Fragment-based reaction discovery of non-ene-type carbon-carbon bond-forming reactions: Catalytic asymmetric oxetane synthesis by screening olefinic reactants without allylic hydrogen

Article abstract of DOI:10.1055/s-0031-1289540

Through fragment-based reaction discovery, catalytic asymmetric [2+2] cycloaddition was found to produce oxetanes from trifluoropyruvate and olefinic reactants without allylic hydrogen. This non-ene-type carbon-carbon bond-forming reaction smoothly proceeded under the influence of chiral Pd or Cu complexes as Lewis acid catalysts. The [2+2] cycloaddition afforded the oxetane derivatives in high yields and enantioselectivities even under 0.1 mol% catalyst loading and solvent-free conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289540

LETTER
2719
Fragment-Based Reaction Discovery of Non-Ene-Type Carbon–Carbon
Bond-Forming Reactions: Catalytic Asymmetric Oxetane Synthesis by
Screening Olefinic Reactants without Allylic Hydrogen
Catalytic
A
symme
o
tric Oxetane
i
Synthe
c
sis hi Mikami,* Kohsuke Aikawa, Junpei Aida
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
Fax +81(3)57342776; E-mail: mikami.k.ab@m.titech.ac.jp
Received 26 August 2011
olefinic reactants were virtually all consumed. After ex-
tensive screening of chiral Lewis acid catalysts and olefin-
ic reactants without allylic hydrogen, we identified that
the reactions shown in Scheme 1 were mediated by Lewis
Abstract: Through fragment-based reaction discovery, catalytic
asymmetric [2+2] cycloaddition was found to produce oxetanes
from trifluoropyruvate and olefinic reactants without allylic hydro-
gen. This non-ene-type carbon–carbon bond-forming reaction
smoothly proceeded under the influence of chiral Pd or Cu com- acid catalysts 1a, 1b, and 2 in particular. Combination of
plexes as Lewis acid catalysts. The [2+2] cycloaddition afforded the
oxetane derivatives in high yields and enantioselectivities even un-
der 0.1 mol% catalyst loading and solvent-free conditions.
trifluoropyruvate (3) with 1,1-diphenylethylene (4) in the
presence of (S)-SEGPHOS-Pd catalyst (1a) gave pyrane 5
via [2+2+2] cycloaddition in high yield and enantioselec-
tivity (94%, 95% ee), along with trace amounts of the
Key words: fragment-based, Lewis acid catalyst, [2+2] cycloaddi-
tion, oxetane, trifluoromethyl
Friedel–Crafts alkylation product (Scheme 1, equation 1).
The use of other chiral transition metal catalysts such as
BINOL-Ti5 and (S,S)-t-Bu-Box-Cu (2),6 however, gave
Development of catalytic asymmetric carbon–carbon
bond-forming (CCF) reactions for molecular skeletal con-
struction is currently one of the most important subjects in
modern organic synthesis.1 Generally, chiral catalysts are
screened in order to establish the best catalysts for a spe-
cific CCF reaction, e.g., the carbonyl-ene reaction of ole-
finic reactants with allylic hydrogen.2 In sharp contrast,
we report here the ‘fragment-based’3 reaction discovery
of a catalytic asymmetric non-ene-type CCF reaction that
has previously been unexplored. By changing chiral
Lewis acid catalysts, carbonyl substrates, and olefinic re-
actants without allylic hydrogen in particular, the catalytic
asymmetric oxetane formation was found to fit with the
complexes of a carbonyl compound and chiral Lewis acid
(Pd, Ti or Cu) catalysts.4–6 The optically active oxetanes
are biologically and synthetically promising, as typically
shown in oxetanocines7 or oxetin.8 Moreover, the oxetane
products, as chiral building blocks9 bearing the quaternary
trifluoromethyl carbinol cores,10 are expected to be of bi-
ological and synthetic importance. Catalytic asymmetric
oxetane formation can thus be found by the fragment-
based reaction discovery approach to non-ene-type cata-
lytic asymmetric CCF, particularly using olefinic reac-
tants without allylic hydrogen.
no reaction product. On the other hand, in the presence of
Pd catalysts 1a or 1b, tert-butyl vinyl ether 6, which is
more reactive as a nucleophile, gave polymerization prod-
ucts. However, (S,S)-t-Bu-Box-Cu catalyst 2 provided the
[2+2+2]-cycloaddition product 7 in 83% yield with a 95:5
diastereomeric ratio (Scheme 1, equation 2).11 Reduction
of the acetal portion of 7 with triethyl hydrosilane and
boron trifluoride diethyl etherate gave the single diaste-
reomer 8, which indicated that the diastereomers of
pyrane 7 are anomers at the anomeric carbon center. By
further tuning the olefinic reactants to tri(isopropyl)silyl
enol ether (9a), oxetane 11a was obtained as the single
product under Cu catalysis in good yield (84%), with ex-
cellent enantioselectivity and diastereoselectivity (98%
ee; cis/trans = 99:1) when the reaction was conducted at –
40 °C for 2.5 hours (Scheme 1, equation 4). In contrast,
the Friedel–Crafts alkylation product 10a was obtained in
65% yield with 95% ee at higher temperature (10 °C;
Scheme 1, equation 3). The Mukaiyama aldol product was
not observed in the reaction of the carbonyl compound 3
even with the silyl enol ether. However, the Pd catalysts 1
gave only polymerization products in this case of tri(iso-
propyl)silyl enol ether (9a), presumably because of the
higher Lewis acidity of the dicationic Pd catalysts 1 than
the t-Bu-Box-Cu catalyst 2.
The highly effective chiral Lewis acid catalysts were first
scrutinized for the non-ene-type catalytic asymmetric
CCF reactions of trifluoropyruvate 3 with olefinic reac-
tants without allylic hydrogen. The progress of a non-ene-
type CCF reaction was monitored by TLC and/or NMR
analyses until products were at least partly formed and
As a proposed reaction mechanism, the attack of tri(iso-
propyl)silyl enol ether (9a) on the complexes of trifluoro-
pyruvate 3 and the Cu catalyst 2 would provide the zwitter
ionic intermediate A (Scheme 2); Path a, which proceeds
through dissociation of a proton, leads to the Friedel–
Crafts-type product 10a and the ring-closing reaction as
shown in path b provides the oxetane 11a.
SYNLETT 2011, No. 18, pp 2719–2724
x
x
.x
x
.2
0
1
1
On the basis of these findings, a range of silyl enol ethers
Advanced online publication: 19.10.2011
9b–d were investigated for [2+2] cycloaddition (Table 1).
DOI: 10.1055/s-0031-1289540; Art ID: Y04511ST
© Georg Thieme Verlag Stuttgart · New York

2720
K. Mikami et al.
LETTER
Ph Ph
O
O
Ph
1a (5 mol%)
(1)
+
CH2Cl2
–40 °C, 4 h
F3C
CO2Et
Ph
Ph
Ph
CF3
CO2Et
4
3
5, 94%, 95% ee
Ot-Bu
Ot-Bu
2 (10 mol%)
O
3
+
(2)
Et2O
CO2Et
CF3
5 °C, 18 h
t-BuO
6
7, 83%, dr 95:5
Et3SiH (9 equiv)
BF3⋅OEt2 (3 equiv)
O
CO2Et
CF3
HO
CH2Cl2
0 °C to r.t., 1 h
8, 75%
F3C OH
CO2Et
single diastereomer
10 °C
(3)
(4)
TIPSO
OTIPS
2 (10 mol%)
10a, 65%, 95% ee
+
3
Et2O, 2.5 h
9a
O
–40 °C
CF3
TIPSO
CO2Et
11a
84%, cis/trans 99:1
98% ee (cis)
chiral Lewis acid catalysts
2+
2+
2+
O
Ph2
P
Ph2
P
O
O
O
O
2OTf–
Pd
Pd
N
N
Cu
P
P
–
–
Ph2
Ph2
2SbF6
2SbF6
t-Bu
t-Bu
O
(S)-BINAP-Pd (1b)
(S)-SEGPHOS-Pd (1a)
(S,S)-t-Bu-box-Cu (2)
Scheme 1 Fragment-based reaction discovery by screening of chiral Lewis acid catalysts and olefinic reactants without allylic hydrogen
path a
action conditions (Table 1, entry 8). The use of a TBS
group resulted in a decrease in both the yield and enantio-
selectivity (Table 1, entry 9). Silyl enol ether 9d, bearing
a sterically more demanding TBDPS group, provided a
higher yield and enantioselectivity, albeit after a longer
reaction time (Table 1, entries 10 vs. 1). In addition, the
reaction with the Z-isomer of 9e proceeded to give the ox-
etane 11e, in which the anomeric silyloxy group and tri-
fluoromethyl substituent were mainly positioned with cis-
orientation (cis/trans 89:11), in high yield with good ste-
reoselectivity (Scheme 3, equation 1). In sharp contrast,
the E-isomer of 9e did not participate in the reaction at all.
In the presence of 5 mol% Cu catalyst 2, the choice of
phenyl vinyl sulfide 9f instead of silyl enol ethers 9a–e
also accomplished excellent enantioselectivity (99% ee;
Scheme 3, equation 2).
CuL*
CuL*
10a
11a
O
O
Friedel–Crafts-type
reaction
O
O
addition
CF3
EtO
CF3
b
EtO
H
a
path b
TIPSO
[2+2] cycloaddition
TIPSO
A
Scheme 2 Plausible reaction mechanisms
In this catalytic system, solvents dramatically affected not
only yield but also the stereoselectivity of the [2+2] cy-
cloaddition; diethyl ether was found to give the best re-
sults (Table 1, entries 1–4). At lower reaction temperature
(–60 °C), oxetane 11a was obtained with almost complete
stereoselectivity (>99% ee; cis/trans = 99:1) in 94% yield
(Table 1, entry 5). High yield and enantioselectivity could
be maintained even with low catalyst loading of 1 mol%
(94% yield, 95% ee, cis/trans = 98:2), while lower cata-
lyst loading up to 0.5 mol% decreased the enantioselectiv-
ity to 88% ee (Table 1, entries 6 and 7 vs. 1). No desired
product was obtained in the reaction using 9b (with TMS
group), because of the decomposition of 9b under the re-
Silyl enol ether 9g (Z/E = 67:33) was then prepared from
1,3-propanediol and the [2+2] cycloaddition was exam-
ined under the optimized conditions (Scheme 4). The re-
action proceeded efficiently to give oxetane 11g with high
enantioselectivity (90% ee) and cis-selectivity (cis/trans =
97:3). An NOE experiment with oxetane 12, which was
Synlett 2011, No. 18, 2719–2724 © Thieme Stuttgart · New York

LETTER
Catalytic Asymmetric Oxetane Synthesis
2721
1) NaH, BnBr
O
Table 1 Enantioselective [2+2] Cycloaddition Catalyzed by t-Bu-
Box-Cu (2)a
THF, reflux, 14 h
TIPSOTf, Et3N
HO
OH
2) (COCl)2, DMSO
Et3N, CH2Cl2
H
OBn
Et2O, 0 °C, 3 h
O
OSi
2 (X mol%)
O
CF3
+
–78 °C to r.t., 3 h
69% (2 steps)
SiO
88%
conditions
F3C
CO2Et
CO2Et
9a–d
3
11a–d
O
CF3
OTIPS
2 (10 mol%)
TIPSO
Solvent Temp Time Yield drc
ee
+
3
CO2Et
Entry Si
X
Et2O
–40 °C, 24 h
OBn
(°C) (h) (%)b cis/trans (%)d
OBn
9g (2 equiv)
(Z/E = 67:33)
11g
1
2
3
4
5
6
7
8
9
TIPS (a)
TIPS (a)
TIPS (a)
TIPS (a)
TIPS (a)
TIPS (a)
TIPS (a)
TMS (b)
TBS (c)
10 Et2O
10 THF
–40
2.5 84 99:1
98
70
0
90%, cis/trans 97:3
90% ee (cis)
–40 24
21 92:8
16 52:48
38 91:9
94 99:1
94 98:2
91 95:5
10 CH2Cl2 –40 24
CF3
OCOAr
BnO
O
CF3
1) LiAlH4, THF
–78 °C, 15 min
TIPSO
O
TIPSO
10 toluene –40
10 Et2O –60
Et2O
6
4
86
>99
95
88
–
8.2%
12.1%
H
2) 4-O2NC6H4COCl
DMAP, Et3N
CH2Cl2, 0 °C, 5 h
OCOAr
OBn
H
10.6%
H
2.1%
2.2%
H
9.6%
12: Ar = 4-O2NC6H4
1
–40 24
–40 48
–40 24
NOE analysis
of cis-isomer
46% (2 steps)
0.5 Et2O
10 Et2O
10 Et2O
Scheme 4
0
–
–40
1.5 38 82:18
95 97:3
98
99
sults are summarized in Table 2. In the first instance, we
employed 10 mol% 1b in dichloromethane at –20 °C to
provide the desired oxetane 11h in higher yield and stere-
oselectivity than those obtained at 0 °C (Table 2, entries 1
vs. 2). Importantly, the reaction with vinylacetate using
t-Bu-Box-Cu 2 did not proceed at all, probably due to the
lower Lewis acidity of 2. In toluene, the yield was in-
creased, while the diastereoselectivity was slightly de-
creased (Table 2, entry 3). The use of (S)-SEGPHOS
instead of (S)-BINAP decreased the yield and both the
diastereo- and enantioselectivity (Table 2, entries 3 vs. 4).
Even with reduced catalyst loadings up to 0.5 and 0.1
mol%, satisfactory yields, high diastereo- and enantiose-
lectivities were obtained with the (S)-BINAP-Pd complex
1b (Table 2, entries 5 and 6). Significantly, the high yield
and stereoselectivity were maintained under solvent-free
conditions even with 0.1 mol% catalyst loading (Table 2,
entry 7).
10 TBDPS (d) 10 Et2O
–40 24
a Ratio of silyl enol ether 9 to trifluoropyruvate 3 = 1:2.
b Isolated yield.
c Determined by 19F NMR analysis (CDCl3).
d Enantiopurity of cis-isomer was determined by chiral GC analysis.
OTIPS
O
CF3
2 (10 mol%)
TIPSO
+
(1)
3
Et2O
CO2Et
–40 °C, 24 h
9e
11e
(Z)-9e: 92%, cis/trans 89:11
95% ee (cis)
(E)-9e: 0%
SPh
O
2 (5 mol%)
CF3
(2)
3
+
PhS
Et2O
CO2Et
–40 °C, 24 h
9f
11f
Highly optically active oxetanes obtained through catalyt-
ic asymmetric [2+2] cycloaddition are of synthetic signif-
icance as chiral building blocks bearing quaternary
trifluoromethyl carbinol units.9,10 Transformation of the
oxetanes was thus executed. Ring opening of oxetane 11h
in methanol under acidic conditions provided the acetal
product 13 in 73% yield. Hydrolysis of the ester group in
13 by treatment with 1 N NaOH led to the monocarboxy-
lic acid 14 quantitatively. Hydrolysis of the acetal group
under acidic conditions and oxidation followed by an ad-
dition of two equivalents of (S)-1-phenylethylamine pro-
vided the corresponding ammonium salt of 2-hydroxy-
1,4-dicarboxylic acid 16 in 63% yield in three steps
(Scheme 5a). X-ray crystal structure analysis of the am-
monium salt 16 was performed and, consequently, the ab-
solute configuration of the quaternary carbon in the
oxetane 11h was determined to be R (Figure 1).13 On the
other hand, the absolute configuration of acetal 13, pre-
pared from 11a, was determined to be S by comparison
71%, dr 75:25
99% ee (major)
Scheme 3
obtained via reduction of the ester group using LiAlH4
following by p-nitrobenzoyl protection of the resultant
alcohol group, indicated a cis-configuration between the
siloxy (OTIPS), benzyloxymethyl (BnOCH2), and trifluo-
romethyl (CF3) substituents.
Catalytic asymmetric oxetane formation using chiral
Lewis acids is novel and is particularly intriguing in view
of the precedent report that Box-Cu-catalyzed oxetane
formation is a less likely process as predicted by the ex-
cellent study based on DFT (UB3 LYP/6-31G*) and two-
layered ONIOM calculations (UB3 LYP/6-31G*:PM3).12
Therefore, oxetane formation was further scrutinized with
the BINAP-Pd catalyst 1b, by tuning the much less expen-
sive and relatively less reactive vinylacetate (9h); the re-
Synlett 2011, No. 18, 2719–2724 © Thieme Stuttgart · New York

2722
K. Mikami et al.
LETTER
Table 2 Enantioselectivity of the [2+2] Cycloaddition Catalyzed by
(S)-BINAP-Pd (1b)a
O
OAc
CF3
1b (X mol%)
AcO
+
3
CO2Et
conditions
11h
9h
Entry X
Solvent
Temp Time Yield drd
ee
(%)c
(%)e
Figure 1 X-ray crystal structure of 16
(°C)
(h)
1
2
3
4b
5
6
7
10
CH2Cl2
CH2Cl2
toluene
toluene
0
5
56
63:37 90:88
85:15 98:94
77:23 98:91
76:24 93:83
92:8 96:51
91:9 96:56
In summary, we have demonstrated a proof of concept for
the fragment-based reaction discovery of non-ene-type
catalytic asymmetric CCF reactions.14 The chiral Lewis
acid catalyzed oxetane formation of trifluoropyruvate 3
has been discovered by changing olefinic reactants with-
out allylic hydrogen in particular. Optically active oxet-
anes are biologically and synthetically important, as
exemplified by oxetanocines or oxetin. Additionally, the
oxetanes are highly promising as chiral building blocks,
having the quaternary trifluoromethyl carbinol cores,
which are of biological and synthetic importance.
10
10
10
–20
–20
–20
–20
–20
15
15
15
48
48
48
52
88
56
0.5 toluene
0.1 toluene
93
61
0.1 solvent-free –20
86
92:8
96:20
a Ratio of vinyl acetate 9h to trifluoropyruvate 3 = 1:2.
b Catalyst 1a was used instead of 1b.
c Isolated yield.
d Determined by 19F NMR analysis (CDCl3).
e Enantiopurity was determined by chiral GC analysis.
Acknowledgment
We are grateful to Takasago International Co. for providing BINAP
and SEGPHOS ligands. We are also grateful to Dr. K. Yoza in Bru-
ker AXS K.K. for X-ray crystal structure analysis. This research
was supported in part by a grant program ‘Collaborative Develop-
ment of Innovative Seeds’ from the Japan Science and Technology
Agency (JST).
with the optical rotation of the acetal (R)-13, which was
prepared from 11h (Scheme 5b).
a)
HC(OMe)3
cat. PTS⋅H2O
MeOH
reflux, 12 h
O
1 N NaOH
(3 equiv)
MeO
CF3
F3C OH
AcO
References and Notes
CO2Et
MeO
CO2Et MeOH–H2O
0–50 °C, 4 h
(1) (a) Comprehensive Asymmetric Catalysis I–III; Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999.
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Jersey, 2010.
(2) (a) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
(b) Mikami, K.; Aikawa, K. In Catalytic Asymmetric
Synthesis, 3rd ed.; Ojima, I., Ed.; Wiley: New Jersey, 2010,
683–737.
11h
(R)-13, 73%
[α]D25 –9.7 (c 0.78, CHCl3)
dr 85:15, 98% ee/94% ee
1) 1 N HCl–toluene
F3C OH
MeO
F3C OH
CO2H
14, quant.
r.t., 12 h
HO2C
CO2H
2) NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH–THF–H2O, r.t., 3 h
MeO
15, quant. (2 steps)
(3) ‘Fragment-based drug discovery’: (a) Hajduk, P. J. Nature
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pyruvate: (a) Aikawa, K.; Kainuma, S.; Hatano, M.;
Mikami, K. Tetrahedron Lett. 2004, 45, 183. (b) BINAP-
Pd-catalyzed carbonyl-ene reaction with glyoxylate: Hao, J.;
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(S)-1-phenylethylamine
(2 equiv)
Me
S
F3C OH
–O2C
+
2
–
MeOH
H3N
Ph
CO2
R
0 °C to r.t., 10 min
16, 63%
then washing with toluene
b)
HC(OMe)3
cat. PTS⋅H2O
MeO
F3C OH
CO2Et
O
CF3
TIPSO
CO2Et
MeOH
MeO
reflux, 12 h
11a
(S)-13, 88%
[α]D25 +9.3 (c 1.39, CHCl3)
cis/trans 98:2, 95% ee
Scheme 5 Oxetanes as chiral building blocks: Determination of the
absolute configuration
(5) BINOL-Ti-catalyzed carbonyl-ene reaction with glyoxy-
late: (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem.
Soc. 1989, 111, 1940. (b) Mikami, K.; Terada, M.; Nakai, T.
J. Am. Chem. Soc. 1990, 112, 3949; However, even with
glyoxylate or fluoral, which are reactive carbonyl substrates
Synlett 2011, No. 18, 2719–2724 © Thieme Stuttgart · New York

LETTER
in the ene reactions, the [2+2] or [2+2+2] reactions did not
Catalytic Asymmetric Oxetane Synthesis
2723
d = 1.06 (m, 21 H), 1.33 (t, J = 7.2 Hz, 3 H), 2.82 (dd,
proceed.
J = 12.6, 4.2 Hz, 1 H), 3.11 (dd, J = 12.6, 5.1 Hz, 1 H), 4.33
(6) For Box-Cu-catalyzed carbonyl-ene reaction with
glyoxylate, see: (a) Evans, D. A.; Burgey, C. S.; Paras, N.
A.; Vojkovsky, T.; Tregay, S. W. J. Am. Chem. Soc. 1998,
120, 5824. (b) Evans, D. A.; Tregay, S. W.; Burgey, C. S.;
Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000, 122,
7936.
(q, J = 7.2 Hz, 2 H), 5.90 (dd, J = 5.1, 4.2 Hz, 1 H); 13
C
NMR (75.5 MHz, CHCl3): d = 11.8, 13.9, 17.5, 37.6 (q, JC–
F = 0.8 Hz), 62.6, 76.1 (q, JC–F = 33.2 Hz), 95.7, 122.3 (q, JC–
F = 283.1 Hz), 167.6; 19F NMR (282 MHz, CDCl3): d = –
79.0 (s, 3 F); FTIR (neat): 2947, 2896, 2870, 1751, 1466,
1390, 1286, 1187, 1113, 1039, 919, 883, 685 cm–1; HRMS
(APCI-TOF): m/z [M + H]+ calcd for C16H29F3O4Si:
371.1865; found: 371.1889; [a]D24 –4.48 (c 1.08, CHCl3) for
98% ee (cis/trans = 99:1); GC (column, CP-Chirasil-Dex
CB, i.d. 0.25 mm × 25 m, CHROMPACK; carrier gas,
nitrogen 75 kPa; column temp. 120 °C; injection and
detection temp. 150 °C): tR = 36.2 (major isomer), 38.3
(minor isomer) min.
(7) (a) Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.;
Fujii, A.; Takita, T. J. Antibiot. 1986, 39, 1623.
(b) Nishiyama, S.; Yamamura, S.; Kato, K.; Takita, T.
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Chem. Rev. 2006, 104, 1. (b) Ma, J.-A.; Cahard, D. J.
Fluorine Chem. 2007, 128, 975. (c) Billard, T.; Langlois, B.
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reported for the Box-Cu-catalysts, see: Audrain, H.;
Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 11543.
(12) Morano, I.; McNamara, J. P.; Hillier, I. H. J. Am. Chem. Soc.
2003, 125, 628.
(13) Crystal data for 16: C21H27F3N2O5; orthorhombic; space
group P212121; a = 6.3390 (11) Å, b = 17.252 (3) Å,
c = 20.143 (4) Å; V = 2202.9 (7) Å3; Z = 4; Dcalc = 1.340
Mgm–3; m = 0.112 mm–1. All measurements were made
with a Bruker APEXII CCD area detector with graphite
monochromated Mo-Ka radiation at 93 K. Of the 9577
reflections that were collected, 3935 were unique
(Rint = 0.0329). R1 = 0.0716, wR = 0.1805, goodness of
fit = 1.052; Flack Parameter = 0.1 (13), shift/error = 0.000.
CCDC-838360 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
(14) Enantioselective [2+2] Cycloaddition Catalyzed by (S,S)-
t-Bu-Box-Cu(2) (Table 2, entry 1); Typical Procedure:
(S,S)-t-Bu-Box-Cu(OTf)2 catalyst was prepared by the
addition of Cu(OTf)2 (3.6 mg, 0.01 mmol) to (S,S)-2,2¢-
isopropylidenebis(4-tert-butyl-2-oxazoline) (3.2 mg, 0.011
mmol) under an argon atmosphere. The mixture was dried
under vacuum for 1 h, then Et2O (1.0 mL) was added under
an argon atmosphere and the resulting suspension was
stirred vigorously for 1 h at r.t. To the solution at –40 °C
were added ethyl trifluoropyruvate 3 (26.5 mL, 0.2 mmol)
followed by tri(isopropyl)silyl enol ether (9a; 20.0 mg, 0.1
mmol). After stirring at –40 °C for 2.5 h, the reaction
mixture was directly loaded onto a short silica gel column
(hexane–EtOAc, 1:1) to remove the catalyst. The solution
was evaporated under reduced pressure. Purification by
silica-gel chromatography (hexane–EtOAc, 20:1) gave the
corresponding oxetane 11a (84% yield) as a clear liquid. The
cis/trans ratio was determined by 19F NMR analysis (cis/
trans, 99:1; the major configuration of the oxetane products
was determined to be cis from the results of NOE
experiments, which are summarized in Scheme 4).
(2S,4R)-Ethyl 2-Trifluoromethyl-4-(triisopropylsiloxy)-
oxetane-2-carboxylate (11a): 1H NMR (300 MHz, CDCl3):
(2S,3R,4R)-Ethyl 3-Benzyloxymethyl-2-trifluoromethyl-
4-(triisopropylsiloxy)oxetane-2-carboxylate (11g): 1H
NMR (300 MHz, CDCl3): d = 1.07 (m, 21 H), 1.31 (t, J = 7.2
Hz, 3 H), 3.62 (ddd, J = 9.6, 5.7, 4.2 Hz, 1 H), 3.75 (dd,
J = 9.6, 4.2 Hz, 1 H), 4.13 (dd, J = 9.6, 9.6 Hz, 2 H), 4.32 (m,
2 H, OCH2CH3), 4.46 (d, J = 18.6 Hz, 1 H), 4.50 (d, J = 18.6
Hz, 1 H), 5.96 (d, J = 5.7 Hz, 1 H), 7.29 (m, 5 H); 13C NMR
(75.5 MHz, CDCl3): d = 11.8, 13.9, 17.5, 47.5, 62.6, 63.1 (q,
JC–F = 2.3 Hz), 73.4, 80.3 (q, JC–F = 32.5 Hz), 97.3, 122.2 (q,
JC–F = 285.4 Hz), 127.7, 127.8, 128.3, 137.7, 167.5; 19
F
NMR (282 MHz, CDCl3): d = –72.8 (s, 3 F); FTIR (neat):
2947, 2869, 1750, 1656, 1466, 1278, 1200, 1091, 1028, 883,
688 cm–1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C24H37F3NaO5Si: 513.2260; found: 513.2281; [a]D25 +30.68
(c 1.39, CHCl3) for 90% ee (cis/trans = 97:3); HPLC
(column, CHIRALPAK AS-H, Hexane/2-Propanol = 97/3,
flow rate 0.6 mL/min, 20 °C, detection, UV 218 nm): tR =
33.6 ( minor isomer), 41.5 (major isomer) min.
Enantioselective [2+2] Cycloaddition Catalyzed by (S)-
BINAP-Pd(1b) (Table 2, entry 3); Typical Procedure:
To a solution of PdCl2[(S)-BINAP] (8.0 mg, 0.01 mmol) in
toluene (1.0 mL) was added AgSbF6 (7.6 mg, 0.022 mmol)
at r.t. under an argon atmosphere. After stirring for 30 min,
ethyl trifluoropyruvate 3 (26.5 mL, 0.2 mmol) and freshly
distilled vinyl acetate 9h (9.3 mL, 0.1 mmol) were added to
the mixture at –20 °C. After stirring at –20 °C for 15 h, Et3N
(50 mL) was added and the mixture was directly loaded onto
a short silica gel column (hexane–EtOAc, 1:1) to remove the
catalyst. The solution was evaporated under reduced
pressure. Purification by silica-gel chromatography
(hexane–EtOAc, 4:1) gave the corresponding oxetane
product 11h as a clear liquid (88% yield). The diastereo-
meric ratio was determined by 19F NMR analysis
(dr = 77:23).
Enantioselective [2+2] Cycloaddition Catalyzed by (S)-
BINAP-Pd(1b) under Solvent-Free Conditions (Table 2,
entry 7): To a solution of PdCl2[(S)-BINAP] (4.0 mg, 0.005
mmol) in ethyl trifluoropyruvate 3 (1.3 mL, 10 mmol) was
added silver hexafluoroantimonate (3.8 mg, 0.011 mmol) at
r.t. under an argon atmosphere. After stirring for 30 min,
freshly distilled vinyl acetate 9h (461 mL, 5 mmol) was
added to the mixture at –20 °C. After stirring at –20 °C for
48 h, Et3N (50 mL) was added and the mixture was directly
loaded onto a short silica gel column (hexane–EtOAc, 1:1)
to remove the catalyst. The solution was evaporated under
reduced pressure. Purification by silica gel chromatography
(hexane–EtOAc, 4:1) gave the corresponding oxetane
product 11h as a clear liquid (86% yield). The diastereo-
meric ratio was determined by 19F NMR analysis (dr = 92:8).
(2R)-Ethyl 4-Acetoxy-2-(trifluoromethyl)oxetane-2-
carboxylate (11h): 1H NMR (300 MHz, CDCl3): d = 1.33 (t,
J = 7.2 Hz, 3 H), 2.12 (s, 3 H), 3.04 (ddq, J = 13.2, 4.2 Hz,
Synlett 2011, No. 18, 2719–2724 © Thieme Stuttgart · New York

2724
K. Mikami et al.
LETTER
679 cm–1; HRMS (APCI-TOF): m/z [M + H]+ calcd for
JH–F = 0.6 Hz, 1 H), 3.27 (dd, J = 13.2, 5.4 Hz, 1 H), 4.36 (q,
J = 7.2 Hz, 2 H), 6.48 (dd, J = 5.4, 4.2 Hz, 1 H); 13C NMR
(75.5 MHz, CDCl3): d = 13.6, 20.5, 33.4, 62.8, 78.1 (q,
JC–F = 34.0 Hz), 93.4, 122.7 (q, JC–F = 283.1 Hz), 165.4,
168.8; 19F NMR (282.4 MHz, CDCl3): d = –79.4 (s, 3 F,
major isomer), –79.3 (s, 3 F, minor isomer); FTIR (neat):
2990, 1764, 1447, 1371, 1308, 1219, 1096, 1037, 961,
C9H11F3O5: 257.0637; found: 257.0680; [a]D25 +42.97 (c
1.21, CHCl3) for 98% ee/94% ee (dr = 85:15); GC (column,
CP-Chirasil-Dex CB, i.d. 0.25 mm × 25 m, CHROMPACK;
carrier gas, nitrogen 75 kPa; column temp 85 °C; injection
and detection temp, 115 °C): tR = 20.0 ( major isomer), 22.0
(minor isomer) min.
Synlett 2011, No. 18, 2719–2724 © Thieme Stuttgart · New York

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