A [3 +2] Dipolar cycloaddition route to 3-hydroxy-3-alkyl oxindoles: An approach to pyrrolidinoindoline alkaloids

Article abstract of DOI:10.1021/ol200547m

A [3+2] cycloaddition approach to the 3-hydroxy-3-alkyl oxindole scaffold is described. Isoxazolines obtained by cycloaddition of nitrile oxide 3 with 3-methylene oxindoles were elaborated to 3-hydroxy-3-cyanomethyl oxindoles employing a one-pot protocol

Full text of DOI:10.1021/ol200547m

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2118–2121
A [3 þ 2] Dipolar Cycloaddition
Route to 3-Hydroxy-3-alkyl
Oxindoles: An Approach to
Pyrrolidinoindoline Alkaloids
Anand Singh and Gregory P. Roth*
Sanford-Burnham Medical Research Institute at Lake Nona, Conrad Prebys Center for
Chemical Genomics, 6400 Sanger Road, Orlando, Florida 32827, United States
groth@sanfordburnham.org
Received February 28, 2011
ABSTRACT
A [3 þ 2] cycloaddition approach to the 3-hydroxy-3-alkyl oxindole scaffold is described. Isoxazolines obtained by cycloaddition of nitrile oxide 3
with 3-methylene oxindoles were elaborated to 3-hydroxy-3-cyanomethyl oxindoles employing a one-pot protocol en route to the
pyrrolidinoindoline moiety which is found in many natural products. The total syntheses of alkaloids (()-alline and (()-CPC-1 were achieved
using this methodology.
Oxindole-based molecules are ubiquitous in the realm of
natural products and pharmaceuticals. A significant subset
of these compounds contains the spirooxindole1 and the
3-hydroxy-3-alkyl-oxindole moieties. Such motifs represent
the substructures of many natural products which have
garnered interest owing to their wide spectrum of biological
activities including antioxidant, anticancer, and neuroprotec-
tive properties (Figure 1).2 Additionally, a remarkable array
of bioactive scaffolds can be generated from these molecules,
(1) (a) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Wang, S. J. Med. Chem. 2006, 49, 3432. (b) Williams, R. M.; Cox, R. J.
Acc. Chem. Res. 2003, 36, 127. (c) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (d) Shangary, S.; Wang, S. Annu. Rev.
Pharmacol. Toxicol. 2009, 49, 223.
(2) (a) Kamano, Y.; Zhang, H. P.; Ichihara, Y.; Kizu, H.; Komiya-
ma, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783. (b) Zhang, H. P.;
Kamano, Y.; Ichihara, Y.; Kizu, H.; Komiyama, K.; ltokawa, H.; Pettit,
G. R. Tetrahedron 1995, 51, 5523. (c) Komakine, N.; Takaishi, Y.;
Honda, G.; Ito, M.; Takeda, Y.; Kodzhimatov, O. K.; Ahurmetov, O.
Natural Medicines 2005, 59, 45. (d) Khuzhaev, V. U.; Zhalolov, I.;
Turguniv, K. K.; Tashkhodzhaev, B.; Levkovich, M. G.; Arpova, S. F.;
Shashkov, A. S. Chem. Nat. Compd. 2004, 40, 269. (e) Rasmussen, H. B.;
MacLeod, J. K. J. Nat. Prod. 1997, 60, 1152. (f) Kagata, T.; Saito, S.;
Shigemori, H.; Ohsaki, A.; Ishiyama, H.; Kubota, T.; Kobayashi, J.
J. Nat. Prod. 2006, 69, 1517. (g) Tang, Y. Q.; Sattler, I.; Thiericke, R.;
Grabley, S.; Feng, X. Z. Eur. J. Org. Chem. 2001, 261. (h) Anthoni, U.;
Christophersen, C.; Nielsen, P. H. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, 1999; Vol. 13, p
163. (i) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H.
(3) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
(4) (a) Garden, S. J.; Tortes, J. C.; Ferreira, A. A.; Silva, R. B.; Pinto,
A. C. Tetrahedron Lett. 1997, 38, 1501. (b) Nakamura, T.; Shirokawa,
S. I.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8, 677.
(c) Luppi, G.; Monari, M.; Correa, R. J.; Violante, F. A.; Pinto, A. C.;
Kaptein, B.; Broxterman, Q. B.; Garden, S. J.; Tomasini, C. Tetrahedron
2006, 62, 12017. (d) Chen, J. R.; Liu, X. P.; Zhu, X. Y.; Li, L.; Qiao,
Y. F.; Zhang, J. M.; Xiao, W. J. Tetrahedron 2007, 63, 10437. (e) Davis,
F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919. (f) Ishimaru, T.; Shibata, N.;
Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc.
2006, 128, 16488. (g) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10,
1593. (h) Miah, S.; Moody, C. J.; Richards, I. C.; Slawin, A. M. Z.
ꢀ
J. Chem. Soc., Perkin Trans. 1 1997, 2405. (i) Suarez-Castillo, O. R.;
ꢀ
ꢀ
ꢀ
Sanchez-Zavala, M.; Melendez-Rodrıguez, M.; Castelan-Duarte, L. E.;
ꢀ
Tetrahedron Lett. 2006, 47, 3199. (i) Carle, J. S.; Christophersen, C.
Morales-Rıos, M. S.; Joseph-Nathan, P. Tetrahedron 2006, 62, 3040. (j)
ꢀ
ꢀ
ꢀ
J. Org. Chem. 1981, 46, 3440. (j) Koguchi, Y.; Kohno, J.; Nishio, M.;
Takahashi, K.; Okuda, T.; Ohnuki, T.; Komatsubara, S. J. Antibiot.
2000, 53, 105. (k) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.;
Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem.
2000, 65, 990. (l) Kobayashi, J.; Suzuki, H.; Shimbo, K.; Takeya, K.;
Morita, H. J. Org. Chem. 2001, 66, 6626.
Suarez-Castillo, O. R.; Sanchez-Zavala, M.; Melendez-Rodrıguez, M.;
Aquino-Torres, E.; Morales-Rıos, M. S.; Joseph-Nathan, P. Hetrocycles
2007, 71, 1539. (k) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2002, 41, 512. (l) Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11949. (m) Ueda, T.; Inada, M.; Okamoto, I.; Morita,
N.; Tamura, O. Org. Lett. 2008, 10, 2043.
r
10.1021/ol200547m
Published on Web 03/22/2011
2011 American Chemical Society

and consequently, they have been the subject of numerous
drug discovery programs in addition to being employed as
valuable synthetic intermediates.3 Although aza-spirooxin-
doles have inspired many studies, the structural diversity and
approaches toward oxygen containing spirooxindoles remain
limited. Synthetic efforts toward the 3-hydroxy-3-alkyl-2-
oxindole scaffold focus on arylation and allylation of isatin4
en route to the constituent natural products and medicinally
relevant compounds. Efficient access to synthetic alternatives
that can provide additional functional diversity would repre-
sent an advance over the aforementioned methods. We report
a [3 þ 2] dipolar cycloaddition reaction between 3-methylene
oxindoles and nitrile oxides as a unified approach toward
novel spirocyclic isoxazolines and 3-alkyl-3-hydroxy oxi-
ndole derivatives. The versatility of these intermediates was
demonstrated by their elaboration to the tricyclic pyrrolidi-
noindoline natural products (()-alline and (()-CPC-1 in
order to explore their bioactivity.
Treatment of 3-methylene oxindole with the in situ
generated nitrile oxide 3 demonstrated that the desired
product could be isolated as a single regioisomer, albeit in
low yield. Investigation into the nature of the base indi-
cated that the reaction provided the best results when the
dipole species was generated with a basic resin (Amberlyst
A21) and introduced directly into the reaction as a solution
in dichloromethane (Table 1).8 Due to the propensity of
the dipole to dimerize, it was necessary to employ an excess
(3 equiv) to achieve good yields. The addition of copper
salts decreased the yield presumably by causing the decom-
position of the oxindole. The cycloaddition reaction was
highly regioselective (>20:1), affording the desired pro-
duct in good yield. The regiochemistry of carbonꢀcarbon
bond formation was unambiguously proved through sin-
gle crystal X-ray diffraction of a derivative obtained via
hydrogenolysis (Figure 2).
Table 1. Optimization of the [3 þ 2] Cycloaddition Reaction
entrya
dipole eqiv
base
TBAF
timeb (h)
yieldc (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
2
2
3
5
5
0
10
15
13
28
49
66
80
Et3N
DIPEA
5
Pyridine
5
Amberlyst A21
Amberlyst A21
Amberlyst A21
Amberlyst A21
5
Figure 1. Examples of natural products containing (or derived
from) 3-alkyl-3-hydroxy oxindoles.
5
15
15
a For entries 3ꢀ6, a solution of the dipole precursor was added to the
reaction through a syringe filled with the basic resin. b Reaction time
after the addition of the dipole. c Isolated yields. The other regioisomer
was not detected by 1H NMR.
3-Methylene oxindoles are valuable building blocks;
however their use has been sporadic in the literature,
presumably due to their relative instability.5,6 We envi-
sioned that another substantially reactive species, such as
the nitrile oxides, would be ideal reaction partners, and we
could achieve fruitful reactivity between them. Our objec-
tive was to harness their reactivity in a productive manner
and couple it with the chemistry of isoxazolines in order
to furnish functionalized, versatile intermediates with
brevity.7
Table 2 illustrates the scope of the cycloaddition reac-
tion. A variety of substituted3-methylene oxindoles under-
went smooth cycloaddition to afford spiroadducts in good
yields. Substitutions at the 5, 6, or 7 positions did not
impact the reactivityand/or regioselectivity. Both electron-
rich and -deficient oxindoles were well tolerated. In the
case of the 7-iodo derivative, the lower yield is at least in
part due to the instability of the dipolarophile. While the
applicability of the unsubstituted N-H oxindoles is a
positive outcome, we confirmed that the corresponding
(5) (a) Rossiter, S. Tetrahedron Lett. 2002, 43, 4671–4673. (b) Loreto,
M. A.; Migliorini, A.; Tardella, P. A.; Gambacorta, A. Eur. J. Org.
Chem. 2007, 2365–2371.
(6) Risitano, F.; Grassi, G.; Foti, F.; Bruno, G.; Rotondo, A.
Heterocycles 2003, 60, 857.
(7) (a) El-Gendy, A. A.; Ahmedy, A. M. Arch. Pharm. Res. 2000, 23,
310. (b) Ankhiwala, M. D. J. Ind. Chem. Soc. 1990, 67, 432. (c) Said,
M, M. J. Saudi Chem. Soc. 2008, 12, 367.
(8) Itoh, K.; Jasperse, C. P.; Sibi, M. P. J. Am. Chem. Soc. 2004, 126,
5366.
Org. Lett., Vol. 13, No. 8, 2011
2119

N-methyl dipolarophile also underwent the cycloaddition
in a facile manner.
the reduction of the isoxazoline 4 to the corresponding
isoxazolidine 5, which then undergoes ring-opening to yield
the enolate-nitrone 6.9 Subsequent protonation and enoliza-
tion provided the observed product. A reaction performed in
CD3OD as solvent resulted in deuterium incorporation at the
benzylic position thereby providing support to our proposed
mechanism.
Table 2. Reaction Scope: Electronically Distinct Dipolarophiles
in the Cycloaddition Reaction
entry
R1
R2
yielda (%)
regioselectivityb
1
H
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
Me
80
79
76
82
84
79
77
66
50
83
81
81
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2
5-CI
5-OMe
5-Me
5-F
3
4
5
6
5-OCF3
6-Br
7-Br
7-I
7
g
h
i
8
9
10
11
12
7-Ph
7-CI
H
j
k
1
a Isolated yields after column chromatography. b Regioisomer ratios
were measured using 1H NMR. All reactions performed at 0.2 M. See
Supporting Information for details.
We initially envisioned elaborating the isoxazolines to two
scaffolds, namely β-hydroxynitriles (available by decarbox-
ylation/elimination) and the corresponding amino alcohols
(via reduction). While several reduction protocols have been
developed for the reduction of unfunctionalized isoxazolines,
the chemoselectivity of the oxindole and ester moieties limited
our options. Treatment of isoxazoline 4a with NaBH4 and
Zn/HCl failed to reduce the imine and NꢀO bonds. We
discovered that hydrogenation using Pd/C resulted in an
unprecedented ring-opening yielding the corresponding ami-
no acid oxime 7 in excellent yield (Figure 2). The identity of
the product was unambiguously confirmed by X-ray diffrac-
tion. Given the weak nature of NꢀO bonds, this outcome
was surprising, although the benzylic nature of the CꢀO
bond being broken (in addition to the formation of amide-
enolate 6) provides a plausible explanation of the sequence of
events taking place. We believe that this reaction proceeds via
Figure 2. Mechanistic rationale for the formation of 7.
The synthetic utility of these novel isoxazolines was de-
monstrated by their conversion to β-hydroxynitrile deriva-
tives by employing a microwave assisted, one-pot sequence
of hydrolysis/decarboxylation (Table 3). The ring-opening
Table 3. One-Pot Conversion of Isoxazolines to Hydroxynitriles
(9) (a) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024. (b) Galos,
J. K.; Koumbis, A. E.; Xiraphaki, V. P.; Dellios, C. C.; Argyropoulou,
E. C. Tetrahedron 1999, 55, 15167. (c) Gallienne, E.; Geffaut, T.; Bolte,
J.; Lemaire, M. J. Org. Chem. 2006, 71, 894. (d) Lemaire, M.; Veny, N.;
Geffaut, T.; Gallienne, E.; Chenevert, R.; Bolte, J. Synlett 2002, 8, 1359.
(e) Schwab, W.; Jager, V. Angew. Chem., Int. Ed. Engl. 1981, 6, 603. (f)
Jager, V.; Bub, V.; Schwab, W. Liebigs Ann. Chem. 1980, 122. (g)
Koroleva, E. V.; Katok, Y. M.; Chernikhova, T. V.; Lakhvich, F. A.
Chem. Heterocycl. Cmpd. 1999, 35, 225. Nitta, M.; Iino, Y. Bull. Chem.
Soc. Jpn. 1986, 59, 2365. (h) Annunziata, R.; Cinquini, M.; Cozzi, F.;
Gilardi, A.; Restelli, A. J. Chem. Soc., Perkin Trans. 1 1985, 2289. (i)
Wade, P. A.; Bereznak, J. F. J. Org. Chem. 1987, 52, 2973. (j) Schreiner,
E. P.; Gstach, H. Synlett 1996, 1131. (k) Churykau, D. H.; Zinovich,
V. G.; Kulinkovich, O. G. Synlett 2004, 11, 1949.
entry
R1
R2
yielda (%)
1
2
3
4
5
6
7
H
H
a
c
e
f
95
86
90
88
82
81
83
5-OMe
5-F
H
H
5-OCF3
6-Br
7-CI
H
H
H
g
k
9
H
Me
a Isolated yields.
2120
Org. Lett., Vol. 13, No. 8, 2011

proceeded smoothly leading to the 3-hydroxy-3-cyanomethyl
oxindole derivatives in good yield. During our optimization
studies, we discovered that potassium acetate was uniquely
effective in this transformation and the use of other bases
such as sodium hydroxide resulted in complex mixtures.
The nitrile functionality provides an opportunity to
access either the oxidized tryptamine derivatives or the
pyrrolidinoindoline scaffold by modulating the reduction
conditions. We discovered that the treatment of nitrile 8a
with LiAlH4 did not provide the desired tricyclic compound
although the starting material was consumed. Attributing
this failure to the excess negative charge on the deprotonated
N-H, we next evaluated this reduction with the N-methyl
and N,O-dimethyl derivatives. While the N-methyl deriva-
tive 9 provided the desired product 12 in good yield, the N,
O-dimethyl derivative 10 suffered extensive decomposition
under the reaction conditions. Successful reduction of the
nitrile functionality to the amine was accomplished by a
nickel chloride/sodium borohydride (NiCl2/NaBH4) system
which promotes the reduction under mild conditions while
concomitantly protecting the resulting amine as the Boc-
derivative (Scheme 1).
Scheme 2. Synthesis of (()-Alline
(93%) which was then converted to the Boc-protected
amine using NiCl2/NaBH4. Our strategy was to employ
the Boc group as a latent methyl moiety. Treatment of the
amine 14 with Red-Al in toluene resulted in the formation of
the N-methyl derivative 18 in situ which then cyclized with
the oxindole functionality to afford the desired alkaloid (()-
CPC-1 (Scheme 3).
Scheme 1. Controlled Reduction of Hydroxynitriles to 1,3-
Aminoalcohols
Scheme 3. Synthesis of (()-CPC-1
In summary, we have described the efficient synthesis of
novel oxa-spirooxindoles resulting from the [3 þ 2] dipolar
cycloaddition of 3-methylene oxindoles with nitrile oxide 3.
The NꢀO bond in the resulting isoxazoline adducts
was found to be remarkably stable to homolytic cleavage
and exhibited a unique mode of ring-opening. The cyclo-
adducts were converted to the corresponding 3-hydroxy-
3-cyanomethyl oxindoles which were successfully elabo-
rated to the pyrrolidinoindoline alkaloids (()-alline and
(()-CPC-1.
Using the cyclization/annulation of the hydroxynitrile
8a as the key step, we targeted the concise syntheses of
alkaloids (()-alline and (()-CPC-1. The synthesis of alline
started with the chemoselective benzyl protection of the
cyanoalcohol 8a to afford the N-benzyl derivative in 92%
yield. LiAlH4 promoted reductive cyclization cleanly
afforded the fused tricyclic intermediate 15 in excellent
yield. Subsequent reductive monomethylation using
HCHO/NaCNBH3 furnished alcohol 16 (Scheme 2). The
debenzylation of the aryl amine proved nontrivial as
hydrogenolysis attempts employing palladium catalysts
failed to provide the desired product under a variety of
conditions. We discovered that the use of sodium naphtha-
lenide smoothly effected the debenzylation at room tem-
perature leading to (()-alline.
Acknowledgment. We thank SBMRI for financial sup-
port, Dr. Maren Pink (Indiana University) for determining
the crystal structure of 7, and Dr. Christopher Petucci
(SBMRI) forassistancewith obtaining accuratemassdata.
Supporting Information Available. Complete experi-
mental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The synthesis of (()-CPC-1 commenced with the bis-
methylation of 8a to provide the N,O-dimethyl derivative 10
Org. Lett., Vol. 13, No. 8, 2011
2121