Stereocontrolled synthesis of spirooxindoles through lewis acid-promoted [5 + 2]-annulation of chiral silyl alcohols

Article abstract of DOI:10.1021/ol901202t

The enantioselective synthesis of stereochemically and structurally diverse spirocyclic oxindoles by [5 + 2]-annulation of chiral crotylsilanes bearing a primary alcohol is described. The annulation products were further elaborated to polycyclic oxindoles

Full text of DOI:10.1021/ol901202t

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3366-3369
Stereocontrolled Synthesis of
Spirooxindoles through Lewis
Acid-Promoted [5 + 2]-Annulation of
Chiral Silyl Alcohols
Yun Zhang and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity, 590
Commonwealth AVenue, Boston, Massachusetts 02215
panek@bu.edu
Received May 28, 2009
ABSTRACT
The enantioselective synthesis of stereochemically and structurally diverse spirocyclic oxindoles by [5 + 2]-annulation of chiral crotylsilanes
bearing a primary alcohol is described. The annulation products were further elaborated to polycyclic oxindoles by Pd(0) catalysis.
Spirooxindoles are commonly occurring heterocyclic ring
systems found in many natural products and pharmaceuti-
cals.1 A range of biologically active compounds possessing
the spiropyrrolidine framework is well documented.1a-c For
instance, coerulescine (1), the simplest spirooxindole found
in nature, displays a local anesthetic effect.2a,b Polycyclic
alkaloid pteropodine (2) has a long history for its medicinal
applications.2c,d The recent discovery of small-molecule
MDM2 inhibitor MI-219 (3) and its analogues has led to
their advanced preclinical development as cancer
therapeutics1d,e (Figure 1). Although azaspirooxindoles have
been extensively studied, the corresponding oxaspirocyclic
(1) Recent reviews: (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 8748. (b) Williams, R. M.; Cox, R. J. Acc. Chem. Res.
2003, 36, 127. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. Recent pharmaceuticals: (d) Shangary, S.; Wang, S. Annu. ReV.
Pharmacol. Toxicol. 2009, 49, 223. (e) 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.
(2) (a) Colegate, S. M.; Anderton, N.; Edgar, J.; Bourke, C. A.; Oram,
R. N. Aust. Vet. J. 1999, 77, 537. (b) Kornet, M. J.; Thio, A. P. J. Med.
Chem. 1976, 19, 892. (c) Abdel-Fattah, M. A.-F.; Matsumoto, K.; Tabata,
K.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. J. Pharm.
Pharmacol. 2000, 52, 1553. (d) Kang, T.-H.; Murakami, Y.; Matsumoto,
K.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J. Pharmacol.
2002, 455, 27.
10.1021/ol901202t CCC: $40.75
Published on Web 07/14/2009
 2009 American Chemical Society

Table 1. Optimization of the Annulation of (S)-5 with 6a
entrya solvent T (°C)
time
yieldb c (%) drd cis/trans
,
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
23
0
12 h
37
70
67
74
1:15
15:1
1:2
10 min
24 h
0
0
10 min
10:1
a All reactions performed at 0.1 M with 1.0 equiv of TMSOTf. b Isolated
yields after purification over silica gel. c Inseparable mixture of diastereomers.
d Product ratios were determined by HPLC and 1H NMR analysis of the crude
material.
Figure 1. Biologically active spirocyclic oxindoles.
oxindoles remain underdeveloped.3 Recent approaches to
oxaspirooxindoles include Lewis acid promoted annulation,4a
oxidative cycloaddition,4b RCM,4c photocycloaddition,4d
base-catalyzed condensation,4e and dipolar cycloaddition.4f
However, very few examples demonstrate enantioselective
preparation of these compounds. Herein, we describe an
efficient protocol for accessing functionalized oxaspiroox-
indoles with high diastereo- and enantioselectivity by mild
Lewis acid promoted [5 + 2]-annulation of chiral silyl
alcohols.5
After 10 min at 0 °C, the cis-isomer could be isolated in 70%
yield (dr ) 15:1). It was also observed that prolonged reaction
time or increased polarity of solvents correlated with increased
amounts of trans-7a (Table 1, entry 3 and 4).
The presence of trans-7a as a function of time suggested
that the cis-product may be epimerizing to the trans-isomer,
possibly through a spiro-ring-opening mechanism involving
intermediates I and II (Scheme 2). In support of this hypothesis,
As part of our ongoing investigations aimed at expanding
the scope of organosilane reactivity, the [4 + 2]-annulations of
crotylsilane 4 and its many structural and stereochemical
counterparts have been previously documented.6 In that regard,
we envisioned ring-expanded oxepene templates could be
constructed via analogous [5 + 2]-annulations6d of silyl alcohol
(S)-5 (Scheme 1). Preliminary screening of electrophilic annu-
Scheme 2. Epimerization of cis-7a to trans-7a
Scheme 1. Annulations of Chiral Crotylsilanes
polar solvents such as THF, CH3NO2, and CH3CN were found
to yield preferentially trans-7a after 12 h at 0 °C as compared
to the lower efficiency in CH2Cl2 (see the Supporting Informa-
tion). In fact, when reactions were performed in dry CH3CN at
low temperatures, indolenium ion I7 was sufficiently stable and
upon aqueous quenching gave rise to isolatable amounts of diol
8 (Table 1, inset). Fortunately, exposure to silica gel during
purification does not influence the diastereomer ratio. Micro-
lation partners identified N-methylisatin dimethyl ketal 6a (Table
1) as a potential substrate for this ring-forming process.4a The
stereoselective formation of a quaternary, spirocyclic center was
especially intriguing, and our efforts turned toward optimizing
this transformation. It was eventually found that when treated
with TMSOTf, silyl alcohol (S)-5 cyclized with 6a to afford
oxepenyl spirooxindole 7a in 37% yield as a 15:1 mixture of
trans- and cis-isomers (Table 1, entry 1).
(3) Recent pharmaceutial applications of oxaspirocylic oxindoles: Cha-
feev, M.; Chowdhury, S.; Fraser, R.; Fu, J.; Kamboj, R.; Hou, D.; Liu, S.
; Seid Bagherzadeh, M.; Sviridov, S.; Sun, S. ; Sun, J. ; Chakka, N.; Hsieh,
T.; Raina, V. Use of spiro-oxindole compounds as therapeutic agents. WO
2008060789, May 22, 2008.
Further experiments revealed that cis-7a could be preferen-
tially prepared under appropriate conditions (Table 1, entry 2).
Org. Lett., Vol. 11, No. 15, 2009
3367

wave irradiation of cis-7a in the presence of BF3·OEt2 provided
the most efficient means of interconverting the stereoisomers
(Scheme 2).
Table 2. [5 + 2]-Annulations of Isatin Derivatives*
The structure and stereochemistry of cis- and trans-7a were
established by X-ray crystallography (Figure 2). Analysis reveals
yielda
time
drb
entry isatin R1 R2 R3 R4 time A (cis/trans)b
B
cis/trans
1
2
3
4
5
6a
H
H
H
H
Me 10 min 70 (15:1) 30 min
1:15
6b Br H
Me 30 min 62 (>20:1)
6c
6d
6e
H
H
H
H
Br Me 30 min 65 (14:1) 30 min
1:13
1:15
1:7
OMe H Me 5 min
71 (15:1) 30 min
H
H H
10 min 76 (>20:1) 12 hc
* Conditions A: 1.0 equiv of (S)-5, 1.0 equiv of TMSOTf, 0.1 M in CH2Cl2,
0° C. Conditions B: 1.0 equiv of BF3·OEt2, 0.1 M in CH3CN, microwave, 300
W, 40 °C. a Isolated yields after purification over silica gel. b Diastereomeric
ratios were determined by 1H NMR analysis. c Conventional heating at 60 °C.
Figure 2. X-ray structures of trans-7a and cis-7a.
analyses of the spirooxindole products indicated complete
chirality transfer from the starting silyl alcohol (see the
Supporting Information). For all cases evaluated, both cis and
trans diastereomers were readily obtained in useful yields and
with exellent diastereoselectivities. 4-Bromoisatin 6b proved
an exception affording only the kinetic product cis-7b (Table
2, entry 2).10 Thermal-promoted epimerization failed perhaps
as the result of the sterically bulky bromine, destabilizing
transition state V en route to the trans-isomer. Isatin dimethyl
ketal 6e also provided both kinetic and thermodynamic products;
however, even prolonged reaction times afforded a 7:1 mixture
of trans- and cis-7e (Table 2, entry 5).
the interatomic distance between the carbonyl oxygen and Ha
in cis-7a (2.388 Å) increases to 2.627 Å (O to Hb) in trans-7a.
Orienting the isatin carbonyl away from the oxepene ring lowers
ground-state energy of the trans-isomer by approximately 3.96
kcal/mol relative to the cis-product.8 This supports our observa-
tion that the cis-spirocycle is the kinetic product.
A plausible mechanistic rationale for the observed stereo-
chemical outcome of the initial annulation reaction is illustrated
in Scheme 3. Formation of the (Z)-oxonium intermediate is
In order to prepare more complex spirooxindoles, we prepared
silyl alcohols 9a-d using an established protocol.11 Because of
the increased steric congestion the original annulation conditions
described above were unable to afford useful amounts of desired
Scheme 3. Proposed Transition State
(4) (a) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem.
Soc. 2007, 129, 1020. (b) Savitha, G.; Niveditha, S. K.; Muralidharan, D.;
Perumal, P. T Tetrahedron Lett. 2007, 48, 2943. (c) Alcaide, B.; Almendros,
P.; Rodrguez-Acebes, R. J. Org. Chem. 2006, 71, 2346. (d) Wang, L; Zhang,
Y; Hu, H-Y; Fun, H; Xu, Jian-H. J. Org. Chem. 2005, 70, 3850. (e) Smet,
M.; Oosterwijck, C. V.; Hecke, K. V.; Meervelt, L. V.; Vandendriessche,
A.; Dehaen, W. Synlett. 2004, 2388. (f) Muthusamy, S.; Gunanathan, C.;
Nethaji, M. J. Org. Chem. 2004, 69, 5631.
(5) (a) Suginome, M.; Iwanami, T.; Yamamoto, A.; Ito, Y. Synlett 2001,
1042. (b) Suginome, M.; Iwanami, T.; Ito, Y. J. Am. Chem. Soc. 2001,
123, 4356. (c) Suginome, M.; Ohmura, T.; Miyake, Y.; Mitani, S.; Ito, Y.;
Murakami, M. J. Am. Chem. Soc. 2003, 125, 11174. (d) Ohmura, T.;
Suginome, M. Org. Lett. 2006, 8, 2503.
(6) (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 1529. (b) Su, Q.;
Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425. (c) Huang, H.; Panek,
J. S. Org. Lett. 2003, 5, 1991. (d) Huang, H.; Panek, J. S. J. Am. Chem.
Soc. 2000, 122, 9836. (e) Huang, H.; Spande, T. F.; Panek, J. S. J. Am.
Chem. Soc. 2003, 125, 626.
favored to avoid peri-like interaction associated with the
corresponding (E)-oxonium intermediate. Designating the aryl
ring as the larger steric contributor9 orients the carbonyl
pseudoaxial. Thus, transition state IV is preferred and leads to
the formation of cis-7a as the major diastereomer under kinetic
conditions.
(7) England, D. B; Merey, G.; Padwa, A. Heterocycles 2007, 74, 491.
(8) The calculated ground-state energy diffence is based on the RHF/
3-21G (*) model of crystal structures cis-7a and trans-7a.
(9) Overman, L. E.; Watson, D. A. J. Org. Chem. 2006, 71, 2587.
(10) The absolute configuration of annulation products was confirmed
by X-ray structure analysis of 6b; see the Supporting Information.
(11) Panek, J. S.; Beresis, R.; Xu, F.; Y.; Yang, M. J. Org. Chem. 1991,
56, 7341.
At this juncture, we sought to expand this methodology to
include additional isatin derivatives 6b-e (Table 2). HPLC
(12) The absolute configuration of the spirocyclic carbon of products
10a-h was confirmed by X-ray crystal structure analysis of 12.
3368
Org. Lett., Vol. 11, No. 15, 2009

product. Reoptimization led to the use of 1.0 equiv of BF3·OEt2 in
refluxing CH2Cl2 to provide the desired products as single
diastereomers (Table 3).12 Unlike annulations with (S)-5, no
olefin carbon. Subsequent elimination involved the only available
syn-ꢀ-hydride (Hc) to form compound 11. The methyl bearing
stereocenter was reintroduced through catalytic hydrogenation, and
the stereochemistry of product 12 was determined by X-ray crystal
analysis.
Cyclization of spirocycle cis-7b was also achieved with excellent
regio- and stereocontrol (Scheme 5). Initially, cis-7b was treated
Table 3. Accessing More Complex Spirooxindoles
Scheme 5. Formation of Tetracyclic Oxindole
time
R2 (h) product (%) cis:trans
yieldb
drc
entrya silane
R1
1
2
3
4
5
6
7
8
9a
9a
9b
9b
9c
9c
9d
9d
Me
Me
Me
Me
o-Br-Bn
o-Br-Bn
Me
H
Me
H
Me
H
2
1
2
1
3
3
5
5
10a
10b
10c
10d
10e
10f
50
47
45
45
60
58
42
36
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
propargyl Me
propargyl
10g
10h
H
a All reactions performed at 0.1 M with 1.0 equiv BF3·OEt2 in refluxing CH2Cl2.
b Isolated yields after purification over silica gel. c Diastereomeric ratios were
determined by 1H NMR analysis.
under similar conditions as 10c, but the unexpected olefin isomer
14 was observed as the only product. However, by adding 1.0 equiv
of silver(I) nitrate,13 olefin isomerization was suppressed and
compound 13 was isolated in 70% yield as a single diastereomer.
The [4.2.1]-bicyclic structures of 13 and 14 were determined by
1D and 2D NMR experiments.14
In summary, we have developed a convenient approach for
directly accessing spirooxindoles with excellent stereocontrol from
enantiomerically enriched crotylsilanes. The complexity of the
spirooxindoles can be enhanced by employing different combina-
tions of functionalized silyl alcohols or substituted isatin reaction
partners. Products were further converted into fused polycyclic ring
systems utilizing intramolecular Heck cyclization, thereby dem-
onstrating skeletal variation. The [5 + 2]-annulation strategy nicely
expands the scope of the Prins cyclization in the construction of
highly functionalized spirocyclic oxindoles.15 Application of this
methodology toward library synthesis and subsequent biological
evaluation of its members are underway.
products from spiro-ring-opening and reclosure pathways were
observed with these cases.
Additional skeletal complexity was achieved by diversification
of the annulation products through intramolecular Heck cyclization.
The cyclization of 10c under standard conditions (cat. Pd(OAc)2,
Et3N, 120 °C) was highly regio- and stereoselective, affording the
pentacyclic oxindole 11 in 86% isolated yield as a single diaste-
reomer (Scheme 4). Proton, COSY, and NOE NMR experiments
Scheme 4. Formation of Pentacyclic Oxindole
Acknowledgment. Financial support from the NIGMS CMLD
initiative (GM-067041) is gratefully acknowledged. We thank
Professors John A. Porco Jr., Aaron B. Beeler, and Dr. Paola
Castaldi (Boston University) for helpful discussions. We are
endebted to Dr. Emil Lobkovsky (Cornell University) for X-ray
crystal data.
Supporting Information Available: Complete experimental
procedures and compound characterization data including X-ray
crystal structures for cis-7a, trans-7a, 7b, and 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901202T
(13) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
4130.
(14) See the Supporting Information.
(15) Castaldi, P. M.; Troast, D. M.; Porco, J. A., Jr. Org. Lett. 2009,
11, (DOI 10.1021/ol901201k).
indicated syn-insertion of the arylpalladium occurred at the proximal
Org. Lett., Vol. 11, No. 15, 2009
3369