Catalytic enantioselective stereoablative alkylation of 3-halooxindoles: Facile access to oxindoles with c3 all-carbon quaternary stereocenters

Article abstract of DOI:10.1002/anie.200902943

From 2 to 1! Racemic tertiary halooxindoles proceed to enantioenriched oxindoles bearing all-carbon quaternary stereocenters as a result of a catalytic enantioselective stereoablative process (see scheme). The application of this procedure allows for the

Full text of DOI:10.1002/anie.200902943

Angewandte
Chemie
DOI: 10.1002/anie.200902943
Asymmetric Catalysis
Catalytic Enantioselective Stereoablative Alkylation of
3-Halooxindoles: Facile Access to Oxindoles with C3 All-Carbon
Quaternary Stereocenters**
Sandy Ma, Xiaoqing Han, Shyam Krishnan, Scott C. Virgil, and Brian M. Stoltz*
The construction of all-carbon quaternary stereocenters
remains one of the most challenging problems in asymmetric
catalysis and has been an area of great interest in our
laboratories.[1,2] Over the past several years, significant effort
from many research groups has been directed toward the
enantioselective synthesis of 3,3-disubstituted oxindoles and
derivatives thereof, given the prevalence of this structural
motif in biologically active molecules and their interesting
molecular architectures (Figure 1).[3–5] Although a number of
catalytic enantioselective approaches to this motif have been
developed (Heck reaction,[6] cyanoamidation,[7] cycloaddi-
tions,[8] arylation,[9] alkylation,[10,11] acyl migration,[12] Claisen
rearrangement,[13] aldol,[14] Mannich,[15] and conjugate addi-
tion reactions[15b]), we pursued an alternative tactic.[16–18] In all
of the reported systems that rely on stereoselective function-
alization of an existing oxindole,[9–15] this unit serves as a
nucleophile. In contrast, we present herein an unusual
strategy for the enantioselective synthesis of substituted
oxindoles with C3 quaternary stereocenters that employs
the oxindole moiety as the electrophilic partner for the facile
and rapid coupling to malonate nucleophiles.
Despite an early report from Hinman and Bauman in
1964,[19] the use of 3-halooxindoles as electrophiles in
substitution chemistry has been limited. Although the addi-
[*] S. Ma, Dr. X. Han, Dr. S. Krishnan, Dr. S. C. Virgil, Prof. B. M. Stoltz
Division of Chemistry and Chemical Engineering and the
Figure 1. Naturally occurring 3,3-disubstituted oxindoles and indolines
Caltech Center for Catalysis and Chemical Synthesis
bearing all-carbon quaternary stereocenters.
California Institute of Technology
1200 E. California Boulevard, MC 164-30,
Pasadena, CA 91125 (USA)
and
Department of Molecular Medicine
Beckman Research Institute at City of Hope
Duarte, CA 91001 (USA)
Fax: (+1)626-564-9297
tion of carbon-based p- and heteroatom-nucleophiles to the
C3 position of oxindoles has been reported, no enantioselec-
tive methods exist.[20] We recently reported the base-pro-
moted addition of malonate esters to 3-halooxindoles by the
in situ formation of a putative o-azaxylylene (Scheme 1a).[21]
In light of these results and our general interest in stereoab-
lative reactions,[22] we sought to develop a catalytic enantio-
selective system (Scheme 1b).[23] We hypothesized that a
Lewis acid could facilitate the base-mediated reaction by
E-mail: stoltz@caltech.edu
[**] We wish to thank the California TRDRP (postdoctoral fellowships to
X.H. and S.K.), Abbott Laboratories, Amgen, Merck, Bristol-Myers
Squibb, Boehringer Ingelheim, the Gordon and Betty Moore
Foundation, and Caltech for financial support. Lawrence Henling
and Dr. Michael Day are gratefully acknowledged for X-ray
crystallographic structure determination. Prof. David Horne is
thanked for helpful discussions. The Bruker KAPPA APEXII X-ray
diffractometer was purchased through an NSF CRIF:MU award to
the California Institute of Technology, CHE-0639094. Dr. David
VanderVelde and Dr. Scott Ross are acknowledged for NMR
assistance.
ꢀ
lowering the pKa of the N H proton of the halooxindole and/
ꢀ
or the Ca H proton of the malonate. Through either pathway,
complexation by a chiral Lewis acid could potentially lead to
asymmetric induction.
We reasoned that the key to implementing a catalytic
enantioselective system would be to identify a base that did
not promote competitive background reactions in the absence
of catalyst. In our initial experiments, we found that exposure
of racemic bromooxindole (ꢁ )-1 to N,N-diisopropylethyl-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902943.
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Table 1: Reaction development.
Entry
X
Ligand
Yield[b] [%]
ee[c] [%]
1
2
3
4
OTf
OTf
OTf
OTf
OTf
3
4
63
45
24
37
49
65
65
61
72
77
6
ꢀ42
ꢀ64
13
81
79
76
84
ent-5
6
7
3
3
3
3
5
6[a]
7
PF6
[d]
[d]
NTf2
8[a]
9
BF4
SbF6
[d]
[d]
[a] Performed at ꢀ78!238C. [b] Yield of isolated product. [c] Deter-
mined by chiral-phase HPLC. [d] The catalyst was generated by in situ
metathesis of [Cu(3)Cl2] with the corresponding AgX salt.[24]
ꢀ
nate (SbF6 ) complex, malonate adduct 2 was produced in
72% yield and 84% ee in less than 10 min (Table 1, entry 9).
Ultimately, we found that employing the preformed [Cu(3)]
(SbF6)2 complex at low temperature (i.e., ꢀ408C) in the
presence of 3 ꢀ molecular sieves[28] produced oxindole 2 in
77% yield and 88% ee (Table 2, entry 1).
Scheme 1. a) Base-mediated addition of malonates to halooxindoles
via a reactive o-azaxylylene intermediate.[21] b) Proposed Lewis acid
catalyzed enantioselective alkylation of 3-halooxindoles. Only the
malonate activated pathway is shown. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene.
On examining the scope of the transformation, we found
that malonate esters could be alkylated with various 3-alkyl
and 3-aryl halooxindoles in good yields and high enantiose-
lectivities (Tables 2 and 3).[29] Methyl, ethyl, and benzyl
malonates each added to bromide (ꢁ )-1, via the putative o-
azaxylylene, with similar levels of selectivity and yield
(Table 2, entries 1–3). Silyl ethers (entries 1–5), benzoate
esters (entry 6), and phthalimides (entries 8–10) were all
tolerated as substituents on the C3 alkyl chain. Additionally,
substituted alkyl chains of various lengths led to alkylation
products in high enantioselectivities (entries 1 and 5). Finally,
substitution of the bromooxindole core at C5 with a methoxy
group produced the malonate addition product in 51% yield
and 91% ee (entry 10).
amine (iPr2NEt) and dimethyl malonate in the absence of a
Lewis acid did not result in formation of adduct 2.[24]
Encouraged by this finding, we then surveyed a variety of
chiral Lewis acids (e.g., CuII, MgII, LaIII, and NiII complexes)
that could potentially promote the asymmetric alkylation.
The combination of copper(II) triflate and (S)-Ph-box (3)
In addition to the reactions of bromooxindoles, dimethyl
malonate reacted smoothly with racemic 3-aryl chlorooxin-
doles to produce the C3-malonate adducts in good yields and
enantioselectivities (Table 3). In these reactions, Et3N proved
to be a better base than iPr2NEt in both yield and
enantioselectivity. Products with phenyl (entry 1), bromo-
phenyl (entry 2), 3,5-dimethylphenyl (entry 3), and naphthyl
substitution at C3 (entry 4) were stereoselectively formed
with this method. Additionally, methoxy substitution on the
oxindole framework at C5 was well tolerated (entry 5).
We proceeded to apply the new method for enantiose-
lective generation of C3-quaternary oxindoles to the synthesis
of natural product scaffolds. To construct the pyrrolidinyl-
spirooxindole core prevalent in a large family of biologically
active alkaloids,[3] we began with malonate adduct 8 (Table 2,
entry 10), which could be recrystallized to 99% ee
(Scheme 2). Oxindole malonate 8 was converted to phthali-
gave the most promising result, producing 2 in 63% yield and
77% ee (Table 1, entry 1).[25,26] Related bis(oxazoline) ligands
4–7 resulted in diminished yields and enantioselectivity
(Table 1, entries 2–5). Given the strong electronic effects
observed in related Lewis acid catalyzed processes, we
investigated the effect of less coordinating counterions.[27]
Although imparting only a moderate influence on chemical
yield, a more pronounced counterion effect was observed for
enantioselectivity. For example, with the hexafluoroantimo-
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Table 2: Alkyl-substituted oxindoles as substrates in the enantioselective
malonate alkylation.
Table 3: Aryl-substituted oxindoles as substrates in the enantioselective
malonate alkylation.
Yield[a] [%]
ee[b] [%]
ꢀ76[c]
Entry
Racemic substrate
R2 T [8C] Yield[a] [%] ee[b] [%]
Entry
1
Substrate
T [8C]
ꢀ20
1
2
3
Me ꢀ40
Et ꢀ40
Bn ꢀ40
77
73
78
88
84
88
76
4
5
Me ꢀ40
Me ꢀ20
78
47
88
86
2
3
0
84
69
81
84
ꢀ40
6
7
Me ꢀ20
Me ꢀ40
51
44
83
84
4
5
0
74
76
74
84
8
Me ꢀ20
63
94
ꢀ20
[a] Yield of isolated product. [b] Determined by chiral-phase HPLC.
[c] (R,R)-3 was employed as ligand.
9
Me ꢀ20
42
51
81
91
In addition to spirocyclic motifs, fused pyrrolidinoindo-
lines are also a key moiety found in many natural products. To
access this family, quaternary C3-aryl oxindole malonate
adduct 12 was subjected to Krapcho decarboxylation[30] and
N-alkylation to give methyl ester 13 (Scheme 3). Finally, ester
13 was converted to methyl amide 14 and reduced with
LiAlH4, providing lactam 15 with the pyrrolidinoindoline
core.
10
Me ꢀ20
[a] Yield of isolated product. [b] Determined by chiral-phase HPLC.
midoester 9 by Krapcho decarboxylation.[30] Cleavage of
phthalimide 9 with hydrazine resulted in rapid formation of
spirocyclic bis(lactam) 10. Double alkylation of oxindole 10
produced bis(p-bromobenzyl)lactam 11, a crystalline com-
pound amenable to single crystal X-ray analysis and deter-
mination of absolute configuration.[31]
In summary, we have discovered a unique copper-
catalyzed enantioselective synthesis of C3-quaternary oxin-
doles. This stereoablative transformation most likely involves
the in situ formation of a highly reactive o-azaxylylene from
C3-halooxindoles followed by enantioselective malonate
addition. Finally, we have demonstrated that our method is
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Scheme 3. The synthesis of a fused indolinopyrrolidinone.
useful for the rapid and stereoselective construction of the
core structures of important biologically active alkaloids.
Mechanistic studies and further synthetic applications of our
method are underway.
Received: June 1, 2009
Published online: September 18, 2009
Keywords: alkylation · asymmetric catalysis · copper ·
.
enantioselectivity · umpolung
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[29] Consistent with our proposal of an o-azaxylylene intermediate,
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[31] The absolute configuration depicted for all products in Tables 2
and 3 is derived by analogy from the X-ray analysis of 11.
Angew. Chem. Int. Ed. 2009, 48, 8037 –8041
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8041