Lewis acid catalyzed asymmetric cycloadditions of nitrones: α′-hydroxy enones as efficient reaction partners

Article abstract of DOI:10.1002/anie.200502308

(Chemical Equation Presented) A fine pair: Excellent levels of regio-, endo/ exo-, diastereo-, and/or enantioselectivity are attained in the Cu-catalyzed cycloaddition of nitrones with α′-hydroxy enones (see scheme). The resulting adducts can be further e

Full text of DOI:10.1002/anie.200502308

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Enantioselective Synthesis
cycloadditions, not only are bidentate alkene substrates
required but also metal–substrate coordination needs to be
notably efficient for optimum selectivity.[7] We report herein
that excellent combined levels of regio-, endo/exo-, and
enantioselectivity may be achieved by using a’-hydroxy
enones as new partners for this reaction.
Recent observations from these laboratories in the con-
text of Diels–Alder and conjugate addition reactions have
shown the role of a’-hydroxy enones in metal-assisted
activation, which likely occurs through formation of 1,4-
metal-chelated species as the reactive intermediates.[8] It was
argued that such a complexation pattern might be effective in
nitrone cycloadditions and hence increase the pool of
available templates for this reaction. To evaluate this
assumption, initial screening reactions were carried out with
the chiral a’-hydroxy enone 1[9] and nitrone 3a in the presence
of several metal triflates (Scheme 1 and Table 1). Data
DOI: 10.1002/anie.200502308
Lewis Acid Catalyzed Asymmetric Cycloadditions
of Nitrones: a’-Hydroxy Enones as Efficient
Reaction Partners**
Claudio Palomo,* Mikel Oiarbide, Elena Arceo,
Jesffls M. García, Rosa López, Alberto Gonzµlez, and
Anthony Linden
Dedicated to Professor J. Plumet
on the occasion of his 60th birthday
The 1,3-dipolar cycloaddition of nitrones to alkenes[1] is an
atom-economic method for the construction of isoxazolidines,
which are important precursors of, for example, alkaloids,
amino acids, b-lactams, and amino sugars.[2] Typically, an
electron-deficient alkene is involved, with the interaction
between the LUMO of the alkene and the HOMO of the
nitrone being the determinant for the relative orientation of
the reactants. However, steric factors often counterbalance
the electronic preferences, particularly in b-unsubstituted
enoyl (acryloyl) systems, and make regiocontrol challeng-
ing.[3,4] Additionally, both endo/exo and p-facial selectivity
have to be addressed. Although amine activation of enals[5]
has emerged as an attractive approach, most methods rely on
the use of Lewis acids to activate the enoyl system toward the
nitrone counterpart.[3,4,6] However, despite the many applica-
tions, success in asymmetric nitrone cycloadditions remains
very scarce compared to that reached in the parent Diels–
Alder cycloaddition and only a limited number of alkene
templates such as N-enoyl derivatives of oxazolidino-
ne,[4a–c,6c–6g] thiazolidinethione,[6a] pyrrolidinone,[6b] and pyra-
zolidinone,[6h] as well as certain alkylidene malonates[6i] have
been employed to fulfill this gap. In metal-catalyzed nitrone
Scheme 1. Regio- and stereocontrolled 1,3-dipolar cycloadditions of
nitrones to a’-hydroxy enones 1 and 2. OTf=trifluoromethylsulfonyl.
Table 1: Screening of the catalyst for the reaction of enone 1 with nitrone
3a (R1 =Bn; Ar=Ph) to give 4a.[a]
Lewis acid
t [h]
Conversion [%]
Regioisomer ratio[b]
Mg(OTf)2
Zn(OTf)2
Cu(OTf)2
La(OTf)3
Yb(OTf)3
72
48
4
15
48
68[c]
81[c]
>99
50
12:88[d]
89:11[e]
ꢀ98:2[e]
98:2[e]
[*] Prof. Dr. C. Palomo, Prof. Dr. M. Oiarbide, Dr. R. López
Departamento de Química Orgµnica I
Facultad de Química
92[c]
85:15[e]
[a] Reactions conducted at room temperature in dry CH2Cl2, with 1:1:0.1
molar ratio of enone 1/3a/Lewis acid. [b] Determined by 1H NMR
spectroscopy. [c] By-products from nitrone and enone decomposition
were detected. [d] Minor isomer corresponds to 4a; configuration of the
major isomer not established. [e] Configuration of the minor isomer not
established.
Universidad del País Vasco
Apdo. 1072, 20080 San Sebastiµn (Spain)
Fax: ( +34)943-015-270
E-mail: qoppanic@sc.ehu.es
E. Arceo, Dr. J. M. García, Prof. Dr. A. Gonzµlez
Departamento de Química Aplicada
Universidad Pfflblica de Navarra (UPNA)
Campus de Arrosadía, 31006 Pamplona (Spain)
revealed that Cu(OTf)2 gave the best results and isoxazolidine
4a could indeed be obtained in high yield and, most notably,
with essentially perfect regio- and diastereoselectivity.
Gratifyingly, the chemical efficiency and the high degree
of regio- and stereocontrol for this Cu(OTf)2-mediated
reaction was found to be quite general over the range of
nitrones 3a–k examined (Table 2). Nitrones bearing electron-
rich, electron-neutral, or electron-poor aryl substituents were
tolerated with almost equal efficiency to give isoxazolidines
4a–k in good yields and with diastereomeric ratios ranging
Dr. A. Linden
Organisch-Chemisches Institut
Universität Zürich
Winterthurerstrasse 190, 8057 Zürich (Switzerland)
[**] This work was financially supported by the University of the Basque
Country and the Ministerio de Educación y Ciencia (MEC, Spain). A
Ramón y Cajal contract to R.L. from the MEC, and a grant to E.A.
from the UPNA are acknowledged. Crystal structure analyses were
performed by A.L.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Asymmetric 1,3-dipolar cycloadditions of enones 1 and 2 with nitrones 3.[a]
(tBOX/Cu) was most successful in
providing the nitrone cycloadducts
8/9 with very high stereoselectivity
and with regioisomeric ratios equal
to or greater than 90:10. To the best
of our knowledge, this represents
the highest combined regio- and
enantioselectivity observed for b-
unsubstituted enoyl substrates.[4,13]
As an apparent limitation, however,
the reaction of 6 with nitrone 3m
provided low endo/exo selectivity,
although excellent regio- and enan-
tiocontrol were still attained.
Nitrone 3
R
Product
t [h]
Yield [%][b]
d.r.[c]
Ar
R1
3a
Ph
PhCH2
PhCH2
PhCH2
PhCH2
H
CH3
H
H
CH3
H
H
CH3
H
H
H
4a
5a
4b
4c
5c
4d
4e
5e
4 f
4g
4h
4i
4
22[d]
24
30[e]
50[d]
8
88
84
68
70
70
83
89
71
91
90
76
89
70
84
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
94:6[f]
3b
3c
4-MeO-C6H4
4-Me-C6H4
3d
3e
3-Me-4-Me-C6H3
4-Cl-C6H4
PhCH2
PhCH2
9[e]
48[d]
0.5
2
3 f
3g
3h
3i
3j
3k
3-Cl-C6H4
3-Cl-4-MeO-C6H3
4-CN-C6H4
3-NO2-4-Me-C6H3
Ph
PhCH2
PhCH2
PhCH2
PhCH2
Ph2CH
2-MeO-PhCH2
28
2
8
H
H
H
ꢀ98:2
90:10[f]
ꢀ98:2
4j
4k
As differently b-substituted,
simple hydroxy enones are readily
Ph
10
[a] Reactions conducted on 0.5-mmol scale in dry CH2Cl2, with 1:1:0.1 molar ratio of enone/nitrone/ available,[8] the method constitutes
catalyst. [b] Yield of isolated product after column chromatography. [c] Determined by 13C NMR
a straightforward route to 3,4,5-
trisubstituted isoxazolidines of
high diastereo- and enantiopurity.
spectroscopy. [d] In the presence of 4-Š molecular sieves and a 1:2:0.2 molar ratio of enone/nitrone/
catalyst. [e] Using 5 mol% of Cu(OTf)2. [f] Configuration of the minor isomer not determined.
For instance, enone 10 reacted with
from 90:10 to greater than 98:2. The reactions were typically
carried out in dichloromethane as solvent using 10 mol%
catalyst, although a loading of 5 mol% catalyst led to similar
results (products 4c and 4e). b-Substituted
enones also behaved well in terms of both
chemical and stereochemical efficiency,
although longer reaction times were required.[10]
For example, the reaction of enone 2 with
nitrones 3a, 3c, and 3e provided cycloadducts
5a, 5c, and 5e in good yields and with remark-
able diastereoselectivity.
nitrones 3m and 3n to give the respective isoxazolidines 11
and 12 with diastereomeric ratios of about 98:2 and enantio-
selectivities higher than 99% (Scheme 2).
The scope of the model is further demon-
strated in the catalytic, enantioselective 1,3-
Scheme 2. Enantioselective approach for b-substituted hydroxy enone substrates.
dipolar cycloaddition of nitrones to simple a’-
hydroxy enone 6[8] (Table 3). A preliminary survey of
The assigned configuration of adducts 4, 8, 5, and 9 was
established by single-crystal X-ray analyses[14] of adducts 4a,
5a, 8m, and 9a (the configurations of the remaining adducts
were assigned by analogy). Addi-
combinations of privileged ligands and metal salts[11,12]
showed that the Evans bis(oxazoline)–CuII complex
7
tionally, the absolute configuration
Table 3: Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones and a’-hydroxy enone 6.[a]
of 8a was deduced from comparison
of the optical rotation values of
elaborated adducts (see below) and
by assuming a uniform reaction
mechanism.
The potential utility of the
method is illustrated in Scheme 3.
For example, treatment of adducts
4a, 4c, and 4e with periodic acid
afforded the corresponding carbox-
ylic acids 13 in high yields and
essentially enantiopure form. Like-
wise, after addition of methyl lith-
ium to 4a and subsequent cleavage
of the diol with lead tetraacetate,
enantiopure acetylisoxazolidine 14
was obtained in 84% yield. Simi-
larly, reduction of 4a and further
scission led to isoxazolidine carbal-
3
Ar
R1
Yield
[%]
Ratio
Product 8
endo/exo[c]
8:9[b]
ee [%][d]
3a
3b
3c
3d
3e
3 f
Ph
PhCH2
PhCH2
PhCH2
PhCH2
CH3
85
99
81
94
55
98
93:7
92:8
92:8
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
76:24
94
92
92
90
96
4-MeO-C6H4
4-Me-C6H4
3-Me-4-Me-C6H3
Ph
ꢀ98:2
90:10
Ph
Ph
ꢀ98:2[e]
ꢀ99
[a] Reactions conducted at 0.5-mmol scale in CH2Cl2 with a 2:1 molar ratio of 6/3. [b] Determined by
13C NMR spectroscopy; absolute configuration of 9 not determined. [c] Determined by 1H NMR
spectroscopy. [d] Determined by HPLC. [e] Reaction conducted at À408C.
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acetate and hexane (1:1), followed by concentration of the
collected solution and subsequent purification by column chro-
matography (silica gel, 1:15 ethyl acetate/hexane), afforded the
corresponding cycloadduct.
Received: July 1, 2005
Published online: September 1, 2005
Keywords: asymmetric catalysis · cycloaddition ·
.
hydroxy enones · Lewis acids · synthetic methods
[1] For reviews, see: a) K. V. Gothelf, K. A. Jørgensen, Chem.
Rev. 1998, 98, 863 – 909; b) K. V. Gothelf, K. A. Jørgensen,
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2002, 1371 – 1387; d) K. V. Gothelf in Cycloaddition Reac-
tions in Organic Synthesis (Eds.: S. Kobayashi, K. A.
Jørgensen), Wiley-VCH, Weinheim, 2002, pp. 211 – 247;
e) K. V. Gothelf, K. A. Jørgensen in Synthetic Applications
of 1,3-Dipolar Cycloaddition, Chemistry toward Hetero-
cycles and Natural Products, (Eds.: A. Padwa, W. H.
Pearson), Wiley, Hoboken, NJ, 2003, pp. 817 – 900.
[2] a) J. N. Martin, R. C. F. Jones in Synthetic Applications of
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Högberg, Org. Prep. Proc. Int. 2001, 33, 103 – 172.
À
Scheme 3. Chemical elaboration of cycloadducts with detachment of the auxiliary Xc
OH. Bn=benzyl; Boc=tert-butoxycarbonyl.
dehyde 15. In all the above examples, the starting (1R)-(+)-
camphor was recovered after scission, ready for reuse. On the
other hand, the oxidative elaboration of adduct 8a gave ent-
13a along with acetone as the only by-product, whereas
hydrogenolytic opening of 8a with concomitant N-protection
(Boc) and further cleavage of the ketol afforded homoserine
derivative 16 in two high-yielding steps. Of practical interest,
both enantiomers of each isoxazolidine product are readily
accessible by appropriate choice of the corresponding
approach.
In conclusion, a’-hydroxy enones considerably expand the
range of metal-catalyzed 1,3-dipolar cycloadditions of nitro-
nes. Conditions have been set that produce the cycloadducts
with very high combined levels of regio- and stereoselectivity.
The potential of the method has been demonstrated using
camphor-derived a’-hydroxy enone 1 in combination with
catalytic Cu(OTf)2, or achiral enones 6 and 10 in combination
with the Evans bis(oxazoline)–CuII catalyst, and by the easy
elaboration of the cycloadducts to diversely functionalized di-
and trisubstituted isoxazolidines in essentially enantiopure
form.
[3] For illustrative examples using stoichiometric chiral auxil-
iaries, see: a) T. Gefflaut, U. Bauer, K. Airola, A. M. P.
Koskinen, Tetrahedron: Asymmetry 1996, 7, 3099 – 3102; b) A.
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Merchµn, P. Merino, Tetrahedron 1997, 53, 3301 – 3318; d) P.
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J. Org. Chem. 2000, 65, 1590 – 1596; e) O. Tamura, A. Kanoh, M.
Yamashita, H. Ishibashi, Tetrahedron 2004, 60, 9997 – 10003.
[4] For illustrative examples using chiral catalysts, see: a) K. V.
Gothelf, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 1998, 63,
5483 – 5488, and references therein; b) T. Saito, T. Yamada, S.
Miyazaki, T. Otani, Tetrahedron Lett. 2004, 45, 9585 – 9587; c) G.
Desimoni, G. Faita, M. Mella, M. Boiocchi, Eur. J. Org. Chem.
2005, 1020 – 1027; d) F. Viton, G. Bernardinelli, E. P. Kündig, J.
Am. Chem. Soc. 2002, 124, 4968 – 4969; e) M. Shirahase, S.
Kanemasa, Y. Oderaotoshi, Org. Lett. 2004, 6, 675 – 678; f) D.
Carmona, M. P. Lamata, F. Viguri, R. Rodríguez, L. A. Oro, A. I.
Balana, F. J. Lahoz, T. Tejero, P. Merino, S. Franco, I. Montesa, J.
Am. Chem. Soc. 2004, 126, 2716 – 2717.
[5] a) W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan, J. Am. Chem.
Soc. 2000, 122, 9874 – 9875; b) S. Karlsson, H.-E. Högberg, Eur.
J. Org. Chem. 2003, 2782 – 2791.
[6] For complexes of NiII: a) H. Suga, T. Nakajima, K. Itoh, A.
Kakehi, Org. Lett. 2005, 7, 1431 – 1434; b) S. Iwasa, H. Maeda, K.
Nishiyama, S. Tsushima, Y. Tsukamoto, H. Nishiyama, Tetrahe-
dron 2002, 58, 8281 – 8287; c) S. Kanemasa, Y. Oderaotoshi, J.
Tanaka, E. Wada, J. Am. Chem. Soc. 1998, 120, 12355 – 12356;
for complexes of PdII: d) K. Hori, H. Kodama, T. Ohta, I.
Furukawa, J. Org. Chem. 1999, 64, 5017 – 5023; For complexes of
MgII and MnII: e) S. Iwasa, Y. Ishima, H. S. Widagdo, K. Aoki, H.
Nishiyama, Tetrahedron Lett. 2004, 45, 2121 – 2124; for com-
plexes of lanthanides: f) H. Kodama, J. Ito, K. Hori, T. Ohta, I.
Furukawa, J. Organomet. Chem. 2000, 603, 6 – 12; g) S. Kobaya-
shi, M. Kawamura, J. Am. Chem. Soc. 1998, 120, 5840 – 5841; for
complexes of CuII: h) M. P. Sibi, Z. Ma, C. P. Jasperse, J. Am.
Chem. Soc. 2004, 126, 718 – 719; for complexes of CoII: i) Z.-Z.
Huang, Y.-B. Kang, J. Zhou, M.-C Ye, Y. Tang, Org. Lett. 2004, 6,
1677 – 1679.
Experimental Section
General procedure for CuII/tBOX (7)-catalyzed 1,3-dipolar cyclo-
additions of nitrones to 6: A flame-dried flask was charged with 2-
hydroxy-2-methylpent-4-en-3-one (6; 0.114 g, 1.0 mmol) and dry
CH2Cl2 (1.5 mL) under N2. The solution was cooled to À208C, and
then freshly dried, powdered molecular sieves (4 Š; 250 mg), a
solution of the corresponding nitrone (0.5 mmol) in CH2Cl2 (1 mL),
and a solution of 7 in CH2Cl2 (0.05m, 1 mL) were added consecutively.
The resulting mixture was stirred at À208C until completion of
reaction. The reaction mixture was then diluted with 5 mL of ethyl
acetate/hexane (1:1), and the solution was directly applied to a short
column of silica gel (1.5 cm ” 1.5 cm). Elution with a mixture of ethyl
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Communications
[7] Nitrones are basic in nature and may show competitive
coordination to the metal, thus provoking inactivation of the
Lewis acid; for more information on this subject, see: S.
Kanemasa, T. Uemura, E. Wada, Tetrahedron Lett. 1992, 33,
7889 – 7892.
[8] For Diels–Alder reactions, see: a) C. Palomo, M. Oiarbide, J. M.
García, A. Gonzµlez, E. Arceo, J. Am. Chem. Soc. 2003, 125,
13942 – 13943; for conjugate additions of carbamates, see: b) C.
Palomo, M. Oiarbide, R. Halder, M. Kelso, E. Gómez-Bengoa,
J. M. García, J. Am. Chem. Soc. 2004, 126, 9188 – 9189; for
Friedel–Crafts reactions, see: c) C. Palomo, M. Oiarbide, B. G.
Kardak, J. M. García, A. Linden, J. Am. Chem. Soc. 2005, 127,
4154 – 4155.
[9] Compound 1 is readily prepared in two steps (75%) from (1R)-
(+)-camphor and methoxyallene, two commodity chemicals that
are available in bulk; see: C. Palomo, M. Oiarbide, J. M. García,
A. Gonzµlez, A. Lecumberri, A. Linden, J. Am. Chem. Soc. 2002,
124, 10288 – 10289.
[10] To avoid decomposition of the nitrone and ensure good yields
and high selectivities, the presence of 4-Š molecular sieves was
required in these instances; for the first observation and
discussion of the effect of molecular sieves in Lewis acid
catalyzed nitrone cycloadditions, see: a) K. V. Gothelf, R. G.
Hazell, K. A. Jørgensen, J. Org. Chem. 1996, 61, 346 – 355;
b) See Ref. [6g].
[11] For the concept of privileged chiral catalysts, see: T. P. Yoon,
E. N. Jacobsen, Science 2003, 299, 1691 – 1693.
[12] For other systems examined, see the Supporting Information.
[13] a) For an exception using NiII complexes, see Ref. [6b]; b) in
Ref. [4c], it is reported that the MgII-promoted reaction of
diphenyl nitrone with N-acryloyl oxazolidinone leads to a
regioselectivity of greater than 98:2, an endo/exo ratio of 97:3,
and 86% ee for the endo isomer.
[14] CCDC-280037–280040 contain the supplementary crystallo-
graphic 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.
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