Noncovalent organocatalytic synthesis of enantioenriched terminal aziridines with a quaternary stereogenic center

Article abstract of DOI:10.1021/ol3017066

A high-yielding and enantioselective access to novel N-Boc terminal aziridines, bearing a quaternary stereogenic center, has been developed via an aza-Michael initiated ring-closure (aza-MIRC) reaction of α-acyl acrylates with an N-tosyloxy tert-butyl carbamate catalyzed by a chiral amino thiourea. The feasibility of the aziridine regioselective ring-opening to valuable α,α-disubstituted α-amino acid esters has been demonstrated.

Full text of DOI:10.1021/ol3017066

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4078–4081
Noncovalent Organocatalytic Synthesis of
Enantioenriched Terminal Aziridines with
a Quaternary Stereogenic Center
Claudia De Fusco,† Tiziana Fuoco,† Gianluca Croce,‡ and Alessandra Lattanzi*,†
ꢀ
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Ponte don Melillo,
84084 Fisciano, Italy, and DISIT-Universita del Piemonte Orientale, Viale T. Michel 11,
ꢀ
15121, Alessandria, Italy
lattanzi@unisa.it
Received June 21, 2012
ABSTRACT
A high-yielding and enantioselective access to novel N-Boc terminal aziridines, bearing a quaternary stereogenic center, has been developed via
an aza-Michael initiated ring-closure (aza-MIRC) reaction of r-acyl acrylates with an N-tosyloxy tert-butyl carbamate catalyzed by a chiral amino
thiourea. The feasibility of the aziridine regioselective ring-opening to valuable R,R-disubstituted R-amino acid esters has been demonstrated.
The development of asymmetric methods for the syn-
thesis of differently substituted aziridines is an area of
intensive research in organic chemistry. These small het-
erocyclic compounds serve as valuable intermediates to
obtain a great number of derivatives by regio- and stereo-
selective ring-opening and ring-expansion reactions.1
Moreover, they are used as chiral ligands/catalysts in
asymmetric synthesis2 and are present as a key motif in
several bioactive compounds and pharmaceuticals.3 Con-
sequently, over recent decades, many efforts have focused
on the development of asymmetric methodologies4 to
prevalently synthesize chiral nonracemic 2,3-disubstituted
aziridines. Despite recent developments, up to now only
one general method has successfully addressed the
highly challenging task of accessing nonracemic terminal
aziridines bearing a quaternary stereogenic center.5 Speci-
ꢁ
fically, Cordova and co-workers developed an organoca-
talytic asymmetric aziridination of R-alkyl-substituted
acryl aldehydes.6 An aza-Michael approach has been
(4) For selected examples, see: (a) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742. (b) Hansen, K. B.;
Finney, N. S.; Jacobsen, E. N. Angew. Chemie, Int. Ed. 1995, 34, 676.
€
(c) Sodergren, J. M.; Alonso, D. A.; Andersson, P. G. Tetrahedron:
Asymmetry 1997, 8, 3563. (d) Doyle, M. P.; Chapman, B. J.; Hu, W.;
Peterson, C. S.; McKervey, M. A.; Garcia, C. F. Org. Lett. 1999, 1, 1327.
(e) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.;
Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1433.
(f) Guthikonda, K.; DuBois, J. J. Am. Chem. Soc. 2002, 124, 13672. (g) Au,
S. M.; Huang, J. S.; Yu, W. Y.; Fung, W. H.; Che, C. M. J. Am. Chem.
Soc. 1999, 121, 9120. (h) Katsuki, T. Synlett 2003, 281. (i) Cui, Y.; He, C.
J. Am. Chem. Soc. 2003, 125, 16202. For asymmetric aziridination
reaction of 2-substituted terminal alkenes, see: (j) Kawabata, H.;
Omura, K.; Uchida, T.; Katsuki, T. Chem. Asian J. 2007, 2, 248.
(k) Minakata, S.; Murakami, Y.; Tsuruoka, R.; Kitanaka, S.; Komatsu,
M. Chem. Commun. 2008, 6363. For organocatalytic asymmetric methodol-
ogies, see: (l) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39,
4518. (m) Fioravanti, S.; Mascia, M. G.; Pellacani, L.; Tardella, P.
Tetrahedron 2004, 60, 8073. (n) Kano, T.; Hato, Y.; Yamamoto, A.;
Maruoka, K. Tetrahedron 2008, 64, 1197. (o) Akiyama, T.; Suzuki, T.;
Mori, K. Org. Lett. 2009, 11, 2445. (p) Hashimoto, T.; Nakatsu, H.;
Yamamoto, K.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 9730.
(q) Huang, L.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892. (r) Larson,
S. E.; Li, G.; Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.;
Antilla, J. C. Org. Lett. 2011, 13, 2188. (s) Hayashi, Y.; Urushima, T.;
Sakamoto, D.; Torii, K.; Ishikawa, H. Chem.;Eur. J. 2011, 17, 11715.
†
ꢀ
Universita di Salerno.
‡
ꢀ
DISIT-Universita del Piemonte Orientale.
(1) (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. (b) Hu, W. E.
Tetrahedron 2004, 60, 2701. (c) Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006. (d) Singh, G. S.;
D'hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080. (e) Florio, S.;
ꢁ
Luisi, R. Chem. Rev. 2010, 110, 5128. (f) Stankovic, S.; D’hooghe, M.;
Catak, S.; Eum, H.; Waroquier, M.; van Speybroeck, V.; De Kimpe, N.;
Ha, H.-J. Chem. Soc. Rev. 2012, 41, 643.
(2) (a) Jacobsen, E. N. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2 pp 607. (b) McCoull, M.; Davis, F. A. Synthesis 2000, 1347.
(3) (a) Burrage, T.; Kramer, E.; Brown, F. Vaccine 2000, 18, 2454.
€
(b) Furmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649. (c) Wakimoto,
T.; Asakawa, T.; Akahoshi, S.; Suzuki, T.; Nagai, K.; Kawagishi, H.;
Kan, T. Angew. Chem., Int. Ed. 2011, 50, 1168.
r
10.1021/ol3017066
Published on Web 08/02/2012
2012 American Chemical Society

exploited, taking advantage of the iminium/enamine
strategy,7 using O-protected diarylprolinols as catalysts
and acylated hydroxycarbamates as an ambiphilic nitro-
gen source (Figure 1).
pioneered by the work of Takemoto,10 were suggested to
activate electron-poor alkenes, and nucleophiles by the
thiourea and the amine groups, respectively. Then, highly
organized transition states are formed leading to high
stereocontrol.11 According to the activation model pro-
posed in amino thioureas catalyzed asymmetric conjugate
additions of R,β-unsaturated imides,12 R-acyl acrylates
were supposed to be able to similarly establish multiple
hydrogen-bonding interactions with the thiourea group
and the nucleophile with the amine moiety of the catalyst.
Once formed, the H-bonded prochiral enolate could have
undergone preferential ring-closure to an enantiomerically
enriched aziridine. Herein, we report our preliminary find-
ings on the asymmetric aziridination of R-acyl acrylates
with an N-tosyloxy tert-butyl carbamate catalyzed by
the Takemoto thiourea in the presence of basic additives.
Novel terminal aziridines, bearing a quaternary stereocen-
ter, were isolated in high yield and good enantioselectivity.
We also showed that these compounds are useful inter-
mediates to access R,R-disubstituted R-amino acid esters
via regioselective ring-opening.
Figure 1. Organocatalytic activation strategies for the asym-
metric aza-MIRC reaction to terminal aziridines with a qua-
ternary stereogenic center.
The functionalized terminal aziridines were isolated in
moderate to satisfactory yield and up to 99:1 enantiomeric
ratio. The increasing demand for efficient methods to
produce this class of functionalized aziridines relies on
their great synthetic potential for further regioselective
ring-opening to R,R-disubstituted R-amino acid deriva-
tives.8 Indeed, nonproteinogenic R,R-disubstituted amino
acids are gaining a lot of importance in various areas such
asbiochemical and drug discovery research, thankstotheir
peculiar biological and chemical properties.
The aziridination process on model R-benzoyl ethyla-
crylate 1a with different N,O-protected hydroxylamines 2
was carried out screening a variety of bifunctional promo-
ters (Figure 2), used at stoichiometric loading, in toluene as
the solvent (Table 1).
With the aim of enlarging access to terminal aziridines
functionalized at the quaternary stereogenic center and
given our interest in developing asymmetric organocata-
lytic Michael type reactions,9 we envisioned a noncovalent
approach for the aza-MIRC reaction catalyzed by bifunc-
tional amino thioureas. This class of organocatalysts, as
(5) For recent reviews on the asymmetric construction of quaternary
stereogenic centers, see: (a) Christoffers, J.; Baro, A. Adv. Synth. Catal.
2005, 347, 1473. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (c) Bella,
M.; Gasperi, T. Synthesis 2009, 1583. (d) Hawner, C.; Alexakis, A.
Chem. Commun. 2010, 46, 7295. (e) Das, J. P.; Marek, I. Chem. Commun.
2011, 47, 4593.
(6) (a) Deiana, L.; Zhao, G.-L.; Lin, S.; Dziedzic, P.; Zhang, Q.;
ꢁ
Leijonmarck, H.; Cordova, A. Adv. Synth. Catal. 2010, 352, 3201.
(b) Deiana, L.; Dziedzic, P.; Zhao, G.-L.; Vesely, J.; Ibrahem, I.; Rios,
Figure 2. Organocatalysts screened in the aziridination.
ꢁ
R.; Sun, J.; Cordova, A. Chem.;Eur. J. 2011, 17, 7904. (c) Desmarchelier,
A.; Pereira de Sant’Ana, D.; Terrasson, V.; Campagne, J. M.; Moreau,
X.; Greck, C.; Marcia de Figueiredo, R. Eur. J. Org. Chem. 2011, 4046.
(d) For the first organocatalytic report on asymmetric aziridination by
O-protected diaryl prolinols, see:Vesely, J.; Ibrahem, I.; Zhao, G.-L.;
Pleasingly, aziridine 3a was isolated in 90% and 92%
yield13 and moderate enantiomeric ratio when using com-
pound 2a and cinchona thioureas 4 and 5, respectively
(entries 1 and 2).
Remarkably, highly reactive and sensitive Michael
acceptor 1a did not undergo competitive formation of
ꢁ
Rios, R.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 778.
(7) For recent reviews on aminocatalysis provided by O-protected
diaryl prolinols, see: (a) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal.
2010, 352, 243. (b) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.;
Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
€
(8) For reviews, see: (a) Vogt, H.; Brase, S. Org. Biomol. Chem. 2007,
5, 406. (b) Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron: Asym-
metry 2007, 18, 569.
(9) (a) Lattanzi, A. Org. Lett. 2005, 7, 2579. (b) Russo, A.; Perfetto,
A.; Lattanzi, A. Adv. Synth. Catal. 2009, 351, 3067. (c) De Fusco, C.;
Tedesco, C.; Lattanzi, A. J. Org. Chem. 2011, 76, 676. (d) Lattanzi, A.;
De Fusco, C.; Russo, A.; Poater, A.; Cavallo, L. Chem. Commun. 2012,
48, 1650. (e) Russo, A.; Galdi, G.; Croce, G.; Lattanzi, A. Chem.;Eur.
J. 2012, 18, 6152.
(11) For reviews on amino thioureas organocatalyzed reactions, see:
(a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (c) Connon, S. J. Synlett
2009, 354. (d) Palomo, C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev.
2009, 38, 632.
(12) (a) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y.
Synlett 2005, 603. (b) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2006, 128, 9413.
ꢁ
(10) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119.
(13) Carbamate-protected aziridines reported in ref 6 were found to
be sensitive to silica gel purification and underwent significant
decomposition.
Org. Lett., Vol. 14, No. 16, 2012
4079

most effective reagent (entry 3).15 To develop a catalytic
process, a variety of basic additives were checked, employ-
ing 30 mol % of catalyst 6a in the aziridination of 1a
with 2a (Table 2). Different organic and inorganic bases
(entries 1À7) were screened, and the use of 1 equiv of
K2CO3 enabled the isolation of product 3a in good yield
and er (entry 7).
Table 1. Aziridination of Alkene 1a with 2 Promoted by
Bifunctional Organocatalystsa
Table 2. Optimization Study on the Aziridination of Alkene 1a
with 2a Catalyzed by Thiourea 6aa
entry organocatalyst
2
time (h) yieldb (%)
erc (%)
1
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2d
2e
5
2
92
90
76
97
42
43
50
71
96
90
72
77
59
40
<10
61
75.5/24.5
À78/22
86/14
2
5
3
6a
7
4
6b
2
78/22
entry
additive
Et3N
time (h)
yieldb (%)
erc (%)
5
6c
5
rac
6d
7
7
5
57/43
1
1
0.5
2
40
58
69
48
68
70
72
67
83
69
39
91
95
73/27
79/21
89/11
89/11
82/18
82.5/17.5
89/11
83/17
84/16
77/23
79/21
83/17
89/11
8
2
68/32
2
Proton Sponge
AcONa
8
9a
21
20
2
À55/45
À55/45
54.5/45.5
72/28
3
9
9b
4
PhCO2Na
Na2CO3
NaHCO3
K2CO3
1.5
3
10
11
12
13
14
15
16
quinine
5
4
3
6
16
2
5
4
À72.5/27.5
86/14
7
8d
9e
10f
11g
12h
13i
K2CO3
1.5
2.5
2
6a
6a
6a
6a
6
1
À62/38
K2CO3
5
K2CO3
20
68/32
K2CO3
2
K2CO3
24
3.5
a Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), organocatalyst
(0.1 mmol) in 2 mL of toluene. b Yield of isolated product. c Determined
by chiral HPLC analysis. d 5 mol % of catalyst 7 was used in the presence
of K2CO3 (0.1 mmol).
K2CO3
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), and 6a
(0.03 mmol) in 2 mL of toluene. b Yield of isolated product. c Determined
by chiral HPLC analysis. d K2CO3 (3 equiv). e Diethyl ether as solvent.
f CHCl3 as solvent. g Chlorobenzene as solvent. h 20 mol % of catalyst
used at À20 °C. i 20 mol % of catalyst used at 0 °C.
polymeration byproduct.14 A significant improvement of
the enantioselectivity up to 86/14 er was observed when
employing thiourea 6a (entry 3). Whereas thiourea 6b
proved to be more active, but less enantioselective, as a
catalyst (entry 4), thiourea 6c, bearing a primary amine
group, yielded a racemic product (entry 5). Squaramide 7
was checked under catalytic conditions, employing K2CO3
(1 equiv) as a scavenger for the p-toluensulfonic acid
formed as side product (entry 6). It proved to be moder-
ately active but considerably less efficient than catalyst 6a.
Thiourea 8 affordedcompound 3ainmoderate yield and er
value (entry 7). Bifunctional catalysts containing a single
H-bond donor moiety, such as sulfonamides 9a,b and
quinine, proved to be fairly good promoters in term of
activity but poorly effective in term of enantioselectivity
(entries 8À10). These findings appear to confirm the
hypothesis that multiple hydrogen-bonding interactions
are necessary to achieve satisfactory stereocontrol as pos-
tulated in Figure 1. The nature of the protecting group on
nitrogen and the leaving group in reagent 2 had a signifi-
cant impact on the outcome of the aziridination when
using the best promoters 4, 5, and 6a (entries 11À16).
N-Tosyloxy tert-butyl carbamate 2a was found to be the
An excess of K2CO3 (3 equiv) proved to be deleterious
(entry 8).16 A solvent screening confirmed toluene as the
optimum medium (entries 9À11). The reaction carried out
in toluene at À20 °C with 20 mol % of 6a furnished the
aziridine in high yield although without improvement of
the asymmetricinduction (entry 12). However, anexcellent
conversion to the product with 89/11 er value could be
achieved working at 0 °C with 20mol % of catalystloading
(entry 13).
With the optimized conditions in hand, the scope of the
aziridination was next investigated(Table3). Thenature of
the ester group in alkene 1 slightly influenced the stereo-
chemical outcome, with the corresponding aziridines being
obtained in good to high yield (entries 1À4). Different
electron-donating or withdrawing substituents on the phe-
nyl ring at para, meta, and ortho-positions or heteroaro-
matic groups were tolerated leading to the aziridine in
generally high yield and up to 91/9 er (entries 5À12). The
cyclohexenyl derivative 1o was regioselectively converted
(15) Reactions performed with phase-transfer catalysts proceeded
with low enantioselectivity (see the Supporting Information for details).
(16) A control experiment performed in absence of 6a and using 1
equiv of K2CO3 led to the formation of 3a in 30% yield after 2 h.
(14) Acrylates of type 1 suffer easy polymerization on standing and
consequently need to be used freshly prepared.
4080
Org. Lett., Vol. 14, No. 16, 2012

Table 3. Asymmetric Aziridination of Alkenes 1 with 2a Cata-
lyzed by Thiourea 6a/K2CO3 Systema
Figure 3. Synthesis of R,R-disubstituted-R-amino acid ester 11a
via deprotection/regioselective ring-opening.
No racemization was observed in deprotection/ring-
opening sequence as attested by chiral HPLC analysis on
the corresponding N-Cbz derivative 12a obtained after
treatment of compound 11a with dibenzyl dicarbonate
(Cbz2O).
It is important to note that the present methodology
enables access to either protected or unprotected terminal
aziridines bearing a quaternary stereocenter.
In conclusion, we have disclosed an effective amino
thiourea-mediated enantioselective organocatalytic ap-
proach to terminal aziridines containing a functionalized
quaternary stereocenter. These difficult to access targets
also underwent regioselective ring-opening to valuable R,
R-disubstituted amino acid esters. Further studies to
broaden the substrate scope of the aziridination and the
synthetic elaboration of aziridines are ongoing in our
laboratory and will be reported in due course.
a Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), 6a (0.02 mmol),
K2CO3 (0.1 mmol) in 2 mL of toluene. b Yield of isolated product.
c Determined by chiral HPLC analysis.
into the product in good yield and 87/13 er (entry 13).
Alkenes bearing amido or phosphonate groups were also
suitable substrates for the aziridination reaction (entries 14
and 15).
The absolute configuration of N-Boc aziridines was
determined to be R by single-crystal X-ray analysis on
compound 3m.17
Acknowledgment. We thank the Italian Ministry of
University and Research (MIUR) and National Projects
PRIN 2008 for financial support. We thank Dr. P. Iannece
(University of Salerno) for MS spectral analyses.
Finally, the synthetic potential of aziridines 3 as inter-
mediates to access R,R-disubstituted R-amino acid esters
was investigated (Figure 3). Enantiomerically enriched
3a was deprotected with tetrabutyl ammonium fluoride
(TBAF) to aziridine 10a in excellent yield. Ring-opening
of compound 10a with an ethereal solution of HCl led
regioselectively to the R-amino ester 11a in high yield.
Supporting Information Available. Experimental proce-
dures, characterization data, 1H and 13C NMR spectra for
new compounds and HPLC traces. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
(17) See the Supporting Information for details.
Org. Lett., Vol. 14, No. 16, 2012
4081