γ-methylidene-δ-valerolactones as a coupling partner for cycloaddition: Palladium-catalyzed [4 + 3] cycloaddition with nitrones

Article abstract of DOI:10.1021/ja073997f

A new type of reagent, γ-methylidene-δ-valerolactones, has been devised, which acts as a four-carbon unit in a palladium-catalyzed cycloaddition reaction through the formation of a 1,4-zwitterionic species. The utility has been demonstrated in the context of stereoselective [4 + 3] cycloaddition with nitrones to provide highly functionalized 1,2-oxazepines, including the asymmetric variant with high enantioselectivity. Copyright

Full text of DOI:10.1021/ja073997f

Published on Web 09/26/2007
γ-Methylidene-δ-valerolactones as a Coupling Partner for Cycloaddition:
Palladium-Catalyzed [4 + 3] Cycloaddition with Nitrones
Ryo Shintani,* Masataka Murakami, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received June 2, 2007; E-mail: shintani@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Intermolecular cycloadditions catalyzed by transition-metal
complexes are useful methods for convergent synthesis of cyclic
materials.1 The development of a new and efficient intermolecular
cycloaddition reaction is, therefore, of high value in organic
chemistry. In this context, Trost described the use of palladium-
trimethylenemethane (TMM) complexes as a 1,3-dipole-like three-
carbon unit in the formation of a cyclic framework almost 30 years
ago (Figure 1a).2 Since then, this method has been applied to the
construction of a variety of cyclic compounds,3 and some asym-
metric variants have also been reported.4 In this Communication,
Figure 1. (a) Trost’s Pd-TMM complexes for [3 + n] cycloadditions. (b)
γ-Methylidene-δ-valerolactones for [4 + n] cycloadditions.
we introduce a new type of reagent, γ-methylidene-δ-valerolactones,
which serves as a four-carbon unit in the palladium-catalyzed
Table 1. Palladium-Catalyzed [4 + 3] Cycloaddition of
γ-Methylidene-δ-valerolactones 1 with Nitrones 2
cycloaddition through the formation of a 1,4-zwitterionic species
(Figure 1b),5 and demonstrate its utility in the [4 + 3] cycloaddition
with nitrones to provide highly functionalized 1,2-oxazepines,6
including the asymmetric variant with high enantioselectivity.
In an initial investigation, we prepared γ-methylidene-δ-vale-
rolactone 1a as a model reagent for our study in two steps from
known compounds, as shown in eq 1, and examined its utility for
a [4 + 3] cycloaddition reaction with nitrone 2a in the presence of
5 mol % of palladium catalyst at 40 °C (Table 1). To our delight,
the reaction proceeded smoothly by the use of PPh3 as a ligand,
giving the desired 1,2-oxazepine 3aa in 95% yield as a mixture of
two diastereomers (72/28; entry 1). The use of other ligands such
as P(Oi-Pr)3 and phosphoramidite 47 also gave 3aa in high yield
(97-99% yield; entries 2 and 3),8 and high diastereoselectivity (90/
10) was achieved with ligand 4. Under these conditions with 4 as
the ligand, several other γ-methylidene-δ-valerolactones underwent
cycloadditions with 2a as well, giving the corresponding 1,2-
oxazepines in high yield with good to excellent diastereoselectivity
(87/13-94/6; entries 4-7).9 The cycloaddition also proceeded with
nitrones having a substituted aryl group at their electrophilic carbon
atoms with high diastereoselectivity (92/8-94/6; entries 8-10).
entry
1
2
ligand
product
yield (%)a
drb
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1c
1d
1e
1e
1e
1e
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
PPh3
P(Oi-Pr)3
3aa
3aa
3aa
3ba
3ca
3da
3ea
3eb
3ec
3ed
95
97
99
95
62
92
96
77
98
98
72/28
78/22
90/10
93/7
87/13
91/9
94/6
92/8
93/7
94/6
4
4
4
4
4
4
4
4
10
1
a Combined yield of two diastereomers. b Determined by H NMR.
A proposed catalytic cycle of this process is illustrated in Figure
2. Thus, oxidative addition of the allyl ester moiety of 1 to
palladium(0), followed by decarboxylation,10,11 gave 1,4-zwitterionic
species A. The anionic carbon of A then attacked the electrophilic
carbon of 2 to give intermediate B, which underwent a ring closure
through a nucleophilic attack of the oxygen atom to the π-allylpal-
ladium moiety, leading to the formation of 1,2-oxazepine 3 along
with regeneration of palladium(0).
Because the step from A to B creates two contiguous tertiary
and quaternary stereocenters, it would be desirable to conduct this
reaction in an asymmetric fashion. On the basis of the ligand effect
described in Table 1, we employed chiral phosphoramidite ligand
(S)-512 in the reaction of 1a with nitrone 2d. Under these conditions,
Figure 2. Proposed catalytic cycle for the palladium-catalyzed [4 + 3]
cycloaddition of 1 with 2.
cycloadduct 3ad was obtained in high yield (98% yield, dr ) 85/
15), and the enantioselectivity of the major diastereomer was 71%
ee (Table 2, entry 1). By changing the nitrogen substituents from
9
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J. AM. CHEM. SOC. 2007, 129, 12356-12357
10.1021/ja073997f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Palladium-Catalyzed Asymmetric [4 + 3] Cycloaddition
of 1 with 2
a four-carbon unit in a cyclic framework by forming a 1,4-
zwitterionic species, and we have demonstrated their utility in the
context of stereoselective [4 + 3] cycloaddition with nitrones,
including some preliminary results of the asymmetric variant. Future
studies will explore further application of these reagents to various
other transition-metal-catalyzed cycloaddition reactions.
Acknowledgment. Support has been provided, in part, by a
Grant-in-Aid for Scientific Research, the Ministry of Education,
Culture, Sports, Science and Technology, Japan (21 COE on Kyoto
University Alliance for Chemistry).
Supporting Information Available: Experimental procedures and
compound characterization data (PDF) and X-ray data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
entry
1
2
ligand
product
yield (%)a
drb
ee (%)c
1
2
3
1a
1a
1b
1e
1e
1e
2d
2d
2d
2d
2b
2c
(S)-5
3ad
3ad
3bd
3ed
3eb
3ec
98
98
99
98
99
89
85/15
81/19
86/14
80/20
70/30
72/28
71
83
84
96
89e
88f
(S,R,R)-6
(S,R,R)-6
(S,R,R)-6
(S,R,R)-6
(S,R,R)-6
References
4
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a Combined yield of two diastereomers. b Determined by 1H NMR. c The
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3aa in <30% yield.
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results in lower yield of 3.
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Figure 3. X-ray structure of 3ec with thermal ellipsoids drawn at the 50%
probability level (Flack parameter ) -0.01(6)).
isopropyl to (R)-1-phenylethyl (ligand (S,R,R)-6),12,13 higher enan-
tioselectivity was observed (83% ee; entry 2). Other γ-methylidene-
δ-valerolactones such as 1b and 1e also provide the cycloadducts
with nitrones 2 with high efficiency in the presence of ligand
(S,R,R)-6 (84-96% ee; entries 3-6). The absolute configuration
of 3ec (entry 6) was determined to be (3S,4R) by X-ray crystal-
lographic analysis, as shown in Figure 3.
The present catalysis using regent 1 is not limited to the couplings
with nitrones. For example, 1a underwent a cycloaddition with
azomethine imine 714,15 to give the corresponding [4 + 3]
cycloadduct (8) with dr ) 87/13, and the major diastereomer was
isolated in 79% yield (eq 2).16
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In summary, we have described the development of γ-meth-
ylidene-δ-valerolactones as a new class of reaction partners in the
palladium-catalyzed cycloaddition reaction. These reagents act as
(16) The relative configuration of 8 was determined by X-ray crystallographic
analysis (see Supporting Information for details).
JA073997F
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J. AM. CHEM. SOC. VOL. 129, NO. 41, 2007 12357