Chiral phosphoric acid-catalyzed addition of thiols to N-acyl imines: Access to chiral N, S-acetals

Article abstract of DOI:10.1021/ol201899c

The first catalytic asymmetric method to prepare enantioenriched N,S-acetals using chiral BINOL phosphoric acids is reported. The reaction combines N-acyl imines with thiols to generate products in excellent yield and enantioselectivity. The addition reac

Full text of DOI:10.1021/ol201899c

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4822–4825
Chiral Phosphoric Acid-Catalyzed
Addition of Thiols to N-Acyl Imines:
Access to Chiral N,S-Acetals
Gajendrasingh K. Ingle,† Michael G. Mormino,† Lukasz Wojtas,‡ and Jon C. Antilla*,†
Department of Chemistry, University of South Florida, 4202 East Fowler Avenue,
Tampa, Florida, 33620, United States, and Department of Chemistry X-ray Facility,
University of South Florida, Tampa, Florida 33620, United States
jantilla@usf.edu
Received July 13, 2011
ABSTRACT
The first catalytic asymmetric method to prepare enantioenriched N,S-acetals using chiral BINOL phosphoric acids is reported. The reaction
combines N-acyl imines with thiols to generate products in excellent yield and enantioselectivity. The addition reaction could also be achieved
with an exceptional substrate to catalyst (S/C) molar ratio. Electron-rich and electron-deficient aromatic N-acyl imines, as well as a broad range of
aliphatic and aromatic thiols, showed excellent reactivity.
Chiral sulfur compounds have been utilized as ligands
for metal-based catalysis,1 as organocatalysts,2 and as
chiral auxiliaries.3 The most versatile method to generate
chiral sulfur-containing molecules is via conjugate addi-
tion of sulfur nucleophiles to R,β-unsaturated compounds
(sulfa-Michael addition) using chiral metal complexes4 or
organocatalysts.5 Other methods to synthesize chiral
sulfur-containing compounds include desymmetrization
of meso-epoxides6 and meso-aziridines7 by sulfur nucleo-
philes as well as thiol additions to allenoates.8
Chiral N,S-acetals are biologically important molecules
present in numerous natural products such as β-lactam
antibiotics,9 the natural product fusaperazine, and the
(6) Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem.
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Chemistry of β-lactams; George, G. I., Ed.; VCH: New York, 1993.
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† Department of Chemistry.
‡ Department of Chemistry X-ray Facility.
(1) (a) Anderson, J. C.; Harding, M. Chem. Commun. 1998, 393–394.
(b) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133–
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5209. (c) Subirats, S.; Jimeno, C.; Pericas, M. A. Tetrahedron: Asym-
metry 2009, 20, 1413–1418.
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(3) (a) Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8, 4219–
4222. (b) Li, A.-H.; Dai, L.-X.; Aggarwal, K. V. Chem. Rev. 2007, 107,
2341–2372.
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Chem. Soc. 1997, 119, 12974–12975. (b) Emori, E.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043–4044. (c) Kanemasa,
S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675–8676.
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(11) Yadav, L. D. S.; Rai, V. K. Tetrahedron Lett. 2008, 49, 5553–
5556.
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1437–1442. (b) Song, Z.-C.; Ma, G. -Y.; Lv, P. ꢀC.; Li, H. ꢀQ.; Xiao,
Z. ꢀP.; Zhu, H. ꢀL. Eur. J. Med. Chem. 2009, 44, 3903–3908. (c) Gomez-
Monterrey, I.; Bertamino, A.; Porta, A.; Carotenuto, A.; Musella, S.;
Aquino, C.; Granata, I.; Sala, M.; Brancaccio, D.; Picone, D.; Ercole,
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41, 338–340. (b) Marigo, M.; Schulte, T.; Franzen, J.; Jørgensen, K. A.
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r
10.1021/ol201899c
Published on Web 08/15/2011
2011 American Chemical Society

Figure 2. Chiral phosphoric acids.
even at 0.005 mol % of catalyst loading. To the best of our
knowledge, this is the first enantioselective synthesis of N,S-
acetal using a chiral catalyst.
Figure 1. Natural products with chiral N,S-acetal functionality.
fungal metabolite (þ)-11,110-dideoxyverticillin, an epi-
dithioketopiperazine alkaloid (Figure 1).10
Table 1. Catalytic Reaction Condition Optimization for the
Enantioselective Addition of Thiophenol to Imine 1a
Recently, Rai et al. synthesized novel tricyclic β-lactams
from hydrazone imines, which were screened for their
antibacterial properties.11 Few cyclic N,S-acetals have
been explored for their therapeutic potential.12 In some
analogs of 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one,
an N,S-acetal containing compound, the “R” enantiomer
was found to be 50 times more potent than the “S”
enantiomer for antiviral activity.13 Recently, lithiated N,
S-acetals of chiral auxiliaries were used as chiral formylat-
ing reagents.14 However, in spite of their promising biolo-
gical and chemical properties, there are no existing
methods for the direct synthesis of acyclic15 or cyclic N,
S-acetals in a catalytic enantioselective manner.
Chiral BINOL phosphoric acids have been utilized as
catalysts for manyorganic transformations (Figure 2).16 In
continuation of our investigation into chiral phosphoric
acid/phosphate salt-catalyzed addition of heteroatoms to
imines,17 we wish to report a highly enantioselective addi-
tion of thiols to N-acyl imines providing chiral N,S-acetals
in excellent yields and enantioselectivities. The reaction
was extremely efficient affording high asymmetric induction
entrya
R
catalyst (R)
solvent
yield (%)b
ee (%)c
1
COPh
COPh
COPh
COPh
COPh
COPh
COPh
COPh
COPh
Boc
PA-1
PA-2
PA-3
PA-4
PA-5
PA-6
PA-5
PA-5
PA-5
PA-5
PA-5
ether
47
45
42
54
72
79
86
65
95
85
0
11
30
43
36
91
0
2
ether
3
ether
4
ether
5
ether
6
ether
7
THF
44
92
99
80
0
8
MTBE
toluene
toluene
toluene
9
10
11
CHPh2
a General conditions: 1.0 equiv of imine and 1.2 equiv of thiophenol.
b Isolated yields. c ee determined by chiral HPLC analysis.
We began our investigation by examining the catalytic
asymmetric addition of thiophenol 2a to N-acyl imine 1a in
ether (Table 1). To our delight, PA-5 was found to be the
best catalyst for this transformation (entry 5). Toluene was
the most suitable solvent for product formation, allowing a
95% yield and 99% ee (entry 9). Boc-protected imine gave
chiral N,S-acetal product, albeit with lower yield and
enantioselectivity (entry 10), while a benzhydryl-protected
imine did not undergo the addition reaction (entry 11).
During the optimization studies (Table 2), we observed
that the addition reaction was extremely fast (entry 1) and
was complete within 30 s. In the absence of catalyst, the
racemic product was obtained in approximately 5 min with
excellent yield asidentifiedby1H NMR (entry 8). Withthis
unexpected reactivity, we decided to examine the efficiency
of the Brønsted acid as a function of catalyst loading. Five
mol % and 2 mol % catalyst loading essentially obtained
the same enantioselectivity. (entry 1 and 2). Lowering the
€
€
(13) Mertens, A.; Zilch, H.; Konig, B.; Schafer, W.; Poll, T.; Kampe,
W.; Seide1, H.; Leser, U.; Leinert, H. J. Med. Chem. 1993, 36, 2526–
2635.
(14) (a) Gaul, C.; Arvidsson, P. I.; Bauer, W.; Gawley, R. E.;
Seebach, D. Chem.;Eur. J. 2001, 7, 4117–4125. (b) Gawley, R. E.;
Campagna, S. A.; Santiago, M.; Ren, T. Tetrahedron: Asymmetry 2002,
13, 29–36.
(15) For examples of acyclic N,S-acetal see: (a) Stacy, G. W.; Day,
R. I.; Morath, R. J. J. Am. Chem. Soc. 1955, 77, 3869–3872. (b)
Katrytzky, A. R.; Szajda, M.; Bayyuk, S. Synthesis 1986, 804–807.
(16) For reviews on chiral phosphoric acid, see: (a) Akiyama, T.;
Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999–1010. (b)
Akiyama, T. Chem. Rev. 2007, 107, 5744–5758. (c) Terada, M. Chem.
Commun. 2008, 4097–4112.
(17) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamad-
havuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696–
15697. (b) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.;
Antilla, J. C. Chem. Commun. 2007, 43, 4477–4479. (c) Li, G.; Fronczek,
F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216–12217. (d)
Zheng, W.; Wojtas, L.; Antilla, J. C. Angew. Chem., Int. Ed. 2010, 49,
6589–6591. For a related chiral phosphate salt-catalyzed reaction, see:
(e) Ingle, G. K.; Liang, Y.; Mormino, M. G.; Li, G.; Fronczek, F. R.;
Antilla, J. C. Org. Lett. 2011, 13, 2054–2057.
Org. Lett., Vol. 13, No. 18, 2011
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Table 2. Catalytic Loading Data for the Enantioselective
Addition of Thiophenol to Imine 1a
Table 3. The Catalytic Asymmetric Addition of Thiophenol to
N-Acyl Imines
entrya
catalyst (mol %)
yield(%)b
erc
1
2
3
4
5
6
7
8
5
95
96
91
95
96
96
96
96
99.5:0.5
99.6:0.4
99.4:0.6
99.4:0.6
98.5:1.5
95.4:4.6
93.8:6.2
1:1
2
1
0.5
0.1
0.01
0.005
0
a General conditions: 1.0 equiv of imine and 1.2 equiv of thiophenol.
b Isolated yields. c Er determined by chiral HPLC analysis.
catalyst loading to 1 mol % and to 0.5 mol %, only a slight
decrease in the enantioselectivity was observed respectively
(entry 3 and 4). Catalyst loading as low as 0.005 mol %,
gave the product with 88% enantiomeric excess (entry 7).18
Asymmetric induction was not observed when 1a was
treated with thiophenol in the presence of 10 mol % of
chiral product 3a. This verified the Brønsted acid as the
sole source of chiral induction in the resulting product,
with no autoinduction observed. Many of the existing
organocatalytic reactions reported in the literature are
performed at 10 mol % or higher catalyst loading and this
can representalimitation ofthistypeofcatalysis. Thereare
only two examples of chiral phosphoric acid catalysts with
significantly lower catalyst loading reported in literature;19
by far this is the most noteworthy illustration of catalyst
efficiency observed to date with these catalysts.20
The scope of nucleophilic addition of thiophenol 2a to
various N-acyl imines was explored using 2 mol % of PA-5
(Table 3). Note that in each case we could optimize further
in terms of lower catalyst loadings but chose 2 mol % for
the general study. To our satisfaction, aromatic imines
with electron withdrawing substituents (3b-e), as well as
electron donating substituents (3f and 3g) were tolerated
under the reaction conditions. Sterically demanding imines
such as a 1-napthyl analogue led to excellent yield and ee
(3h). Aliphatic imines were discovered to be poor sub-
strates, with products being obtainedinlow yieldsand ee.21
a General conditions: 1.0 equiv of imine and 1.2 equiv of thiophenol.
b Isolated yields. c ee determined by chiral HPLC analysis.
Encouraged by the excellent reactivity of aromatic imine
substrates, we evaluated the scope of the addition reaction
with respect to thiol nucleophiles. The results are summar-
ized in Scheme 1. Under the optimum reaction conditions,
thiophenols bearing electron donating (4b and 4c) as well
as electron withdrawing (4d) substituents led to the for-
mation of N,S-acetal products in excellent yields and
enantioselectivities. Napthyl-2-thiol was also found to be
an excellent nucleophile for the addition reaction (4e).
However, aromatic thiols with strong electron withdraw-
ing groups such as 3,5-bis(trifluoromethyl)thiophenol
yielded N,S-acetal with lower asymmetric induction (4f).
In the case of aliphatic thiols 5 mol % of catalyst was
needed in order to achieve high levels of selectivity. Cyclo-
hexyl, hydrocinnamyl, iso-butyl and n-heptyl thiols were
found to be excellent nucleophiles furnishing the N,S-
acetals in good yields and ee (4gꢀj). 2-Chlorobenzylthiol
was found to be an exceptionally active nucleophile,
achieving excellent enantioselectivity even at 2 mol %
catalyst loading (4k).
(18) To ensure complete conversion to the product, all of the reac-
tions were stirred for 5 min.
(19) For an aza ene type reaction using BINOL Phosphoric acid,
0.05 mol % of catalyst loading and a 93% ee was reported; for details,
see: (a) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed.
2006, 45, 2254–2257. For an enantioselective protonation, a reaction
using N-triflyl phosphoramides, with 0.05 mol % catalyst loading and a
86% ee, was reported; for details, see:(b) Cheon, C. H.; Yamamoto, H.
J. Am. Chem. Soc. 2008, 130, 9246–9247.
The substrate scope is very broad with respect to the
thiols. We successfully synthesized a chiral amido-thiol
using liquefied H2S in greater than 99.0% ee (4l). Boc
protected L-cysteine ester gave the addition product in 95/5
(20) See Supporting Information for HPLC traces and catalyst
loading data.
(21) For example, with a t-butyl N-acyl substrate, 2.0 equiv of imine
and 1.0 equiv of 2a were used, and the resulting product 3i was isolated in
51% yield and 31% ee (see Supporting Information).
(22) (a) For a review on selenium containing β-lactams, see: (a)
Garud, D. R.; Ninomiya, M.; Koketsu, M. Heterocycles 2010, 81 (24),
39–2463. For an example of chiral organoselenium compound synth-
esis, see:(b) Yang, M.; Zhu, C.; Yuan, F.; Huang, Y.; Pan., Y. Org. Lett.
2005, 7, 1927–1930.
4824
Org. Lett., Vol. 13, No. 18, 2011

Scheme 1. Catalytic Asymmetric Addition of Thiols to N-Acyl
Iminesa
Scheme 2. Catalytic Asymmetric Addition of Seleophenol to
Imine 1a
analysis of compound 4b, and the stereochemistry of all other
products was assigned by analogy (see Supporting Informa-
tion).
To summarize, we have developed the first method to
synthesize chiral N,S-acetals catalyzed by a BINOL
phosphoric acid. This addition reaction has a broad
substrate scope and the resulting N,S-acetals were ob-
tained in high yields and excellent enantioselectivities.
The BINOL phosphoric acid was found to be an ex-
tremely efficient catalyst for the transformation, result-
ing in asymmetric induction at extremely low catalyst
loading. This methodology has given access to new
chiral sulfur compounds, which have the potential to
be used as synthetic building blocks. Moreover, these
new sulfur compounds themselves could also be
exploited for potential therapeutic benefit.
a General conditions: 1.0 equiv of imine and 1.2 equiv of thiophenol,
isolated yields and ee determined by chiral HPLC analysis. b 5 mol %
catalyst loading. c Reaction was performed at ꢀ78 °C.
Acknowledgment. We thank the National Institutes of
Health (NIH GM-082935) and the National Science
Foundation (NSF-0847108) for financial support.
dr (4m). Selenophenol yielded the expected result, forming
the addition product with 97% ee22 (Scheme 2). The
absolute configuration of the N,S-acetals was determined
unambiguously to be “R” using single X-ray crystallographic
Supporting Information Available. Characterization,
chiral HPLC conditions, experimental preparation and
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 18, 2011
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