Stereoselective synthesis of spirocyclic oxindoles via prins cyclizations

Article abstract of DOI:10.1021/ol901201k

The synthesis of spirocyclic oxindole pyran and oxepene frameworks using highly stereoselective Prins cyclizations of homoallylic and bishomoallylic alcohols and isatin ketals is described.

Full text of DOI:10.1021/ol901201k

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3362-3365
Stereoselective Synthesis of Spirocyclic
Oxindoles via Prins Cyclizations
M. Paola Castaldi, Dawn M. Troast, and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment (CMLD-BU), Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu
Received May 28, 2009
ABSTRACT
The synthesis of spirocyclic oxindole pyran and oxepene frameworks using highly stereoselective Prins cyclizations of homoallylic and bis-
homoallylic alcohols and isatin ketals is described.
Exo-methylene pyrans are present in a variety of biologically
active natural products.1 We recently employed the intramo-
lecular silyl-modified Sakurai (ISMS) reaction2 to construct
the exomethylene pyran subunit of the macrocyclic core of
(-)-zampanolide (1, Figure 1a).3 We envisioned use of this
powerful methodology to access a variety of exomethylene
tetrahydropyrans (3 and 4, Figure 1b) using diverse ketals
and acetals (5 and 6, Figure 1b) for diversity-oriented
synthesis4 and chemical library development (Figure 1b). As
part of our studies, we also considered preparation of pyran
(1) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
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A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-Paloma, L.;
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Nishiwaki, M.; Nakata, T. Heterocycles 2006, 69, 487.
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Figure 1. (a) Representative exo-methylene pyran spirooxindole
Sanchez, C. C; Keck, G. E. Org. Lett. 2005, 7, 3053. (c) Aubele, D. L.;
Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485. (d) Troast,
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V.; Vuori, K.; Wipf, P. Org. Lett. 2009, 11, 65.
molecules. (b) Initial synthesis plan.
spirooxindole hybrid molecules5 (7, Figure 1b) from allyl-
silanes 8 and isatin ketals 9 in order to merge fragments of
two biologically interesting motifs. The spirooxindole core
structure is represented in numerous pharmacological agents
and alkaloids6 including the anticancer agent MI-63 (2,
Figure 1a).7 In this communication, we report how our initial
10.1021/ol901201k CCC: $40.75
Published on Web 07/14/2009
 2009 American Chemical Society

synthesis plan evolved to identify stereoselective, Lewis acid-
mediated Prins cyclizations to access both enantioenriched
spirocyclic oxindole pyrans and oxepenes.
Scheme 2. Spirooxindole Pyrans via Prins Cyclizations
In initial studies, allyl silane 12 and derived silyl ether 13
(Scheme 1) were prepared employing Cu(I)-catalyzed8
Scheme 1. Preparation of Allylsilane 13
a Isolated yield.
an endocyclic alkene14 was isolated in moderate yield. A
control experiment employing ketal 14 in the ISMS reaction
with CH2Cl2 as a solvent afforded product 16 and its
endocyclic olefin isomer (1:2 ratio).
ring-opening of chiral, nonracemic epoxide 11 with vinyl
Grignard 10.9 After optimization of ISMS reaction condi-
tions, ketals 14 and acetal 1510 were successfully employed
in the synthesis of spirocyclic exo-methylene pyran 16 and
2,6-syn-disubstituted pyran 1711 (Table 1, entries 1 and 2).
Scheme 3
.
Diastereoselective Synthesis of Spirooxindoles
Table 1. Use of Allylsilane 13 in ISMS Reactions*
a
1
Ratio of 27:28 determined by H NMR analysis of a crude sample.
Based on these observations and given that spiroannulation
did not occur at low temperature (-78 °C), we performed
the reaction at higher temperatures which afforded spiroox-
indoles 22 and 23 in good overall yield (Scheme 2, entry
1). The apparent isomerization of the double bond (endocy-
clic vs exocyclic olefin) suggested the possibility of a
mechanistic pathway which was different than the expected
ISMS reaction. Intramolecular Prins-type cyclization15 of
homoallylic silyl ether 20 derived from desilylation of 13
could account for such an outcome. To support this hypoth-
esis, homoallylic silyl ether 20 was synthesized and employed
in the reaction to afford products 22 and 23 in good overall
yield (Scheme 2, entries 2 and 3). An additional spirooxin-
* Reaction conditions: allylsilane 13 (1.1 equiv), TMSOTf (0.3 equiv),
2,6-t-Bu-4-Me-pyridine (DBMP) (0.05 equiv), 4 Å MS, 14 h. a Isolated
yields. b Not observed, N-methylisatin and desilylated allylsilane 20
recovered.
Subjection of N-methyl isatin dimethylketal 1812 (Table 1)
and allyl silane 13 to optimized ISMS reaction conditions
(Table 1, entry 3) did not afford the desired spiroannulated
product 19 and led only to recovery of silyl ether13 20
(Scheme 2) and N-methyl isatin. Warming of the reaction
to room temperature afforded product 21, presumably from
direct allylation of the derived isatin oxonium ion with
allylsilane 13 (Table 1, entry 4). Attempts to convert
compound 21 into the desired spiroannulated product under
acidic conditions afforded a complex mixture of products.
When CH2Cl2 was used as solvent, spirooxindole 22 bearing
(6) (a) Kang, T.-H.; Matsumoto, K.; Murakami, Y.; Takayama, H.;
Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J. Pharamacol. 2002, 444, 39.
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K. Tetrahedron: Asymmetry 1993, 4, 201.
Org. Lett., Vol. 11, No. 15, 2009
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Table 2. Amide-Directed Hydrogenation
spirooxindole
catalyst
H2
solvent
MeOH
MeOH
EtOH/benzene
CH2Cl2
conversiona (%)
ratioa
2:1
22
23
22
22 + 23
Pd/C
Pd/C
50 psi
50 psi
50 psi
1 atm
96
99
7:1
Wilkinson’s catalyst RhCl(PPh3)3
Crabtree’s catalyst [Ir(cod)py(PCy3]PF6
99
only 32
a
1
Conversion and ratios of 31:32 determined by H NMR analysis of crude samples.
dole pyran synthesis sequence is shown in Scheme 3.
Preparation of homoallylic alcohol 2416 by epoxide ring-
opening, followed by treatment with isatin ketal 18 and
TMSOTf, afforded spirooxindoles 27 and 28 (Scheme 3).
The relative stereochemistry and alkene position of major
stereoisomer 27 were confirmed by X-ray crystallographic
analysis.11
mol)11 shows destabilizing 1,3-diaxial interactions in car-
bocation 30 which is derived from Prins cyclization through
TS-2.
In order to confirm the relative stereochemistry at the spiro
center of minor regioisomer 23 generated during the Prins
cyclization, we subjected both regioisomers 22 and 23 to
metal-catalyzed hydrogenation. Interestingly, using catalytic
amounts of Pd/C, a mixture of chromatographically separable
In order to explain the stereochemical outcome of the Prins
cyclizations, we propose a chair transition state (Figure 2)
1
diastereoisomers 31 and 32 were observed by H NMR
analysis of crude samples, indicating that regioisomers 22
and 23 had the same relative stereochemistry at the spiro
center (Table 2).
In light of the poor diastereoselectivity observed using
standard hydrogenation conditions, we next evaluated the
possibility of amide-directed hydrogenation.18 While use of
Wilkinson’s catalyst did not generate the desired hydroge-
nated product, use of Crabtree’s catalyst19 led to the
production of 32 in excellent diastereoselectivity (dr >30:1)
indicating complete substrate control in the amide-directed
hydrogenation (Table 2).
In order to broaden the scope of the methodology to access
spirocyclic oxindoles, we prepared a series of homoallylic
alcohols (24, 33-36) and isatin ketals (18, 37,20 38) for
examination in the Prins cyclization (Table 3). Cyclizations
were found to be successful with isatin ketals bearing NH
functionality to afford spirooxindole products 39-43. Intro-
duction of a bulky bromine substituent on the 4-position of
the isatin ketal (Table 3, entries 2, 4 and 5) resulted in
improved diastereoselectivity and noticeably influenced the
product olefin regiochemistry (cf. entries 3 and 4), which
may be explained by highly regioselective elimination of a
carbocation intermediate distal from the bromo-oxindole
moiety (cf. 29, Figure 2).
Figure 2. Proposed transition states.
in which the larger aryl substituent of the oxindole moiety
adopts a pseudo-equatorial orientation17 (TS-1) leading to
the observed diastereoisomer (cf. 22 and 23, Scheme 2). An
alternative chair (TS-2) leading to the disfavored diastere-
oisomer has significant steric interactions between the isatin
carbonyl oxygen and the R substituent on the chiral center.
Examination of molecular models of the proposed intermedi-
ate tertiary carbocations 29 and 30 obtained using Spartan
conformational searches (AM1) followed by DFT minimiza-
tion (performed using a 6-31G* basis set; ∆E ) 8.25 kcal/
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K. V.; Meervelt, L. V.; Vandendriessche, A.; Dehaen, W. Synlett 2004,
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2006, 71, 2346.
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(11) See the Supporting Information for complete experimental details.
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2007, 692, 2415.
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3364
Org. Lett., Vol. 11, No. 15, 2009

Table 3. Prins-Type Spiro-annulation
Table 4. Diastereoselective Synthesis of Spirooxindole
Oxepenes
a Isolated yields. b rr ) regioisomeric ratio; major isomer shown.
Reaction conditions: TMSOTf (1.0 equiv), -40 °C to rt, 3 h, CH2Cl2.
a Isolated yields b Reaction conditions: TMSOTf (1.0 equiv), -40 °C
to rt, 14 h, CH2Cl2. c TMSOTf (1.0 equiv), -40 to 0 °C, 3 h, CH2Cl2.
d Isolated as an inseparable mixture of regioisomers. Hydrogenation was
necessary to facilitate products separation. f rr ) regioisomeric ratio; major
isomer shown.
reoselective Prins-type cyclizations of both homoallylic and
bis-homoallylic alcohols and isatin ketals. The protocol is
highly complementary to related annulations involving chiral
organosilanes.24 Further studies involving related annulations
and library synthesis applications are in progress and will
be reported in due course.
Considering the well-documented racemization observed
during Prins cyclization due to competitive oxonia-Cope
rearrangement (Figure 3),21 we also measured the enantio-
Acknowledgment. Financial support from the NIGMS
(P41 GM076263 and P50 GM067041) is gratefully acknowl-
edged. We thank Ms. Jiayi Yuan (Boston University) for
preliminary studies, Professors James Panek, Aaron Beeler,
Ramesh Jasti, and Ms. Yun Zhang (Boston University) for
helpful discussions, and Dr. Emil Lobkovsky (Cornell
University) for X-ray crystallographic analysis.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all compounds. X-ray
crystal structure coordinates and files in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Possible racemization of Prins cyclization products via
2-oxonia-Cope rearrangement.
meric excess of the spirocyclic products. In all cases, we
did not observed erosion in enantiopurity (Tables 3 and 4).
These findings are consistent with the observations that
stabilization of the intermediate tetrahydropyranyl cation
raises the transition states energy for ring-opening and
effectively eliminates the oxonia-Cope rearrangement.21a,b
Finally, we extended the methodology to intramolecular
Prins cyclization of bis-homoallylic alcohols (Table 4, 44,
4522) and isatin ketals (Table 4, 18, 37, 38) to generate
spirocyclic oxindole oxepenes14b,23 46-50 in high diastereo-
and regioselectivity (Table 4). The relative stereochemistry
of spirooxindole 46 was confirmed Via X-ray crystallographic
analysis.11
OL901201K
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In conclusion, enantiopure spirocyclic oxindole pyrans and
oxepenes have been efficiently synthesized by highly ste-
(24) Zhang, Y.; Panek, J. Org. Lett. 2009, 11, (DOI 10.1021/ol901202t).
Org. Lett., Vol. 11, No. 15, 2009
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