Asymmetric 1,3-dipolar cycloadditions of nitrones and methacrolein catalyzed by chiral bis-titanium Lewis acid: A dramatic effect of N-substituent on nitrone

Article abstract of DOI:10.1021/ol702123n

(Chemical Equation Presented) Highly stereoselective 1,3-dipolar cycloadditions of methacrolein and nitrones could be realized by the use of bis-titanium chiral Lewis acid catalyst. Key to the success is the introduction of bulky N-substituent on nitrone

Full text of DOI:10.1021/ol702123n

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4805-4808
Asymmetric 1,3-Dipolar Cycloadditions
of Nitrones and Methacrolein Catalyzed
by Chiral Bis-Titanium Lewis Acid:
A Dramatic Effect of N-Substituent on
Nitrone
Takuya Hashimoto, Masato Omote, Taichi Kano, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received August 29, 2007
ABSTRACT
Highly stereoselective 1,3-dipolar cycloadditions of methacrolein and nitrones could be realized by the use of bis-titanium chiral Lewis acid
catalyst. Key to the success is the introduction of bulky N-substituent on nitrone to attenuate the undesired Lewis acid nitrone complexation.
−
The Lewis acid-catalyzed asymmetric Diels-Alder reaction
of methacrolein and dienes is one of the most important and
fundamental cycloaddition reactions, and enables the forma-
tion of one all-carbon quaternary stereocenter and additional
stereocenters at one time depending on the substitution
pattern of the diene (Scheme 1, eq 1).1,2 This attractive feature
of this catalysis has promoted the development of various
chiral Lewis acid catalysts over the past decades.
philes, such as 3-(2-alkenoyl)-2-oxazolidinone.4 Namely, in
the chiral Lewis acid activation of such bidentate carbonyl
substrates, R-substitution of the carbonyl substrates is not
normally amenable due to a problematic A1,3 strain between
the template and the R-substituent.5
The results of research focusing on the use of R,â-
unsaturated aldehydes in the asymmetric 1,3-dipolar cy-
In sharp contrast to its prosperity in the field of asymmetric
catalysis, methacrolein has rarely been employed in the
asymmetric 1,3-dipolar cycloadditions of nitrone, another
important class of cycloadditions (Scheme 1, eq 2).3 The
main cause of this lack might be attributed to the long-
standing substrate limitation of using bidentate dipolaro-
Scheme 1. Use of Methacrolein in [4 + 2] and [3 + 2]
Cycloadditions
(1) For reviews on the Lewis acid-catalyzed asymmetric Diels-Alder
reactions, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 388. (b) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
(2) For reviews on the formation of quaternary stereocenters, see: (a)
Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Christoffers, J.; Baro, A.
AdV. Synth. Catal. 2005, 347, 1473. (c) Christoffers, J.; Baro, A., Eds.
Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2005. (d) Douglas, C. J.; Overman, L.
E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
10.1021/ol702123n CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/11/2007

cloadditions of nitrone appeared recently, which offered an
opportunity to implement the reaction of nitrone and meth-
acrolein by the judicious choice of Lewis acids.6,7 Although
high endo selectivity was generally attained, these studies
suffered from poor regioselectivity or the preferential forma-
tion of 3,5-endo isomer without exception. Thus, despite the
intriguing structure of vicinally substituted 3,4-endo adduct
including one all-carbon quaternary center, the 3,4-endo
selective reaction still remains an elusive goal. It should also
be noted that chiral organocatalysts do not provide a solution
to this problem because of their poor ability to discriminate
the enantiotopic face of methacrolein.8,9
Figure 1. Chiral bis-titanium Lewis acids 1a and 1b.
Our approach to addressing this issue is the use of chiral
bis-titanium Lewis acid (S,S)-1a (Figure 1), which has
recently been revealed to catalyze various asymmetric
transformations including 1,3-dipolar cycloadditions of N-
benzyl nitrones and acrolein.10 Along the line of this research,
the reaction of methacrolein and N-benzylidenebenzylamine
N-oxide 2 (R ) CH2Ph) was conducted in the presence of a
catalytic amount of (S,S)-1a. The reaction was sluggish even
at 0 °C, providing the cycloadduct only in disappointingly
low yield with a moderate enantioselectivity of 75% ee
(Table 1, entry 1). However, the sterically congested 3,4-
endo adduct 3 was obtained exclusively, in contrast to the
previous reports from other groups. Intrigued by this unusual
outcome, we set out to realize a practical asymmetric 1,3-
dipolar cycloaddition reaction of methacrolein and nitrones.
Table 1. Comparison of the Reactivity and Selectivity of
N-Substituted Nitronesa
(3) For reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV.
1998, 98, 863. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000,
1449. (c) Gothelf, K. V. In Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany,
2002; Chapter 6, p 211. (d) Kanemasa, S. In Cycloaddition Reactions in
Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2002; Chapter 7, p 249. (e) Pellissier, H. Tetrahedron
2007, 63, 3235.
entry
R
catalyst
yield (%)c
ee (%)d
(4) For some recent examples employing bidentate dipolarophiles, see:
(a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 718.
(b) Suga, H.; Nakajima, T.; Itoh, K.; Kakehi, A. Org. Lett. 2005, 7, 1431.
(c) Palomo, C.; Oiarbide, M.; Arceo, E.; Garc´ıa, J. M.; Lo´pez, R.; Gonza´lez,
A.; Linden, A. Angew. Chem., Int. Ed. 2005, 44, 6187. (d) Evans, D. A.;
Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351.
(5) For an approach that circumvented this problem by using acrylimides,
see: Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P. Org.
Lett. 2005, 7, 2349.
(6) (a) Viton, F.; Bernardinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc.
2002, 124, 4968. (b) Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org.
Lett. 2002, 4, 2457. (c) Ohtsuki, N.; Kezuka, S.; Kogami, Y.; Mita, T.;
Ashizawa, T.; Ikeno, T.; Yamada, T. Synthesis 2003, 1462. (d) Kezuka, S.;
Ohtsuki, N.; Mita, T.; Kogami, Y.; Ashizawa, T.; Ikeno, T.; Yamada, T.
Bull. Chem. Soc. Jpn. 2003, 76, 2197. (e) Shirahase, M.; Kanemasa, S.;
Oderaotoshi, Y. Org. Lett. 2004, 6, 675. (f) Carmona, D.; Lamata, M. P.;
Viguri, F.; Rodr´ıguez, R.; Oro, L. A.; Balana, A. I.; Lahoz, F. J.; Tejero,
T.; Merino, P.; Franco, S.; Montesa, I. J. Am. Chem. Soc. 2004, 126, 2716.
(g) Carmona, D.; Lamata, M. P.; Viguri, F.; Rodr´ıguez, R.; Oro, L. A.;
Lahoz, F. J.; Balana, A. I.; Tejero, T.; Merino, P. J. Am. Chem. Soc. 2005,
127, 13386. (h) Carmona, D.; Lamata, M. P.; Viguri, F.; Ferrer, J.; Garc´ıa,
N.; Lahoz, F. J.; Mart´ın, M. L.; Oro, L. A. Eur. J. Inorg. Chem. 2006,
3155. (i) Carmona, D.; Lamata, M. P.; Viguri, F.; Rodr´ıguez, R.; Fischer,
T.; Lahoz, F. J.; Dobrinovitch, I. T.; Oro, L. A. AdV. Synth. Catal. 2007,
349, 1751.
1
2
3
4
5
PhCH2
Ph2CH
Ph2CH
1-NpCH2
(2-tolyl)2CH
(S,S)-1a
(S,S)-1a
(S,S)-1b
(S,S)-1b
(S,S)-1b
10
58
80
24
75
90
93
78
trace
a The reaction of nitrones and methacrolein (3 equiv) was performed in
the presence of 10 mol % of (S,S)-1 in CH2Cl2. b Determined by 1H NMR
spectroscopy. c Isolated yield. d Determined by HPLC analysis with use of
chiral columns after the reduction of the aldehyde moiety.
On the basis of the premise that poor reactivity of the
Lewis acid-catalyzed 1,3-dipolar cycloadditions of nitrone
is due to the unfavorable interaction of Lewis acid and
electronegative oxygen of nitrone,11 we assumed that kinetic
destabilization of a Lewis acid-nitrone complex by steric
repulsion between the N-substituent on nitrone and the ligand
of Lewis acid catalyst might be an effective approach to
increase the reactivity (Scheme 2).
With this consideration in mind, the N-benzyl group on
nitrone was replaced by a sterically more demanding
N-diphenylmethyl group, which was anticipated not to
change the electronic property of the dipole significantly.12
To our delight, the reaction proceeded smoothly and the
cycloadduct was obtained in a remarkably higher yield of
58%, maintaining the preferential formation of one regio-
(7) For a B3LYP/6-31G study, see: Barba, C.; Carmona, D.; Garc´ıa, J.
I.; Lamata, M. P.; Mayoral, J. A.; Salvatella, L.; Viguri, F. J. Org. Chem.
2006, 71, 9831.
(8) (a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 9874. (b) Karlsson, S.; Ho¨gberg, H.-E. Tetrahedron:
Asymmetry 2002, 13, 923. (c) Karlsson, S.; Ho¨gberg, H.-E. Eur. J. Org.
Chem. 2003, 2782. (d) Chow, S. S.; Nevalainen, M.; Evans, C. A.; Johannes,
C. W. Tetrahedron Lett. 2007, 48, 277. (e) Rios, R.; Ibrahem, I.; Vesely,
J.; Zhao, G.-L.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 5701.
(9) Sakakura, A.; Suzuki, K.; Ishihara, K. AdV. Synth. Catal. 2006, 348,
2457.
(10) (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 1708. (b) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto,
T.; Maruoka, K. Chem.-Eur. J. 2003, 9, 4405. (c) Kano, T.; Hashimoto,
T.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 11926. (d) Kano, T.;
Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174.
(11) For a similar strategy with achiral bulky Lewis acid, see: Kanemasa,
S.; Ueno, N.; Shirahase, M. Tetrahedron Lett. 2002, 43, 657.
(12) Tamura, O.; Kanoh, A.; Yamashita, M.; Ishibashi, H. Tetrahedron
2004, 60, 9997.
4806
Org. Lett., Vol. 9, No. 23, 2007

gated.13 1-Cyclopentenyl and 1-methyl-1-propenyl groups
could be successfully incorporated into the products with
91% ee and 88% ee, respectively (entries 8 and 9). The
modest yields observed in some cases imply the intervention
of the Lewis acid inhibition by the substrate as well as the
product inhibition, since prolongation of the reaction time
did not improve the yield.
Scheme 2. Kinetic Destabilization of Lewis Acid-Nitrone
Complex by Steric Repulsion
To strengthen the synthetic utility of 1,3-dipolar cycload-
ditions of N-diphenylmethyl nitrones, the procedure for the
effective removal of the diphenylmethyl group in the
cycloadduct was then surveyed. After several unfruitful
attempts utilizing hydrogenation conditions, we succeeded
in cleaving the C-N bond oxidatively as shown in Scheme
3.14 Thus, after the reduction of the aldehyde moiety of the
isomer; additionally, a high enantioselectivity of 90% was
observed. Further improvement could be realized by the
introduction of 6,6′-I2-BINOL into the bis-titanium Lewis
acid catalyst ((S,S)-1b) and, in this case, the cycloadduct 3
could be obtained in 80% yield with almost complete
stereoselectivity (93% ee, endo/exo ) >20/1, 3,4-endo/3,5-
endo ) >20/1). The reaction with less hindered N-(1-
naphthylmethyl) nitrone led to a poor conversion (entry 4),
and more sterically demanding N-bis(2-tolyl)methyl nitrone
was inert under the reaction condition (entry 5).
Scheme 3. Removal of the N-Diphenylmethyl Group
The generality of this reaction was then examined employ-
ing various N-diphenylmethyl nitrones as illustrated in Table
2. The reaction system was applicable to nitrones bearing
cycloadduct, the alcohol was treated with 1.1 equiv of
N-bromosuccinimide in CH2Cl2 followed by acidic hydrolysis
of thus formed hemiaminal, which gave N-unprotected
isoxazolidine 4 in 81% yield.
The relative and absolute stereochemistry of the cycload-
duct was unequivocally determined by X-ray crystallographic
analysis of the deprotected cycloadduct 4 after the complex-
ation with (+)-(S)-camphorsulfonic acid (Figure 2).15
Table 2. Asymmetric 1,3-Dipolar Cycloadditions of
Methacrolein and Various Nitronesa
a The reaction of nitrones and methacrolein (3 equiv) was performed in
the presence of 10 mol % of (S,S)-1b in CH2Cl2. b Determined by 1H NMR
spectroscopy. c Isolated yield. d Determined by HPLC analysis with use of
chiral columns after the reduction of the aldehyde moiety. e Performed with
20 mol % of (S,S)-1b.
Figure 2. X-ray structure of 4‚(+)-(S)-camphorsulfonic acid
complex. Hydrogen atoms are omitted for clarity. Thermal ellipsoids
are shown at the 50% probability level.
Further extension of this catalytic system was achieved
by employing crotonaldehyde as the dipolarophile. As in the
electronically neutral aromatic groups irrespective of the
substitution patterns or the ring size, and the cycloadducts
were obtained in high yields with an excellent level of
enantioselection (entries 2-5). Electronic properties of the
aromatic rings on nitrone slightly affected the reactivity and
these reactions provided the cycloadducts in moderate yields
with high enantioselectivities (entries 6 and 7). To further
expand the utility of our methodology, nitrones incorporating
alkenyl groups at the C-terminus of nitrone were investi-
(13) Use of C-isopropyl nitrone (R1 ) i-Pr) led to the formation of 3,5-
isomer in low yield, suggesting the dominance of the steric factor over the
electronic control.
(14) Laurent, M.; Belmans, M.; Kemps, L.; Ce´re´siat, M.; Marchand-
Brynaert, J. Synthesis 2003, 570.
(15) CCDC-655706 (4‚(+)-(S)-camphorsulfonic acid complex) 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.
Org. Lett., Vol. 9, No. 23, 2007
4807

1, Table 3), while the reaction with N-benzyl nitrone gave
the cycloadduct in 36% yield with 63% ee (entry 1 in
parentheses). As a clear superiority of (S,S)-1b was not
observed in this case, the generality was investigated with a
simpler catalyst (S,S)-1a.
Table 3. Asymmetric 1,3-Dipolar Cycloadditions of
Crotonaldehyde and Nitronesa
In summary, we have succeeded in 3,4-endo selective
asymmetric 1,3-dipolar cycloadditions of nitrones and meth-
acrolein by the use of chiral bis-titanium Lewis acids. The
clear advantage of using N-diphenylmethyl nitrones was also
demonstrated in the reaction with crotonaldehyde. This
strategy offers a new benchmark reaction for the chiral Lewis
acid catalyzed asymmetric 1,3-dipolar cycloadditions of
nitrones.
entry
R1
yield (%)c
ee (%)d
1
2
3
4
5
Ph
82 (36)e
93
83
50
83
87 (63)e
89
88
89
92
4-tolyl
4-MeOC6H4
t-Bu
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
i-Pr
a The reaction of nitrones and crotonaldehyde (1.5 equiv) was performed
in the presence of 10 mol % of (S,S)-1a in CH2Cl2. b Determined by 1H
NMR spectroscopy. c Isolated yield after the reduction of the aldehyde
moiety in situ, considering the possibility of epimerization at the C4 position.
d Determined by HPLC analysis with use of chiral columns. e Performed
with N-benzyl nitrone under otherwise identical conditions.
Supporting Information Available: Experimental de-
tails, characterization data for new compounds, and crystal
data for compound 4‚(+)-(S)-camphorsulfonic acid complex.
This material is available free of charge via the Internet at
http://pubs.acs.org.
case of the reaction with methacrolein, use of N-diphenyl-
methyl nitrone was apparently advantageous providing the
single isomer of the cycloadduct in 82% with 87% ee (entry
OL702123N
4808
Org. Lett., Vol. 9, No. 23, 2007