Chiral phosphoric acid-catalyzed desymmetrization of meso-aziridines with functionalized mercaptans

Article abstract of DOI:10.1021/ol902123h

Conditions for the phosphoric acid-catalyzed highly enantioselective ring-opening of meso-aziridines with a series of functionalized aromatic thiol nucleophiles are described. The procedure utilizes commercially available aromatic thiols, a series of meso

Full text of DOI:10.1021/ol902123h

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5186-5189
Chiral Phosphoric Acid-Catalyzed
Desymmetrization of meso-Aziridines
with Functionalized Mercaptans
Shawn E. Larson, Juan C. Baso, Guilong Li, and Jon C. Antilla*
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue
CHE205A, Tampa, Florida 33620
jantilla@cas.usf.edu
Received September 14, 2009
ABSTRACT
Conditions for the phosphoric acid-catalyzed highly enantioselective ring-opening of meso-aziridines with a series of functionalized aromatic
thiol nucleophiles are described. The procedure utilizes commercially available aromatic thiols, a series of meso-aziridines, and a catalytic
amount of VAPOL phosphoric acid to explore the substrate scope of this highly enantioselective reaction.
Aziridines are considered by many to be useful precursors
for the production of advanced targets of interest primarily
because of unique ring-opening chemistry that can allow for
direct access to a variety of chiral amines.1 In the case of
nucleophilic ring-opening of aziridines, a judicious choice
of the nucleophile can allow for the preparation of a variety
of functionalized products.1a
We believe many have the opinion that stereocontrolled
chemistry would be vital for achieving a high degree of
synthetic utility for such ring-opening strategies. This control
can be realized in cases where chiral catalysts allow for ring-
opening desymmetrization reactions of meso-aziridines.2
Examples include the implementation of catalytic chiral metal
complexes that can allow for a high enantioselectivity of the
resulting ring-opened product using primarily azide- or
cyanide-based nucleophiles.3 As part of a recent study that
has focused on chiral Brønsted acid-catalyzed additions using
heteroatom nucleophiles,4 we discovered unique reactivity
whereby chiral phosphoric acids5 could activate aziridines
(3) (a) Li, Z.; Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611.
(b) Mita, T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 11252. (c) Fukuta, Y.; Mita, T.; Fukuda, N.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312. (d) Fujimori,
I.; Mita, T.; Maki, K.; Shiro, M.; Saro, A.; Furusho, S.; Kanai, M.; Shibasaki,
M. Tetrahedron 2007, 63, 5820. (e) Wu, B.; Gallucci, J. C.; Parquette, J. R.;
RajanBabu, T. V. Angew. Chem., Int. Ed. 2009, 48, 1126.
(4) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang,
Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem.
Commun. 2007, 4477. (c) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am.
Chem. Soc. 2008, 130, 12216.
(1) (a) Yudin, A. K. Aziridines and Epoxides in Organic Synthesis;
Wiley-VCH: Weinheim, 2006. (b) Masahiko, H.; Ono, K.; Hoshimi, H.;
Oguni, Nobuki Tetrahedron 1996, 52, 7817.
(5) For reviews with considerable chiral phosphoric acid coverage, see:
(a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999.
(b) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (c) Akiyama, T.
Chem. ReV. 2007, 107, 5744. (d) Terada, M. Chem. Commun. 2008, 4097.
(e) Adair, G.; Mukherjee, S.; List, B. Aldrichchim. Acta 2008, 41, 31.
(2) For a review on the desymmetrization of meso-aziridines, see:
Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082.
10.1021/ol902123h CCC: $40.75
Published on Web 10/19/2009
 2009 American Chemical Society

for enantioselective ring-opening chemistry with trimethyl-
silyl azide (TMS-N3).6
these conditions having excellent yield and ee. Several
additional catalysts were screened, but those evaluated gave
poor selectivity results. For example, with catalyst PA-2
(entry 8) or PA-3 (entry 9) we found the enantioselectivities
dropped to low levels. Unfortunately, when the catalyst
loading was decreased to 5 mol % a lower yield and ee for
6aa was also found (entry 10) Table 1.
Our discovery prompted us to expand the scope of this
chemistry by investigating the ring opening with sulfur-based
nucleophiles. This expansion of substrate scope would allow
for the preparation of interesting chiral ꢀ-amino thioethers.7
At the start of our study the previous methodology reporting
catalytic asymmetric ring-opening desymmetrization reac-
tions utilizing thiols were rare, with low enantiomeric
excesses being found.8 Late in our investigation using thiols,
a publication by Della Sala9 described an enantioselective
ring-opening of meso-aziridines using (phenylthio)trimeth-
ylsilane (TMS-SPh) and the catalyst system we reported6 in
our above azide chemistry. Interestingly, this report implied
that silylated nucleophiles were required, and the authors
explained their chemistry by invoking our previously pos-
tulated mechanism involving the importance of silicon being
present on the nucleophile. However, in this paper we reveal
that silylated thiols are not necessary as simple unsubstituted
thiols can be used to obtain the same ring-opened product
with excellent yield and enantioselectivity using the same
chiral VAPOL phosphoric acid catalyst PA-1 (Figure 1).
Table 1. Optimization of the Aziridine Ring-Opening with
PhSH
entry
catalyst (S)
solvent
yield,a
%
ee,b
70
%
1
2
3
4
5
6
7
8
9
PA-1
PA-1
PA-1
PA-1
PA-1
PA-1
PA-1c
PA-2
PA-3
PA-1d
toluene
DCM
EtOAc
MeCN
THF
MTBE
ether
ether
74
91
89
82
95
99
95
78
64
65
86
31
40
12
96
97
0
ether
ether
11
89
10
a Isolated yields. b Ee values were determined by chiral-HPLC (see the
Supporting Information). c With (R)-PA-1 as the catalyst a 96% yield and
96% ee favoring the opposing enantiomer was found for product 6aa.
d Reaction with 5 mol % of catalyst (S)-PA-1.
Figure 1. Chiral phosphoric acids.
Inspired by the high degree of catalytic activity and
selectivity, we wanted to establish the generality of the
reaction. In Table 2, we show the details of our investigations
into varying the thiol substrate. We found that the reaction
was very general for arene thiols. For example, we were able
to perform the reaction with naphthyl-2-thiol (entry 2) and
a variety of ortho-, meta-, or para-substituted thiophenols
(entries 3-7). Electron-withdrawing substituents on the
thiophenol were not detrimental to the reactivity and
selectivity as chloro, fluoro, trifluoromethyl groups were all
tolerated (entries 8-11). Likewise, electron-donating sub-
stituents on the arene were shown to be compatible with
phenoxy, methoxy, and methyl sulfide groups in the para
position (entries 12-14). Esters were shown to be compatible
with the ring-opening chemistry (entry 15), as were 2-me-
thylfuran-3-thiol (entry 16), benzo[d]thiazole-2-thiol (entry
17), and 1-phenyl-1H-tetrazole-5-thiol (entry 18), albeit in
moderate yield and selectivity. Unfortunately, the use of alkyl
thiols also leads to lower enantioselectivities. For example,
while benzyl thiols were moderately good substrates (entries
19 and 20), longer chain thiols like 2-phenylethanethiol (entry
21) and n-hexanethiol (entry 22) were relatively poor reaction
partners with these conditions.
During our optimization process, we quickly became aware
that silylated nucleophiles were not necessary for the
phosphoric acid-catalyzed thiophenol ring-opening reactions
of substituted N-benzoylaziridine substrates. As in the
chemistry by Della Sala, we found that the 3,5 dinitro
substitution was necessary to achieve the best enantios-
lectvity.9 Nonpolar solvents like toluene provided moderate
enantioselectivity for the reaction (entry 1), while dichlo-
romethane (DCM) gave improved ee (entry 2). Polar solvents
like EtOAc (entry 3), MeCN (entry 4), or tetrahydrofuran
(THF) gave much lower enantioselectivity (entry 5), fol-
lowing a trend found in many other reactions involving chiral
phosphoric acid catalysis.4a,6 Both methyl tert-butyl ether
(entry 6) and diethyl ether (entry 7) were excellent solvents
for the thiophenol ring-opening, with the product found in
(6) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C.
J. Am. Chem. Soc. 2007, 129, 12084.
(7) (a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. ReV. 2007, 107,
5133. (b) Pellissier, H. Tetrahedron 2007, 63, 1297.
(8) (a) Hayashi, M.; Ono, K.; Oshimi, H.; Oguni, N. Tetrahedron 1996,
52, 7817. (b) Luo, Z.-B.; Hou, X.-L.; Dai, L.-X. Tetrahedron: Asymmetry
2007, 18, 443. (c) Wang, Z.; Sun, X.; Ye, S.; Wang, W.; Wang, B.; Wu, J.
Tetrahedron: Asymmetry 2008, 19, 964. (d) Lattanzi, A.; Della Sala, G.
Eur. J. Org. Chem. 2009, 1845.
We were also pleased to find that the aziridine substrate
could be varied with little compromise in yield or enanti-
(9) Della Sala, G.; Lattanzi, A. Org. Lett. 2009, 11, 3330.
Org. Lett., Vol. 11, No. 22, 2009
5187

Table 2. Enantioselective Ring-Opening of 4a with Thiols 5a-v
Table 3. Enantioselective Ring-Opening of Aziridines 4a-g
with Thiophenol
a Isolated yields. b Ee values were determined by chiral-HPLC (see the
Supporting Information).
oselectivity (Table 3). Our previous study with TMS-N3 ring-
openings utilized aziridines with nitrogen protected by a 3,5-
trifluoromethyl-substituted benzoyl group.6 However, in these
thiol studies this substrate, while reactive, gave a much lower
enantioselectivity for the ring-opened product (entry 2).
Substitution in the para position of the benzoyl group on
the aziridine proved to be detrimental to the selectivity, with
the ring-opened product being obtained in a nearly racemic
form (entry 3).
a Isolated yields. b Ee values were determined by chiral-HPLC (see the
Supporting Information).
bond activation of the aziridine N-acyl moiety and the
incoming thiol could be invoked to explain the mecha-
nism.10 This is in contrast to the previous phosphoric acid
catalyzed methodology for aziridine ring-openings that
may be following a mechanism based on silicon ca-
talysis.6,9
In conclusion, we have discovered a catalytic enantiose-
lective process for the ring-opening of meso N-acyl aziridines
in a high yielding, enantioselective manner. In comparison
to known methods,8,9 we believe our procedure is attractive
due to the reactions procedural simplicity. Finally, the
We continued the study by investigating the reaction
with two additional meso aziridines with fused ring
systems and two substrates with acyclic substituents. The
fused cyclohexene-based substrate 4d was shown to be
an excellent reaction partner with thiophenol (entry 4). A
fused cycloheptane 4e was also a suitable substrate for
the reaction (entry 5). Both methyl (entry 6) and n-propyl
(entry 7) 1,2-disubstituted meso aziridines could be used
in the ring-opening chemistry, providing high yield and
enantioselectivity of the respective products using PA-1
as the catalyst.
Our discovery that simple, nonsilylated aromatic thiols
can be used for these chiral phosphoric acid-catalyzed
additions strongly suggests that a more simple hydrogen-
(10) For a description of this type of mechanism with regard to imine
activations, see a “three point contact model” description in: Simon, L.;
Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741.
5188
Org. Lett., Vol. 11, No. 22, 2009

reaction is the first of its type to tolerate a wide range of
aromatic and heteroaromatic thiols.
for the preparation of important starting materials and for
helpful discussions.
Supporting Information Available: Experimental pro-
cedures, characterization, chiral HPLC conditions, and
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the Petroleum Research
Fund (PRF 45899-G1) and the National Institutes of Health
(NIH GM-082935) for financial support. We thank Dr. Emily
B. Rowland (Salem State College) and Dr. Gerald B.
Rowland (MIT or Massachusetts Institute of Technology)
OL902123H
Org. Lett., Vol. 11, No. 22, 2009
5189