Remote Tris(pentafluorophenyl)borane-Assisted Chiral Phosphoric Acid Catalysts for the Enantioselective Diels-Alder Reaction

Article abstract of DOI:10.1055/s-0035-1560369

Tris(pentafluorophenyl)borane-assisted chiral supramolecular phosphoric acid catalysts were developed for the model Diels-Alder reaction of α-substituted acroleins with cyclopentadiene. Two remotely coordinated tris(pentafluorophenyl)boranes should help to increase the Bronsted acidity of the active center in the supramolecular catalyst and create effective bulkiness for the chiral cavity. The prepared supramolecular catalysts acted as not only conjugated Bronsted acid-Bronsted base catalysts but also bifunctional Lewis acid-Bronsted base catalysts with the addition of a central achiral Lewis acid source such as catecholborane.

Full text of DOI:10.1055/s-0035-1560369

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Remote Tris(pentafluorophenyl)borane-Assisted Chiral Phosphoric
Acid Catalysts for the Enantioselective Diels–Alder Reaction
Manabu Hatano
Hideyuki Ishihara
Yuta Goto
Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University,
Furo-cho, Chikusa, Nagoya 4648603, Japan
ishihara@cc.nagoya-u.ac.jp
Received: 28.08.2015
Accepted after revision: 21.10.2015
Published online: 07.09.2015
DOI: 10.1055/s-0035-1560369; Art ID: st-2015-b0678-c
Abstract Tris(pentafluorophenyl)borane-assisted chiral supramolecu-
lar phosphoric acid catalysts were developed for the model Diels–Alder
reaction of α-substituted acroleins with cyclopentadiene. Two remotely
coordinated tris(pentafluorophenyl)boranes should help to increase the
Brønsted acidity of the active center in the supramolecular catalyst and
create effective bulkiness for the chiral cavity. The prepared supramo-
lecular catalysts acted as not only conjugated Brønsted acid–Brønsted
base catalysts but also bifunctional Lewis acid–Brønsted base catalysts
with the addition of a central achiral Lewis acid source such as catechol-
borane.
Key words Diels–Alder reaction, phosphoric acid, Brønsted acid, Lewis
acid, supramolecular catalyst, chiral cavity, molecular recognition
The design of simple artificial enzymes is an ongoing
challenge in modern organic chemistry. In particular, tai-
lor-made chiral supramolecular catalysts might be attrac-
tive for use as artificial enzymes, since every part of a su-
pramolecular catalyst can be fine-tuned for each substrate
to establish higher-ordered substrate-selectivity and/or
stereoselectivity.1,2 In this regard, we previously developed
enantioselective Diels–Alder reactions with anomalous en-
do/exo-selectivities through the use of conformationally
flexible chiral supramolecular Lewis acid catalyst 1 (Figure
1, a).3,4
Based on the chiral deep and narrow cavity control of
the transition states in the reaction of α-substituted acrole-
ins and cyclopentadiene, anomalous endo products were
Figure 1 Design of conformationally flexible chiral supramolecular cat-
alysts
successfully obtained in a highly enantioenriched fashion
for the first time.5 Two coordinated tris(pentafluorophe-
nyl)boranes in catalyst 1 should not only create effective
bulkiness for the chiral cavity but also help to increase the
Lewis acidity of the active center based on the Lewis acid
assisted Lewis acid (LLA)6 catalyst system. To further devel-
op such a supramolecular methodology, we envisioned that
we might be able to use conformationally flexible chiral su-
pramolecular Brønsted acid catalyst 2 based on the Lewis
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acid assisted Brønsted acid (LBA)6 catalyst system (Figure 1,
b). By taking advantage of the conjugated Brønsted acid–
Brønsted base bifunction of chiral phosphoric acids 2,7,8 al-
dehydes (i.e., acroleins) should be able to doubly coordinate
with the active centers (Figure 2, a). Moreover, the addition
of an achiral Lewis acid source (MLn) should provide bifunc-
tional Lewis acid–Brønsted base catalysts (Figure 2, b).
Overall, introduction of the phosphoric acid to the center of
supramolecular catalysts might provide additional oppor-
tunities for versatile molecular recognition according to the
size and/or substitution pattern of acroleins. In this context,
we have developed remote tris(pentafluorophenyl)borane-
assisted chiral phosphoric acid catalysts for the enantiose-
lective Diels–Alder reaction of α-substituted acroleins with
cyclopentadiene as a probe reaction.
leased from the supramolecular catalysts 2B(C6F5)3–(R)-3a
and 2B(C6F5)3–(R)-3b, the highly basic phosphoryl moiety
and pyrrolidine-derived amido moiety would tightly coor-
dinate with the proton of the phosphoric acid at –78 °C. The
corresponding species B(C6F5)3–(R)-3a and B(C6F5)3–(R)-3b,
which might be inactive (Table 1, entries 6 and 12), would
then be formed (Figure 3). Simultaneously, achiral B(C6F5)3,
which might induce a racemic reaction pathway (Table 1,
entries 5 and 11), would be released. In sharp contrast,
2B(C6F5)3–(R)-3c, which has a much less basic isoindoline-
derived amido moiety, was tolerated under the reaction
conditions at –78 °C for 30 minutes before the addition of
substrates 4 and 5a, and exo-6a was obtained with 85% ee
(Table 1, entry 17). The inter-/intramolecular coordination-
exchange between the proton center and B(C6F5)3 might
still occur due to the weak basicity of the isoindoline-de-
rived amido moiety even at –78 °C. As a result, active
2B(C6F5)3–(R)-3c would be regenerated from less active
B(C6F5)3–(R)-3c. These considerations might be supported
by finding that the catalytic activity of 2B(C6F5)3–(R)-3c
(entry 16) was much higher than those of competitive
B(C6F5)3–(R)-3c (Table 1, entry 18) and free B(C6F5)3 (Table
1, entry 19).11
Figure 2 Chiral supramolecular phosphoric acid catalysts as (a) a Brøn-
sted acid–Brønsted base system, and (b) a Lewis acid–Brønsted base
system
First, we examined the Diels–Alder reaction of meth-
acrolein 5a with cyclopentadiene 4 in dichloromethane at
–78 °C in the presence of chiral supramolecular catalysts
(10 mol%), which were prepared in situ from chiral phos-
phoric acid (R)-3a and achiral boron Lewis acids, such as
BF3·Et2O, BBr3, and B(C6F5)3 (Table 1). The reaction did not
proceed with the use of (R)-3a alone (Table 1, entry 1). In
contrast, the combined use of (R)-3a and Lewis acids
showed strong catalytic activities (Table 1, entries 2–4). In
particular, as expected, bulky B(C6F5)3 was more effective
than BF3·Et2O and BBr3, and higher enantioselectivity (53%
ee) was observed (Table 1, entry 4). Fortunately, the enantio-
selectivity was significantly improved when amide-type
(R)-3b and (R)-3c were used in place of phosphoryl-type
(R)-3a, and exo-6a was obtained with 90% ee (Table 1, en-
tries 10 and 16). Moreover, for (R)-3b and (R)-3c as well as
(R)-3a, BF3·Et2O and BBr3 were not effective (Table 1, entries
8, 9, 14, and 15).
In this reaction, preparation of the catalyst at room tem-
perature in advance was critical,9 and compounds 4 and 5a
were added within five minutes just after the mixture of
catalysts was cooled to –78 °C.10 In this regard, the enantio-
selectivity significantly decreased when compounds 4 and
5a were added to the mixture of 2B(C6F5)3–(R)-3a or
2B(C6F5)3–(R)-3b after cooling at –78 °C for 30 minutes (Ta-
ble 1, entries 5 and 11). Once B(C6F5)3 is adventitiously re-
Figure 3 Possible formations of B(C6F5)3–(R)-3a and B(C6F5)3–(R)-3b
with intramolecular hydrogen bonding and the release of achiral
B(C6F5)3
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To confirm the complexation of the optimized supramo-
lecular catalyst 2B(C6F5)3–(R)-3c, spectroscopic analyses
were performed at room temperature (Scheme 1). We
found a peak at 1697.146 in ESI–MS analysis (negative
mode), which might be unambiguously attributed to
{[2B(C6F5)3–(R)-3c] + 2H2O – H}– (see the Supporting Infor-
mation). Moreover, peaks at δ = –137.0, –159.5, and –166.3
ppm in 19F NMR (CD2Cl2) were slightly shifted from the
original peaks of B(C6F5)3 at δ = –130.2, –147.1, and –161.4
ppm. However, a peak at δ = 4.6 ppm in 31P NMR (CD2Cl2)
was scarcely shifted from the original peak at δ = +4.0 ppm.
These observations suggest that coordination to B(C6F5)3 at
the carbonyl groups of the 3,3′-substituents would precede
coordination at the central P=O moiety, probably due to ste-
Table 1 Screening of Chiral Supramolecular Catalystsa
(R)-3a–c (10 mol%)
Lewis acid (20 mol%)
(2S)
CHO
+
+
(2S)
CHO
MS 4Å, CH2Cl2
–78 ºC, 1 h
CHO
endo-(2S)-6a
exo-(2S)-6a
4
5a
(minor)
(major)
O
N
O
O
O
P
N
O
O
O
O
O
O
O
O
O
O
P
P
P
H
O
H
O
P
O
H
O
N
N
O
O
O
O
(R)-3a
(R)-3b
(R)-3c
Entry
(R)-3
(R)-3a
Lewis acid
Yield (%)
endo-6a/exo-6a
ee (%) of exo-6a
1
2
–
0
>99
98
–
–
2
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3b
(R)-3b
(R)-3b
(R)-3b
(R)-3b
(R)-3b
(R)-3c
(R)-3c
(R)-3c
(R)-3c
(R)-3c
(R)-3c
–
BF3·Et2O
BBr3
7:93
8:92
8:92
8:92
19:81
–
3
14
–53b
–31b
–1b
–
4
B(C6F5)3
B(C6F5)3
B(C6F5)3
–
98
5c
>99
20
6d
7
0
8
BF3·Et2O
BBr3
>99
>99
>99
62
7:93
5:95
5:95
11:89
–
0
9
0
10
11c
12d
13
14
15
16
17c
18d
19e
B(C6F5)3
B(C6F5)3
B(C6F5)3
–
90
8
0
–
0
–
–
BF3·Et2O
BBr3
98
6:94
10:90
8:92
9:91
–
0
96
0
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
>99
>99
0
90
85
–
>99
7:93
–
a Unless otherwise noted, the reaction of 5a (0.5 mmol) with 4 (2.5 mmol) was carried out with the use of (R)-3 (10 mol%), Lewis acid (20 mol%), and MS 4Å in
CH2Cl2 at –78 °C for 1 h. Compounds 4 and 5a were added to the mixture of catalysts within 5 min just after cooling to –78 °C.
b Enantioselectivity of exo-(2R)-6a.
c Compounds 4 and 5a were added to the mixture of catalysts after it was cooled to –78 °C for 30 min.
d The reaction was carried out with the use of (R)-3 (10 mol%), B(C6F5)3 (10 mol%), and MS 4Å under standard conditions.
e The reaction was carried out with the use of B(C6F5)3 (20 mol%) alone.
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Scheme 1 Spectroscopic analyses of 2B(C6F5)3–(R)-3c at room temperature
ric constraints at the narrow inner space.12 Unfortunately,
the hydrogen-bonding structures of B(C6F5)3–(R)-3a and
B(C6F5)3–(R)-3b, as shown in Figure 3 have not yet been
confirmed directly (see the Supporting Information for
31P NMR analysis.). However, in 31P NMR (CD2Cl2) analysis at
–78 °C, a peak at δ = –4.1 ppm of 2B(C6F5)3–(R)-3b gradually
decreased, and many other peaks between δ = –5 ppm and
δ = –25 ppm were predominantly observed within 30 min-
utes.13 In sharp contrast, the decomposition of 2B(C6F5)3–
(R)-3c to other species at –78 °C was much slower than that
of 2B(C6F5)3–(R)-3b, and ca. 70% of 2B(C6F5)3–(R)-3b was
still observed at δ = –0.7 ppm for at least 30 minutes.13
Next, we examined the substrate specificity for α-sub-
stituted acroleins. In place of methacrolein 5a, α-ethylacro-
lein 5b could be used in the presence of 2B(C6F5)3–(R)-3c,
and the corresponding normal exo-6b was obtained with
84% ee (Table 2, entry 3). Partially due to steric mismatch
with the chiral cavity, α-isopropylacrolein 5c and α-bromo-
acrolein 5d, which are bulkier than 5a and 5b, might be un-
suitable for the chiral cavity of 2B(C6F5)3–(R)-3c, and low
enantioselectivities were observed (Table 2, entries 5 and
7). Moreover, a racemic pathway also might be promoted in
the case of highly reactive 5d (Table 2, entry 7). As com-
pared with thermal conditions (Table 2, entries 2, 4, 6, and
8), a supramolecular catalyst induced a slight exo prefer-
ence for 6a and 6b (Table 2, entries 1 and 3).
anomalous exo-(2R)-6e. These results suggest that
2B(C6F5)3–(R)-3c might have an exo-inducing chiral cavity
as a supramolecular catalyst.
Finally, we used tiglic aldehyde 7 as a much less reactive
α,β-disubstituted acrolein, which did not give product 8
under thermal conditions in toluene at 110 °C. Supramolec-
Table 2 Substrate Specificity with the Use of 2B(C6F5)3–(R)-3ca
(R)-3c (10 mol%)
(2)
CHO
B(C6F5)3 (20 mol%)
+
+
R
R
(2)
R
CHO MS 4Å, CH2Cl2
–78 ºC, 1 h
CHO
endo-6
4
5
exo-6
(anomalous, minor) (normal, major)
Entry 5 (R)
Product Yield (%)
endo-
6/exo-6
ee (%) of
exo-6
1
5a (Me)
5a (Me)
5b (Et)
5b (Et)
5c (i-Pr)
5c (i-Pr)
5d (Br)
5d (Br)
6a
6a
6b
6b
6c
6c
6d
6d
>99
94 (40 °C, 3 h)
>99
8:92
16:84
2:98
90 (2S)
2b
3
–
84 (2S)
4b
5
73 (110 °C, 24 h) 24:76
–
72
15:85
–
23 (2R)
6b
7
<5 (110 °C, 3 h)
–
>99
>99 (r.t., 3 h)
15:85
15:85
18 (2R)
Moreover, with the use of α-nonsubstituted acrolein 5e,
moderate anomalous exo-selectivity was observed (en-
do/exo = 49:51) (Scheme 2).14 Although the enantioselectiv-
ities of endo-6e and exo-6e were low (30% ee and 25% ee,
respectively), an unusual disagreement in stereoselectivity
(R/S) was observed between normal endo-(2S)-6e and
8b
–
a The reaction of 5 (0.5 mmol) with 4 (2.5 mmol) was carried out with the use
of (R)-3c (10 mol%), B(C6F5)3 (20 mol%), and MS 4Å in CH2Cl2 at –78 °C for 1
h.
b The reactions were carried out under thermal conditions without any cata-
lysts in CH2Cl2 at room temperature to 40 °C or in toluene at 110 °C.
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In this preliminary stage, further information based on
experimental and theoretical studies will be necessary to
discuss possible structures of the supramolecular catalysts
in situ. In this regard, the previous supramolecular catalyst
1 has been calculated to be the C1-symmetric syn confor-
mation due to the sp3 boron Lewis acid center.3 In contrast,
we can speculate that supramolecular catalyst 2B(C6F5)3–
(R)-3c would have an anti conformation as shown in Figure
4 (b), unlike a sterically hindered syn conformation as
(R)-3c (10 mol%)
B(C6F5)3 (20 mol%)
+
CHO
H
+
(2R)
(2S)
H
CHO MS 4Å, CH2Cl2
–78 °C, 1 h
H
CHO
endo-(2S)-6e
(normal)
exo-(2R)-6e
(anomalous)
25% ee
4
5e
30% ee
98% (endo-6e/exo-6e = 49:51)
cf. thermal conditions (r.t., 3 h): 99% (endo-6e/exo-6e = 80:20)
Scheme 2 Anomalous exo-induced Diels–Alder reaction of acrolein 5e
with cyclopentadiene 4 catalyzed by 2B(C6F5)3–(R)-3c
ular catalyst 2B(C6F5)3–(R)-3c showed low reactivity, and
exo-8 was obtained in 38% yield with 56% ee (Scheme 3, a).
To improve both the yield and the enantioselectivity, we
changed the Brønsted acid–Brønsted base catalyst system
(Figure 2, a) to a Lewis acid–Brønsted base catalyst system
(Figure 2, b), by using an additional achiral Lewis acid part-
ner. After screening the acid sources,15 we found that cate-
cholborane was highly effective as a boron Lewis acid cen-
ter for 2B(C6F5)3–(R)-3c, and exo-8 was obtained in 71%
yield with 75% ee (Scheme 3, b).16 Although the enantiose-
lectivity has still been moderate, these results represent at
least a partial demonstration of our conceptual catalytic
system in Figure 2.
Figure 4 Possible structures and chiral cavities of supramolecular cata-
lysts (ArF = C6F5). (a) Syn-conformation for 2B(C6F5)3–(R)-3c. (b) Anti-
conformation for 2B(C6F5)3–(R)-3c. (c) Anti-conformation for 2B(C6F5)3–
(R)-3c–catecholborane.
Scheme 3 Effect of the addition of catecholborane to 2B(C6F5)3–(R)-3c
in the Diels–Alder reaction of 7 with 4
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shown in Figure 4 (a), due to the essentially C2-symmetric
conjugated phosphoric acid moiety. Catecholborane-intro-
duced supramolecular catalyst might have similar struc-
tures although the field would then be C1-symmetric, as
shown in Figure 4 (c). In anti conformations, as shown in
Figure 4 (b and c), a shallow and wide chiral cavity would
be formed around the active center which would induce
substrate specificity with an exo-preference.3b
In summary, we have developed bulky and strong Lewis
acid B(C6F5)3-assisted chiral phosphoric acids, which were
designed for the model Diels–Alder reaction of α-substitut-
ed acroleins with cyclopentadiene.17 The corresponding su-
pramolecular catalysts acted not only as highly activated
conjugated Brønsted acid–Brønsted base catalysts but also
as bifunctional Lewis acid–Brønsted base catalysts with the
addition of a central achiral Lewis acid source such as cate-
cholborane. Further investigations with these asymmetric
supramolecular methodologies with the use of chiral phos-
phoric acids, which might contribute to the construction of
a conformationally flexible, bulky, and chiral cavity for
higher-ordered catalysis, are currently underway.18
Salvatella, L. Acc. Chem. Res. 2000, 33, 658. (c) Barba, C.;
Carmona, D.; García, J. I.; Lamata, M. P.; Mayoral, J. A.; Salvatella,
L.; Viguri, F. J. Org. Chem. 2006, 71, 9831. (d) Wannere, C. S.;
Paul, A.; Herges, R.; Houk, K. N.; Schaefer, H. F. III.; von Ragué
Schleyer, P. J. Comput. Chem. 2007, 28, 344.
(6) Yamamoto developed the pioneering concept of combined acid
catalysis. See reviews: (a) Ishibashi, H.; Ishihara, K.; Yamamoto,
H. Chem. Rec. 2002, 2, 177. (b) Yamamoto, H.; Futatsugi, K.
Angew. Chem. Int. Ed. 2005, 44, 1924. (c) Yamamoto, H.;
Futatsugi, K. In Acid Catalysis in Modern Organic Synthesis; Vol.
1; Yamamoto, H.; Ishihara, K., Eds.; Wiley-VCH: Weinheim,
2008, 1–34.
(7) For reviews on chiral phosphoric acids, see: (a) Akiyama, T.
Chem. Rev. 2007, 107, 5744. (b) Terada, M. Synthesis 2010, 1929.
(c) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047.
(8) Reviews on acid–base combination chemistry, see: (a) Kanai,
M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491.
(b) Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686.
(c) Ishihara, K. Proc. Jpn. Acad. Ser. B 2009, 85, 290. (d) Shibasaki,
M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009,
42, 1117.
(9) For 2B(C6F5)3–(R)-3a/3b/3c, the aging time (0.5–2 h) at r.t. in
advance showed no significant differences in the Diels–Alder
reaction.
(10) Lower enantioselectivities (ca. 60% ee) were observed when a
solution of the catalyst 2B(C6F5)3–(R)-3b or 2B(C6F5)3–(R)-3c at
r.t. was added to the solution of 4 and 5a at –78 °C.
Acknowledgment
Financial support was partially provided by JSPS, KAKENHI
(15H05755, 26288046, and 26105723), Program for Leading Gradu-
ate Schools ‘IGER program in Green Natural Sciences’, MEXT, Japan.
(11) Compound 5a is too reactive to evaluate meaningful differences
in the catalytic activity between 2B(C6F5)3–(R)-3c and free
B(C6F5)3. However, the catalytic activity of 2B(C6F5)3–(R)-3c was
much higher than that of free B(C6F5)3. See Scheme 3 and the SI.
(12) To confirm whether or not the coordination of the P=O moiety
to B(C6F5)3 would occur, we used (R)-3,3′-Ph2BINOL-derived
phosphoric acid, which may avoid competitive coordinations. In
31P NMR (CD2Cl2) analysis at r.t., a singlet peak at δ = +1.7 ppm
changed to δ = –1.0 ppm with a small upfield shift, which sug-
gests the coordination of the P=O moiety to B(C6F5)3. Next,
as with 2B(C6F5)3–(R)-3c, almost the same shifted peaks at δ =
–137.0, –158.8, and –165.8 ppm were observed in 19F NMR
(CD2Cl2) at r.t.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560369.
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References and Notes
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J. Am. Chem. Soc. 1994, 116, 12115. (b) Kündig, E. P.; Saudan, C.
M.; Alezra, V.; Viton, F.; Bernardinelli, G. Angew. Chem. Int. Ed.
2001, 40, 4481. (c) Kano, T.; Tanaka, Y.; Maruoka, K. Org. Lett.
2006, 8, 2687. (d) Hayashi, Y.; Samanta, S.; Gotoh, H.; Ishikawa,
H. Angew. Chem. Int. Ed. 2008, 47, 6634. Also see ref 3.
(15) We examined Me3Al, Et3Al, i-Bu2AlH (DIBAL-H), Me2AlNTf2, allyl-
trimethylsilane, pinacolborane, 9-borabicyclo[3.3.1]nonane (9-
BBN), etc. However, the combined use of these achiral Lewis
acid sources to 2B(C6F5)3–(R)-3c showed low reactivities (0–15%
yields), and the sole exception was catecholborane. In this
regard, the combined use of a stoichiometric amount of cate-
cholborane with chiral phosphoric acid catalyst in the enantio-
selective reduction of ketones was reported by Antilla. See:
Zhang, Z.; Jain, P.; Antilla, J. C. Angew. Chem. Int. Ed. 2011, 50,
10961.
(5) In general, endo/exo-selectivity in the Diels–Alder reaction
depends on the substrates, see: (a) Hoffmann, R.; Woodward, R.
B. J. Am. Chem. Soc. 1965, 87, 4388. (b) García, J. I.; Mayoral, J. A.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 564–570

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(16) We examined the reactions of acroleins 5a–e with cyclopenta-
diene 4 with the use of a supramolecular catalyst, which was
prepared from (R)-3c, B(C6F5)3, and catecholborane, However,
better enantioselectivities were not observed compared with
2B(C6F5)3–(R)-3c as shown in Table 2 and Scheme 2. The results
are summarized in the SI.
(17) Typical Procedure for the Diels–Alder Reaction: To a mixture
of (R)-3c (31.9 mg, 0.050 mmol) and powdered MS 4Å (200 mg)
in a Schlenk tube under a nitrogen atmosphere, tris(pentafluo-
rophenyl)borane (51.2 mg, 0.10 mmol) and freshly distilled
CH2Cl2 (2 mL) were added via a cannula, and this suspension
was stirred at r.t. for 1 h. Next, the mixture was cooled to –78 °C,
and as soon as possible (within 5 min) after cooling to –78 °C,
methacrolein 5a (95% purity, 43.4 μL, 0.50 mmol) and freshly
distilled cyclopentadiene 4 (203 μL, 2.5 mmol) were added at
–78 °C. After that, the resultant mixture was stirred at –78 °C
for 1 h. To quench the reaction, Et3N (0.2 mL) was poured into
the reaction mixture at –78 °C. The product mixture was
warmed to r.t. and directly purified by silica gel column chro-
matography (eluent: pentane–Et2O, 9:1). Solvents were
removed under 200 Torr at 20 °C by a rotary evaporator, and the
product 6a was obtained (68.2 mg, >99% yield). 1H NMR (400
MHz, CDCl3): δ = 0.76 (d, J = 12.0 Hz, 1 H), 1.01 (s, 3 H), 1.39 (m,
2 H), 2.25 (dd, J = 12.0, 3.9 Hz, 1 H), 2.82 (br s, 1 H), 2.90 (br s, 1
H), 6.11 (dd, J = 6.0, 3.0 Hz, 1 H), 6.30 (dd, J = 6.0, 3.0 Hz, 1 H),
9.69 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 20.1, 34.6, 43.2,
47.6, 48.5, 53.9, 133.1, 139.6, 205.9. HRMS (EI): m/z [M]+ calcd
for C9H12O: 136.0888; found: 136.0893. The endo/exo ratio of 6a
was determined by NMR analysis. 1H NMR (CDCl3): δ = 9.40 [s, 1
H, CHO (endo-6a)], 9.69 [s, 1 H, CHO (exo-6a)]; see ref 3a. The
enantioselectivity and absolute stereochemistry of 6a were
determined by GC analysis according to the literature (see ref.
3a).
(18) We just recently reported boron tribromide assisted chiral
phosphoric acid catalyst for a highly enantioselective Diels–
Alder reaction of 1,2-dihydropyridines. See: Hatano, M.; Goto,
Y.; Izumiseki, A.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc.
2015, 137, 13472.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 564–570