Oxazaborolidinone-catalyzed enantioselective Diels-Alder reaction of acyclic α,β-unsaturated ketones

Article abstract of DOI:10.1021/jo702043g

(Chemical Equation Presented) allo-Threonine-derived O-acyl-β-phenyl- oxazaborolidinones are demonstrated to be powerful and highly enantioselective Lewis acid catalysts for the Diels-Alder reaction of simple acyclic enone dienophiles, expanding the scope of ketone dienophiles and dienes. With 10 to 20 mol % of catalyst, the Diels-Alder adducts are obtained in 76-98% ee with high endo-selectivity. The catalyst exhibits high activity for the reaction with the less reactive β-substituted dienophiles and the less reactive 1,3-cycohexadiene and 1,3-butadiene derivatives. The application of the catalysts to the Diels-Alder reaction of furan is also described.

Full text of DOI:10.1021/jo702043g

Oxazaborolidinone-Catalyzed Enantioselective Diels-Alder Reaction
of Acyclic r,â-Unsaturated Ketones
Ram Shanker Singh, Shinya Adachi, Fumi Tanaka, Toyonao Yamauchi, Chieko Inui, and
Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki,
Sakyo-ku, Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
ReceiVed September 17, 2007
allo-Threonine-derived O-acyl-B-phenyl-oxazaborolidinones are demonstrated to be powerful and highly
enantioselective Lewis acid catalysts for the Diels-Alder reaction of simple acyclic enone dienophiles,
expanding the scope of ketone dienophiles and dienes. With 10 to 20 mol % of catalyst, the Diels-Alder
adducts are obtained in 76-98% ee with high endo-selectivity. The catalyst exhibits high activity for the
reaction with the less reactive â-substituted dienophiles and the less reactive 1,3-cycohexadiene and
1,3-butadiene derivatives. The application of the catalysts to the Diels-Alder reaction of furan is also
described.
Introduction
be discriminated in complexation by chiral Lewis acids. In
addition, the less electron-deficient nature of the ketone dieno-
philes necessitates enhanced acidity of catalysts.
Corey and co-workers reported that a cationic oxazaborolidine
1a of high Lewis acidity is a highly enantioselective catalyst
for the asymmetric Diels-Alder reaction of ketone dienophiles.4
A wide application of the cationic boron catalyst has been
established in natural product syntheses.8 Yamamoto and co-
workers reported oxazaborolidine-derived catalyst 1b whose
Lewis acid-catalyzed asymmetric Diels-Alder reactions have
attracted great attention for their ability to construct complex
carbocyclic frameworks in an enantiomerically enriched form
starting from simple substrates.1 The reaction of unsaturated
aldehydes, especially with an R-substituent,2 and bidentate
alkenoyl-oxazolidinones3 as dienophiles has been extensively
developed in earlier studies. On the other hand, the asymmetric
Diels-Alder reaction of ketone dienophiles has been reported
most recently,4-7 in spite of the prevalence of enantiopure
ketones in natural products. The carbonyl oxygen of a ketone
has sterically and electronically similar lone pairs, difficult to
(4) (a) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 9992. (b) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388.
(c) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979. (d) Ryu, D.
H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800. (e) Liu, D.;
Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498.
(1) For recent reviews of enantioselective Diels-Alder reactions, see:
(a) Maruoka, K. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; p 467. (b) Evans, D. A.; Johnson, J. S. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: New York, 1999; Vol. 3, p 1177. (c) Oppolzer,
W. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: New York, 1991; Vol. 5. (d) Kagan, H. B.; Riant, O. Chem. ReV.
1992, 92, 1007. (e) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289.
(2) (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650 and references
cited therein. (b) Ishihara, K.; Gao, Q.; Yamamoto, H. J. Am. Chem. Soc.
1993, 115, 10412.
(5) Hawkins, J. M.; Nambu, M.; Loren, S. Org. Lett. 2003, 5, 4293.
(6) Futatsugi, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 1484.
(7) Other approaches for the asymmetric Diels-Alder reaction of
ketone: (a) Chiral secondary amine catalyst: Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. (b) Wilson, R. M.; Jen, W.
S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616. (c) Chiral
Brønsted acid catalyst: Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc.
2006, 128, 9626. (d) Chiral transition metal Lewis acid: Rickerby, J.; Vallet,
M.; Bernardinelli, G.; Viton, F.; Ku¨ndig, E. P. Chem. Eur. J. 2007, 13,
3354.
(8) (a) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 5984. (b) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 13708. (c) Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958.
(d) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740.
(3) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; Matt, P.;
Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, S. A.; Campos,
K. R. J. Am. Chem. Soc. 1999, 121, 7582.
10.1021/jo702043g CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/06/2007
212
J. Org. Chem. 2008, 73, 212-218

EnantioselectiVe Diels-Alder Reaction
acidity is enhanced by another Lewis acid, SnCl4.6,9 Hawkins
and co-workers showed that dichloroboron complex 2, devel-
oped previously for ester dienophiles,10 also catalyzes the
reaction of ketone dienophiles with high selectivity.5
TABLE 1. Asymmetric Diels-Alder Reaction of Ethyl Vinyl
Ketone and Cyclopentadiene Catalyzed by OXB 3a-ca
yield
ee
entry
catalyst
mol %
(%)
endo:exo
(%)b
1c
2
3
4
5
3a
3a
3a
3a
3b
3c
40
40
20
10
10
10
74
80
75
88
82
74
96:4
98:2
96:4
96:4
96:4
94:6
84
91
91
92
72
68
6
a Unless otherwise noted, reactions were carried out by using cyclopen-
tadiene (5 equiv) and 2,6-di-tert-butylpyridine (0.25 equiv with respect to
3) in CH2Cl2 at -78 °C for 22-24 h. b Determined by chiral stationary
phase GC. c The reaction was carried out in the absence of 2,6-di-tert-
butylpyridine.
We have recently reported that allo-threonine-derived ox-
azaborolidinones (OXB) 3 are efficient catalysts for asymmetric
Michael reaction of simple acyclic enones with silyl ketene S,O-
acetals.11,12 The high enantioselectivity and absolute stereo-
chemical course of the reaction are rationalized in terms of the
activated complex model shown in 4.11b Although the recently
developed catalysts are well designed to obviate inherent
difficulties in the asymmetric Diels-Alder reaction of ketones,
the scope of ketone dienophiles and dienes should be expanded
further in view of the high synthetic utility of the enantiose-
lective transformation. Herein, we wish to report that OXB
catalysts 3 are also effective in the asymmetric Diels-Alder
reaction of acyclic enones.13 The OXB catalysts exhibited high
enantioselectivity predicted from the activated complex model
4. In spite of their apparently weaker Lewis acidity, OXB
catalysts 3 showed high activity in the reaction of the less
reactive dienes and dienophiles.
TABLE 2. Asymmetric Diels-Alder Reaction of Benzalacetone
with Cyclopentadiene Catalyzed by OXB 3a,c,da
temp
(°C)
time
(h)
yield
(%)
eec
(%)
entry
OXB
mol %
endo:exob
1
2
3
4
5
6
3a
3a
3c
3c
3c
3d
20
20
20
10
10
20
-60
-60
-60
-60
-78
-60
24
72
24
72
72
72
65
77
95
96
15
90
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
90
91
92
91
92
88
a Reactions were carried out by using cyclopentadiene (5 equiv) and 2,6-
di-tert-butylpyridine (0.25 equiv with respect to 3) in CH2Cl2. b Determined
by 1H NMR analysis (500 MHz, CDCl3). c The ee was determined by chiral
phase HPLC.
In the presence of O-p-biphenoyl OXB 3a (40 mol %), the
Diels-Alder reaction proceeded smoothly at -78 °C to give
the corresponding endo adduct 7a diastereo- and enantioselec-
tively (entry 1). The addition of 2,6-di-tert-butylpyridine (0.25
equiv with respect to catalyst 3a) improved the enantioselectivity
(entry 2). The additive was used to trap a trace amount of HCl
that could contaminate the catalyst in preparation from O-(p-
biphenoyl)-N-tosyl-(L)-allo-threonine and dichlorophenylborane.
Under these conditions, the amount of catalyst could be reduced
to 10 mol % keeping the superior level of enantioselectivity
(92% ee) as well as high endo selectivity (96:4) (entry 4). The
enantioselectivity was dependent upon the O-acyl group in OXB
catalysts. For the reaction of ethyl vinyl ketone with cyclopen-
tadiene, the selectivity was decreased in the order of O-p-
biphenoyl 3a, O-2-naphthoyl 3b, and O-benzoyl 3c (entries 5
and 6). The trend in enantioselectivity is similar to that observed
in the asymmetric Michael reaction.11c
Results
The potential of the OXB catalysts 3 in the ketone Diels-
Alder reaction was first evaluated with ethyl vinyl ketone (5a)
and cyclopentadiene (6a) (eq 1, Table 1).
A phenyl group in â-position reduces the reactivity of
dienophile14 and, to the best of our knowledge, there was no
precedent for their asymmetric Diels-Alder reaction. To access
the activity of OXB catalysts 3, we examined the reaction of
benzalacetone (5b) with cyclopentadiene (eq 2, Table 2). At
(9) For the activation of an oxazaborolidine by AlBr3, see ref 4e.
(10) (a) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794.
(b) Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994, 116,
1657.
(11) (a) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku,
A. Org. Lett. 2001, 3, 2101. (b) Wang, X.; Harada, T.; Iwai, H.; Oku, A.
Chirality 2003, 15, 28. (c) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.;
Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046.
(d) Harada, T.; Adachi, S.; Wang, X. Org. Lett. 2004, 6, 4877.
(12) Harada, T.; Kusukawa, T. Synlett 2007, 1823.
-60 °C for 24 h, the reaction of 5b was catalyzed by 3a (20
mol %) to give the corresponding adduct endo-7b in 65% yield
(13) For preliminary accounts of this work, see: Singh, R. S.; Harada,
T. Eur. J. Org. Chem. 2005, 3433.
(14) Dinwiddie, J. G., Jr.; McManus, S. P. J. Org. Chem. 1963, 28, 2416.
J. Org. Chem, Vol. 73, No. 1, 2008 213

Singh et al.
eed (%)
TABLE 3. OXB-Catalyzed Asymmetric Diels-Alder Reaction of Ketone Dienophiles 5a-pa
dienophile
entry
R1
R2
OXB
cond.b
product
yield (%)
endo:exoc
1
2
3
4
5
6
7
8
9
10
11
12e
13
14
15e
16e,f
17e
5c
5a
5d
5e
5b
5f
5g
5h
5i
H
H
Me
Me
Ph
Me
Et
Me
Et
Me
Me
Me
Me
Me
Me
Me
3a
3a
3a
3a
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3a
3a
3a
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
7c
7a
7d
7e
7b
7f
7g
7h
7i
52
88
85
90
95
83
96
97
98
91
53
91
4
>98:2
96:4
85
92
87
94
92
91
91
91
90
93
90
91
90
93
61
8
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
98:2
p-FC6H4
p-ClC6H4
m-ClC6H4
p-CF3C6H4
m-CF3C6H4
p-MeC6H4
5j
7j
5k
5k
5l
5m
5n
5o
5p
7k
7k
7l
7m
7n
7o
7p
p-MeOC6H4
Ph
Ph
Ph
Me
Et
i-Pr
H
95
71
33
25
84:16
>98:2
2-cyclohexenone
44
a Unless otherwise noted, reaction was carried out with cyclopentadiene (5 equiv), OXB 3a,c (10 mol %), and 2,6-di-tert-butylpyridine (2.5 mol %) in
CH2Cl2. b Condition A: at -78 °C for 24 h. Condition B: at -60 °C for 72 h. c Determined by 500 MHz 1H NMR analysis. d Determined by chiral
stationary phase GC or HPLC. e 20 mol % of the catalyst was used. f The reaction was carried out for 44 h.
together with the recovery of 5b (26%) (entry 1). The product
was obtained with high endo selectivity and with satisfactory
enantioselectivity (90% ee). Full conversion of 5b was not
attained even after 72 h under these conditions (entry 2). In
contrast, O-benzoyl OXB 3c exhibited higher activity. The
reaction was accomplished within 24 and 72 h with a 20 and
10 mol % catalyst loading, respectively (entries 3 and 4).
Although OXB 3c exhibited reduced enantioselectivity in the
reaction of ethyl vinyl ketone (Table 1, entry 6), high selectivity
(91-92% ee) comparable to that of the O-biphenoyl derivative
was obtained. At -78 °C, the reaction was sluggish owing to
the deposition of both dienophile 5b and catalyst 3c (entry 5).
O-(3,5-Di(tert-butyl)benzoyl) OXB 3d exhibited a catalytic
activity comparable to 3c but with slight lowering of the
enantioselectivity (entry 6).
The scope of ketone dienophiles in the OXB-catalyzed
asymmetric Diels-Alder reaction was demonstrated by the
results summarized in Table 3. At -78 °C with 10 mol % of
OXB 3a, not only vinyl ketones 5a,c but also propenyl ketones
5d,e reacted with cyclopentadiene to give the corresponding
endo adducts in high ee (entries 1-4). By using OXB 3c (10
mol %) at -60 °C, a variety of benzalacetone derivatives with
an electron-withdrawing group at the para- or meta-position
underwent smooth reaction to give the endo adducts enantiose-
lectively (90-93% ee) (entries 6-10).15 Substitution of an
electron-donating group, however, significantly lowered the
reactivity of dienophiles. A 20 mol % catalyst loading was
required for the reaction of p-methylbenzalacetone (5k) (entry
12). The reaction of p-methoxy derivative 5l was very sluggish
(entry 13). Enantioselectivity was always higher for ethyl
ketones than the corresponding methyl ketones derivatives (entry
1 vs 2, 3 vs 4, and 5 vs 14). Decreased enantioselectivity was
observed for isopropyl ketone 5n (entry 15). OXB catalyst 3a
did not show enantioselectivity for the reaction of unsaturated
aldehyde 5o and cyclic ketone 5p (entries 16 and 17).
With the high catalytic activity of OXB 3a,c established in
the Diels-Alder reactions of cyclopentadiene, attention was
directed to the less reactive dienes. It has been reported that
the reactivity of 1,3-cyclohexadiene (6b), 2,3-dimethyl-2,3-
butadiene (6c), and 2,4-hexadiene (6d) is 2600, 1500, and 1300
times lower than that of cyclopentadiene.16 OXB 3a was found
to catalyze the reaction of these less reactive dienes (Table 4).
By using 20 mol % of catalyst 3a at -78 °C, reaction of 6b-d
with ethyl vinyl ketone proceeded in an efficient manner to give
the corresponding adducts 7q-s in relatively high ee as well
as with high diastereoselectivity (entries 1-3). The reaction of
ethyl vinyl ketone with 1-phenylthiobutadiene (6e)17 and 1-(ben-
zyloxycarbonylamino)butadiene (6f),18 employing 20 mol % of
catalyst 3c at -40 °C, afforded the corresponding adducts 7t,u
in low yield, but with high endo selectivity and moderate ee
(entries 4 and 5). The apparent lower reactivity of dienes 6e,f
is probably due to their low solubility under the reaction
conditions.
Diels-Alder Reaction of Furan. The Diels-Alder reaction
of furan provides potentially useful, stereoselectively function-
alized intermediates, 7-oxabicyclo[2.2.1]hept-2-enes. However,
furan is generally held to be a poor diene.3,19,20 A few examples
of the catalytic asymmetric Diels-Alder reaction of furans have
been reported for R-haloacroleins,21 acryl oxazolidinones,3 and
2,2,2-trifluoroethyl acrylate.9 No report has appeared on the
reaction of ketone dienophiles. The Diels-Alder reaction of
ethyl vinyl ketone (5a) with furan (6g) was investigated by using
OXB catalyst 3 (eq 4).
Under the standard conditions (10 mol % OXB 3a, -78 °C,
in CH2Cl2), the reaction of 5a with 6g proceeded rapidly to
give, after 0.3 h, the adduct 7v in 59% yield as a 22:78 mixture
of exo and endo isomers, both of which were produced in low
ee (Table 5, entry 1). Enantioselectivity was almost lost when
the reaction was carried out for 2 h under otherwise the
214 J. Org. Chem., Vol. 73, No. 1, 2008

EnantioselectiVe Diels-Alder Reaction
TABLE 4. Asymmetric Diels-Alder Reaction of Dienes 6b-f with
SCHEME 1
Ethyl Viniyl Ketonea
a Unless otherwise noted, reaction was carried out with a diene (5 equiv),
a catalyst (20 mol %), and 2,6-di-tert-butylpyridine (2.5 mol %) in CH2Cl2
at -78 °C for 22 h. b Determined by 500 MHz 1H NMR analysis.
c Determined by chiral stationary phase GC or HPLC. d Reaction was carried
out at -40 °C for 24 h with 3 and 1.5 equiv of a diene for entries 4 and 5.
reversal in the absolute configuration of the exo-enantiomer was
observed in these reactions. Further improvement was obtained
by employing O-benzoyl OXB 3c (10 mol %) in toluene (entry
7). Under these conditions, endo-7v was obtained in 98% ee
with high diastereoselectivity (endo:exo ) 93:7). O-p-Anisoyl
OXB 3e exhibited selectivities between those of 3a and 3c (entry
9).
TABLE 5. OXB-Catalyzed Asymmetric Diels-Alder Reaction of
a
Ethyl Vinyl Ketone with Furan
time yield
(h)
endo
exo
Under the optimal conditions with 10 mol % of 3c in toluene
at -78 °C for 0.3 h, not only 5a but also methyl vinyl ketone
(5c) and pentyl vinyl ketone (5q) reacted with furan to give the
corresponding endo adduct 7w,x in high enantioselectivity (eq
5). Attempted reaction of â-substituted enones such as 5d did
not give the corresponding cycloadducts.
entry OXB solvent
(%) endo:exob ee (%)c ee (%)c
1
2
3
3a
CH2Cl2
Et2O
0.3
2
0.3
2
0.3
2
0.3
2
59
39
18
21
80
75
88
75
68
70
22:78
21:79
72:28
66:34
82:18
57:43
93:7
81:19
84:16
81:19
24
5
15
8
95
94
91
76
98
95
95
95
24
21d
17
30d
36
0
4
5
toluene
6
7
8
9
3c
3e
0.3
2
21
10
10
a Reaction was carried out with furan (5 equiv) and a catalyst (10 mol
%) at -78 °C. b Determined by 500 MHz 1H NMR analysis. c Determined
by chiral stationary phase GC after converting into exo- and endo-1-(7-
oxabicyclo[2.2.1]hept-2-yl)propan-1-one by hydrogenation with Pd/C. d En-
riched with the opposite enantiomer.
Discussion
same conditions (entry 2). Marked effect of solvent was
observed on diastereo- and enantioselectivity in the Diels-Alder
reaction with furan. Endo-selectivity and high enantioselectivity
were observed by carrying out the reaction in ether for 0.3 h
whereas the product yield was low (entry 3). High yield (80%),
as well as high enantioselectivity (91% ee), was obtained with
endo-selectivity by carrying out the reaction in toluene (entry
5). Diastereoselectivity was decreased by the longer reaction
time in ether or toluene (entries 4 and 6). Interestingly, the
There are four possible coordination modes of an acyclic
enone to Lewis acids (ML*n) (Scheme 1). Except for the
(16) (a) Ru¨cker, C.; Lang, D.; Sauer, J.; Frige, H.; Sustman, R. Chem.
Ber. 1980, 113, 1663. (b) Fringuelli, F.; Taticchi, A. Dienes in the Diels-
Alder Reaction; Wiley & Sons: New York, 1990.
(17) Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43, 1208.
(18) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Syn. Collect.
1988, 6, 95.
(19) Brion, F. Tetrahedron Lett. 1982, 23, 5299.
(20) For HfCl4-catalyzed reaction, see; Hayashi, Y.; Nakamura, M.;
Nakao, S.; Inoue, T.; Shoji, M. Angew. Chem., Int. Ed. 2002, 41, 4079.
(21) Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979.
(15) The absolute structure of 7g was established by the crystallographic
analysis. See the Supporting Information.
J. Org. Chem, Vol. 73, No. 1, 2008 215

Singh et al.
SCHEME 2
sterically congested s-cis-syn isomer, other isomers are seem-
ingly feasible for activated complexes. We have recently shown
that OXBs have a strong tendency to be coordinated by pyridine
derivatives from the face syn to the substituent attached to the
oxazaborolidinone ring.22 Assuming a similar facial selectivity
for enone coordination with respect to the OXB ring, four
possible activated complex models (A-D) are conceivable
corresponding to the four coordination modes.
The approach of dienes from the open front side of the
activated complex A (s-cis-anti) ()4) and B (s-trans-syn) would
lead to the enantiomers obtained in the OXB-catalyzed reaction
while, on the other hand, C (s-trans-anti) and D (s-cis-syn)
would give the opposite enantiomer. Low enantioselectivity was
observed for cyclic enone 5p with the fixed s-trans structure
(Table 3, entry 17). Low selectivity was also observed for
isopropyl ketone 5n in which anti coordination by OXB 3 might
be sterically less favorable (entry 15). These observations
suggest strongly that the OXB-catalyzed Diels-Alder reaction
of acyclic enones proceeds not through s-trans-syn complex B
but through s-cis-anti complex A.
The observed activity of OXB 3a,c is comparable or even higher
than that of cationic boron catalyst 1a,b4,6.9 or dichloroboron
complex 25 judging from reaction temperatures, catalyst amounts,
and applicability to the less reactive dienes and dienophiles. In
comparison with these catalysts, OXB 3 has a less rigid chiral
environment around the boron atom, which might be responsible
for its high activity. The acyloxy moiety of 3 is conformationally
flexible to some extent due to the presence of three rotatable
bonds (CHMe-O, O-CO, and CO-Ar), serving as a “soft
fence” to induce enantioselectivity. The activated complex 4
()A in Scheme 1) could accommodate space for structural
change in the transition state to stabilize the transition state and
facilitate the Diels-Alder reaction.
In the reaction of benzalacetone (5b), O-benzoyl OXB 3c
showed higher catalytic activity in comparison with O-p-
biphenoyl derivative 3a. The observation can be rationalized
by considering an unfavorable interaction in the transition state
between the phenyl group of 5b and the p-phenyl group of 3a.
The approach of cyclopentadiene toward activated complex A
(R, R1 ) Ph) would result in a steric congestion in the transition
state between these phenyl groups, which could not be fully
accommodated by the structural modification of the acyloxy
moiety.
In contrast to the high enantioselectivity observed for acyclic
enones, OXB 3a did not show selectivity for cinnamaldehyde
(5o) (entry 16). The result implies that the reaction of the enal
(R2 ) H) proceeded concurrently through complexes A and C.
For ketone dienophiles, s-trans-anti complex C (R2 * H) is
unfavorable owing to an 1,3-allylic strain, which might be a
major factor for the preference of the s-cis-anti complex A in
the reaction of acyclic enones. The allylic interaction in complex
C also might be responsible for the general trend of slightly
higher enantioselectivity for ethyl ketones (R2 ) CH3CH2) in
comparison with methyl ketones (R2 ) CH3).
The mechanism of the Diels-Alder reaction has long been a
topic of discussion.24 The reaction may take place through either
a concerted or a stepwise mechanism involving the formation
of a zwitterion or biradical intermediate. Recent experimental25
and theoretical studies26,25b on the reaction of furans point out
that the mechanism changes from concerted to stepwise with
an increased electron deficiency in the dienophile. In the OXB-
catalyzed furan Diels-Alder reaction, solvents and reaction time
The catalytic activity of OXB 3 is unexpectedly high in view
of the moderate acidity of boron-based neutral Lewis acids.23
(24) Houk, K. H.; Gonzalez, J.; Li. Y. Acc. Chem. Res. 1995, 28, 81.
(25) (a) Itoh, K.; Kitoh, K.; Sera. A. Heterocycles 1999, 51, 243. (b)
Itoh, K.; Kitoh, K.; Kishimoto, S. Can. J. Chem. 2006, 84, 392.
(26) (a) Domingo, L. R.; Picher, M. T.; Zaragoza´, R. J. J. Org. Chem.
1998, 63, 9183. (b) Domingo, L. R.; Picher, M. T.; Andre´s, J.; Oliva, M.
J. Org. Chem. 1999, 64, 3026. (c) Domingo, L. R.; Picher, M. T.; Aurell.
M. L. J. Phys. Chem. A 1999, 103, 11425.
(22) Harada, T.; Yamamoto, Y.; Kusukawa, T. Chem. Commun. 2005,
859.
(23) (a) Ishihara, K. In Lewis Acids in Organic Synthesis; Yamamoto,
H., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, p 135. (b)
Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527.
216 J. Org. Chem., Vol. 73, No. 1, 2008

EnantioselectiVe Diels-Alder Reaction
a solution of O-(p-biphenoyl)-N-tosyl-(L)-allo-threonine8c (140 mg,
0.309 mmol) in CH2Cl2 (2.5 mL) under argon atmosphere at room
temperature was added dichlorophenylborane (40 µL, 0.31 mmol).
After being stirred for 30 min, the mixture was concentrated in
vacuo. To a solution of the resulting OXB 3a in CH2Cl2 (1.7 mL)
at -78 °C were added 2,6-di-tert-butylpyridine (17 µL, 0.77 mmol),
ethyl vinyl ketone (260 mg, 3.09 mmol), and 1,3-cyclopentadiene
(1.04 mL, 15.5 mmol). The resulting solution was stirred at
-78 °C for 24 h. The mixture was quenched by the addition of
saturated aqueous NaHCO3 and filtered. The filtrate was extracted
three times with ether, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash chromatography (SiO2, gradient
elution with 1-2% ethyl acetate in hexane) to give 408 mg (2.72
had a remarkable effect on the diastereo- and enantioselectivity
(Table 5). High enantioselectivity was obtained with endo-
selectivity by carrying out the reaction in toluene for 0.3 h
(entries 5, 7, and 9). Diastereoselectivity was decreased by the
longer reaction time together with a decrease in the enantiose-
lectivity (entries 8 and 10) or reversal in the absolute config-
uration of the minor exo-enantiomer (entry 6). While the
observation is difficult to rationalize based on the retro-Diels-
Alder reaction,27 it can be understood by postulating a limiting
concerted and a stepwise mechanism (Scheme 2). The concerted
Diels-Alder reaction of furan catalyzed by OXB 3 would
produce endo-7v as a major diastereomer and enantiomer.
Assuming an activated complex model 4, the major enantiomer
of a minor exo adduct (exo-7v) would be the one with 1R,2S,4R
configuration.28 The stepwise reaction of furan would proceed
without enantioselectivity to give racemic zwitterion intermedi-
ate rac-10, which would cyclized to give rac-exo-7v as a major
diastereomer with minor formation of rac-endo-7v. Due to the
stabilization of intermediate rac-10 in CH2Cl2, the Diels-Alder
reaction of furan in this solvent proceeded mainly through the
stepwise mechanism, with minor competition of the concerted
pathway, resulting in exo selective formation of the adducts in
low enantioselectivity (entries 1 and 2). On the other hand, in
the less polar toluene, the reaction proceeded primarily through
the concerted pathway to give endo-7v diastereo- and enanti-
oselectively (entries 5, 7, and 9). In toluene, however, the
initially produced endo-7v is slowly transformed to the ther-
modynamically more stable ent-exo-7v through tight ion pair
endo-9 and exo-9. As a result, in the reaction for 2 h, the
enantioselectivity of the exo adducts was decreased with OXB
3c and 3e (entries 8 and 10) or reversed with OXB 3a (entry
6).
mmol, 88%) of the adduct 7a: [R]23 -104 (c 1.1, CHCl3) (92%
D
ee). Lit.4a for the (1R,2R,4R)-enantiomer: [R]23 +111 (c 0.76,
D
CHCl3) (97% ee). Endo-exo ratio was determined by GC analysis,
using a OV-1 column (30 m, 1.8 kg/cm2, initial temperature
50 °C, 10 deg/min ramp to 320 °C); retention times 6.5 (endo) and
6.2 min (exo). Enantioselectivity was determined by GC analysis,
using a Chrompack Cp-Cyclodextrin-â-236-M-19 column (30 m,
1.8 kg/cm2, initial temperature 50 °C, 2 deg/min ramp to 200 °C);
retention times 26.9 (major) and 26.7 min (minor).
1-[(1S,2S,4S)-7-Oxabicyclo[2.2.1]hept-5-en-2-yl]propan-1-
one (7v): Typical Procedure for Asymmetric Diels-Alder
Reaction with Furan. To a solution of O-(benzoyl)-N-tosyl-(L)-
allo-threonine3c (75.5 mg, 0.200 mmol) in CH2Cl2 (2 mL) under
argon atmosphere at room temperature was added dichlorophe-
nylborane (28.5 µL, 0.22 mmol). After being stirred for 30 min,
the mixture was concentrated in vacuo. To a mixture of the resulting
OXB 3c in toluene (6.4 mL) at -78 °C were added ethyl vinyl
ketone (168 mg, 2.00 mmol) and furan (0.73 mL, 10 mmol). The
resulting solution was stirred at -78 °C for 0.3 h. The mixture
was quenched by the addition of saturated aqueous NaHCO3 and
filtered. The filtrate was extracted three times with ether, dried
(MgSO4), and concentrated in vacuo. The toluene solution of the
crude product was subjected to a flash chromatography (SiO2,
gradient elution with 0-25% Et2O in hexane) to obtain 269 mg
(1.77 mmol, 88%) of a 93:7 mixture of endo-7v and exo-7v. The
endo and exo adducts were isolated by flash chromatography. endo-
Conclusion
The results in this report demonstrate that allo-threonine-
derived OXB catalysts, especially O-p-biphenoyl and O-benzoyl
OXB 3a,c, are highly effective in asymmetric Diels-Alder
reactions of acyclic ketone dienophiles. With 10 to 20 mol %
of the catalysts, the Diels-Alder adducts were obtained in high
endo selectivity and enantioselectivity. The catalysts exhibit high
activity for the less reactive dienophiles such as benzalacetone
derivatives and for the less reactive dienes such as 1,3-
cyclopentadiene. The application of catalyst 3c to the Diels-
Alder reaction of furan has also proven to be possible by using
toluene as a solvent. The remarkable solvent effect as well as
isomerization of the kinetically favored endo adduct to the
thermodynamically favored exo adduct was discussed in terms
of a limiting concerted and a stepwise mechanism. The observed
absolute structures of the Diels-Alder adducts are consistent
with the activation complex model 4. The moderately flexible
nature of the acyloxy was proposed to be responsible for the
high activity of the neutral boron complex 3.
7v (98% ee): Rf 0.33 (SiO2, 30% ethyl acetate in hexane); [R]23
D
-75.2 (c 1.00, CHCl3) (96% ee);29 1H NMR (500 MHz, CDCl3) δ
1.03 (3H, t, J ) 7.2 Hz), 1.59 (1H, dd, J ) 4.0 and 11.2 Hz), 2.00
(1H, ddd, J ) 4.8, 9.1, and 11.3 Hz), 2.33-2.50 (2H, m), 3.20
(1H, td, J ) 4.3 and 9.0 Hz), 5.01 (1H, dd, J ) 1.1 and 4.7 Hz),
5.17 (1H, br d, J ) 4.7 Hz), 6.15 (1H, dd, J ) 1.5 and 5.9 Hz),
6.40 (1H, dd, J ) 1.7 and 5.9 Hz); 13C NMR (125.8 MHz, CDCl3)
δ 7.6, 27.4, 35.8, 50.8, 78.9, 79.2, 134.8, 136.8, 208.9; HRMS (EI)
calcd for C9H12O 152.0837, found 152.0838. exo-7v (36% ee): Rf
1
0.27 (SiO2, 30% ethyl acetate in hexane); H NMR (500 MHz,
CDCl3) δ 1.08 (3H, t, J ) 7.3 Hz), 1.51 (1H, dd, J ) 8.5 and 11.4
Hz), 1.62 (1H, br s), 2.03 (1H, td, J ) 4.4 and 11.4 Hz), 2.47-
2.61 (3H, m), 5.07 (1H, br d, J ) 4.4 Hz), 5.09 (1H, d, J ) 1.0
Hz), 6.36 (1H, dd, J ) 1.6 and 5.8 Hz), 6.38 (1H, dd, J ) 1.6 and
5.8 Hz); 13C NMR (125.8 MHz, CDCl3) δ 7.9. 28.4, 34.5, 49.8,
78.0, 79.9, 134.9, 136.8, 210.9; HRMS (EI) calcd for C9H12O
152.0837, found 152.0832.
Endo-exo ratio was determined by 500 MHz 1H NMR analysis.
The absolute stereochemistry was assumed by analogy. A 93:7
mixture of the endo and exo adduct was hydrogenated in the
presence of Pd/C (10%) in hexane to give 1-(7-oxabicyclo[2.2.1]-
hept-2-yl)propan-1-one as a mixture of endo and exo isomers.
Enantioselectivity was determined by GC analysis, using a BETA
DEX 225 (m) column (30 m, 1.8 kg/cm2, initial temperature
Experimental Section
1-[(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-yl]propan-1-one4a (7a):
Typical Procedure for Asymmetric Diels-Alder Reaction. To
(27) If retro-Diels-Alder reaction were responsible for the endo-exo
isomerization, complete racemization of exo-7v (entry 8) would be observed
in full equilibrium, where the thermodynamically more stable exo isomer
would be a major component.
(28) In accord with this supposition, treatment of a 85:15 mixture of
endo-7v (87% ee) and exo-7v (50% ee) with aq KOH (1 M)/Et2O at room
temperature gave a 48:52 mixture of endo-7v (64% ee) and ent-exo-7v (56%
ee) in 31% yield.
(29) Specific rotation was measured for the product of the reaction with
OXB 3c (5 mol %) at -78 °C for 0.3 h in toluene (34% yield, endo:exo )
86:14, endo; 96% ee, exo; 23% ee).
J. Org. Chem, Vol. 73, No. 1, 2008 217

Singh et al.
90 °C, 1 deg/min ramp to 170 °C); retention times 26.3 (major
endo enantiomer), 28.2 (minor endo enantiomer), 37.9 (major exo
enantiomer), and 36.9 min (minor exo enantiomer). endo-1-(7-
Oxabicyclo[2.2.1]hept-2-yl)propan-1-one: 1H NMR (500 MHz,
CDCl3) δ 1.06 (3H, t, J ) 7.4 Hz), 1.38 (1H, m), 1.50 (1H, m),
1.58 (1H, m), 1.63-1.77 (2H, m), 1.98 (1H, dd, J ) 4.7 and 11.8
Hz), 2.33-2.48 (2H, m), 3.18 (1H, m), 4.59 (1H, t, J ) 5.3 Hz),
4.76 (1H, t, J ) 5.2 Hz), a minor exo-isomer resonates at 4.64
(1H, t, J ) 5.0 Hz) and 4.72 (1H, d, J ) 4.9 Hz); 13C NMR (125.8
MHz, CDCl3) δ 7.6, 20.1, 29.9, 31.6, 36.6, 55.7, 77.4, 78.1,
209.2.
Acknowledgment. Financial support from the Ministry of
Education, Science, Sports and Culture of the Japanese Govern-
ment [Grant-in-Aid for Scientific Research (No. 17550101)] is
gratefully acknowledged.
Supporting Information Available: Preparation of OXB
ligands and data for Diels-Alder adducts 7a-x, including X-ray
data of 7g. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO702043G
218 J. Org. Chem., Vol. 73, No. 1, 2008