C O M M U N I C A T I O N S
Scheme 3. Stereochemical Model of the Rearrangement
Table 2. Substrate Scope in the Oxindole Rearrangement (eq 1)a
entry L* 3/4
R1
R2
R3
R4
t (min) yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
6
a
b
c
d
e
f
Me
Me
Me
Bn
i-Pr
t-Bu
t-Bu
t-Bu Me
t-Bu Me
Me
H
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
105
15
50
35
40
15
15
10
30
20
20
10
20
20
20
20
30
97
75
70
74
91
85
60
82
77
89
100
100
82
73
60
82
95
45
71
35
72
H
H
H
H
H
H
H
H
H
H
H
H
H
74
89c
92
f
H
5a
5a
g
g
a
a
b
c
g
h
i
82c
82c,d
89 (91)b
88c,d
83
10 7d
11 7d
12 7d
13 7d
14 7d
15 7d
16 7d
17 7d
Me
Me
Me
Me
Me
Me
H
Et
92
58
t-Bu Me
Me
Me
Me
Me OMe
Me Br
Me
91
Acknowledgment. Financial support was provided by the NSF
(Grant CHE-0616885). The assistance of Dr. Patrick Carroll in
obtaining the crystal structure is gratefully acknowledged.
87
j
H
85
a Reaction Conditions: 0.025 M 2, 20 mol % L*Pd(SbF6)2, CH2Cl2, 0
°C. b Reaction performed on a 1 mmol scale with 95% yield. c Reaction
performed at room temperature. d Run using 5 mol % L*Pd*(SbF6)2.
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
tary providing the best selectivity with the smaller C3 methyl
ester and the larger C2′ groups (Table 2, entries 10-14). Notably,
reactions conducted on a larger scale proceeded with slightly
improved enantioselectivity (entry 10). Furthermore, high enan-
tioselection was retained with either electron donating or electron
withdrawing substitution on the aromatic ring (Table 2, entries
15-17). It was found that catalyst loadings could be lowered to
5 mol % with no loss in enantioselectivity (Table 2, entries 9,
11).
Because palladium(II) catalysts are employed here, the possibility
of π-allyl cation chemistry (i.e., 8) needed to be considered. On the
basis of the results with other Lewis acids such as copper and zinc
complexes (good to excellent enantioselectivity, but poor turnover),
our preliminary hypothesis centers on a Lewis acid-catalyzed mech-
anism.18 Further support for this pathway was found in the lack of
any deuterium scrambling with labeled substrate d-3c (Scheme 2).
References
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Asymmetry 1996, 7, 1847–1882. (b) Castro, A. M. M. Chem. ReV. 2004,
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Chem. Soc. ReV. 1999, 28, 43–50. (b) Hiersemann, M.; Abraham, L. Eur.
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(4) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229.
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(6) Gradl, S. N.; Trauner, D. The Meerwein-Eschenmoser-Claisen Rearrange-
ment. In The Claisen Rearrangement; Hiersemann, M., Nubbemeyer, U.,
Eds.; Wiley-VCH: Weinheim, 2007; pp 367-396.
(7) Booker-Milburn, K. I.; Fedouloff, M.; Paknoham, S. J.; Strachan, J. B.;
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Y.; Hirota, H.; Ohta, T.; Williams, R. M.; Tsukamoto, S. Angew. Chem.,
Int. Ed. 2007, 46, 2254–2256.
Scheme 2. Deuterium Labeling
(9) Selected biological agents: (a) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.;
Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita,
Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005,
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G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.;
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A. K.; Dreyfuss, P. D.; Schreiber, S. L J. Am. Chem. Soc. 2007, 129, 1020–
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yield chiral oxindoles containing spiro ring systems at C3: Trost, B. M.;
Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396–12397.
(14) See Supporting Information.
The absolute configuration of the products was established through
crystal structures of derivatives (see Supporting Information). Stere-
ochemical models predicated on two-point coordination of the substrate
ꢀ-amidoester moiety to a Lewis acidic palladium complex are in accord
with the stereochemical outcomes for both the PHOX (Scheme 3) and
bisphosphine catalysts. These models are also consistent with the
selectivity trends of the different substrates described above. For
example, larger ester groups destabilize TS1 thereby leading to lower
selectivity with the PHOX catalyst (Table 2, entry 10 vs 12).
Insummary,thefirstcatalytic,enantioselectiveMeerwein-Eschenmoser
Claisen rearrangement has been developed. This method constitutes a
mild entry to a range of oxindoles bearing a quaternary stereocenter.
Future studies will focus on further optimization, as well expansion
of the substrate scope.
(15) Allen, J. V.; Dawson, G. J.; Frost, C. G.; Williams, J. M. J. Tetrahedron
1994, 50, 799–808.
(16) Surprisingly, lowering the temperature to improve enantioselectivity caused
a disproportionate change in the rate (>12 h at-20 °C).
(17) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.;
Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320–325.
(18) Alternately,rearrangementviadoublebondactivationmaybepossible:Watson,
M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129,
5031–5044.
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