Chiral ammonium hypoiodite salt-catalyzed enantioselective oxidative cycloetherification to 2-acyl tetrahydrofurans

Article abstract of DOI:10.1246/cl.160004

2-Acyl tetrahydrofuran is a fundamental structure in natural products and pharmaceuticals. We achieved chiral quaternary ammonium hypoiodite salt-catalyzed enantioselective oxidative cycloetherification of δ-hydroxyketone derivatives. The corresponding 2-acyl tetrahydrofurans were obtained in high chemical yield with high enantioselectivity.

Full text of DOI:10.1246/cl.160004

Received: January 3, 2016 | Accepted: January 8, 2016 | Web Released: January 16, 2016
CL-160004
Chiral Ammonium Hypoiodite Salt-catalyzed Enantioselective Oxidative Cycloetherification
to 2-Acyl Tetrahydrofurans
Muhammet Uyanik, Hiroki Hayashi, Hirokazu Iwata, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya, Aichi 464-8603
(
E-mail: ishihara@cc.nagoya-u.ac.jp)
a) Baiker et al.7
2
-Acyl tetrahydrofuran is a fundamental structure in natural
5
wt% Pd/Al2O3
products and pharmaceuticals. We achieved chiral quaternary
ammonium hypoiodite salt-catalyzed enantioselective oxidative
cycloetherification of δ-hydroxyketone derivatives. The corre-
sponding 2-acyl tetrahydrofurans were obtained in high
chemical yield with high enantioselectivity.
Cinchonidine (15 mol%)
OH
OH
O
O
H2 (30 bar), THF, RT
O
O
1
2% yield, 42% ee
b) Zhou et al.8
OH
O
CuOTf (5 mol%)
Sa,S,S)-SpiroBOX (6 mol%)
O
(
OBn
X
OBn
Keywords: 2-Acyl tetrahydrofuran
|
X
N2
NaBArF (6 mol%)
O
Chiral ammonium hypoiodite catalysis
|
2 2
CH Cl , RT
(
X = CH2, H2)
up to 81% yield, 95% ee
Oxidative cycloetherification
c) Smith et al.9
R
O
O
1
. t-BuCOCl, i-Pr2NEt
CH2Cl2, RT
Tetrahydrofuran (THF) is a ubiquitous and privileged core
structure in biologically active compounds.1 In particular, a
R
Nu
O
2
. (S)-Tetramisole·HCl (5 mol%)
O
CO2H
tetrahydro-2-furoyl skeleton is found in many pharmaceuticals,
i-Pr NEt, RT
2
O
such as terazosin,2 alfuzosin,3 faropenem,4 and cathepsin K
3. NuH, RT
up to 76% yield, 99% ee
(>99:1 dr)
5
inhibitor (Figure 1). While some of these are used as racemic
d) This work:
mixtures, the configuration at the C2-position of 2-acyl THFs is
often important for their biological activities.2 For the synthe-
sis of these pharmaceuticals, tetrahydrofuran-2-carboxylic acid
­5
HO
R2 R2
*R4NI 4 (1–10 mol%)
2 R2
R
O
O
Ph
N
ROOH
R1
R1
Z
2
­5
R1 R1
MTBE, RT
(
1) has been used to introduce the tetrahydro-2-furoyl moiety.
H
N
O
Thus, the development of a straightforward method for the
preparation of enantioenriched 1 is an important subject in
synthetic organic chemistry and medicinal chemistry.
Although numerous methods have been developed for the
asymmetric synthesis of tetrahydrofurans, little is known about
2
Z
3
high yield, high ee
Scheme 1. Previous examples and this work on the enantio-
selective synthesis of 2-acyl THFs.
1
the direct enantioselective synthesis of 2-acyl THF. Conven-
tionally, biologically active compounds that contain a chiral
tetrahydro-2-furoyl moiety have been prepared by the enzyme-
catalyzed kinetic resolution of racemic mixtures or the diastereo-
selective hydrogenation of furan-2-carboxylic acid derivatives
8
give the corresponding 2-acyl THFs (Scheme 1b). Although
high enantioselectivities were achieved, the substrates were
limited to highly reactive α-diazoesters. On the other hand, Smith
and colleagues reported a chiral Lewis base-promoted enantio-
selective Michael addition/lactonization reaction of enone acids
6
with chiral auxiliaries. In contrast, to the best of our knowledge,
9
only three enantioselective methods have been developed for the
preparation of 2-acyl THFs. Baiker and colleagues developed
enantioselective hydrogenation of furan-2-carboxylic acid by
followed by nucleophilic ring-opening (Scheme 1c). Although
the corresponding cis-3-substituted 2-acyl THFs were obtained
with excellent enantio- and diastereoselectivities, in situ activa-
tion of carboxylic acid with pivaloyl chloride is required to
generate a Michael donor. Moreover, compound 1, which is an
essential core for many pharmaceuticals, as shown in Figure 1,
is not easily synthesized. Thus, the development of an efficient
and highly enantioselective method for the synthesis of highly
valuable 2-acyl THF derivatives is still needed. Here, we report
chiral hypoiodite salt-catalyzed enantioselective oxidative cyclo-
etherification of δ-hydroxyketones 2 to 2-acyl THF 3 in high
yield and with high enantioselectivity (Scheme 1d).
7
using Pd/Al2O3 and cinchonidine catalysts (Scheme 1a).
However, the product was obtained with low enantioselectivity.
Zhou and colleagues reported a copper-catalyzed enantioselec-
tive intramolecular O­H insertion of ω-hydroxy-α-diazoesters to
O
NH2
OMe
OMe
N
O
N
O
N
N
OMe
OMe
N
H
N
N
N
O
Terazosin
Alfuzosin
Recently, we have developed enantioselective oxidative
cyclization reactions of β-(2-hydroxyphenyl) ketones 5 into 2-
acyl-2,3-dihydrobenzofuran derivatives 6 catalyzed by chiral
NH2
O
HO2C
O
O
N
O
O
H
N
H
N
∗
10
11a
NH
quaternary ammonium hypoiodite salt catalysts (Scheme 2).
OH
N
H
O
S
O
O
The hypoiodite salts were generated in situ from the corre-
sponding ammonium iodides 4 in the presence of hydrogen
peroxide, tert-butyl hydroperoxide (TBHP), or cumene hydro-
O
O
H H
OH
Cathepsin K inhibitor
Faropenem
1
11­13
Figure 1. 2-Acyl THF-derived pharmaceuticals.
peroxide (CHP) as an oxidant.
Chem. Lett. 2016, 45, 353–355 | doi:10.1246/cl.160004
© 2016 The Chemical Society of Japan | 353

Ar
O
1
. MeOTf
I–
then DBU/n-BuOH
3
a
OH
N+
(91% ee)
2.1 M NaOH, THF/MeOH
O
(
R)-1 (91% ee)
8
7% yield (for 2 steps)
O
Ar
Ar = {3,5-[3,5-(CF3)2C6H3]2C6H3}
Scheme 3. Derivatization of 3a to (R)-1.
Z
O
4
(10 mol%)
H
O
H
Table 2. Enantioselective cycloetherification of substituted
δ-hydroxyketones 2
3
0% H2O2 (2 equiv)
O
Z
a
MTBE (0.02 M), RT, 35 min
5
6: 99% yield, 88% ee
4
(10 mol%)
R2 R2
O
2 R2
O
R
CHP (2 equiv)
Scheme 2. Enantioselective cycloetherification of β-(2-
hydroxyphenyl) ketones 5.
H
R1
R1
O
Z
Z
MTBE (0.2 M), RT
R1 R1
H
O
2
3
Table 1. Enantioselective cycloetherification of δ-hydroxy-
ketones 2a
Entry
1
Product
3
Time/h
3, Yield/%, ee/%
95, 92
58, 92
31, 92
93, 92
2
24
24
6
O
4 (10 mol%)
Oxidant (2 equiv)
O
b
O
2
3
c
Z
3b
HO
Z
Z
MTBE (x M), RT
O
d
H
O
4
2a
3a
O
a
b
Entry Oxidant
x/M Time/h
3a, Yield /%, ee /%
5
6
7
8
3c
3d
2
2
98, 95
95, 89
95, 78
30, 59
Z
c
O
1
2
3
4
30% H2O2 0.02
TBHP
CHP
24
18
2
<5 , ®
O
0.02
0.02
0.2
55, 82
75, 90
Ph
Ph
Z
d
O
CHP
2
81, 91 (98)
O
aIsolated yield. bEvaluated by HPLC analysis. The absolute
configuration of 3a was determined by comparing the optical
rotation of 1 derived from 3a to the value in the literature.
EtO2C
EtO2C
Z 3e
3f
2
O
6a­6c
O
c
d
Unreacted 2a was recovered (>95%). After a single recrystal-
Z
24
lization. For details, see the Supporting Information.
O
aUnless otherwise noted, a solution of 2 (0.1 mmol), 4 (10 mol %)
and CHP (2 equiv) in MTBE (0.2 M) was stirred at room
temperature. Isolated yields are reported. Ee was determined by
We envisioned that our chiral hypoiodite catalysis could be
used for the enantioselective synthesis of 2-acyl THFs 3 by
using δ-hydroxyketones 2 as substrates. However, the oxidative
cyclization of δ-hydroxyketone 2a did not proceed and only a
trace amount of the desired product 3a was obtained under
conditions identical to those for β-(2-hydroxyphenyl) ketone 5
with hydrogen peroxide as an oxidant (Table 1, Entry 1 versus
Scheme 2). Since the cyclization of 2 proceeded much more
slowly than that of 5, a catalyst-inactivation path (i.e.,
disproportionation or reductive decomposition of hypoiodite
HPLC analysis. The absolute configuration of 3b­3f was assigned
by analogy. bReaction was performed with 4 (1 mol %) in the
c
presence of K2CO3 (1 equiv) in MTBE (0.02 M). Reaction was
performed with 4 (1 mol %) in MTBE (0.02 M). dReaction was
performed with 2b (4.1 mmol) and 4 (2 mol %) in the presence of
K CO (1 equiv) in MTBE (0.02 M).
2
3
γ,γ-dialkyl-substituted 2b and 2c gave the corresponding 2-
acyl THFs 3b and 3c in higher chemical yield with higher
enantioselectivities than that of 3a (Entries 1 and 5). The catalyst
loading could be reduced to 1 mol % for the oxidation of highly
reactive 2b without reducing the enantioselectivity (Entry 2).
Although the reaction did not proceed to completion, the
chemical yield of 3b was increased about 2-fold (TON was up
to 58) in the presence of 1 equivalent of potassium carbonate,
which is required to regenerate the catalytic active species from
11,13
species)
studies,
might proceed preferentially. As in our previous
to decelerate the oxidation of iodide and suppress
11b,13b
the catalyst-inactivation path, alkyl hydroperoxides were eval-
uated as weaker oxidants instead of hydrogen peroxide. As a
result, the desired product 3a was obtained in 55% yield with
82% ee by the use of TBHP in methyl tert-butyl ether (MTBE)
(Entry 2). The reactivity and enantioselectivity were further
increased by the use of CHP in place of TBHP (Entry 3).
Moreover, to our delight, 3a could be obtained in higher
chemical yield under more concentrated conditions (0.2 M)
without any loss of enantioselectivity (Entry 4). In sharp
contrast, highly diluted conditions (0.02 M) were required to
induce high enantioselectivity for the oxidative cyclization of
ketophenols 5 (Scheme 2).11 Almost optically pure 3a could be
obtained after a single recrystallization (Entry 4).
11b
inert species (Entry 2 versus Entry 3).
This method could
be applied to a gram-scale reaction. The oxidation of 2b on a
1.1-gram scale with 2 mol % of 4 in the presence of potassium
carbonate gave 3b in 93% yield (1.02 g) with 92% ee (Entry 4).
The oxidation of γ,γ-diphenyl- and γ,γ-diester-substituted 2d
and 2e gave the corresponding 3 quantitatively (Entries 6 and 7).
However, the enantioselectivity was reduced to 78% ee for 3e
(Entry 7). On the other hand, the oxidation of β,β-dimethyl-
substituted 2f was sluggish, presumably due to steric reasons,
and 3f was obtained in low chemical yield with moderate
enantioselectivity (Entry 8).
The (N-phenylimidazol-2-yl)carbonyl group of 3a was
easily transformed to give (R)-1 (Scheme 3).2
­5
We examined various substituted δ-hydroxyketones 2 under
optimized conditions (Table 2). The oxidative cyclization of
354 | Chem. Lett. 2016, 45, 353–355 | doi:10.1246/cl.160004
© 2016 The Chemical Society of Japan

In summary, we developed a quaternary ammonium hypo-
iodite salt-catalyzed oxidative cyclization of δ-hydroxyketones
to give chiral THF derivatives with high enantioselectivity. This
environmentally benign method could provide various chiral
8
9
S.-F. Zhu, X.-G. Song, Y. Li, Y. Cai, Q.-L. Zhou, J. Am.
Chem. Soc. 2010, 132, 16374.
D. Belmessieri, A. de la Houpliere, E. D. D. Calder, J. E.
Taylor, A. D. Smith, Chem.®Eur. J. 2014, 20, 9762.
2-acyl THFs for the discovery of new drug candidates, which
10 Selected reviews for spirobis(binaphthyl)-based quaternary
ammonium PTC catalysis: a) T. Ooi, K. Maruoka, Angew.
Chem., Int. Ed. 2007, 46, 4222. b) S. Shirakawa, K.
Maruoka, Angew. Chem., Int. Ed. 2013, 52, 4312.
11 a) M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science
2010, 328, 1376. b) M. Uyanik, H. Hayashi, K. Ishihara,
Science 2014, 345, 291. c) M. Uyanik, N. Sasakura, E.
Kaneko, K. Ohori, K. Ishihara, Chem. Lett. 2015, 44, 179.
might be difficult to access by previous methods.
Financial support for this project was partially provided by
CREST from JST, JSPS.KAKENHI (Nos. 24245020, 25105722,
15H05755 and 15H05484), the Program for Leading Graduate
Schools: IGER Program in Green Natural Sciences (MEXT),
and JSPS Research Fellowships for Young Scientists (H.H.).
1
2 Selected reviews for the iodide/ROOH oxidation system:
a) M. Uyanik, K. Ishihara, ChemCatChem 2012, 4, 177.
b) P. Finkbeiner, B. J. Nachtsheim, Synthesis 2013, 45, 979.
c) X.-F. Wu, J.-L. Gong, X. Qi, Org. Biomol. Chem. 2014,
12, 5807. Selected examples: d) M. Kirihara, Y. Asai, S.
Ogawa, T. Noguchi, A. Hatano, Y. Hirai, Synthesis 2007,
3286. e) T. Froehr, C. P. Sindlinger, U. Kloeckner, P.
Finkbeiner, B. J. Nachtsheim, Org. Lett. 2011, 13, 3754.
f) C. Zhu, Y. Wei, ChemSusChem 2011, 4, 1082. g) J.-S.
Tian, K. W. J. Ng, J.-R. Wong, T.-P. Loh, Angew. Chem., Int.
Ed. 2012, 51, 9105. h) A. Yoshimura, K. R. Middleton, C.
Zhu, V. N. Nemykin, V. V. Zhdankin, Angew. Chem., Int. Ed.
2012, 51, 8059. i) Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu,
X. Wan, Angew. Chem., Int. Ed. 2012, 51, 3231. j) B. Tan,
N. Toda, C. F. Barbas, III, Angew. Chem., Int. Ed. 2012, 51,
12538. k) R. A. Kumar, G. Saidulu, K. R. Prasad, G. S.
Kumar, B. Sridhar, K. R. Reddy, Adv. Synth. Catal. 2012,
354, 2985. l) T. Nobuta, N. Tada, A. Fujiya, A. Kariya, T.
Miura, A. Itoh, Org. Lett. 2013, 15, 574. m) K. Kiyokawa, T.
Kosaka, S. Minakata, Org. Lett. 2013, 15, 4858. n) Z. Jia, T.
Nagano, X. Li, A. S. C. Chan, Eur. J. Org. Chem. 2013, 858.
o) Y.-P. Zhu, M.-C. Liu, Q. Cai, F.-C. Jia, A.-X. Wu,
Chem.®Eur. J. 2013, 19, 10132. p) H.-M. Huang, Y.-J. Li,
Q. Ye, W.-B. Yu, L. Han, J.-H. Jia, J.-R. Gao, J. Org. Chem.
2014, 79, 1084. q) K. Moriyama, M. Takemura, H. Togo,
J. Org. Chem. 2014, 79, 6094. r) J.-L. Gong, X. Qi, D. Wei,
J.-B. Feng, X.-F. Wu, Org. Biomol. Chem. 2014, 12, 7486.
s) Q. Jiang, B. Xu, A. Zhao, J. Jia, T. Liu, C. Guo, J. Org.
Chem. 2014, 79, 8750. t) W. Xu, B. J. Nachtsheim, Org. Lett.
2015, 17, 1585. u) S. Tang, K. Liu, Y. Long, X. Gao, M.
Gao, A. Lei, Org. Lett. 2015, 17, 2404. v) K. Yasui, T. Kato,
K. Kojima, K. Nagasawa, Chem. Commun. 2015, 51, 2290.
w) P. Swamy, M. M. Reddy, M. Naresh, M. A. Kumar, K.
Srujana, C. Durgaiah, N. Narender, Adv. Synth. Catal. 2015,
357, 1125.
Supporting Information is available on http://dx.doi.org/
1
0.1246/cl.160004.
References and Notes
1
2
a) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407.
b) E. J. Kang, E. Lee, Chem. Rev. 2005, 105, 4348. c) J. P.
Wolfe, M. B. Hay, Tetrahedron 2007, 63, 261. d) G. Jalce,
X. Franck, B. Figadère, Tetrahedron: Asymmetry 2009, 20,
2
537.
a) J. J. Kyncl, B. W. Horrom, PCT Int. Appl. WO 9200073,
992. b) M. Liu, D. Zhang, M. Yang, T. Zhao, X. Wang, Y.
1
Zhang, J. Han, H. Liu, Chirality 2012, 24, 1047. c) X. Chen,
C. Zhao, X. Li, T. Wang, Y. Li, C. Cao, Y. Ding, M. Dong, L.
Finci, J. Wang, X. Li, L. Liu, Nat. Chem. Biol. 2015, 11, 19.
d) L. Martz, SciBX 2015, 7, doi:10.1038/scibx.2014.1367.
a) F. Lefèvre-Borg, S. E. O’Connor, H. Schoemaker, P. E.
Hicks, J. Lechaire, E. Gautier, F. Pierre, C. Pimoule, P.
Manoury, S. Z. Langer, Br. J. Pharmacol. 1993, 109, 1282.
b) M. S. Reddy, B. K. Reddy, C. K. Reddy, M. K. Kumar,
S. T. Rajan, V. Mummadi, ARKIVOC 2007, Part xiii, 41.
a) I. Milazzo, G. Blandino, F. Caccamo, R. Musumeci, G.
Nicoletti, A. Speciale, J. Antimicrob. Chemother. 2003, 51,
3
4
7
21. b) A. Gnanaprakasam, S. Venugopal, V. Ganapathy,
P. S. Udayampalayam, PCT Int. Appl. WO 2008-035153,
008.
2
5
6
N. Kobayashi, T. Koji, H. Kunii, M. Ishikawa, D. Morita, JP
Patent 2014-003160, 2014.
Selected examples: a) P. C. Bélanger, H. W. R. Williams,
Can. J. Chem. 1983, 61, 1383. b) Y. Fujima, Y. Hirayama,
M. Ikunaka, Y. Nishimoto, Tetrahedron: Asymmetry 2003,
1
4, 1385. c) M. Sebek, J. Holz, A. Börner, K. Jähnisch,
Synlett 2009, 461. Homobenzotetramisole-catalyzed kinetic
resolution of carboxylic acids: d) X. Yang, V. B. Birman,
Chem.®Eur. J. 2011, 17, 11296.
7
a) M. Maris, W.-R. Huck, T. Mallat, A. Baiker, J. Catal.
13 a) M. Uyanik, D. Suzuki, T. Yasui, K. Ishihara, Angew.
Chem., Int. Ed. 2011, 50, 5331. b) M. Uyanik, D. Suzuki, M.
Watanabe, H. Tanaka, K. Furukawa, K. Ishihara, Chem. Lett.
2015, 44, 387.
2
003, 219, 52. b) M. Maris, T. Mallat, E. Orglmeister, A.
Baiker, J. Mol. Catal. A: Chem. 2004, 219, 371. c) M. Maris,
T. Bürgi, T. Mallat, A. Baiker, J. Catal. 2004, 226, 393.
Chem. Lett. 2016, 45, 353–355 | doi:10.1246/cl.160004
© 2016 The Chemical Society of Japan | 355