A Chiral Electrophilic Selenium Catalyst for Highly Enantioselective Oxidative Cyclization

Article abstract of DOI:10.1021/jacs.6b01462

Chiral electrophilic selenium catalysts have been applied to catalytic asymmetric transformations of alkenes over the past two decades. However, highly enantioselective reactions with a broad substrate scope have not yet been developed. We report the first successful example of this reaction employing a catalyst based on a rigid indanol scaffold, which can be easily synthesized from a commercially available indanone. The reaction efficiently converts β,γ-unsaturated carboxylic acids into various enantioenriched γ-butenolides under mild conditions.

Full text of DOI:10.1021/jacs.6b01462

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A Chiral Electrophilic Selenium Catalyst for
Highly Enantioselective Oxidative Cyclization
Yu Kawamata, Takuya Hashimoto, and Keiji Maruoka
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01462 • Publication Date (Web): 11 Apr 2016
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A Chiral Electrophilic Selenium Catalyst for Highly Enantioselective
Oxidative Cyclization
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Yu Kawamata, Takuya Hashimoto and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Supporting Information Placeholder
since the catalysis had to be conducted at ambient temperature to
overcome the turnover-limiting oxidative deselenylation, applica-
tion of previous chiral electrophilic selenium reagents demon-
strated poor enantioselectivity or very limited scope. A common
feature of these catalysts consists of a chiral acyclic side chain-
tethered heteroatom which interacts with the selenium non-
covalently for asymmetric induction.7 We suspected that the chiral
environment created by such interaction might lose rigidity at
ambient temperature. Accordingly, an innovative, robust catalyst
design which enables high enantioselectivities even at ambient
temperature is indispensable. Up till now, highly enantioselective
selenofunctionalization could only be achieved by recently-
emerged organocatalytic methods, which activate stoichiometric
amount of achiral electrophilic selenium by acid or base.8-10
ABSTRACT: Chiral electrophilic selenium catalysts have been
applied to catalytic asymmetric transformations of alkenes over
the last two decades. However, highly enantioselective reactions
with a broad substrate scope have not yet been developed. We
report the first successful example of this reaction employing a
catalyst based on a rigid indanol scaffold, which can be easily
synthesized from a commercially available indanone. The reaction
efficiently converts β,γ-unsaturated carboxylic acids into various
enantioenriched γ-butenolides under mild conditions.
Asymmetric catalysis constitutes a robust synthetic tool which
ensures high enantioselectivities in many transformations.1 Since
the middle of the twentieth century, a vast array of elements has
been exploited as catalytic centers, surrounded by judiciously
constructed chiral environment. However, there are still some
elements which elude these efforts and remain underutilized de-
spite their promising catalytic activities. Chiral selenium catalyst
is one such example. Chiral nucleophilic selenium catalysts are
rare and only a few have been successfully developed so far;2,3
while in the case of chiral electrophilic selenium catalysis, there
has been no general catalyst which achieves high enantioselectivi-
ties over a range of substrates.
Scheme 1. Strategies for Asymmetric Selenofunctionaliza-
tion.
a) Stoichiometric use of chiral electrophilic selenium reagents
R*Se
R1
SeR*
SeR*
R2
R1
Nu
R1
R2
R2
seleniranium
Nu
b) Chiral electrophilic selenium catalysis
1/2 (R*Se)2
Conventionally, chiral electrophilic selenium reagents have
been utilized in stoichiometric amounts for asymmetric seleno-
functionalization of unactivated alkenes, which installs a selenium
functionality and a nucleophile in an anti-specific manner via a
three-membered seleniranium intermediate (Scheme 1a).4 A varie-
ty of chiral selenium reagents have been developed to date, which
demonstrated high stereoselectivity mostly when the reactions
were carried out at cryogenic temperature. The selenium moiety
introduced can be later transformed into other functionalities un-
der oxidative or reductive conditions, suitable for natural product
and pharmaceutical syntheses.5 Catalytic use of chiral electro-
philic selenium species can be achieved by regenerating the cata-
lyst via in situ oxidative deselenylation, allowing asymmetric
introduction of a nucleophile and successive transformation of the
selenium functionality to be realized in a single reaction (Scheme
1b).6 The implementation of this sequence of transformations was
first documented by Tomoda et al. in the 1990s in the form of
asymmetric conversion of β-methylstyrene into an enantioen-
riched allylic ether.6a Since this represents a powerful strategy for
accessing various optically active allylic compounds from unacti-
vated alkenes, several chiral electrophilic selenium catalysts have
been examined over the past decades (Scheme 1c).6b-6f However,
XY (oxidant)
R1
R2
R1
R2
+
Nu
R*Se X
Nu
deselenylation
selenofunctionalization
X
SeR*
SeR*
R1
R2
R1
R2
Nu
Nu
XY
oxidation
c) Preceding chiral electrophilic selenium catalysts (ref 6a, c, e)
Ph
Se–Y non-bonding interaction rigidifys
the catalyst structure.
O
O
)
)
)
O
2
2
2
Se SMe
Se
Se NMe2
N
Ph
MeO
MeO
O
Me
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Herein, we describe the electrophilic selenium-catalyzed, first
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highly enantioselective oxidative cyclization of β,γ-unsaturated
carboxylic acids, which affords various enantioenriched γ-
butenolides with up to 97% ee.6f The key to this success is the
design of a rigid catalyst based on an indanol scaffold which can
be practically synthesized by establishing robust optical resolution
and selenylation routes.
The data in Table 1 summarize the effect of various parameters
on this reaction. With the optimal catalyst 1a, the oxidative cy-
clization of β,γ-unsaturated carboxylic acid 5a smoothly complet-
ed within 2 h to give the desired γ-butenolide 6a in quantitative
yield with high enantioselectivity (entry 1). The absolute configu-
ration of the product was determined by comparison of the optical
rotation value reported in the literature. NFSI15 was selected as an
oxidant since iodine (III)6f,16 and persulfate6a-6d gave low yields
due to insufficient oxidizing ability or poor solubility (entries 2
and 3). The structure of the catalyst had a great impact on the
enantioselectivity. When the catalyst TBS group was replaced
with a bulkier TIPS group (1b), slight decrease of enantioselectiv-
ity was observed (entry 4), whereas the catalyst 1c with a small
methyl group substantially diminished the enantioselectivity (en-
try 5). Interestingly, the catalyst 1d bearing a free hydroxy group
still catalyzed the reaction smoothly, albeit with low enantioselec-
tivity (entry 6). In addition, gem-dimethyl group was found to be
essential for achieving high enantioselectivity (entry 7). The reac-
tion temperature is also important since the reaction was signifi-
cantly slowed down at 0 ºC (entry 8). The productivity and selec-
tivity of the reaction were slightly eroded in the absence of CaCO3
(entry 9). It should also be mentioned that the methoxy group at
the ortho-position of the selenium is attached for the synthetic
reason (see, Scheme 3). We have confirmed that the catalyst hav-
ing the methoxy group at the para-position worked with similar
reactivity and selectivity (data not shown). At last, the reaction
was carried out on a 1.0 mmol scale to verify the robustness of
this procedure (entry 10).
We began this research by designing a new chiral electrophilic
selenium catalyst in the intramolecular oxidative cyclization of
β,γ-unsaturated carboxylic acid. In the new catalyst design, we
opted for an indanol scaffold, 11,12 which previously enabled us to
effectively control the enantioselectivity of thiyl radical catalyzed
cyclization.13 Extensive screening of a variety of catalyst designs
led us to find a suitable catalyst 1a, which showed excellent enan-
tioselectivity at ambient temperature in the target reaction
(Scheme 2).
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Scheme 2. The Highly Enantioselective Oxidative Cycliza-
tion.
The catalyst 1a can be easily synthesized from commercially
available 6-methoxyindanone through a sequence of high-yielding
reactions (Scheme 3). The key enantiopure indanol (S)-2 was
obtained by the optical resolution of rac-2 by using phenylalanine
derivative 3. Two diastereomers (S,S)- and (S,R)-3 were separated
by recrystallization and column chromatography. Then ortho-
lithiation and the reaction with elemental selenium were conduct-
ed to install diselenide at 7-position. However, this typical proto-
col gave the corresponding diselenide as an inseparable mixture of
products.14 To overcome this hurdle, we devised the installation of
the requisite selenium functionality as a p-methoxybenzyl sele-
nide (4), which can also generate an electrophilic selenium cata-
lyst directly under oxidative reaction conditions as shown in eq. 1.
Table 1. Selenium-Catalyzed Oxidative Cyclization of β,γ-
Unsaturated Carboxylic Acid: Effect of Reaction Parame-
ters.a
Scheme 3. Catalyst Synthesis.
entry
change from the standard conditions
none
% yieldb
% eed
95
91
–
1
2
3
4
5
6
7
8
9
99c
13
0
PhI(OCOCF3)2 instead of NFSI
Na2S2O8 instead of NFSI
1b instead of 1a
1c instead of 1a
92
74
72
71
9
85
62
14
82
93
88
1d instead of 1a
1e instead of 1a
0 ºC
no CaCO3
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enantioselectivity, lower enantioselectivity was observed in the
case of 4-methoxyphenyl product 8j.
Table 3. Substrate Scope for Aromatic Substrates.a
10
1.0 mmol scale
>99
95
a
Reactions performed with 5a (0.1 mmol), oxidant (0.11
mmol), catalyst 1 (0.01 mmol) in solvent (0.7 mL) at room tem-
perature. NMR yield. Yield of isolated product. Determined
by chiral HPLC.
b
c
d
7
After establishing the optimal reaction conditions, the oxidative
cyclization of aliphatic β,γ-unsaturated carboxylic acids 5 was
explored (Table 2). Generally, the reaction reached completion
within 2 h to afford the product in high yield with excellent enan-
tioselectivity at room temperature. γ-Butenolides with linear,
branched, and cyclic aliphatic substitutions were obtained in ex-
cellent yields with uniformly high enantioselectivities (6b-6d).
Oxygen- and nitrogen-containing functional groups were both
tolerated in these reaction conditions (6e and 6f). In addition,
ester, nitrile and ketal groups were also accommodated (6g-6i). A
substrate bearing alkyne moiety was also applicable to this reac-
tion (6j).17 Finally, optically pure citronellal-derived substrate
underwent clean reaction in excellent diastereoselectivity, demon-
strating that a stereogenic center adjacent to the transformed dou-
ble bond did not affect the stereoselectivity (6k).18
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Table 2. Substrate Scope for Aliphatic Substrates.a
a
Reactions performed with 7 (0.1 mmol), NFSI (0.11 mmol),
TMSOCOCF3 (0.12 mmol), catalyst 1a (0.01 mmol) in toluene
(0.7 mL) at 10 ºC. Yield of isolated product.
Finally, we explored transformations to which enantioenriched
γ-butenolides have not been applied previously. The first example
is tandem cuprate 1,4-addition/aldol reaction (Scheme 4, I).20 The
reaction proceeded to give the desired product 9 bearing four
consecutive stereogenic centers, isolated as a single diastereomer
in 80% yield without erosion of optical purity. The second exam-
ple is DIBAL reduction of γ-phenyl butenolide 8a (Scheme 4, II).
Although 8a is prone to racemize under basic conditions, this
reaction afforded a chiral (Z)–allyl alcohol 10 without substantial
decrease of optical purity.
Scheme 4. Synthetic Applications of the Products.
a
Reactions performed with 5 (0.1 mmol), NFSI (0.11 mmol),
CaCO3 (0.3 mmol), catalyst 1a (0.01 mmol) in toluene (0.7 mL) at
room temperature. Yield of isolated product.
Next, the oxidative cyclization of γ-aryl substrates 7 was ex-
plored. This was conducted under slightly modified reaction con-
ditions (at 10 ºC using TMSOCOCF3 instead of CaCO3) for im-
proved enantioselectivity (see Supporting Information for de-
tails).19 Under these conditions, a range of aromatic substrates
gave the corresponding γ-butenolides in excellent yields with
good enantioselectivities (Table 3). Generally, γ-butenolides with
various electron-deficient groups were obtained with ees above
80% (8b-8f). The product with an ortho-substituted aryl group
was also obtained with high enantioselectivity (8g). Slightly lower
ee value was observed in the case of biphenyl product (8h). Alt-
hough 3-methoxyphenyl product 8i was obtained with comparable
In conclusion, we achieved the first highly enantioselective ox-
idative cyclization of β,γ-unsaturated carboxylic acids into various
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(10) Zhang, H.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2014, 136,
16485.
(11) Use of tetralol as stoichiometric chiral selenylating reagents has
been reported, see: (a) Wirth, T.; Fragale, G. Chem. Eur. J. 1997, 3,
1894. (b) Wirth, T.; Fragale, G. Synthesis 1998, 162. (c) Uehlin, L.;
Fragale, G.; Wirth, T. Chem. Eur. J. 2002, 8, 1125.
(12) The non-bonding interaction between the selenium and indanol
oxygen is considered to be small. Fragale, G.; Neuburger, M.;
Wirth, T. Chem. Commun. 1998, 1867.
(13) Hashimoto, T.; Kawamata, Yu.; Maruoka, K. Nat. Chem. 2014, 6,
702.
enantioenriched γ-butenolides catalyzed by a chiral electrophilic
selenium catalyst. To achieve this goal, we successfully devel-
oped a rigid catalyst based on an indanol scaffold and identified
suitable reaction conditions to perform the reaction smoothly.
This study will encourage further development of chiral electro-
philic selenium catalysts and their applications based on their
broad reactivity,4,5 as well as the use of chiral indanol scaffolds in
other asymmetric catalyst designs.
Supporting Information
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(14) The corresponding triselenide is known to be formed along with the
target diselenide. Santi, C.; Tragale, G.; Wirth, T. Tetrahedron:
Asymmetry 1998, 9, 3625.
(15) (a) Trenner, J.; Depken, C.; Weber, T.; Breder, A. Angew. Chem.
Int. Ed. 2013, 52, 8952. (b) Krätzschmar, F.; Kaßel, M.; Delony, D.;
Breder, A. Chem. Eur. J. 2015, 21, 7030. (c) Ortgies, S.; Breder, A.
Org. Lett. 2015, 17, 2748. (d) Zhang, X.; Guo, R.; Zhao, X. Org.
Chem. Front. 2015, 2, 1334. (e) Deng, Z.; Wei, J.; Liao, L.; Huang,
H.; Zhao, X. Org. Lett. 2015, 17, 1834.
(16) (a) Shahzad, S. A.; Venin, C.; Wirth, T. Eur. J. Org. Chem. 2010,
3465. (b) Singh, F. V.; Wirth, T. Org. Lett. 2011, 13, 6504.
(17) The reaction of substrates with an additional alkene moiety was
inefficient.
(18) The use of ent-1a as catalyst resulted in the formation of epi-6k in
81% yield with 97:3 dr (see the Supporting Information for detail).
(19) We assume that use of TMSOCOCF3 generates a catalyst which has
trifluoroacetate as a counteranion, thereby affecting the enantiose-
lectivity slightly.
Experimental details and characterization data for new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was partially supported by a Grant-in-Aid for Scientific
Research from the MEXT (Japan). Y.K. thanks a Grant-in-Aid for
the Research Fellowship of JSPS for Young Scientists.
(20) Mao, B.; Geurts, K.; Fañanás-Mastral, M.; van Zijl, A. W.; Fletch-
er, S. P.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2011, 13, 948.
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