Catalytic asymmetric synthesis of stable oxetenes via Lewis acid-promoted [2 + 2] cycloaddition

Article abstract of DOI:10.1021/ja2085299

A highly enantioselective and atom-economical [2 + 2] cycloaddition of various alkynes with trifluoropyruvate using a dicationic (S)-BINAP-Pd catalyst has been established. This is the first enantioselective synthesis of stable oxetene derivatives, whose

Full text of DOI:10.1021/ja2085299

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Catalytic Asymmetric Synthesis of Stable Oxetenes via Lewis
Acid-Promoted [2 + 2] Cycloaddition
Kohsuke Aikawa, Yuta Hioki, Natsumi Shimizu, and Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
S Supporting Information
b
Scheme 1. (a) Four-Membered Heterocycles; (b) [2 + 2]
Cycloadditions of Alkynes with Carbonyl Compounds
ABSTRACT: A highly enantioselective and atom-economical
[2 + 2] cycloaddition of various alkynes with trifluoropyr-
uvate using a dicationic (S)-BINAPÀPd catalyst has been
established. This is the first enantioselective synthesis of
stable oxetene derivatives, whose structure has been clarified
by X-ray analysis. This catalytic process offers a practical syn-
thetic method for oxetene derivatives (catalyst loading: up to
0.1 mol %), which can serve as novel chiral building blocks
for pharmaceuticals and agrochemicals and can also be trans-
formed into a variety of enantiomerically enriched CF3-
substituted compounds with high stereoselectivity.
aturated four-membered heterocyclic compounds bearing
S
one heteroatom in the ring, such as oxetanes and azetidines,
have received attention as small-molecule modules of key biophy-
sical and chemical properties of pharmaceutically relevant scaffolds
(Scheme 1a).1 Particularly intriguing are oxetanes, which bear an
oxygen atom in the ring and would be expected to serve as widely
available building blocks for the synthesis of natural and unnatural
compounds with significant biological activities.1aÀc In sharp con-
trast, oxetenes are considerably less stable under thermal and acidic
conditions because the double bond increases the ring strain. Some
oxetene derivatives have been synthesized to date, but their isolation
and purification are much more difficult.2 Furthermore, enantio-
merically enriched oxetenes have never been prepared by asym-
metric synthetic methods. Oxetenes have been reported as reaction
intermediates in photochemical or Lewis acid-promoted [2 + 2]
cycloadditions (Scheme 1b). Photoinduced [2 + 2] cycloaddition of
nπ* excited-state carbonyl compounds with alkynes gives labile
oxetene intermediates (eq 1 in Scheme 1b).2e,h,3 The correspond-
ing α,β-unsaturated carbonyl compounds are obtained through
electrocyclic ring opening of the thermodynamically unstable
oxetenes. Lewis acid-promoted [2 + 2] cycloaddition also provides
the oxetene intermediates, but ring opening to give α,β-unsatu-
rated carbonyl compounds readily takes place because of the Lewis
acid, even at low reaction temperatures (eq 2 in Scheme 1b).4,5
We have developed a variety of catalytic asymmetric CÀC
bond-forming reactions using chiral dicationic Pd complexes as
efficient Lewis acid catalysts.6,7 Here we present a highly
enantioselective and atom-economical [2 + 2] cycloaddition of
various alkynes 2 with ethyl trifluoropyruvate (3) catalyzed by
the chiral cationic BINAPÀPd complex 1 (eq 3 in Scheme 1b).
This is not only the first synthetic method for stable oxetene
derivatives stabilized by the CF3 group but also a new entry to
chiral CF3-containing building blocks for pharmaceuticals and
agrochemicals. Currently, the development of useful methods to
provide enantiomerically enriched organofluorine compounds
bearing the CF3 group in particular is strongly desired.8 This
catalytic process affords a variety of stable and enantiomerically
enriched oxetene derivatives bearing the CF3 group.
We recently reported a catalytic asymmetric alkynylation
reaction based on the formation of a stable β-cation intermediate
using 3 and alkynylsilane 2a, which possesses phenyl and tri-
methylsilyl groups at the terminal positions.9 The chiral complex
1 catalyzes the reaction to produce the corresponding propargylic
alcohol 6 in 85% yield with 99% ee after desilylation by treatment
with acid (eq 1 in Scheme 2).9 During the course of this research
project, we found that the use of alkynylsilane 2b bearing a more
electron-rich p-methoxyphenyl group facilitated a [2 + 2]
cycloaddition to afford oxetene 4b and hydrolyzed α-hydroxy-
γ-ketoester 5b in a 4.2:1 ratio as determined by 1H and 19F NMR
analyses. Being sensitive to acidic conditions, 4b was hydrolyzed
to 5b even through a thin pad of silica gel (eq 2 in Scheme 2).
Protodesilylation and hydrolysis of the four-membered enol ether
structure can provide 5b, as hydrolysis of oxetenes 4m and 4n
(see below) also led to 5b. With basic alumina, however, column
chromatography gave only 4b in 88% yield with 99% ee without
hydrolysis or electrocyclic ring opening. To synthesize more stable
oxetenes, the more sterically demanding dimethylphenylsilyl group
in alkynylsilane 2c was employed; the combination of 2c and 3 in
the presence of 1 (2 mol %) afforded the stable oxetene 4c in
Received: September 15, 2011
Published: November 09, 2011
r
2011 American Chemical Society
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Scheme 2. Catalytic Asymmetric [2 + 2] Cycloaddition
versus Alkynylation
Table 1. Catalytic Asymmetric Synthesis of Stable Oxetene
Derivatives Using 3 and a Variety of Alkynes 2dÀy
excellent yield (93%) and enantioselectivity (99% ee); 4c could be
isolated and purified by silica-gel column chromatography without
conversion to 5b or α,β-unsaturated ketone 7 (eq 3 in Scheme 2).
Heat treatment of 4c in toluene-d8 resulted in electrocyclic ring
opening2À5 to gave 7 quantitatively.10 Monitoringof the reaction at
70 °C revealed a long half-life of 110.6 h. The absolute configura-
tion of 4b was determined to be R by derivatization to the known
α-hydroxy-γ,δ-unsaturated ester.11
It was predicted that electron-rich aryl substituents on the
alkyne, which can stabilize the vinyl cation intermediate,9 would
play an important role in facilitating the formation of the oxetene.
Thus, a range of internal alkynes without a silyl group could be
used in the [2 + 2] cycloaddition with 3 in the presence of
complex 1 (Table 1). The reactions of p-methoxyphenyl-sub-
stituted alkynes 2dÀn with various substitution patterns were
initially investigated in CH2Cl2 (entries 1À12). Alkynes 2dÀh
with aliphatic and aromatic groups gave the desired products in
good-to-excellent yields and enantioselectivities (entries 1À6).
In particular, even with a catalyst loading of 0.1 mol %, the good
yield (83%) and excellent enantioselectivity (98% ee) were
maintained in the reaction with alkyne 2d (entry 2). Alkynes
2f and 2g with electron-donating and -withdrawing aromatic
substituents, respectively, gave good yields and asymmetric
inductions (entries 4 and 5). The reactions using alkynes 2iÀk
with electron-withdrawing groups (CO2Et, CHO, and CF3)
required slightly higher temperatures [room temperature (rt)
to 40 °C] to provide the corresponding oxetenes with good-to-
excellent enantioselectivities (91À97% ee) (entries 7À9). The
[2 + 2] cycloaddition of alkynes bearing iodide (2l) and
pinacolborane (2m) proceeded smoothly at À20 °C within 1 h
to give the highly enantioenriched oxetenes (entries 10 and 11).
Terminal alkyne 2n gave the corresponding oxetene 4n in good
yield but with low enantioselectivity (entry 12). In spite of
reduced reactivity, alkynes 2o and 2p bearing a phenyl group
instead of the p-methoxyphenyl group could also be used (entries
13 and 14). Especially with the sterically less demanding methyl
and phenyl groups in alkyne 2o, use of the sterically more
demanding (S)-DTBM-SEGPHOS ligand was essential to en-
hance the enantioselectivity (entry 13). The reactions of alkynes
2q and 2r bearing p-tolyl and m-methoxyphenyl groups,
a 10/1 toluene/CH2Cl2 (1.0 M) was used as the solvent. b (S)-DTBM-
SEGPHOS was used instead of (S)-BINAP. c E/Z = 10/1. d Isolated
f
yields. e 19F NMR yield. Determined by chiral HPLC analyses. g En-
antiopurity of the E isomer.
respectively, gave the products in good yields but with reduced
levels of stereoinduction (entries 15 and 16). More bulky
1-naphthyl-substituted alkynes 2sÀu afforded excellent enan-
tioselectivities (98% ee) (entries 17À19). Alkynes 2vÀx with
electron-rich heteroaromatic substituents also gave excellent
results (97À99% ee) (entries 20À22). Notably, the aromatic
substituent could be replaced with a vinyl group to provide the
corresponding oxetene 4y in good yield (88%) and enantios-
electivity (89% ee) (entry 23). The absolute configuration of 4d
was shown to be R by X-ray analysis of 17 (see below).11 The
absolute configurations of other oxetene products were tentatively
assigned by analogy to 4b and 4d.
The structure of oxetene 4z obtained by the reaction of extremely
bulky internal alkyne 2z bearing tert-butyl and 2,4,6-trimethylphenyl
(Mes) groups was determined by X-ray analysis of a single crystal
(Scheme 3).11 The four-membered ring consists of two CÀO single
bonds (1.429 and 1.461 Å), a CÀC single bond (1.529 Å), and a
CÀC double bond (1.341 Å). The C2ÀC1ÀO angle is obtuse
(97.93°), but the remaining three bond angles of the oxetene are all
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Scheme 3. X-ray Structure of Oxetene 4za
Scheme 5. Proposed Reaction Mechanism
a Selected bond lengths (Å) and angles (deg): C1ÀC2, 1.341; C1ÀO,
1.429; C2ÀC3, 1.529; C3ÀO, 1.461; C1ÀC2ÀC3, 86.96; C2ÀC3ÀO,
88.73; C1ÀOÀC3, 86.38; C2ÀC1ÀO, 97.93.
Scheme 6. Reactions of Alkynes and Diethyl Ketomalonate
Scheme 4. Synthesis of 9 Using Ynamide 8 as the Nucleophile
acute (86.96, 88.73, and 86.38°). To the best of our knowledge, this
is the first structural confirmation of an oxetene by X-ray analysis.
The reaction of ynamide 8 as an internal alkyne was next exe-
cuted in the presence of complex 1 (Scheme 4), as there have
been only a few reports of catalytic asymmetric transforma-
tions involving ynamides.12 Fortunately, the reaction proceeded
smoothly at À78 °C to give the corresponding stable oxetene 9,
which was isolated by silica-gel column chromatography in
excellent yield (>99%) and enantioselectivity (99% ee). Even
in the case of a catalyst loading of 0.5 mol %, high enantioselec-
tivity (97% ee) was preserved along with a good yield (86%).
In our proposed reaction mechanism (Scheme 5),13 bidentate
coordination of trifluoropyruvate 3 to dicationic Pd complex 1
would initially form the reactive structure A, constructing the
efficient asymmetric environment.6,7,9 Attack on trifluoro-
pyruvate 3 by alkene 2 or 8 as the nucleophile would generate
intermediate B, which can be stabilized by the strong electron-
withdrawing nature of the CF3 substituent.8 A subsequent ring-
closing reaction would provide the corresponding oxetene 4 or 9.
With these reaction parameters defined, other carbonyl com-
pounds were examined in the present [2 + 2] cycloaddition. The
reactions with ethyl glyoxylate or benzaldehyde instead of 3 did
not proceed at all, and trifluoroacetophenone gave complex
products even at low temperature. However, the reaction of di-
ethyl ketomalonate (10) and alkyne 2d was promoted to provide
α,β-unsaturated ketone 11a (70% yield) and α-hydroxy-γ-
ketomalonate 11b (23% yield) via the electrocyclic ring-opening
reaction and hydrolysis of the labile oxetene, respectively (eq 1 in
Scheme 6). In this reaction, no oxetene could be detected. The use
of ynamide 8 with 10 produced only the α,β-unsaturated ketone 12
in 96% yield (eq 2 in Scheme 6). On the other hand, after the stable
oxetene 4d was prepared in situ by the reaction of 2d and 3 in
the presence of complex 1, the addition of H2O (10 equiv) to the
reaction mixture followed by an increase in the reaction temperature
solely provided α-hydroxy-γ-ketoester 5d as the hydrolyzed pro-
duct of 4d (eq 3 in Scheme 6). These results indicate that the
unprecedented stability of oxetenes obtained by our catalytic system
using 3 stems from the unique character of the not only electron-
withdrawing but also bulky CF3 substituent.14,15
With these successes for a wide scope of alkynes, we could use
the oxetene derivatives as chiral building blocks for the enantio-
selective syntheses of CF3-substituted compounds (Scheme 7).
While treatment of 4d with Pd/C under H2 in ethanol gave the
ring-opened product 14 quantitatively (eq 2 in Scheme 7), the
use of 4d and 4k in ethyl acetate as a solvent stereoselectively
afforded oxetanes 13d and 13k in good yields (eq 1 in Scheme 7).
Reduction of the ester group in 4d using NaBH4 followed by TBS
protection of the alcohol provided 15 without decomposition of
the oxetene skeleton (eq 3 in Scheme 7). Interestingly, oxidation
of 4d with mCPBA gave monobenzoate-protected vicinal diol 16
bearing contiguous quaternary carbon centers as a single diaster-
eomer in 87% yield (eq 4 in Scheme 7). Subsequent reduction of
the carbonyl group and migration of the chlorobenzoyl group
produced monoprotected triol 17 in 42% yield. X-ray analysis
unambiguously disclosed the absolute and relative configurations
of 17 with three contiguous chiral centers. In addition, 4l was
converted into 4e in 61% yield in the presence of palladium catalyst,
PhB(OH)2, and KF in THF (eq 5 in Scheme 7).
In conclusion, we have developed a highly enantioselective
and atom-economical [2 + 2] cycloaddition of a diverse array of
alkynes with trifluoropyruvate using a chiral dicationic BINAPÀPd
catalyst to provide unprecedentedly stable oxetene derivatives.
The reaction takes place with good-to-excellent yields and
various substituents on the internal alkynes. This catalytic pro-
cess offers not only the first synthetic method of stable oxetene
derivatives but also a new entry to oxetenes as novel chiral trifluo-
romethyl building blocks for pharmaceuticals and agrochemicals.
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Scheme 7. Transformations of Oxetenes
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, com-
b
pound characterization data, and CIF files. This material is avai-
lable free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mikami.k.ab@m.titech.ac.jp
’ ACKNOWLEDGMENT
We thank Takasago International Co. for providing the BINAP
and DTBM-SEGPHOS ligands and Dr. K. Yoza (Bruker AXS
K.K.) for X-ray analysis. This work was supported in part by the
grant program “Collaborative Development of Innovative Seeds”
from the Japan Science and Technology Agency (JST).
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