Highly enantioselective synthesis of β-amidophenylthioethers by organocatalytic desymmetrization of meso- aziridines

Article abstract of DOI:10.1021/ol901209n

The desymmetrization of W-acylaziridines with Me₃SiSPh, catalyzed by commercially available (R) and (S)-VAPOL hydrogen phosphate, produced β-(N-acylamino)phenylthioethers in a highly enantioselective and efficient manner (78-99% ee). The select

Full text of DOI:10.1021/ol901209n

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3330-3333
Highly Enantioselective Synthesis of
ꢀ-Amidophenylthioethers by
Organocatalytic Desymmetrization of
meso-Aziridines
Giorgio Della Sala* and Alessandra Lattanzi
Department of Chemistry, UniVersity of Salerno, Via Ponte Don Melillo 8,
84024 Fisciano (SA), Italy
gdsala@unisa.it
Received May 29, 2009
ABSTRACT
The desymmetrization of N-acylaziridines with Me3SiSPh, catalyzed by commercially available (R) and (S)-VAPOL hydrogen phosphate, produced
ꢀ-(N-acylamino)phenylthioethers in a highly enantioselective and efficient manner (78-99% ee). The selection of the suitable aziridine/nucleophile/
catalyst molar ratio is crucial to obtain high ee’s.
Chiral ꢀ-aminosulfur compounds found various applications
both in pharmacology and in stereoselective synthesis.
Particularly worthy of interest are ꢀ-aminothioethers featuring
two contiguous stereogenic centers on carbons linked to
nitrogen and sulfur. Some of them are described to be
apoptosis promoters.1 Moreover, thanks to their chelating
ability, they are widely employed as chiral ligands in
asymmetric catalysis.2
ephedra alkaloids, with two pre-existing adjacent stereogenic
carbons.3 Clearly, this approach seriously limits the variety
of accessible final structures. Alternatively, the second
stereogenic center may be formed in a diastereoselective step,
for example by sulfenylation,4 or the products can be
eventually obtained in racemic form and then the enantiomers
would separate.5
A process in which the two stereogenic centers are formed
simultaneously starting from achiral material and with high
enantioselectivity would be desirable. In this light, an
intriguing approach is represented by the desymmetrization
of meso-aziridines with thiols promoted by chiral catalysts.
They are generally synthesized starting from natural or
commercially available enantiopure precursors, mostly de-
rived from the chiral pool, such as ꢀ-aminoalcohols from
(1) (a) Bruncko, M.; Hong, D.; Elmore, S.; Kunzer, A. R.; Lynch, C. L.;
McClellan, W.; Park, C. -M.; Petros, A. M.; Song, X.; Wang, X.; Tu, N.;
Wendt, M. D.; Shoemaker, A.; Mitten, M. U.S. Patent 2007072860, 2007.
(b) Augeri, D. J.; Baumeister, S. A.; Bruncko, M.; Dickman, D. A.; Ding,
H.; Dinges, J.; Fesik, S. W.; Hajduk, P. J.; Kunzer, A. R.; McClellan, W.;
Nettesheim, D. G.; Oost, T.; Petros, A. M.; Rosenberg, S. H.; Shen, W.;
Thomas, S. A.; Wang, X.; Wendt, M. D. U.S. Patent 2002086887 , 2002.
(2) See the following reviews and references cited therein: (a) Mellah,
M.; Voituriez, A.; Schulz, E. Chem. ReV. 2007, 107, 5133–5209. (b)
Pellissier, H. Tetrahedron 2007, 63, 1297–1330.
(3) (a) Petra, D. G. I.; Kamer, P. C. J.; Spek, A. L.; Schoemaker, H. E.;
van Leeuwen, P. W. N. M. J. Org. Chem. 2000, 65, 3010–3017. (b) Page,
P. C. B.; Heaney, H.; Reignier, S.; Rassias, G. A. Synlett 2003, 22–28. (c)
Bernardi, L.; Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti,
G.; Ricci, A.; Varchi, G. Eur. J. Org. Chem. 2002, 277, 6–2784.
(4) Gordon, E. M.; Godfrey, J. D.; Delaney, N. G.; Asaad, M. M.; Von
Langen, D.; Cushman, D. W. J. Med. Chem. 1988, 31, 2199–2211.
(5) Ekegren, J. K.; Roth, P.; Ka¨llstro¨m, K.; Tarnai, T.; Andersson, P. G.
Org. Biomol. Chem. 2003, 1, 358–366.
10.1021/ol901209n CCC: $40.75
Published on Web 07/08/2009
 2009 American Chemical Society

Although some highly enantioselective metal-catalyzed6-9
and organocatalyzed desymmetrization10 of activated aziri-
dines have been described,11 very few are examples employ-
ing thiols or their synthetic analogs as nucleophiles, and the
methods reported are of limited scope or moderate enanti-
oselectivity.12
cently Antilla et al. reported an excellent asymmetric
synthesis of ꢀ-acylamino-azides (49-97% yield, 70-95%
ee) by desymmetrization of acylaziridines with trimethylsilyl
azide, catalyzed by phosphoric acid VAPOL PA (VAPOL
hydrogen phosphate; Scheme 1, X ) N3, Ar ) 3,5-bis-
The first desymmetrization of activated meso-aziridines
with arenethiols was reported by Oguni et al.12a The reaction
of three 4-nitrobenzoyl aziridines with 4-t-butylbenzenethiol,
promoted by an equimolecular amount of zinc-dicyclohexyl-
tartrate complex, gave the opening products with 84-93%
ee and 89-98% yield. Anyway, the enantioselectivity
decreased drammatically when differently substituted are-
nethiols were used.
Scheme 1. meso-Acylaziridine Desymmetrization with Me3SiN3
and Me3SiSPh Catalyzed by (R)-VAPOL PA
Asymmetric organocatalysis is an ever growing area of
investigation in organic synthesis, thanks to the advantages
arising from the simplicity of the procedures, mild conditions,
and use of inexpensive and readily avalaible materials.13
Organocatalytic desymmetrizations of sulfonylaziridines with
arenethiols involving the use of chiral Brønsted base catalysts
under homogeneous12b and phase transfer conditions have
been recently reported.12c The resulting ꢀ-aminothioether
derivatives were obtained with ee not exceeding 73%. We
recently used R,R-diaryl-prolinols as bifunctional organo-
catalysts,14 obtaining ꢀ-acylamino-arylthioethers in good
yield and moderate enantioselectivities (up to 61% ee).15
A different organocatalytic approach for an enantioselec-
tive aziridine opening is based on the employment of silylated
nucleophiles in the presence of a chiral Lewis base. The
hypervalent adduct between the silane and the basic catalyst
is characterized by increased Lewis acidity of the silicon
atom and increased nucleophilicity of the peripherical
electronegative group.16 This principle was successfully
applied to the desymmetrization of meso-epoxides.17 Re-
(trifluoromethyl)benzoyl).10 Some experimental proofs sup-
ported the mechanism depicted in Scheme 2, with VAPOL
Scheme 2
.
Proposed Mechanism of meso-Acylaziridine
Desymmetrization (X ) N3, SPh)
(6) TMSN3 as nucleophile: (a) Li, Z.; Ferna´ndez, M.; Jacobsen, E. N.
Org. Lett. 1999, 1, 1611–1613. (b) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312–6313
.
(7) TMSCN as nucleophile: (a) Mita, T.; Fujimori, I.; Wada, R.; Wen,
J.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 11252–11253.
(b) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Saro, A.; Furusho, S.; Kanai,
M.; Shibasaki, M. Tetrahedron 2007, 63, 5820–5831. (c) Wu, B.; Gallucci,
J. C.; Parquette, J. R.; RajanBabu, T. V. Angew. Chem., Int. Ed. 2009, 48,
1126–1129
.
(8) For arylamines as nucleophiles, see: Arai, K.; Lucarini, S.; Salter,
M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007,
129, 8103–8111
.
(9) For carbon nucleophiles, see: Mu¨ller, P.; Nury, P. Org. Lett. 1999,
1, 439–441
.
(10) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C.
J. Am. Chem. Soc. 2007, 129, 12084–12085.
(11) For a review on desymmetrization of meso-aziridines, see: Schneider,
C. Angew. Chem., Int. Ed. 2009, 48, 2082–2084.
(12) (a) Hayashi, M.; Ono, K.; Oshimi, H.; Oguni, N. Tetrahedron 1996,
52, 7817–7832. (b) Wang, Z.; Sun, X.; Ye, S.; Wang, W.; Wang, B.; Wu,
J. Tetrahedron: Asymmetry 2008, 19, 964–969. (c) Luo, Z.-B.; Hou, X.-L.;
Dai, L.-X. Tetrahedron: Asymmetry 2007, 18, 443–446.
(13) For recent general reviews, see: (a) Asymmetric Organocatalysis;
Berkessel, A., Gro¨ger, B., Eds; Wiley-VCH: Weinheim, 2005. (b) Enan-
tioselectiVe Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007. (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724. (d)
Pellissier, H. Tetrahedron 2007, 63, 9267–9331. (e) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660.
PA acting as a Lewis base promoter rather than a proton
catalyst. Notably, an excess of aziridine compared to silyl
nucleophile (molar ratio 1.5/1) was required in most cases
to afford satisfactory enantioselectivities.
We reasoned that to obtain the phenylthioether derivatives,
commercially avalaible (phenylthio)trimethylsilane (2b) could
(14) For a review on prolinols as organocatalysts, see: Lattanzi, A. Chem.
Commun. 2009, 1452–1463.
(15) Lattanzi, A.; Della Sala, G. Eur. J. Org. Chem. 2009, 1845–1848.
(16) For an excellent review on Lewis base catalysis, see: Denmark,
S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638.
Org. Lett., Vol. 11, No. 15, 2009
3331

Table 1. Desymmetrization of Aziridines 1a-d in DCEa
Table 3. Desymmetrization of Aziridines 1c-j
a General reaction conditions: 1 equiv of 1 (0.08 mmol), 1.5 equiv of
2b (0.12 mmol), 0.10 equiv of (R)-VAPOL PA (0.008 mmol), 0.4 mL of
DCE. b Isolated yields. c Determined by chiral HPLC. d Three percent of
10a. e Six percent of 10a. f 2b (3.0 equiv) was used. g Twenty-six percent
of 10a.
be used as the nucleophile in the presence of VAPOL PA
as catalyst (Scheme 1, X ) SPh).
Initially, DCE (1,2-dichloroethane) was used, as previously
optimized solvent for the azide nucleophile.10 An excess of
nucleophile 2b compared to the aziridines 1a-d was
employed, since we regarded the latter as synthetically more
valuable reagents (Table 1).
a Method A: 1 equiv of 1 (0.08 mmol), 1.5 equiv of 2b (0.12 mmol),
0.10 equiv of (R)-VAPOL PA (0.008 mmol), 0.8 mL of CCl3CH3. Method
B: 1 equiv of 1 (0.08 mmol), 1.5 equiv of 2b (0.12 mmol), 0.20 equiv of
(R)-VAPOL PA (0.016 mmol), 0.8 mL of CCl3CH3. Method C: 1.5 equiv
of 1 (0.12 mmol), 1 equiv of 2b (0.08 mmol), 0.10 equiv of (R)-VAPOL
PA (0.008 mmol), 0.8 mL of CCl3CH3. b Isolated yields. c Determined by
chiral HPLC. d (S)-VAPOL PA was used. e (1S,2S)-3c was obtained.
f Product isolated by precipitation from the reaction mixture. The value in
parentheses was measured by direct chiral HPLC injection of the crude
mixture.
Table 2. Solvent Effect in the Desymmetrization of 1ca
Under these conditions, opening of 4-nitrobenzoyl aziridine
1a at room temperature afforded the product 3a in moderate
yield and enantioselectivity (entry 1, Table 1). The absolute
configuration of 3a was established to be (1R,2R) by
comparison of the optical rotation reported in the
literature.12a,18 As expected, both the reactivity and the ee
were improved with aziridine 1b (entry 2, Table 1). Interest-
ingly, faster and more enantioselective opening of aziridine
1c occurred (entry 3, Table 1). The reaction was complete
in a short time even at 0 °C, affording the product in high
yield and with 94% ee (entry 4, Table 1).
Unfortunately, when the same conditions were applied to
less reactive five-membered ring aziridine 1d, the product
3d was formed with a significantly lower ee and was
accompanied by a small amount of chloride opening product
10a (entries 5-6, Table 1). Apparently, nucleophilic sub-
stitution of 2b on DCE, catalyzed by the phosphoric acid,
afforded (2-chloroethylthio)benzene and Me3SiCl, which
entry
solvent
time (h)
% yieldb
% eec
1
2
3
4
5
6
7
8
THF
3.5
7
2
1.5
1.5
5
1
2
7
1
92
100
93
90
94
6
17
69
66
66
69
74
74
81
89
87
93
CH3CN
toluene
CH2Cl2
1,2-dichlorobenzene
CHCl2CHCl2
PhCl
83d
100
100
93
94
97
CCl4
9
CHCl3
10
11e
12e,f
CCl3CH3
CCl3CH3
CCl3CH3
3
3
97
a General reaction conditions: 1 equiv of 1 (0.08 mmol), 1.5 equiv of
2b (0.12 mmol), 0.10 equiv of (R)-VAPOL PA (0.008 mmol), 0.4 mL of
solvent. b Isolated yields. c Determined by chiral HPLC. d Eight percent of
10b. e Reaction performed at 0 °C. f Solvent (0.8 mL) was used.
3332
Org. Lett., Vol. 11, No. 15, 2009

ultimately gave 10a.19 When 3.0 mol equiv of 2b were used,
the conversion was improved, but a great amount of 10a
was obtained and 3d was recovered in an almost racemic
form (entry 7, Table 1). The in situ formation of Me3SiCl,
and possibly HCl, playing as additional acid catalysts
involved in the opening of aziridines, can be invoked, thus
justifying the enantioselectivity drop. Unlike Me3SiN3,
Me3SiSPh is incompatible with DCE in the presence of a
Lewis base. Hence, the performance of several different
solvents, less prone to nucleophilic substitution was checked
(Table 2).
catalyst (method B; entries 8, 11, Table 3). Finally, the
reverse ratio of the reagents 1h-j and 2b (method C) led to
a remarkable enhancement of the ee’s (entries 9, 12, 14,
Table 3).
In conclusion, we developed a highly enantioselective and
efficient method for the synthesis of enantioenriched ꢀ-ami-
nothioethers, based on the organocatalytic desymmetrization
of meso-N-acylaziridines. This easy procedure employs
phosphoric acid VAPOL PA, commercially avalaible in both
enantiomeric forms. The scope is fairly general, leading to
opened products with the best ee’s reported to date.
Further work will be devoted to extend the scope to
different silylthioether as nucleophiles, including the synthetic
elaboration of the products obtained.
Acknowledgment. We are grateful to the Ministero
Italiano dell’Universita` e Ricerca Scientifica (MIUR) for
financial support. Our thanks to Rosa Zarra, Department of
Chemistry, University of Salerno, for ESI-MS and elemental
analyses.
In the desymmetrization reaction of 1c, CCl3CH3 allowed
the isolation of the product in high yield and enantioselec-
tivity, when working at 0 °C (entry 12, Table 2).
This new protocol (method A) was applied to the opening
of a wide range of 3,5-dinitro-benzoyl aziridines 1c-j (Table
3). We were very pleased to observe that the corresponding
acylaminothioethers 3 were generally obtained in high yield
and enantioselectivity. No trace of product arising from
chloride opening was observed. The opposite enantiomer of
3c was isolated when using (S)-VAPOL PA as the catalyst
(entry 2, Table 3). The presence of a carbon-carbon double
bond is compatible with the above conditions (entry 3, Table
3).
Supporting Information Available: Experimental pro-
cedures, synthesis of racemic products and characterization
of unknown compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL901209N
(17) (a) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A.
J. Org. Chem. 1998, 23, 2428–2429. (b) Tao, B.; Lo, M. M.-C.; Fu, G. C.
J. Am. Chem. Soc. 2001, 123, 353–354. (c) Nakajima, M.; Saito, M.;
Uemura, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43, 8827–8829.
(18) This assigment was consistent with the reported (1R,2R) configu-
ration for the product of desymmetrization with trimethylsilyl azide
promoted by (R)-VAPOL PA (ref 10).
Substrates 1h-j showed to be more problematic (entries
7, 10, 13, Table 3). For the less reactive seven-membered
ring aziridine 1h and for compound 1i, a slight increase of
the enantioselectivity was obtained by using 20% mol of
(19) In the opening of 1d in DCE, (2-chloroethylthio)benzene was
isolated from the reaction mixtures.
Org. Lett., Vol. 11, No. 15, 2009
3333