Thiourea-catalyzed highly enantio- and diastereoselective additions of oxindoles to nitroolefins: Application to the formal synthesis of (+)-physostigmine

Article abstract of DOI:10.1021/ja903520c

(Chemical Equation Presented) Oxindoles and their indoline derivatives are common structural motifs found in a wide array of natural and biologically active molecules. Most catalytic methods for the asymmetric syntheses of these compounds rely heavily on

Full text of DOI:10.1021/ja903520c

Published on Web 06/05/2009
Thiourea-Catalyzed Highly Enantio- and Diastereoselective Additions of
Oxindoles to Nitroolefins: Application to the Formal Synthesis of
(+)-Physostigmine
Tommy Bui, Salahuddin Syed, and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received April 30, 2009; E-mail: carlos@scripps.edu
Chart 1
Oxindoles are important building blocks found in many phar-
maceuticals and in alkaloid natural products.1 Most catalytic
methods for the synthesis of these compounds require the use of
transition metals.2-6 Alternative catalytic procedures include asym-
metric alkylation of oxindoles and the asymmetric Black rearrange-
ment reaction of indolyl carbonates; the former has limited
success.7,8 We envisioned the nucleophilic addition of oxindoles
to nitroolefins as an alternative organocatalytic method for the
synthesis of these structural motifs (Figure 1). This approach may
provide access to a wide range of spiral oxindoles or indoline
derivatives bearing a quaternary center at the C3 position.
and nitroolefin was necessary for high selectivity. For this reason,
catalyst 3e was employed in the 1,4-addition reaction.23 With this
catalyst, a significant improvement in ee was observed (entry 5).
Moreover, no external base was required for the reaction to proceed,
indicative of the bifunctional nature of 3e (entry 5 vs 6). Slight
differences in dr and ee were observed in these cases, suggesting
the structure of the base had an effect on these two parameters.
This led to the design of catalyst 3f, which proved most effective.
A subsequent solvent screen resulted in selection of conditions that
significantly increased the ee without diminishing the yield and dr
(entries 7-10). These results are consistent with previous reports
that nonpolar solvents without Lewis basic sites are generally
optimal in conjunction with these types of thiourea catalysts.23
Finally, with newly synthesized catalyst 3f, product 4a was obtained
in excellent yield, dr, and ee (entries 11 and 12 vs 10).24
Next, the scope of the 1,4-addition reaction with respect to both
the nucleophile and electrophile was investigated (Table 2). Oxindole
products bearing various substituents at C3 were obtained in good
yields with good to excellent dr and ee (entries 1-5). A slight variation
in dr was observed. Various electron-rich and -poor nitrostyrene
derivatives with different substitution patterns on the aromatic ring
were also examined (entries 6-10). High dr and ee were obtained in
Over the past several years, numerous reports on thiourea-
catalyzed asymmetric C-C bond-forming reactions have been
published.9 The carbon nucleophiles employed in these reactions
include cyanide, indole derivatives, silyl ketene acetals, enamines,
and stable enolates derived from 1,3-carbonyl compounds.10-14 In
contrast, the use of oxindoles as nucleophiles in the analogous
transformation has been limited.15-17 Herein, we report the first
examples of thiourea-catalyzed, highly enantio- and diastereose-
lective additions of oxindoles to nitroolefins and the application of
this methodology to the formal synthesis of (+)-physostigmine.
There were challenges associated with the proposed 1,4-addition
reaction. One was the creation of a chiral quaternary center at C3,
which is sterically congested, as the Michael reaction is generally
sensitive to sterics.18 Another was control of both the relative and
absolute configurations of the two newly created stereogenic centers.
It was not clear whether catalysts that imparted chirality to the
oxindole or nitroolefin alone or to both would be required in order
to achieve high asymmetric induction.
The addition of oxindole 1a to nitrostyrene 2a in the presence
of catalyst 3a (10 mol %) (Chart 1) was examined (Table 1).19,20
Gratifyingly, the desired product 4a was obtained in good yield
and good diastereomeric ratio (dr), albeit with low enantiomeric
excess (ee) (entry 1). A variant of 3a was also tested, but the results
were unsatisfactory (entry 2). It appeared that thiourea catalysts
having cinchona alkaloid scaffolds did not effectively provide good
asymmetric induction. Thus, cyclohexane-derived thiourea catalysts
3c and 3d (Chart 1) were explored.21,22 These catalysts were
expected to activate solely nitroolefins by H-bonding and were used
in combination with an external base to promote the reaction.
Unfortunately, 4a was obtained with low to moderate ee (entries 3
and 4). These results suggested that activation of both the oxindole
Table 1. Optimization Studies
entry
catalyst
solvent
yield (%)a
drb
ee (%)c
1
2
3a
3b
3c
3d
3e
THF
THF
THF
THF
THF
82
57
88
80
87
10:1
5:1
5:1
2:1
6:1
31
5
60
2
74
d
3
d
4
d
5
6
7
8
9
10
11
12
3e
3e
3e
3e
3e
3f
3f
THF
84
80
77
95
87
96
91
4:1
7:1
5:1
6:1
5:1
78
89
87
93
95
99
92
xylene
toluene
CH2Cl2
CHCl3
CHCl3
CH2Cl2
10:1
9:1
a Isolated yield. b Determined by 1H NMR analysis of the crude
reaction mixture. c Determined by chiral-phase HPLC analysis.
d Reaction run in the presence of 1 equiv of Hunig’s base.
Figure 1. Synthetic route to oxindole derivatives.
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8758 J. AM. CHEM. SOC. 2009, 131, 8758–8759
10.1021/ja903520c CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Addition of Oxindoles to Nitroolefins
References
(1) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b) Rahman,
A. U.; Basha, A. Indole Alkaloids; Harwood Academic Publishers:
Amsterdam, 1997.
(2) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477. (b) Doumay, A. B.; Hatanaka, K.; Kodanko, J. J.;
Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem.
Soc. 2003, 125, 6261.
entry
R
R1
product
yield (%)a
drb
ee (%)c
(3) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308. (b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (c)
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
(4) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(5) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921.
(6) Kozlowski, M. C.; Linton, E. C. J. Am. Chem. Soc. 2008, 130, 16162.
(7) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872.
(8) (a) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131,
14. (b) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs,
E. J. Am. Chem. Soc. 2006, 128, 925.
(9) Reviews on organocatalysts, including urea and thiourea catalysts: (a)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (b)
Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (c) Connon,
S. J. Synlett 2009, 354. (d) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc.
Jpn. 2008, 81, 785.
(10) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(11) (a) Herrea, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576. (b) See ref 21.
1
2
3
4
5
6
7
8
Me
Et
allyl
cinamyl
4-Br-Bn
allyl
allyl
allyl
allyl
allyl
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
96
95
89
90
86
92
91
91
92
72
97
95
68
10:1
5:1
6:1
11:1
5:1
6:1
9:1
5:1
7:1
3:1
99
96
94
92
88
91
95
90
92
89
99
94
93
4-Br-C6H4
3-Br-C6H4
4-MeO-C6H4
4-OH-C6H4
3,4-Cl2-C6H3
2-furyl
9
10
11
12
13
4j
4k
4l
allyl
allyl
allyl
6:1
>20:1
>20:1
n-C7H15
(MeO)2CH
4m
a Isolated yield. b Determined by 1H NMR analysis of the crude
reaction mixture. c Determined by chiral-phase HPLC analysis.
Scheme 1
(12) (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
(b) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919.
(13) (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. (b) Tsogoeva,
S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.; Huthmacher, K.
Eur. J. Org. Chem. 2005, 4995. (c) Huang, H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2006, 128, 7170.
(14) (a) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185.
(b) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y. Tetrahedron
2006, 62, 365. (c) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006,
128, 6048.
(15) Aldol and Mannich reactions using oxindoles as nucleophiles: (a) Ogawa,
S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2007, 46, 8666. (b) Tian, X.; Jiang, K.; Peng, J.; Du, W.;
Chen, Y.-C. Org. Lett. 2008, 10, 3583.
(16) There is a single report on the use of oxindoles as nucleophiles in 1,4-
additions to R,ꢀ-unsaturated aldehydes with moderate ee: Galzerano, P.;
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem. Eur. J. [Online early access]. DOI:
10.1002/chem.200802466. Published Online: Jan 29, 2009.
(17) Related catalytic oxygenation and fluorination of oxindoles: (a) Ishimaru,
T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanesmasa, S. J. Am.
Chem. Soc. 2006, 128, 16488. (b) Ishimaru, T.; Shibata, N.; Horikawa, T.;
Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed.
2008, 47, 4157.
(18) Reviews of asymmetric conjugate additions to nitroolefins: (a) Berner,
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877. (b) Almasi,
D.; Alonso, A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(19) Pioneering work on the development of cinchona-derived thiourea catalysts: (a)
Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
(b) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
(20) The cinchona alkaloid catalysts hydroquinine, hydroquinidine, and (DHQD)2-
PHAL gave 0, 10, and 28% ee, respectively. These results imply that a chiral
tertiary amine alone is not sufficient for attaining high asymmetric induction.
(21) Catalyst 3c: Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558.
(22) The pyrrole nitrogen was not basic enough to affect this transformation.
(23) Thiourea-catalyzed additions of 1,3-carbonyl compounds to nitroolefins: (a)
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
(b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
most of these cases. Heteroaromatic nitroolefins were also viable
substrates (entry 11). More interestingly, the addition reaction of
aliphatic nitroolefins proceeded smoothly to afford products 4l and
4m in moderate to good yields with high dr and ee (entries 12-13).
Both relative and absolute configurations at the two newly created
centers were established by X-ray dispersion analysis of a sulfonamide
derived from product 4a.25 The configuration of the stereogenic center
at C3 was R and that at the remaining stereocenter was S. These data
indicated that compound 4n might be further elaborated to give (+)-
esermethole, which is a known intermediate in the synthesis of (+)-
physostigmine.26
To illustrate the synthetic utility of this methodology and further
confirm the absolute stereochemistry of this reaction, we undertook
the formal synthesis of (+)-physostigmine. The addition of oxindole
2f to nitroethylene in the presence of catalyst 3e (10 mol %)
afforded product 4n with 83% ee (Scheme 1).27-29 A single
recrystallization provided 4n with 96% ee. Raney nickel reduction
of this compound followed by methyl carbamate formation provided
the key intermediate 5n, which underwent reductive cyclization to
afford (+)-esermethole in 72% overall yield over three steps.30
In summary, we have demonstrated a novel organocatalytic
approach to the synthesis of pyrrolidinoindolines using 1,4-addition
of oxindole derivatives to nitroolefins as a key step. The addition
reaction was general with respect to oxindoles and nitroolefins and
provided the desired products bearing a chiral quaternary center at
C3 in good yield with good to excellent dr and ee. These features
make this method synthetically viable and attractive, as illustrated
in the formal synthesis of (+)-physostigmine. Further investigations
of the scope and synthetic utility of this chemistry are underway,
and the results will be reported in due course.
(24) Methylene chloride was an effective solvent for 3f-mediated catalysis, but
both the dr and ee were slightly lower than when chloroform was used as
solvent (entry 12 vs 11).
(25) See the Supporting Information.
(26) Selected previous syntheses of (-)-physostigmines: (a) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. (b)
Asakawa, K.; Noguchi, N; Takashima, S.; Nakada, M. Tetrahedron:
Asymmetry 2008, 19, 2304. (c) See refs 3b and 7.
(27) Use of nitroethylene as an acceptor in amine-catalyzed asymmetric Michael
reactions of aldehydes: Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am.
Chem. Soc. 2008, 130, 5608.
(28) With 3f, the reaction stalled, perhaps because of catalyst poisoning or the
polymerization of nitroethylene. 3e provided similar ee’s when the reaction
was performed between-15 and-20 °C; the former gave a slightly better yield.
THF was used instead of chloroform because of the solubility characteristics
of 2f.
Acknowledgment. This research was supported by The Skaggs
Institute for Chemical Biology.
(29) With the N-methyl protecting group, there was no reaction. We believe the
Boc protecting group enhanced the acidity of the methine proton, thereby
allowing the enolization of 2f to be more facile.
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, and a transition state
proposal. This material is available free of charge via the Internet at
http://pubs.acs.org.
(30) The absolute configuration of (+)-esermethole was determined by comparing
the optical rotation of the synthesized material with the literature value.
JA903520C
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J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8759