Lithium BINOL phosphate catalyzed desymmetrization of meso-epoxides with aromatic thiols

Article abstract of DOI:10.1021/ol502527q

A highly enantioselective method for desymmetrization of meso-epoxides using thiols is reported. This is the first example of epoxide activation achieved using metal BINOL phosphates. The reaction has a broad scope in terms of epoxide substrates and aroma

Full text of DOI:10.1021/ol502527q

Letter
pubs.acs.org/OrgLett
Lithium BINOL Phosphate Catalyzed Desymmetrization of meso-
Epoxides with Aromatic Thiols
Gajendrasingh Ingle, Michael G. Mormino, and Jon C. Antilla*
Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, Florida 33620, United States
S
* Supporting Information
ABSTRACT: A highly enantioselective method for desym-
metrization of meso-epoxides using thiols is reported. This is
the first example of epoxide activation achieved using metal
BINOL phosphates. The reaction has a broad scope in terms
of epoxide substrates and aromatic thiol nucleophiles. The
resulting β-hydroxyl sulfides are obtained in excellent yield and
enantioselectivity.
he recent finding by Ishihara that a chiral calcium
phosphate complex was responsible for high selectivity
limited substrate scope. Therefore, developing a new, versatile
catalytic system for such a transformation is highly desired.
In an ongoing effort to attain activation of new electrophiles
by phosphate metal complexes, we hypothesized that the
phosphate-bound Lewis acidic metal center could activate
epoxides toward nucleophilic addition, generating chiral 1,2-
functionalized compounds. Herein, we report the first example
of highly enantioselective ring opening of meso-epoxides with
thiols catalyzed by a Li-BINOL phosphate.
We began our investigation by screening alkali, alkaline earth,
and transition metal BINOL phosphates for the desymmetriza-
tion of cyclohexene oxide with thiophenol (Table 1). Calcium
and magnesium phosphate did not catalyze the desymmetriza-
tion reaction (entries 1 and 2). To our delight, Sr-TRIP-
BINOL phosphate [Sr(P1)] catalyst allowed us to obtain the
desired epoxide ring-opened product, although with no
enantioselectivity (entry 3).
Sterically hindered Zn-BINOL phosphate catalysts [Zn(P1)2
and Zn(P2)2] afforded good yield of the product, albeit with
poor asymmetric induction (entries 4 and 5). However, it is
worth noting that just Zn-BINOL phosphate [Zn(P3)2], which
does not bear any sterically demanding substituents at the 3,3′-
positions of the BINOL scaffold, generated the product with
60% ee (entry 6). We observed excellent yield and moderate
asymmetric induction with a lithium complex of 9-anthryl and
TRIP-BINOL phosphate [Li(P2) and Li(P1)] as the catalyst
(entries 7 and 8). Upon increasing the catalyst loading of
[Li(P1)] to 20 mol %, a slight enhancement (60% ee) in the
asymmetric induction was observed (entry 9). A marked
improvement in the enantioselectivity was found when
molecular sieves were used, indicating that the residual water
in the reaction mixture has a deleterious effect on the
enantioselectivity (entry 10). Upon extensive optimization, a
lithium complex of H8-TRIP-BINOL phosphate [Li(P4)] and
p-xylene was found to be the most suitable catalyst and solvent,
T
in the addition of 1,3-dicarbonyl compounds to imines has
resulted in considerable interest in chiral biaryl ligated metal
phosphates.1 Since then, various alkali and alkaline earth metal
complexes of BINOL or VAPOL phosphates have been shown
to catalyze a number of reactions involving imines,2 oxindoles,3
trifluoropyruvates,4 β,γ-unsaturated α-ketoesters,5 enamides,6
and enecarbamates.7 Although the metal phosphates have been
successful in activating a broad spectrum of functional groups,
activation of carbonyl functionality such as aldehydes8 and
ketones9 is rare, while epoxide activation using metal
phosphates remains an unattained challenge.
Asymmetric nucleophilic ring opening of meso-epoxides is a
powerful method to synthesize chiral 1,2- functionalized β-
hydroxy compounds.10 Although a wide range of azide,11
amine,12 oxygen,13 and carbon-centered nucleophiles14 have
been employed for the desymmetrization of meso-epoxides, the
use of thiols remains relatively limited.15 The β-hydroxy sulfide,
a synthetic precursor for chiral S,O ligands,16 is also found in
many biologically active molecules.17 The potent calcium
channel blocker Diltiazem is an example of a β-hydroxy sulfide
with only one diastereomer exhibiting the desired biological
activity.18
One of the first examples of thiolysis of epoxides with
excellent yield and enantioselectivity was reported by
Shibasaki15c using a gallium−lithium−bis(binaphthoxide) com-
plex. The scope of the reaction was restricted to only tert-butyl
thiol. In another example, a Ga−Ti-salen catalyzed desymmet-
rization reaction produced the β-hydroxy sulfide with only
moderate asymmetric induction, and sub-ambient temperature
was required for the observed selectivity.15e Recently, TRIP
phosphoric acid catalyzed epoxide ring opening with thiols was
reported. This method, though unsuccessful with typical
aromatic thiols, was successful with 2-mercaptobenzathiozole
as well as its derivatives, and the products were obtained with
moderate to good enantioselectivities.19 Overall, the existing
catalytic systems are either unsuccessful in attempts to attain
superior levels of asymmetric induction or they exhibited
Received: August 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502527q | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization for Catalytic
Desymmetrization of Cyclohexene Oxide with Thiophenol
Table 2. Epoxide Substrate Scope for Catalytic
Desymmetrization Reaction with Thiophenol
a
b
c
entry
catalyst
solvent
yield (%)
ee (%)
1
2
Ca(P1)
Mg(P1)
Sr(P1)
Zn(P2)2
Zn(P1)2
Zn(P3)2
Li(P2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
p-xylene
p-xylene
toluene
toluene
0
0
0
0
4
8
0
3
46
80
88
93
78
90
90
92
93
97
82
0
4
5
d
6
60
7
20
40
8
Li(P1)
d
9
Li(P1)
60
de
,
10
11
12
13
14
15
Li(P1)
83
88
91
de
,
Li(P4)
de
,
Li(P4)
e
Li(P4)
87
H(P1)
0
0
Li(O-i-Pr)
95
a
Reaction conditions: 1.0 equiv of epoxide and 1.2 equiv of thiol were
b
c
a
used. Isolated yields. Enantioselectivity was determined using chiral
HPLC. 20 mol % catalyst was used. Using 4 Å MS.
Reaction conditions: 1.0 equiv of epoxide and 1.2 equiv of thiol were
d
e
b
used. Isolated yields. Enantioselectivity was determined using chiral
HPLC analysis, and the absolute configuration of the products was
confirmed by comparing optical rotations of compounds 3a and 3h
with the reported literature values, and the configuration of the other
respectively (entry 12). Decreasing the catalyst loading to 10
mol % resulted in a minimal drop in yield and enantioselectivity
(entry 13). In control experiments, chiral phosphoric acid
catalysis did not yield any product (entry 14), while racemic β-
hydroxyl sulfide was obtained in excellent yield when Li(O-i-
Pr) was used as a catalyst for the ring opening reaction (entry
15).
c
compounds was analogously assigned.15l 20 mol % catalyst was used.
d
e
f
10 mol % catalyst was used. Reaction stirred for 96 h at rt. 2.2 equiv
g
of thiol was used. Reaction conditions: Zn(P3)2 (10 mol %), toluene,
48 h, rt.
After establishing the optimal reaction conditions, we
explored the use of various epoxides for nucleophilic addition
with thiols. The reactions were performed at 10 and 20 mol %
of catalyst loading; the results are summarized in Table 2.
Epoxides fused to six-membered rings were found to be
excellent substrates, resulting in good yields and excellent
enantioselectivities (entries 1−3). The reaction of cycloheptene
oxide produced the ring-opened product with good asymmetric
induction but only in modest yield (entry 4). The use of
cyclopentene oxide as a substrate for this reaction obtained the
β-hydroxyl sulfide in excellent yield, but only moderate ee was
observed (entry 5). We then explored the enantioselective ring
opening of both cis- and trans-1,4-cyclohexadiene dioxide. The
reaction of trans-1,4-cyclohexadiene dioxide gave 1,3-ring-
opened product in 67% yield and with extremely good
enantioselectivity when 2 equiv of thiol was used (entry 6).
cis-1,4-Cyclohexadiene dioxide achieved excellent yield and ee
for the mono-ring-opened product (entry 7). For acyclic
epoxide, Li-BINOL phosphate did not yield the desymmetriza-
tion product. Unexpectedly, upon further screening, we
observed excellent asymmetric induction and yield with a Zn-
BINOL phosphate complex for the stilbene oxide desymmet-
rization with thiophenol (entry 8). To the best of our
knowledge, the only other example of Zn-phosphate as a
catalyst was reported for an enantioselective cyclopropanation
reaction.20
Next, we explored the scope of thiol nucleophiles for the
epoxide ring opening reaction. The reaction worked well with
10 mol % catalyst loading. The results are summarized in Table
3. Aromatic thiols with electron-withdrawing groups produced
β-hydroxy sulfides in excellent yield and asymmetric induction
(4b and 4c). Thiols with electron-donating substituents were
also well-tolerated, generating the ring-opened product with
excellent yield and enantioselectivity (4d−4g). Bulky thiols,
such as 2-naphthylthiol, were also found to be excellent
substrates, affording the product with 94% ee (4h). We also
examined thiols with heteroatom-containing functional groups.
2-Amino thiophenol as a substrate resulted in exclusively the β-
B
dx.doi.org/10.1021/ol502527q | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phosphate is better able to activate aromatic thiols for the
epoxide ring opening reaction (Figure 1).
Table 3. Catalytic Ring Opening of 4,5-Epoxycyclohexene
with Thiols
Figure 1. Proposed TS for desymmetrization of meso-epoxides with
thiols catalyzed by lithium BINOL phosphate.
Overall, we have developed a highly enantioselective method
for desymmetrization of meso-epoxides using thiols. This is the
first example of epoxide activation achieved using a BINOL
phosphate metal complex. The reaction has a broad substrate
scope in terms of epoxides and also is successful with a wide
range of aromatic thiols. This new catalytic activation of
epoxides has features superior to existing options in terms of
selectivity, being able to achieve higher levels of asymmetric
induction in the ring-opened products. This new activation
protocol could potentially be used for the desymmetrization of
epoxides with an even broader scope of nucleophiles such as
azides and amines, as well as for kinetic resolution studies.
a
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization with spectral data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Reaction conditions: 1.0 equiv of epoxide and 1.2 equiv of thiol were
■
b
c
S
used. Isolated yields. Enantioselectivity was determined using chiral
HPLC, and the absolute configuration of the compounds in this table
was analogously assigned (for more information, see footnote of Table
2). Product was protected with the 3,4-dinitrobenzoyl group for
chiral HPLC analysis. Reaction time: 24 h.
d
e
AUTHOR INFORMATION
Corresponding Author
■
hydroxy sulfide product with excellent yield and asymmetric
induction (4i). Also, the reaction employing methyl thio-
salicylate yielded the epoxide desymmetrization product in 96%
ee (4j). These results indicate that heteroatom-containing
thiols are compatible with the lithium phosphate catalytic
system.
*E-mail: jantilla@usf.edu.
Notes
The authors declare no competing financial interest.
Chiral organo-selenium compounds are useful intermediates
in many asymmetric transformations.15l,21 Fortuitously, we
were able to extend the lithium phosphate catalyzed epoxide
ring opening methodology to a selenophenol nucleophile,
resulting in a chiral β-arylseleno alcohol in excellent yield and
94% ee at ambient temperature (4k). It is worth mentioning
that the other methods reported in the literature required lower
reaction temperature to achieve similar levels of asymmetric
induction.15l,21 The absolute configuration of the products was
confirmed by comparing optical rotations of compounds 3a and
3h with the reported literature values,15l and the configuration
of the other compounds was analogously assigned.
Desymmetrization of meso-epoxide catalyzed by Li-BINOL
phosphates has a wide substrate scope in terms of aromatic
thiols. Regrettably, when aliphatic thiols were employed, we
observed little to no product formation. We hypothesize that
the phosphate-bound lithium metal acts as a Lewis acid,
activating the epoxide, and the phosphoryl moiety behaves as a
Brønsted basic site, activating the thiophenol. We reason that,
because aromatic thiols have lower pKa values relative to that of
aliphatic thiols, the phosphoryl oxygen moiety of the Li-BINOL
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (NIH GM-082935)
and the National Science Foundation CAREER program (NSF-
847108) for financial support.
REFERENCES
■
(1) (a) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew.
Chem., Int. Ed. 2010, 49, 3823. (b) Klussmann, M.; Ratjen, L.;
Hoffmann, S.; Wakchaure, V.; Goddard, R.; List, B. Synlett 2010, 2189.
(2) (a) Ingle, G. K.; Liang, Y.; Mormino, M. G.; Li, G.; Fronczek, F.
R.; Antilla, J. C. Org. Lett. 2011, 13, 2054. (b) Larson, S. E.; Li, G.;
Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C.
Org. Lett. 2011, 13, 2188. (c) Shi, S.-H.; Huang, F.-P.; Zhu, P.; Dong,
Z.-W.; Hui, X.-P. Org. Lett. 2012, 14, 2010. (d) Nimmagadda, S. K.;
Zhang, Z.; Antilla, J. C. Org. Lett. 2014, 16, 4098.
(3) (a) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am.
Chem. Soc. 2011, 133, 3339. (b) Zhang, Z.; Zheng, W.; Antilla, J. C.
Angew. Chem., Int. Ed. 2011, 50, 1135.
(4) Rueping, M.; Bootwicha, T.; Kambutong, S.; Sugiono, E.
Chem.Asian J. 2012, 7, 1195.
(5) Lv, J.; Li, X.; Zhong, L.; Luo, S.; Cheng, J.-P. Org. Lett. 2010, 12,
1096.
C
dx.doi.org/10.1021/ol502527q | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) Drouet, F.; Lalli, C.; Liu, H.; Masson, G.; Zhu, J. Org. Lett. 2011,
13, 94.
(7) Alix, A.; Lalli, C.; Retailleau, P.; Masson, G. J. Am. Chem. Soc.
(19) Wang, Z.; Law, W. K.; Sun, J. Org. Lett. 2013, 15, 5964.
(20) Lacasse, M.-C.; Poulard, C.; Charette, A. B. J. Am. Chem. Soc.
2005, 127, 12440.
(21) (a) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Bonini,
R.; Marini, F.; Bagnoli, L.; Temperini, A. Org. Lett. 2004, 6, 4751.
(b) Okamoto, K.; Nishibayashi, Y.; Uemura, S.; Toshimitsu, A.
Tetrahedron Lett. 2004, 45, 6137. (c) Yang, M.; Zhu, C.; Yuan, F.;
Huang, Y.; Pan, Y. Org. Lett. 2005, 7, 1927.
2012, 134, 10389.
(8) (a) Hanamoto, T.; Furuno, H.; Sugimoto, Y.; Inanaga, J. Synlett
1997, 1, 79. (b) Hayano, T.; Sakaguchi, T.; Furuno, H.; Ohba, M.;
Okawa, H.; Inanaga, J. Chem. Lett. 2003, 32, 608. (c) Terada, M.; Soga,
K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122.
(d) Momiyama, N.; Tabuse, H.; Terada, M. J. Am. Chem. Soc. 2009,
131, 12882. (e) Jain, P.; Antilla, J. C. J. Am. Chem. Soc. 2010, 132,
11884.
(9) (a) Hatano, M.; Ikeno, T.; Matsumura, T.; Torii, S.; Ishihara, K.
Adv. Synth. Catal. 2008, 350, 1776. (b) Zhang, Z.; Jain, P.; Antilla, J. C.
Angew. Chem., Int. Ed. 2011, 50, 10961. (c) Zhang, Z.; Antilla, J. C.
Angew. Chem., Int. Ed. 2012, 51, 11778.
(10) (a) Nielsen, L. P. C.; Jacobsen, E. N. Aziridines and Epoxides in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006; p 229.
(b) Pineschi, M. Eur. J. Org. Chem. 2006, 4979.
(11) (a) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E.
N. J. Am. Chem. Soc. 1995, 117, 5897. (b) Leighton, J. L.; Jacobsen, E.
N. J. Org. Chem. 1996, 61, 389. (c) Jacobsen, E. N. Acc. Chem. Res.
2000, 33, 421.
(12) (a) Sekine, A.; Ohshima, T.; Shibasaki, M. Tetrahedron 2002, 58,
75. (b) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Massaccesi,
M.; Melchiorre, P.; Sambri, L. Org. Lett. 2004, 6, 2173. (c) Arai, K.;
Salter, M. M.; Yamashita, Y.; Kobayashi, S. Angew. Chem. 2007, 46,
955. (d) Gao, B.; Wen, Y.; Yang, Z.; Huang, X.; Liu, X.; Feng, X. Adv.
Synth. Catal. 2008, 350, 385.
(13) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936. (b) Jacobsen, E. N.; Kakiuchi, F.; Konsler, R.
G.; Larrow, J. F.; Tokunaga, M. Tetrahedron Lett. 1997, 38, 773.
(c) Nozaki, K.; Nakano, K.; Hiyama, T. J. Am. Chem. Soc. 1999, 121,
11008. (d) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto,
N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
2252.
(14) (a) Shimizu, K. D.; Cole, M. B.; Krueger, C. A.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1704. (b) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi,
M. Gazz. Chim Acta 1997, 127, 273. (c) Oguni, N.; Miyagi, Y.; Itoh, K.
Tetrahedron Lett. 1998, 39, 9023. (d) Schaus, S. E.; Jacobsen, E. N.
Org. Lett. 2000, 2, 1001. (e) Bandini, M.; Cozzi, P. G.; Melchiorre, P.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 84. (f) Belokon,
Y.N.; Chusov, D.; Peregudov, A. S.; Yashkina, L. V.; Timofeeva, G. I.;
Maleev, V. I.; North, M.; Kagan, H. B. Adv. Synth. Catal. 2009, 351,
3157.
(15) (a) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 14, 1643.
(b) Yamashita, H. Bull. Chem. Soc. Jpn. 1988, 61, 1213. (c) Iida, T.;
Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119,
4783. (d) Wu, M. H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 5252.
(e) Wu, J.; Hou, X. L.; Dai, L. X.; Xia, L. J.; Tang, M. H. Tetrahedron:
Asymmetry 1998, 9, 3431. (f) Boudou, M.; Ogawa, C.; Kobayashia, S.
Adv. Synth. Catal. 2006, 348, 2585. (g) Zhou, Z.; Li, Z.; Quanyong,
W.; Liu, B.; Li, K.; Zhao, G.; Zhou, Q.; Tang, C. J. Organomet. Chem.
2006, 691, 5790. (h) Nandakumar, M. V.; Tschop, A.; Krautscheid, H.;
̈
Schneider, C. Chem. Commun. 2007, 275. (i) Chen, Y.-J.; Chen, C.
Tetrahedron: Asymmetry 2007, 18, 1313. (j) Tschop, A.; Nandakumar,
̈
M. V.; Pavlyuk, O.; Schneider, C. Tetrahedron Lett. 2008, 49, 1030.
(k) Sun, J.; Yuan, F.; Yang, M.; Pan, Y.; Zhu, C. Tetrahedron Lett.
2009, 50, 548. (l) Sun, J.; Yang, M.; Yuan, F.; Jia, X.; Yang, X.; Pan, Y.;
Zhu, C. Adv. Synth. Catal. 2009, 351, 920. (m) Nandakumar, M. V.;
Ghosh, S.; Schneider, C. Eur. J. Org. Chem. 2009, 6393.
(16) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133.
(17) (a) Wipf, P.; Jeger, P.; Kim, Y. Bioorg. Med. Chem. Lett. 1998, 8,
351. (b) Martinelli, M. J.; Vaidyanathan, R.; Khau, V. V.; Staszak, M. A.
Tetrahedron Lett. 2002, 43, 3365.
(18) (a) Schwartz, A.; Madan, P. B.; Mohacsi, E.; O’Brien, J. P.;
Todaro, L. J.; Coffen, D. L. J. Org. Chem. 1992, 57, 851. (b) Yamada,
S.-i.; Mori, Y.; Morimatsu, K.; Ishizu, Y.; Ozaki, Y.; Yoshioka, R.;
Nakatani, T.; Seko, H. J. Org. Chem. 1996, 61, 8586.
D
dx.doi.org/10.1021/ol502527q | Org. Lett. XXXX, XXX, XXX−XXX