Enantioselective diels-alder reaction of acyclic enones catalyzed by allo-threonine-derived chiral oxazaborolidinone

Article abstract of DOI:10.1002/ejoc.200500356

An allo-threonine-derived O-(p-biphenylcarbonyloxy)-B-phenyl- oxazaborolidinone is demonstrated to be a powerful and highly enantioselective Lewis acid catalyst for the enantioselective Diels-Alder reaction of simple acyclic enone dienophiles, expanding the scope of ketone dienophiles and dienes. With 10-20 mol% of the catalyst, the Diels-Alder adducts are obtained with up to 94 % ee and high endo selectivity. The catalyst exhibits a high activity in the reaction with the less reactive β-substituted dienophiles and the less reactive 1,3-cycohexadiene and 1,3-butadiene derivatives. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500356

SHORT COMMUNICATION
Enantioselective Diels–Alder Reaction of Acyclic Enones Catalyzed by
allo-Threonine-Derived Chiral Oxazaborolidinone
Ram Shanker Singh[a] and Toshiro Harada*[b]
Keywords: Asymmetric catalysis / Asymmetric synthesis / Boron / Cycloaddition / Lewis acids
An allo-threonine-derived O-(p-biphenylcarbonyloxy)-B-
phenyl-oxazaborolidinone is demonstrated to be a powerful
and highly enantioselective Lewis acid catalyst for the enan-
tioselective Diels–Alder reaction of simple acyclic enone
dienophiles, expanding the scope of ketone dienophiles and
dienes. With 10–20 mol% of the catalyst, the Diels–Alder ad-
ducts are obtained with up to 94% ee and high endo selectiv-
ity. The catalyst exhibits a high activity in the reaction with
the less reactive β-substituted dienophiles and the less reac-
tive 1,3-cycohexadiene and 1,3-butadiene derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
catalyst also for the asymmetric Diels–Alder reaction of
acyclic enones exhibiting high enantioselectivity predicted
from the activated complex 2 with the expansion of the
scope of dienophiles and dienes.
Introduction
Lewis acid catalyzed asymmetric Diels–Alder reaction
has attracted great attention for their ability to construct
complex carbocyclic frameworks in an enantiomerically en-
riched form starting from simple substrates.[1] Earlier stud-
ies have focused mainly on the reaction of unsaturated alde-
hydes, especially with an α-substituent,[2] and bidentate alk-
enoyl-oxazolidinones.[3] Despite of the prevalence of
enantiopure ketones in natural products, the asymmetric
Diels–Alder reaction of ketone dienophiles has been re-
ported most recently.[4–6] The carbonyl oxygen atom of a
ketone has sterically and electronically similar lone pairs
which are difficult to be discriminated in complexation by
chiral Lewis acids. In addition, the less electron-deficient
nature of the ketone dienophiles necessitates an enhanced
acidity of catalysts. Although recently developed catalysts
are well designed to obviate such inherent difficulties,[4–6]
the scope of ketone dienophiles and dienes is needed to be
expanded further in view of the high synthetic utility of the
enantioselective transformation.
Results and Discussion
The potential of the OXB catalyst 1 in ketone Diels–Al-
der reactions was first evaluated with ethyl vinyl ketone and
cyclopentadiene [Equation (1), Table 1]. The reaction with
OXB 1a (40 mol%) in dichloromethane at –78 °C gave the
endo adduct in 84% ee (Entry 1). The enantioselectivity was
improved in the presence of 2,6-di-tert-butylpyridine
(0.25 equiv. with respect to catalyst 1a) (Entry 2).[8] Under
these conditions, the amount of the catalyst could be re-
duced to 10 mol% keeping the superior level of enantio-
selectivity (92% ee) as well as the high endo selectivity (96:4)
(Entry 4). In accord with our previous observation in the
asymmetric Michael reactions,[7b] the O-acyl group in the
OXB catalysts is influential to the enantiofacial discrimi-
nation: 2-Naphthoyl and benzoyl derivatives 1b,c exhibited
a lower ee in comparison with the p-biphenylcarbonyloxy
derivative (Entries 5 and 6).
We have recently reported that allo-threonine-derived ox-
azaborolidinone (OXB) 1a is an efficient catalyst for the
asymmetric Michael reaction of simple acyclic enones with
silyl ketene S,O-acetals.[7] The high enantioselectivity and
absolute stereochemical course of the reaction are rational-
ized in terms of the activated complex model shown in 2.[7b]
Herein, we wish to report that OXB 1a serves as an efficient
[a] Venture Laboratory, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
[b] Department of Chemistry and Materials Technology, Kyoto In-
stitute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Fax: +81-75-724-7514
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 3433–3435
DOI: 10.1002/ejoc.200500356
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3433

R. S. Singh, T. Harada
SHORT COMMUNICATION
2600, 1500, and 1300 times lower than that of cyclopentadi-
ene.[9] OXB 1a was found to catalyze the reaction of these
less reactive dienes (Scheme 1). By using 20 mol% of cata-
lyst 1a, the reaction with ethyl vinyl ketone proceeded in an
efficient manner at –78 °C for 22 h to give the correspond-
ing adducts with relatively high ee as well as high diastereo-
selectivity.
(1)
Table 1. Asymmetric Diels–Alder reaction of ethyl vinyl ketone and
cyclopentadiene catalyzed by OXB 1a–c.[a]
Entry
Catalyst
mol%
Yield (%) endo/exo ee (%)[b]
1[c]
2
3
4
5
1a
1a
1a
1a
1b
1c
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 cy-
clopentadiene (5 equiv.) and 2,6-di-tert-butylpyridine (0.25 equiv.
with respect to 1) 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.
Scheme 1.
The absolute configuration of the Diels–Alder adducts
corresponds to the approach of dienes from the predicted
open front side of the activated complex model 2 in which
an acyclic enone is coordinated in an s-cis-anti fashion. The
lower enantioselectivity for the secondary alkyl ketone and
the cycloalkenone (Table 2, Entries 7 and 8) is also consis-
tent with this model. Aside from a high enantiofacial dis-
crimination of enones, the activity of catalyst 1a for the less
reactive substrates is unexpectedly high in view of the rela-
tively lower acidity of the boron-based neutral Lewis acid
complexes.[10] The acyloxy moiety in 2 is conformationally
nonrigid due to the three rotatable bonds and could accom-
modate the space for the structural change in the transition
state of the Diels–Alder reaction. The stabilization of the
transition state in such a way might be the origin of the
high Lewis acidity of the OXB catalyst 1a.
In summary, OXB 1a was demonstrated to be an efficient
catalyst for asymmetric Diels–Alder reactions of acyclic en-
one dienophiles. With 10–20 mol% of the catalyst, the
Diels–Alder adducts were obtained with up to 94% ee and
high endo selectivity. The OXB catalyst exhibits a high ac-
tivity for the reaction with the less reactive β-substituted
dienophiles and the less reactive 1,3-cycohexadiene and 1,3-
butadiene derivatives. It is noteworthy that the reactions
with catalyst 1a afford the enantiomers of adducts obtain-
able with previously reported catalysts[3–5] with a similar or
higher level of enantioselectivity.
The scope of ketone dienophiles is demonstrated by the
results summarized in Equation (2) and Table 2. At –78 °C
with 10 mol% of 1a, not only vinyl ketones but also pro-
penyl ketones react with cyclopentadiene to give the corre-
sponding endo adducts with high ee (Entries 1–4). A phenyl
group in β-position reduces the reactivity of dienophiles
and, to the best of our knowledge, there was no precedent
for their asymmetric Diels–Alder reaction. A high level of
enantioselectivity was obtained for the β-phenyl dienophiles
by carrying out the reaction at –60 °C with 20 mol% of the
catalyst (Entries 5 and 6). Decreased enantioselectivity was
observed for a secondary alkyl ketone and cycloalkenone
(Entries 7 and 8).
(2)
Table 2. OXB-catalyzed asymmetric Diels–Alder reaction of ketone
dienophiles.[a]
Entry
Dienophile
Conditions Yield endo/exo ee[b,c]
R1
R2
(%)
(%)
1
2
3
4
5
6
7
8
H
H
Me
Me
Ph
Ph
Ph
Me
Et
Me
Et
Me
Et
iPr
A
A
A
A
B
B
B
B
52
88
85
90
77
59
71
25
Ͼ98:2
96:4
Ͼ98:2
Ͼ98:2
Ͼ98:2
98:2
85
92
87
94
91
90
61
44
Experimental Section
1-[(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-yl]propan-1-one:[4b] Typical
procedure for the asymmetric Diels–Alder reaction (Table 2, Entry
2): To a solution of O-(p-biphenylcarbonyloxy)-N-tosyl-l-allo-thre-
onine[7b] (140 mg, 0.309 mmol) in CH2Cl2 (2.5 mL) under argon at
room temperature was added dichlorophenylborane (40 μL,
0.31 mmol). After being stirred for 30 min, the mixture was concen-
trated in vacuo. To a solution of the resulting OXB 1a 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-cyclo-
pentadiene (1.04 mL, 15.5 mmol). The resulting solution was
stirred at –78 °C for 24 h. The mixture was quenched by the ad-
98:2
Ͼ98:2
2-cyclohexenone
[a] Conditions A: 1a (10 mol%), –78 °C, 24 h. Condition B: 1a
(20 mol%), –60 °C, 72 h. [b] Product ratios determined by chiral
stationary phase GC or HPLC. [c] Absolute configuration was de-
termined by comparison wizh the literature optical rotation (Entries
1–4 and 8) or by analogy (Entries 5–7).
It has been reported that the reactivity of 1,3-cyclohexa-
diene, 2,3-dimethyl-2,3-butadiene, and 2,4-hexadiene is dition of saturated aqueous NaHCO3 and filtered. The filtrate was
3434 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2005, 3433–3435

Enantioselective Diels–Alder Reaction of Acyclic Enones
SHORT COMMUNICATION
[4] a) E. J. Corey, T. Shibata, T. W. Lee, J. Am. Chem. Soc. 2002,
124, 3808; b) D. H. Ryu, T. W. Lee, E. J. Corey, J. Am. Chem.
Soc. 2002, 124, 9992; c) D. H. Ryu, E. J. Corey, J. Am. Chem.
Soc. 2003, 125, 6388; d) G. Zhou, Q.-Y. Hu, E. J. Corey, Org.
Lett. 2003, 5, 3979; e) D. H. Ryu, G. Zhou, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 4800; Q.-Y. Hu, P. D. Rege, E. J. Corey,
J. Am. Chem. Soc. 2004, 126, 5984; f) Q.-Y. Hu, G. Zhou, E. J.
Corey, J. Am. Chem. Soc. 2004, 126, 13708.
[5] For an enantioselective Diels–Alder reaction catalyzed by chi-
ral secondary amines, see: A. B. Northrup, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2002, 124, 2458.
[6] J. M. Hawkins, M. Nambu, S. Loren, Org. Lett. 2003, 5, 4293.
[7] a) T. Harada, H. Iwai, H. Takatsuki, K. Fujita, M. Kubo, A.
Oku, Org. Lett. 2001, 3, 2101; b) X. Wang, S. Adachi, H. Iwai,
H. Takatsuki, K. Fujita, M. Kubo, A. Oku, T. Harada, J. Org.
Chem. 2003, 68, 10046; c) T. Harada, S. Adachi, X. Wang, Org.
Lett. 2004, 6, 4877.
[8] The additive was used to trap a small amount of HCl contami-
nating the catalyst in the preparation from O-(p-biphenylcar-
bonyloxy)-N-tosyl-l-allo-threonine and dichlorophenylborane.
[9] a) C. Rücker, D. Lang, J. Sauer, H. Frige, R. Sustman, Chem.
Ber. 1980, 113, 1663; b) F. Fringuelli, A. Taticchi, Dienes in the
Diels–Alder Reaction, Wiley & Sons, New York, 1990.
[10] For chiral boron Lewis acids in asymmetric synthesis, see; K.
Ishihara, in Lewis Acids in Organic Synthesis (Ed.: H. Yamam-
oto), Wiley-VCH, Weinheim, 2000, vol. 1, p. 135.
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
(88%) of the adduct. [α]2D3 = –104 (c = 1.1, CHCl3) (92% ee); ref.[4b]
for the (1R,2R,4R) enantiomer: [α]2D3 = +111 (c = 0.76, CHCl3)
(97% ee). The endo/exo ratio and enantioselectivity were deter-
mined by GC analysis using an OV-1 (30 m) column and Chrom-
pack Cp-Cyclodextrin-β-236-M-19 column (30 m), respectively.
Supporting Information: Describes experimental procedures and an-
alytical data for the Diels–Alder products of this article (see also
footnote on the first page of this article).
[1] For recent reviews of enantioselective Diels–Alder reactions,
see: a) K. Maruoka, in: Catalytic Asymmetric Synthesis Second
Edition (Ed.: I. Ojima), Wiley-VCH, New York, 2000, p. 467;
b) D. A. Evans, J. S. Johnson, in: Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, New York, 1999, vol. 3, pp. 1177; c) W. Oppolzer, in:
Comprehensive Organic Synthesis (Ed.: B. M. Trost), Pergamon
Press, New York, 1991; vol. 5; d) H. B. Kagan, O. Riant, Chem.
Rev. 1992, 92, 1007; e) L. C. Dias, J. Braz. Chem. Soc. 1997, 8,
289.
[2] a) E. J. Corey, Angew. Chem. Int. Ed. 2002, 41, 1650 and refer-
ences cited therein; b) K. Ishihara, Q. Gao, H. Yamamoto, J.
Am. Chem. Soc. 1993, 115, 10412.
[3] D. A. Evans, D. M. Barnes, J. S. Johnson, T. Lectka, P. Matt,
S. J. Miller, J. A. Murry, R. D. Norcross, S. A. Shaughnessy,
K. R. Campos, J. Am. Chem. Soc. 1999, 121, 7582.
Received May 18, 2005
Published Online: June 21, 2005
Eur. J. Org. Chem. 2005, 3433–3435
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3435