Enantioselective construction of spirocyclic oxindolic cyclopentanes by palladium-catalyzed trimethylenemethane-[3+2]-cycloaddition

Article abstract of DOI:10.1021/ja075335w

The palladium catalyzed [3+2] trimethylenemethane (TMM) cycloaddition is an efficient method for the construction of cyclopentanes. Herein, we report a catalytic asymmetric protocol for the synthesis of spirocyclic oxindolic cyclopentanes in excellent yie

Full text of DOI:10.1021/ja075335w

Published on Web 09/20/2007
Enantioselective Construction of Spirocyclic Oxindolic Cyclopentanes by
Palladium-Catalyzed Trimethylenemethane-[3+2]-Cycloaddition
Barry M. Trost,* Nicolai Cramer, and Steven M. Silverman
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 17, 2007; E-mail: bmtrost@stanford.edu
Scheme 1
The transition metal-catalyzed [3+2] trimethylenemethane (TMM)
cycloaddition is a powerful and versatile method for the construction
of cyclopentanes.1 Pd-TMM complexes generated from 3-acetoxy-
2-trimethylsilylmethyl-1-propene and catalytic amounts of palladium
react with electron deficient olefins to produce exo-methylenecy-
clopentanes in a highly chemo-, regio-, and diastereoselective
manner.2 The ubiquity of cyclopentane containing natural products
makes the development of an efficient asymmetric process highly
desirable. However, applications of this methodology in asymmetric
catalysis are very rare.3 Our ongoing efforts toward the synthesis
of complex oxindole alkaloids prompted us to investigate the
reactivity of 3-alkylidene-oxindoline-2-ones 1 toward Pd-TMM
complexes.4 We chose the cyano-substituted TMM-precursor 2,5
reasoning it could enhance the asymmetric induction. Furthermore,
this provides an increase in molecular complexity by the creation
of an additional stereogenic center as well as installation of a
synthetically valuable and versatile functionality.
Table 1. Selected Optimization Studiesa
The initially formed Pd-TMM complex 3a equilibrates rapidly
to the most stabilized species 3b,6 which then adds across the
activated double bond of 1 to form the exo-methylenecyclopentane
(Scheme 1). Our initial experiments with hexamethylphosphorous
triamide (HMPT) as ligand for palladium showed that the desired
cycloadduct formed in excellent yield as a cis/trans mixture (Table
1, entry 1). A screen to elucidate the influence of the oxindole
nitrogen substituent with our previously utilized ligand L1,3a
revealed that electron withdrawing groups significantly improved
the reactivity (entries 5-9). Among them, the methoxycarbonyl
group provided the optimal balance between reactivity, selectivity,
and ease of removal. In all these cases L1 gave predominantly the
cis-cyclopentane 5 (1:3 ratio for entry 9). This contrasts the reaction
with HMPT as ligand (entry 1), where a 2:1 ratio favoring the
corresponding trans product 4 was observed. Our attempts to
optimize the conditions for the formation of both diastereomers
resulted in good diastereo- and excellent enantioselectivities for
either trans-4 (95% ee and 4.3:1 dr with L3, entry 15) and cis-5
(99% ee and 1:6.2 dr with L2, entry 16).7 This remarkable
divergence of L2 and L3,8 differing only by the position of their
naphthyl-substituents on the pyrrolidine part of the ligand, might
be rationalized as depicted in Scheme 1: The bulky 1-naphthyl-
substituents of L3 preferentially orient the aromatic oxindole part
of the substrate 1 under the BINOL portion of the ligand. The
2-naphthyl-substituents of L2 are shielding an area closer to the
phosphorus center of the ligand, favoring an orientation of the
oxindole benzene ring away from the BINOL-portion of the ligand.
entry
ligand
T,
°
C
R
% yield
4 / 5
4 % ee
5 % ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
HMPT
L1
L1
L1
L1
L1
L1
L1
L1
L4
L4
L5
L6
L7
L3
L2
23 CO2Me
23
23 Me
23 PMB
23 Ts
23 Boc
23 Acetyl
23 CO2Me
99
b
2:1
H
91
60c
50
95
98
94
93
86
84
0
99
0
97
97
1:1
1:1
1:2
1:1.1
1:2.2
1:2.3
1:3
4.3:1
4.5:1
-
91
53
74
85
72
80
83
87
-
27
-
92
96
93
89
73
97
73
60
-
27
-
95
99
0
CO2Me
23 CO2Me
CO2Me
0
23 CO2Me
23 CO2Me
23 CO2Me
1.1:1
-
4.3:1
0
CO2Me
-20 CO2Me
1:6.2
a R′ ) R′′ ) Me; all reactions were performed at 0.2 M in toluene with
2.5% Pd2dba3‚CHCl3, 10% ligand, 1.5 equiv 2 and stirred for 12 h. Yields
were combined isolated yields; ee’s were determined by HPLC with a chiral
stationary phase column. b Complex mixture. c Conversion.
of the substituents of the oxindole portion had little influence on
the ee (85-96% with L3 for trans-4 and 92-99% with L2 for
cis-5).
However, the diastereoselectivity is sensitive to the benzenoid
substitution pattern, wherein L2 gave optimal dr with no substitution
(entry 1) and L3 gave optimal dr with the more highly substituted
systems (entries 2, 4, and 5). An X-ray crystal structure analysis
of 6-chloro-substituted cycloadduct 5b (entry 2) unambiguously
allowed the determination of the absolute configuration to be R at
C3. Exchanging the oxindole residue by the related benzofuranone
1f (entry 6) gave comparable results as illustrated by the parent
substrate 1a (entry 1).
We also explored the influence of an unsymmetrical substitution
pattern on both sides of the double bond, thus creating a third
stereocenter in the cycloadduct (Table 3). A smooth addition was
observed even with the sterically demanding trisubstituted olefins
With these conditions elaborated, we then turned our attention
toward the scope of the reaction as summarized in Table 2. Variation
9
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J. AM. CHEM. SOC. 2007, 129, 12396-12397
10.1021/ja075335w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Initial Scope of the Substituted TMM [3+2]
bearing a t-butyl group (1g, 1h entry 1 and 2). The observed
stereochemistry at C1 and C2 of the resulting cycloadducts 4g/4h
and 5g/5h reflects the double bond geometry of the substrate,9
supporting our proposed approach depicted in Scheme 1.10 However,
the observed ee values with L3 were only modest, compared to
the reaction with L2 which still proceeded in high selectivity (entry
1 and 2). Electron rich enol ethers (1i, entry 3) are tolerated as
well as substrates bearing an additional electron withdrawing ethyl
ester group on the double bond (1j, entry 4).11 A substrate with a
fully unsymmetrical tetrasubstituted double bond formed the
expected cyclopentane with two adjacent all carbon quaternary
stereogenic centers (1k, entry 5).12 With this highly hindered
substrate the use of the more reactive ligand L2 was mandatory to
maintain complete conversion. Interestingly, regardless of the used
ligand, the trans adduct is formed preferentially.
In summary, we have demonstrated a catalytic asymmetric
palladium-catalyzed [3+2] cycloaddition with cyano-substituted
Pd-TMM-complexes leading to spirocyclic oxindolic cyclopen-
tanes. Remarkably, L2 and L3 complement each other by providing
the opposite diastereomers of the cycloadduct. The reaction proceeds
with sterically demanding olefins under mild conditions generating
arrays of up to three stereogenic centers with excellent yields and
enantiomeric excesses. Further extension of the reaction scope and
its application in the synthesis of complex target molecules using
cycloadducts such as 4d and 4e of Table 2 are ongoing projects in
our laboratory.
Cycloadditiona
entry
substrate 1
ligand
% yield
4 / 5
4
% ee
5
% ee
1
(R ) H)
L2b
L3c
L2b
L3c
L2c
L3d
97
97
90
99
94
94
96
97
99
1:6.2 4a
4.3:1
1:2.7 4b
19:1
96 5a >99
1a
92
95
92
77
99
84
99
80
2
3
4
5
(R ) 6-Cl)
1b
99 5b
93
95 5c
85
(R ) 6-MeO)
1:2.7 4c
1c
4:1
1.3:1
14:1
(R ) 6,7-MeO) L2b
4d >99 5d
1d
L3c
L2b
96
1:2.3 4e
15:1
1:5.7 4f >99 5f >99
4.6:1 94 92
99 5e >99
L3c
99
86 76
6
L2b
L3c
99
91
a All reactions were performed at 0.2 M in toluene and stirred for 12 h;
yields were combined isolated yields; ee’s were determined by HPLC with
a chiral stationary phase column. b At -20 °C. c At 0 °C. d At 23 °C.
Acknowledgment. We thank the NSF and the NIH (Grant
GM13598) for their generous support of our programs. N.C. is a
Feodor-Lynen fellow of the Alexander von Humboldt Foundation.
We thank Dr. V. G. Young, Jr. from the University of Minnesota
for the X-ray crystal structures and Johnson Matthey for generous
gifts of palladium salts.
Table 3. Scope of the Substituted TMM [3+2] Cycloadditiona
Supporting Information Available: Experimental procedures and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49.
(2) (a) Trost, B. M. Angew. Chem., Int. Ed. 1986, 25, 1. (b) Trost, B. M.
Pure Appl. Chem. 1988, 60, 1615. (c) Chan, D. T. In Cycloaddition
Reactions in Organic Synthesis; Kobayashi, S.; Jørgensen, K. A.; Eds.;
Wiley-VCH: Weinheim, Germany, 2002; pp 57-84 and references cited
therein.
(3) (a) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schwo¨rer, U. J. Am.
Chem. Soc. 2006, 128, 13328. (b) Yamamoto, A.; Ito, Y.; Hayashi, T.
Tetrahedron Lett. 1989, 30, 375.
(4) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129,
3086.
(5) Trost, B. M.; Nanninga, T. N.; Satoh, T. J. Am. Chem. Soc. 1985, 107,
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(6) Gordon, D. J.; Fenske, R. F.; Nanninga, T. N.; Trost, B. M. J. Am. Chem.
Soc. 1981, 103, 5974.
(7) The parent unsubstituted TMM-donor gave under identical reaction
conditions a quantitative yield and 71% ee with L2.
(8) Trost, B. M.; Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc., in
press.
(9) Partial equilibration of the double bond prior to the cycloaddition occurs
when using the more nucleophilic HMPT as ligand.
(10) With this substrate class, a scrambling of the double-bond geometry
through bond rotation of an intermediate species is not observed, which
is in accordance with both a stepwise mechanism and fast ring closure
(Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1980, 102, 6359. Trost,
B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105, 2326.) or a concerted
mechanism described by Singleton (Singleton, D. A.; Schulmeier, B. E.
J. Am. Chem. Soc. 1999, 121, 9313).
a All reactions were performed at 0.2 M in toluene with 2.5%
Pd2dba3‚CHCl3, 10% ligand, 1.5 equiv 2 and stirred for 12 h; yields were
combined isolated yields; ee’s were determined by HPLC with a chiral
stationary phase column. b At -20 °C. c At 0 °C. d At 23 °C. e 4:6 and 4:7
with 6 and 7 being tentatively assigned structures.
(11) Double bond migration of preferentially one product isomer occurred.
(12) Peterson, E. A.; Overman, L. E. Proc Natl Acad Sci U.S.A. 2004, 101,
11943.
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