
Aziridine 1d, bearing the 1-naphthoyl-substitution on the
nitrogen atom, gave the product in good yield and 61% ee
(Entry 4).
Entry
2
4
Yield [%][b]
ee [%][c]
1[d]
2[e]
3
PhSH
4c
4h
4i
71 (68)
50
64 (65)
61
61 (Ͼ99)
4-tBuC6H4SH
4-MeC6H4SH
2-MeC6H4SH
4-MeOC6H4SH
4-BrC6H4SH
54
55 (93)
50
4[e]
5
4j
4k
4l
4m
79
82
52
56
6[d]
7
2-naphthalenethiol
77
37
[a] Reaction performed at 0.2 mmol scale of 1a, 1.1 equiv. of 2,
20 mol-% of 3a at c = 0.4 . [b] Yields after flash chromatography;
yields after recrystallization are reported in parentheses. [c] ee de-
termined by chiral HPLC; ees after recrystallization are reported
in parentheses. [d] Reaction performed at c = 0.2 . [e] Using
30 mol-% of 3a.
Table 2. Desymmetrization of meso-aziridines 1 with thiophenol
(2a) promoted by compounds 3a and 3d in CHCl3 at 25 °C.[a]
Good yields of the ring-opened products were generally
observed. The nature of substituents seems to slightly affect
the stereocontrol, as para- and ortho-substituted ben-
zenethiols afforded compounds 4 in comparable ees (En-
tries 2–6).[17] A lower ee was observed when sterically more
demanding 2-naphthalenethiol was used (Entry 7). Com-
pounds 4 were obtained as solids, and their optical purity
could be efficiently enhanced to excellent ee values after
only a single recrystallization, which makes the methodol-
ogy synthetically more attractive (Entries 1 and 3).[18]
Conclusions
We have developed a novel catalytic desymmetrization
methodology of N-acylaziridines with benzenethiols pro-
moted by simple α,α-diaryl--prolinols. Among the cata-
lysts tested, commercially available α,α-diphenyl--prolinol
proved to be the most efficient. The products were isolated
in good yields and moderate ees, which can be improved to
high levels by a single recrystallization. With this work we
showed that α,α-diaryl--prolinols can act as promoters to
be considered useful in mechanistically different processes.
This contributes to enlarge their synthetic applications and
find a place among well-known classes of bifunctional or-
ganocatalysts. Further investigations on the full scope of
the desymmetrization of meso-aziridines are underway.
[a] Reaction performed at 0.2 mmol scale of 1a, 1.1 equiv. of 2a,
20 mol-% of 3 at c = 0.2 . [b] Yields after flash chromatography.
[c] Determined by chiral HPLC analysis.
The use of 3d led to a satisfactory conversion, but a lower
ee was detected (Entry 5). The ortho-methoxyphenyl-substi-
tuted aziridine afforded the product in good yield and 57%
ee when catalyst 3a was used (Entry 6). Again, the use of
promoter 3d was detrimental for the stereocontrol (En-
try 7). When the ortho-(trifluoromethyl)phenyl-substituted
aziridine was employed, a good conversion was observed
with catalyst 3a, but the enantioselectivity dropped to 36%
(Entry 8). Surprisingly, N-tosylaziridine 1g reacted slug-
gishly either in chloroform or toluene as the solvents (En-
tries 9 and 10).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterizations of unknown
aziridines and ring-opened products.
Acknowledgments
The scope of the reaction with respect to different ben-
zenethiols using aziridine 1d with 20 mol-% of 3a in chloro-
form was investigated next (Table 3).
The Ministero Italiano dell’Università
(MIUR) is gratefully acknowledged for financial support. Dr. Pa-
trizia Iannece is acknowledged for MS analyses.
e Ricerca Scientifica
Eur. J. Org. Chem. 2009, 1845–1848
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1847

A. Lattanzi, G. Della Sala
SHORT COMMUNICATION
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Received: January 28, 2009
Published Online: March 16, 2009
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