Catalytic enantioselective ring-opening reaction of meso-aziridines with α-isothiocyanato imides

Article abstract of DOI:10.1002/chem.201300297

Open up your chemistry! By using cinchonine-based trimeric quaternary ammonium salts as catalysts, meso-aziridines can be ring-opened, in an enantioselective manner, through nucleophilic addition of the sulfur atom of α-isothiocyanato imides (see scheme;

Full text of DOI:10.1002/chem.201300297

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DOI: 10.1002/chem.201300297
Catalytic Enantioselective Ring-Opening Reaction of meso-Aziridines with
a-Isothiocyanato Imides
Yi-Ming Cao,[a] Fu-Ting Zhang,[a] Fang-Fang Shen,[a] and Rui Wang*[a, b]
Catalytic asymmetric transformations employing a-iso-
thiocyanato compounds have recently been successful and
have captured considerable attention as powerful methods
for the synthesis of various kinds of useful chiral com-
pounds. By using this kind of versatile reactant as the nucle-
ophile, the enantioselective Aldol-type,[1] Mannich-type,[2]
and Michael addition reactions[3] have been developed to
access the highly optically active b-hydroxy/amino-a-amino
acid derivatives and spiro compounds. In a general mode of
these reactions, the a-isothiocyanato compounds serve both
as a nucleophile and electrophile; they are enolized by de-
Scheme 1. Proposed reaction mode of a-isothiocyanato compounds.
protonation at their a-carbon atom by a base catalyst and
then nucleophilic attack at the electron-deficient double
bonds (ketone/aldehyde, imine, or olefin). The anion (O, N,
or C) generated in the addition process is subsequently
quenched by the electron-deficient carbon atom in the iso-
thiocyanate moiety.[4] Based on the above-mentioned reac-
tion course, we hypothesized that the enolized a-isothiocya-
nato compounds intermediate (Scheme 1, I1) might also be
able to self-cyclize by trapping the oxygen anions of the
enolate by the isothiocyanate. Thus, the enolized intermedi-
ate undergoes an equilibrium in a-isothiocyanate–thiooxa-
zole (I2, I3) tautomerism. As the electrophiles employed in
previous work were all restricted to electron-deficient
double bonds, which prefer to undergo the nucleophilic
attack by the enolate, no adducts of thiols were isolated. We
envisaged that if a kind of appropriate electrophile were
used to trap the thiooxazole intermediate (I2), not only the
scope of reaction type of the versatile a-isothiocyanato com-
pounds could be extended, but also a new methodology for
the synthesis of useful 2-thiooxazole-containing organic mol-
ecules could be developed.
To test our hypothesis, a-isothiocyanato imide 2a was
treated with tert-butoxycarbonyl (Boc) anhydride and 4-di-
methylaminopyridine (DMAP) in the presence of catalytic
N,N-diisopropylethylamine (DIPEA) at room temperature
in CH2Cl2 (Scheme 2). To our delight, the product I3’ was
isolated in 83% yield, thus demonstrating the existence of
the thiooxazole intermediate under the basic conditions. We
[a] Y.-M. Cao, F.-T. Zhang,+ F.-F. Shen,+ Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, State Key Laboratory of Applied Organic Chemistry
Institute of Biochemistry and Molecular Biology
School of Life Science, Lanzhou University
Lanzhou 730000 (P. R. China)
Scheme 2. Trapping the thiooxazole intermediate by aziridine ring open-
ing. PG=3,5-dinitrobenzoyl.
E-mail: wangrui@lzu.edu.cn
[b] Prof. Dr. R. Wang
State Key Laboratory of Chiroscience
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University, Kowloon
Hong Kong (P. R. China)
then focused on the development of a suitable reaction that
is able to trap the desired intermediate and afford the prod-
ucts with practical significance. Aziridines are considered to
be very useful precursors for the production of a variety of
chiral amines by the asymmetric nucleophilic ring-opening
reaction.[5] Different kinds of nucleophiles were employed in
the catalytic enantioselective ring opening of meso-aziri-
E-mail: bcrwang@polyu.edu.hk
[+] These two authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300297.
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Table 1. Optimization of the asymmetric ring opening.[a]
dines.[6] Recently, the catalytic asymmetric meso-aziridine
ring opening with sulfur-based nucleophiles has also been
developed,[7] the chiral b-aminosulfur adducts of such reac-
tions have considerable usefulness both in drug develop-
ment and asymmetric catalysis (chiral ligand synthesis).[8]
However, the sulfur-based nucleophiles used in the enantio-
selective ring-opening reaction are mainly confined to thio-
phenols and their derivatives, and this substrate scope limi-
tation is a large obstacle of such methodology for the syn-
thesis of diverse chiral b-aminosulfur adducts. We envi-
sioned that an activated meso-aziridine would prefer to un-
dergo the sulfur-based nucleophilic attack of the thiooxazole
intermediate I2 rather than the enolate I1 generated from
the a-isothiocyanato imide (see Scheme 1) and such a reac-
tion not only can extend the scope of thiol nucleophiles in
the aziridine ring-opening process, but also provides b-ami-
nothiooxazole compounds with significant biological activi-
ties (Figure 1).[9] To explore the feasibility of the proposed
transformation, aziridine 1a and a-isothiocyanato imide 2a
were chosen for the model reaction. Gratifyingly, in the
presence of K2CO3 and catalytic tetra-n-butylammonium
Entry
1
Cat.
Base
T
Yield
[%][b]
ee
[8C]
[%][c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1a
1a
1a
4a
4a
4b
4c
4d
4e
4 f
4 f
4 f
4 f
4 f
4 f
4 f
4g
K2CO3 (aq) 30% wt.
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
K2CO3 (s)
Cs2CO3 (s)
Cs2CO3 (s)
Cs2CO3 (s)
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
À40
À25
93
98
99
85
93
95
96
95
94
98
99
99
93
96
40
50
48
43
19
55
66
3
36
47
35
70
92
92
9
10
11
12
13[d]
14[e]
Figure 1. Bioactive 2-thiooxazole or b-aminothiooxazole containing com-
pounds.
[a] Unless otherwise specified, the reaction was performed on a 0.1 mmol
scale with 1 (1.1 equiv), 2 (1.0 equiv), base (3.0 equiv), and catalyst
(20 mol%) in solvent (4 mL). The reaction time was 1 h. [b] Yield of iso-
lated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] The reaction time is 72 h. [e] The reaction time is 18 h.
bromide (TBAB), the reaction proceeded smoothly in tol-
uene at room temperature, providing the adduct 3aa in
97% yield (Scheme 2).[10]
Encouraged by the successful synthesis b-aminothiooxa-
zole adduct 3aa, we decided to develop an asymmetric ver-
sion of such a transformation, since the acquirement of opti-
cally active products would be vital for its application on the
synthesis of bioactive compounds as well as chiral ligands.
As it was demonstrated above that the reaction proceeded
efficiently by using phase-transfer catalysis (PTC), our initial
investigation began with the reaction between meso-aziri-
dines 1 and isothiocyanato imide 2a in PTC conditions at
room temperature in the presence of a chiral quaternary
ammonium salt at a 20 mol% loading (Table 1).[11,12] To our
delight, readily accessible cinchona alkaloid-type catalyst 4a
in combination with solid K2CO3 gave the desired product
in excellent yield and a promising 50% enantiomeric excess
(ee) (Table 1, entry 2). However, the further steric tuning of
the catalyst 4a did not achieve a more satisfactory result
(entries 3, 4). To address the need for enhanced enatioselec-
tivity, we then screened various cinchona alkaloid-based di-
meric or trimeric quaternary ammonium salts, which may
provide a stronger chiral environment for the reaction tran-
sition state.[13] It was recognized that the distance between
the quaternary ammonium catalytic centers was crucial for
the stereocontrol, since although 4d afforded a very poor
result (entry 5), the catalyst 4e with a relatively shorter dis-
tance between ammonium ion gave the product in an in-
creased 55% ee (entry 6). The trimeric catalyst 4 f with a
bulkier environment gave the product with the best enatio-
selectivity (66% ee, entry 7). Variation of the protecting
group on meso-aziridines 1 had significant effect on the
result in terms of stereochemical control (entries 7–11), and
the 3,5-di-tert-butylbenzoyl-protected substrate 1b furnished
the product in an almost racemic form (entry 8). It was re-
vealed that the strong electron-withdrawing 3,5-dinitroben-
zoyl group was the most suitable one in this process. A fur-
ther increased ee was achieved when Cs2CO3 was used
(entry 12). Lowering the temperature had a dramatically in-
cremental effect on the enatioselectivity. When the reaction
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Catalytic Enantioselective Ring-Opening Reaction of meso-Aziridines
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was conducted at À408C, it gave the product in a satisfacto-
ry 92% ee, despite the longer time needed for the comple-
tion of the reaction (entry 13).[14] Additionally, the dihydro-
cinchonine-based trimeric catalyst 4g was also tested in the
model reaction, and the product was afforded with the same
excellent results as 4 f produced, but in a shorter time with a
milder temperature (entry 14).
With the optimized reaction conditions in hand, the sub-
strate scope of the catalytic asymmetric ring-opening reac-
tion was next investigated and a series of chiral b-amino-
thiooxazole compounds were synthesized (Scheme 3). Be-
sides 1a, other types of six-membered ring meso-aziridines
resulted in the formation of the products in excellent yield
and with good to excellent ee (3ja, 3ka, 3la). In addition to
a-isothiocyanato imide 2a, a-substituted substrate 2b also
proved to be amendable to this method, giving the 4-methyl
2-thiooxazole containing compound 3ab with excellent re-
sults. The structure of 3aa was determined by X-ray crystal-
lography and its absolute configuration was determined
from a known compound (see the Supporting Information
for details).[15]
Since the readily accessible 2-amino ethanol derivative
with appropriate protecting group can be transformed to the
corresponding aziridine under basic conditions, we surmised
that this kind of compound may serve as the precursor of
the reactant and generate the aziridine in situ in our estab-
lished catalytic system. Gratifyingly, the racemic compound
5 reacted smoothly in the process, furnishing the desired
product 3aa in excellent yield and ee (Scheme 4). The pre-
sented improved method allows the use of more easily avail-
able chemical compounds as reactants and thereby increases
its practicability.
Scheme 4. Reaction with a 2-amino ethanol derivative. PG=3,5-dinitro-
benzoyl.
In summary, aziridines were discovered to be suitable
electrophiles for trapping the 2-thiooxazole intermediate
generated from a-isothiocyanato imide under basic condi-
tions, and a catalytic asymmetric ring-opening reaction of
a-isothiocyanato imides to meso-aziridines was developed.
This procedure not only extends the scope of sulfur-based
nucleophiles for enantioselective ring opening of meso-aziri-
dines, but also provides an efficient methodology for the
synthesis of a variety of chiral b-aminothiooxazole com-
pounds with practical significance. Further applications of
using a-isothiocyanato compounds in the asymmetric organ-
ic synthesis are ongoing.
Scheme 3. Synthesis of chiral b-aminothiooxazole compounds. Unless
otherwise specified, the reaction was performed on a 0.1 mmol scale with
1 (1.1 equiv), 2 (1.0 equiv), base (3.0 equiv), and catalyst (20 mol%) in
solvent (4 mL) at À258C. PG=3,5-dinitrobenzoyl.
Experimental Section
Catalyst 4g (0.020 mmol, 20 mol%), a-isothiocyanato imide 2a
(0.10 mmol, 1.0 equiv), and meso-aziridine 1a (0.11 mmol, 1.1 equiv)
were dissolved in dry toluene (4 mL) at À258C and then Cs2CO3
(0.3 mmol, 3 equiv) was added to the reaction. After 18 h, the mixture
was concentrated and applied to silica gel for purification of the desired
product 3aa. Yield is of isolated product, and the enantiomeric excess
was determined by HPLC analysis on a chiral stationary phase.
also reacted smoothly, and the corresponding products were
obtained in excellent yield and with good enantioselectivity
(3aa, 3 fa, 3ga). Different ring sizes of the substrates were
tolerated in the presented catalytic system, affording 3ha
and 3ia with good results (a seven-membered ring substrate
is comparably reluctant to undergo this reaction as more
than 96 h was needed to complete the transformation). Azir-
idines containing acyclic aliphatic and aryl substituents also
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Acknowledgements
We are grateful for the grants from the National Natural Science Founda-
tion of China (Nos. 91213302, 20932003, and 21272102), the Key National
S&T Program “Major New Drug Development” of the Ministry of Sci-
ence and Technology of China (2012ZX09504001–003) and the Program
for Changjiang Scholars and Innovative Research Team in University
(PCSIRT: IRT1137).
Keywords: asymmetric synthesis · aziridines · isothiocyanato
compounds · ring-opening reactions · synthetic methods
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or trimeric quaternary ammonium salts, see: a) S.-S. Jew, J.-H. Lee,
B.-S. Jeong, M.-S. Yoo, M.-J. Kim, Y.-J. Lee, J. Lee, S.-H. Choi, K.
Lee, M. S. Lah, H.-G. Park, Angew. Chem. 2005, 117, 1407–1409;
Angew. Chem. Int. Ed. 2005, 44, 1383–1385; b) H.-G. Park, B.-S.
Jeong, M.-S. Yoo, J.-H. Lee, B.-S. Park, M. G. Kim, S.-S. Jew, Tetra-
hedron Lett. 2003, 44, 3497–3500; c) H.-G. Park, B.-S. Jeong, M.-S.
Yoo, J.-H. Lee, M.-K. Park, Y.-J. Lee, M.-J. Kim, S.-S. Jew, Angew.
Chem. 2002, 114, 3162–3164; Angew. Chem. Int. Ed. 2002, 41, 3036–
3038; d) H.-G. Park, B.-S. Jeong, M.-S. Yoo, M.-K. Park, H. Huh, S.-
[14] When the cinchonidine derived 4 f was employed, the ent-3aa was
obtained with poor enatioselectivity (30% ee).
[15] CCDC-920508 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/
data_request/cif.
Received: January 25, 2013
Revised: May 8, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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R. Wang et al.
Asymmetric Synthesis
Y.-M. Cao, F.-T. Zhang, F.-F. Shen,
R. Wang* ...................... &&&& — &&&&
Catalytic Enantioselective Ring-
Opening Reaction of meso-Aziridines
with a-Isothiocyanato Imides
Open up your chemistry! Using cin-
chonine-based trimeric quaternary
ammonium salts as catalysts, meso-azir-
idines can be ring opened, in an enan-
tioselective manner, through nucleo-
philic addition of the sulfur atom of a-
isothiocyanato imides (see scheme;
PG=protecting group). This synthetic
method provides an efficient way to
access useful chiral b-aminothiooxa-
zole compounds.
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!