Stereoselective synthesis of spirooxindole amides through nitrile hydrozirconation

Article abstract of DOI:10.1021/ol102246d

Spirooxindole amides can be prepared by the intramolecular addition of functionalized indoles into acylimines that are accessed from nitriles by hydrozirconation and acylation. The stereochemical outcome at the quaternary center was controlled by the ster

Full text of DOI:10.1021/ol102246d

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5112-5115
Stereoselective Synthesis of
Spirooxindole Amides through Nitrile
Hydrozirconation
Chunliang Lu, Qing Xiao, and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh,
PennsylVania 15260, United States
florean@pitt.edu
Received September 19, 2010
ABSTRACT
Spirooxindole amides can be prepared by the intramolecular addition of functionalized indoles into acylimines that are accessed from nitriles
by hydrozirconation and acylation. The stereochemical outcome at the quaternary center was controlled by the steric bulk of the substituent
at the 2-position of the indole unit. The products are well-suited for diversification to prepare libraries.
The spirooxindole unit is earning the status of “privileged
structure” in synthetic and medicinal chemistry, as evidenced
by a number of recent reviews1 and the rapid development
of new methods for their synthesis.2 The biological activity
that a number of spirooxindoles exhibit has spawned library
syntheses3 that led to the identification of potent MDM2
inhibitors,4 adjuvants of the actin polymerization inhibitor
latrunculin B,3a and antimalarial agents.5 We have developed
a new protocol for stereoselective spirooxindole synthesis
in accord with our interest in preparing structurally diverse
amides through nucleophilic addition reactions to acylimines.
These acylimines derive from nitriles via a sequence of nitrile
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10.1021/ol102246d  2010 American Chemical Society
Published on Web 10/20/2010

hydrozirconation followed by acylation.6 The oxindole
preparation proceeds (Scheme 1) through the generation of
cyanohydrin ether 5 through a one-pot sequential acetaliza-
tion reaction with BnOTMS and BiBr3 followed by TMSCN
addition.9 Ozonolysis and Fischer indole synthesis with
benzyl phenylhydrazine provided 6. Cyclization substrate 7
was prepared by chlorination with NCS. The corresponding
silyloxyindole 8 was prepared by oxidizing 6 with DMSO
and HCl through a variation on an established10 protocol to
form the oxindole followed by silylation by TIPSOTf and
Et3N.11
Scheme 1
.
Spirooxindole Formation through Acylimine
Addition
Scheme 3. Oxindole Formation through Nitrile
Hydrozirconation, Acylation, and Intramolecular Addition
indolyl acylimines (1) to form stereoisomeric spirooxindoles
2 or 3 through a Friedel-Crafts alkylation reaction, with
the configuration of the quaternary stereocenter being
controlled by the steric bulk of the substituent at the
2-position of the indole. The products of this sequence are
structurally unique and contain multiple sites for diversifica-
tion, making the route well-suited for applications in
diversity-oriented synthesis.
Chloroindoles, shown by Horne and co-workers7 to be
effective oxindole enolate surrogates, and silyloxyindoles
served as the nucleophilic components for the cyclization
reactions in this study. A representative route for their
preparation is shown in Scheme 2. Aldehyde 4, prepared
Spirooxindole formation was demonstrated (Scheme 3) by
subjecting 7 to Cp2Zr(H)Cl12 followed by acylation with
hydrocinnamyl chloride to form an acylimine13 that folds
preferentially into a reactive conformation (9) in which the
benzyloxy and acylimine groups adopt pseudoequatorial
orientations and the C2-center of the indole occupies a
pseudoaxial orientation. The minor conformation (10) places
the indole C2 in a pseudoequatorial orientation. Addition at
the 3-position of the indole followed by hydrolysis of the
chloroiminium ion intermediate provided spirooxindoles 11
and 12 in 73% and 10% yields, respectively. The structures
of the products were assigned based on extensive analyses
of their NOESY spectra. This selectivity indicates that the
aryl group is sterically more demanding14 than the chlorine
substituent in the transition states.
Scheme 2. Substrate Synthesis
The scope of the reactions with the 2-chloroindoles is
shown in Table 1. Aliphatic, branched aliphatic, R,ꢀ-
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through a known8 periodate-mediated cleavage of com-
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Org. Lett., Vol. 12, No. 22, 2010
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at the indole 4- and 6-positions, in anticipation of further
structural manipulations of the spirooxindole products, is
compatible with the reaction conditions (entries 8 and 9).
These substrates reacted somewhat less efficiently than the
corresponding nonhalogenated substrate due to inductive
deactivation by the chloro group and, in the case of 21, steric
interactions in the transition state, but useful quantities of
the products could be isolated.
Table 1. Chloroindole Reaction Scopea
In accord with our interest15 in exploring the impact of
stereochemical diversity16 in library synthesis, we sought to
devise a protocol for preparing spirooxindoles in which the
quaternary carbon is inverted. This can be achieved by
changing the chloro substituent at the 2-position of the indole
structure to a group that is more sterically demanding than
the arene ring. Utilizing silyloxyindole substrate 8 in the
cyclization reactions accomplished this objective (Table 2).
Table 2. Cyclizations with Silyloxyindole Substratesa
a Representative procedure: Cp2Zr(H)Cl (1.25 equiv) was added to a
0.1 M solution of the indole nitrile in CH2Cl2 under Ar. After stirring at rt
for 15 min, the acid chloride was added. The mixture stirred overnight at
rt. b See the Supporting Information for substrate synthesis schemes. c Ratio
of isolated, purified diastereomers. d Combined yield of diastereomers.
e Single isomer at the quaternary centersdr refers to the ratio of trans and
cis amido ethers. f Sc(OTf)3 (0.1 equiv) was added to promote cyclization.
a Representative procedure: Cp2Zr(H)Cl (1.25 equiv) was added to a
0.1 M solution of the indole nitrile in CH2Cl2 under Ar. After stirring at rt
for 15 min, the acid chloride and Sc(OTf)3 were added. The mixture stirred
overnight at rt. b The ratio refers to the quaternary center. The value in
parentheses refers to the ratio of the major stereoisomer to all other
stereoisomers. c Combined yield of all stereoisomers. The yield of the major
stereoisomer is in parentheses. d ZnCl2 was used instead of Sc(OTf)3.
unsaturated, and heteroatom-functionalized acid chlorides
serve as suitable electrophiles for the transformation. N-
Methoxymethylindoles are effective substrates (entries 4-9),
though they are less reactive than the N-benzylindoles and
in some cases require the addition of a Sc(OTf)3 to promote
the cyclization (entries 6 and 7). This reactivity difference
can be ascribed to the inductive attenuation of indole
nucleophilicity by the methoxy group. When Sc(OTf)3 is
used to promote the cyclization, the stereoisomer that has a
cis-relationship between the amide and benzyloxy groups
forms as a minor product, presumably as a result of a
competing chelation-controlled transition state. Aromatic acid
chlorides can be used as electrophiles for this transformation,
though product yields were <25% (not shown). Chlorination
Several issues related to these transformations are notewor-
thy. The overall yield of spirooxindole products from these
reactions is comparable to the yields from the chloroindole
substrates, indicating that the potentially labile enolsilane
moiety is compatible with the reaction conditions. The
(15) Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069.
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46.
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Org. Lett., Vol. 12, No. 22, 2010

reactions of 8 are slower than the reactions of the chloroin-
dole substrates and require a full equivalent of Lewis acid
despite the presence of a strongly electron-donating silyloxy
group. We attribute this effect to the steric demands in the
cyclization transition states. Control of the quaternary center
is good to excellent, though the trans:cis ratio between the
alkoxy and amide groups is lower than what was observed
for the chloroindole substrates. The trans and cis stereoiso-
mers were separable by flash chromatography, with the cis-
isomer reproducibly being the less polar stereoisomer. On
the basis of the unusually downfield 1H NMR chemical shift
of the C4 hydrogen in the cis-isomer, we postulate that the
polarity arises from a hydrogen bond between the oxygen
and the arene hydrogen. Changing the Lewis acid from
Sc(OTf)3 to ZnCl2 results in the cis-isomer being the major
product (entry 5) as a result of chelation between the
acylimine and the benzyloxy group.
Scheme 4. Spirooxindole Functionalizations
The spirooxindole products have numerous points for
structural diversification as a prelude to library synthesis.
Several of these opportunities are shown in Scheme 4. Benzyl
ether cleavage was effected through standard hydrogenolysis
conditions to afford the corresponding alcohol, which can
undergo subsequent acylation as seen in the conversion of
17 to 29. The acrylamide products are very versatile,
undergoing Heck reaction17 to form 30, thiolate addition18
to form 31, and cross metathesis19 to form 32. Regioselective
oxindole bromination can be achieved with NBS, and the
resulting aryl bromide engages in a Suzuki reaction,20 as seen
in the preparation of 33 from 11.
We have shown that indolyl cyanohydrin ethers can be
converted to spirooxindole amides through a sequence of
hydrozirconation, acylation, and intramolecular nucleophilic
addition. Three of the four possible relative stereochemical
outcomes can be prepared as major products through this
process. The quaternary stereocenter can be controlled by
adjusting the steric bulk of the substituent at the 2-position
of the indole, while the relative configuation between the
amide and benzyloxy groups can be influenced by choosing
a chelating or nonchelating Lewis acid to promote the
cyclization. The capacity for stereochemical diversification,
the abundant opportunities for functionalizing the products,
and the wide range of biological activities that spirooxindoles
effect make this method a very attractive entry to library
synthesis.
Acknowledgment. We thank the National Institutes of
Health, Institute of General Medicine (P50-GM067082), for
financial support of this project.
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Cheng, K.; Chen, Q.; Wolff, M. S.; Tong, X.; Holt, T. G.; Waters, M. G.;
Hammond, M. L.; Tata, J. R.; Colletti, S. L. J. Med. Chem. 2009, 52, 2587.
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Supporting Information Available: Experimental pro-
tocols and spectral characterization of all new products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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J. Am. Chem. Soc. 2003, 125, 11360. (b) Garber, S. B.; Kingsbury, J. S.;
Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.
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