Construction of a spirooxindole amide library through nitrile hydrozirconation-acylation-cyclization cascade

Article abstract of DOI:10.1021/co4000387

A library of spirooxindoles containing varied elements of structural and stereochemical diversity has been constructed via a three step, one pot nitrile hydrozirconation-acylation-cyclization reaction sequence from common acyclic indole intermediates. The resulting library was evaluated for novelty through comparison with MLSMR and Maybridge compound collections.

Full text of DOI:10.1021/co4000387

Research Article
pubs.acs.org/acscombsci
Construction of a Spirooxindole Amide Library through Nitrile
Hydrozirconation-Acylation-Cyclization Cascade
Matthew G. LaPorte,*,† Sammi Tsegay,† Ki Bum Hong,† Chunliang Lu,† Cheng Fang,‡ Lirong Wang,‡
Xiang-Qun Xie,‡ and Paul E. Floreancig*,†
‡
†Department of Chemistry, Chemical Methodologies and Library Development, and Department of Pharmaceutical Sciences,
School of Pharmacy, Computational Chemical Genomics Screening Center, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: A library of spirooxindoles containing varied
elements of structural and stereochemical diversity has been
constructed via a three step, one pot nitrile hydrozirconation-
acylation-cyclization reaction sequence from common acyclic
indole intermediates. The resulting library was evaluated for
novelty through comparison with MLSMR and Maybridge
compound collections.
KEYWORDS: nitrile hydrozirconation-acylation-cyclization cascade, spirooxindoles
INTRODUCTION
■
The 2-oxindole motif has proven to be a valuable functionality as
witnessed by the marketed pharmaceutical agents Sutent
(anticancer), Requip (Parkinson’s disease), and Zeldox (schiz-
ophrenia and bipolar disorder).1 This interesting heterocyclic
core is contained in numerous biologically active spirocyclic-
containing natural products such as rychnophylline, gelsemine,
and spirotryprostatin B (Figure 1). These and many other spiro-
oxindoles have received significant attention from synthetic and
medicinal chemists resulting in many elegant synthetic
approaches originating primarily from isatins and derivatives.2−4
Recognition of these factors has led several groups to assemble
diversely substituted chemical libraries upon these heterocyclic
scaffolds (Figure 2),5 and interest persists in developing new
synthetic strategies to construct these important heterocyclic
Figure 1. Oxindole marketed drugs and spirooxindole natural products.
structures. We recently reported a stereoselective approach to
amide containing spirooxindoles through a nitrile zirconation,
acylation, and cyclization cascade process.6 This manuscript
intermediates that undergo acylation upon treatment with hydro-
cinnamoyl chloride (Scheme 2).7 The resulting spirooxindoles
will detail the assembly of a uniquely substituted library of
are produced via Friedel−Crafts cyclizations with the indole-2-
substituent providing the conformational control. In these cases,
the less sterically hindered 2-chloro indole substrate adopts a
pseudoaxial conformation (I), whereas larger moieties such as the
triisopropylsiloxy group prefer pseudoequatorial orientation (II).
The hydrozirconation-acylation-cyclization cascade of 3{1} and
3{2} affords spirooxindoles 4 and 5 bearing versatile functionalities
spirooxindoles using this convenient methodology. A chemical
diversity analysis will be provided through structural comparison
with the MLSMR compound collection.
RESULTS AND DISCUSSION
■
Our approach began with the preparation of the pivotal 2-chloro-
and 2-triisopropylsiloxyindoles (3{1} and 3{2}, respectively)
that contain the pendant cyanohydrin-benzylether functionality
(Scheme 1).6
Received: April 23, 2013
Revised: May 30, 2013
Published: June 3, 2013
Hydrozirconation of nitriles 3{1} and 3{2} using freshly pre-
pared Schwartz’ reagent (Cp2Zr(H)Cl) provides metallo-imine
© 2013 American Chemical Society
344
dx.doi.org/10.1021/co4000387 | ACS Comb. Sci. 2013, 15, 344−349

ACS Combinatorial Science
Research Article
Figure 2. Representative spirooxindole libraries.
Scheme 1. Preparation of Indoles 3{1-2}
Scheme 2. Nitrile Hydrozirconation-Acylation-Cyclization Cascade
345
dx.doi.org/10.1021/co4000387 | ACS Comb. Sci. 2013, 15, 344−349

ACS Combinatorial Science
Research Article
Scheme 3. Preparation of an Ester Containing Library
Scheme 5. Preparation of Additional Spirooxindole Library
the functionalization of the hydroxyl group. The O-benzyl group
can readily be removed under mild hydrogenolysis conditions
(Scheme 3). Subsequent acylations were accomplished in high
yields either through treatment with the corresponding acyl
chlorides or through carbodiimide mediated acid couplings
(7{1−9}, Scheme 3). To modulate the clogP’s of the final ester
containing analogues, various heterocyclic groups were appended
(entries 8−11).
Scheme 4. Preparation of syn-Amido Ester Analogues
The hydroxyl group of 6 was also used to introduce additional
elements of stereochemical diversity through oxidation followed
by selective ketone reduction (d.r. > 20/1, Scheme 4). In this case,
the axial-alcohol functionality was converted to a complementary
subset of syn-amido ester analogues containing small alkyl and
heteroaromatic groups (10{1−6}).
To complete the diastereomeric set of oxindoles from the
common acyclic indole intermediate (not shown), the 2-siloxy
indole cyanohydrin 3{2} was subjected to the hydrozirconation-
acylation conditions in the presence of Sc(OTf)3 to provide the
spirocyclic oxindoles 5 with high selectivity.6 The alcohol group
was unmasked and converted to a diverse group of esters in a
manner described earlier (Scheme 5). The relative stereochemistry
was unequivocally established by single X-ray crystallography of the
p-nitrobenzoate derivative 15{5} (Figure 3).
Additional structural variations of nonester containing
analogues were accomplished through derivatizations of the
spirooxindole heterocyclic core (Scheme 6). Various heterocycles
or amino-propyl substitutions could be efficiently incorporated
through Suzuki couplings utilizing either the iodo- or the pinacol
ester-containing spirooxindole scaffolds (16{1} and 16{2},
respectively).8−10 Despite the incorporation of numerous hetero-
atom containing functionalities, the lipophilicities of this
sublibrary were significantly increased although calculated PSA
values remained below 130 (Scheme 6).
that can be modified to incorporate additional elements of
diversity. Our initial library construction was directed toward
346
dx.doi.org/10.1021/co4000387 | ACS Comb. Sci. 2013, 15, 344−349

ACS Combinatorial Science
Research Article
Figure 3. X-ray structure of 15{5}.
Scheme 6. Spirooxindole Derivatizations
Figure 4. MW and cLogP distribution of spirooxindole library.
We have generated more polar analogues via removal of the
N-benzyl group using dissolving metal conditions (Scheme 7).11
In these cases, the isopropylamide spirooxindoles proved
compatible for the N-debenzylation reaction conditions and
produced much lower molecular weight compounds and
increased product polarities.6a The acetate 20{2} was obtained
directly using ethyl acetate as solvent during reaction workup and
extraction.
With the completion of this spirooxindole amide library,
the compiled physical chemical properties have been evaluated
with the majority of analogues having MWs between 500 and
600 (Figure 4). Many of these compounds were lipophilic
(cLogP’s >6), but incorporation of numerous heterocycles upon
the scaffold helped modulate the overall polarities (vide supra).
Figure 5. Tanimoto coefficient (Tc) comparisons of spirooxindoles vs
MLSMR collection.
347
dx.doi.org/10.1021/co4000387 | ACS Comb. Sci. 2013, 15, 344−349

ACS Combinatorial Science
Research Article
Figure 6. 3D Chemistry space matrix analyses of spirooxindoles vs Maybridge HitFinder library.
The structural novelty of this library was compared to the
NIH Molecular Libraries Small Molecule Repository
(MLSMR) using chemistry space BCUT metrics as well as
2-dimensional fingerprint calculations.12 Using these parame-
ters, the new spirooxindole-based library displayed favorable
chemical diversity with an average Tanimoto coefficient (Tc) of
<0.7 when evaluated against the 430,000 compounds in the
NIH MLSMR collection (Figure 5).13,14 Representative library
structures that exhibit the highest and lowest similarities are
also represented in Figure 5. These spirooxindoles have been
deposited into the MLSMR to serve as novel biological
screening candidates.15,16
To further illustrate the structural uniqueness of the described
spirooxindole library, perspective 3D chemistry space views were
constructed against the Maybridge HitFinder library (Figure 6).
Space coordinates for each compound were generated using
3-dimensional BCUT metric calculations based upon four
principal molecular property descriptions consisting of charge,
polarity, and hydrogen bond donor/acceptor abilities. The
3-dimensional chemical space representation of the spirooxindoles
348
dx.doi.org/10.1021/co4000387 | ACS Comb. Sci. 2013, 15, 344−349

ACS Combinatorial Science
Research Article
Scheme 7. Unsubstituted Spirooxindoles
REFERENCES
■
(1) (a) Millemaggi, A.; Taylor, R. J. K. Eur. J. Org. Chem. 2010, 4527−
4547. (b) Zesiewicz, T. A.; Hauser, R. A. Expert Opin. Invest. Drugs 1999,
8, 697−710. (c) Serretti, A.; De Ronchi, D.; Lorenzi, C.; Berardi, D.
Curr. Med. Chem. 2004, 11, 343−358.
(2) For a review of syntheses of spirocyclic-oxindole natural products,
see: Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003−3025.
(3) For a recent perspective on enantioselective spirooxindole
syntheses, see: Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol.
Chem. 2012, 10, 5165−5181.
(4) For an example of spirooxindoles via intramolecular Heck-
reactions of non-isatin intermediates, see: Overman, L. E.; Watson, D. A.
J. Org. Chem. 2006, 71, 2587−2599.
(5) (a) Lo, M.M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077−16086. (b) Dai, C.;
Liang, B.; Stephenson, C. R. J. Beilstein J. Org. Chem. 2012, 8, 986−993.
(c) Brummond, K. M.; Osbourn, J. M. Beilstein J. Org. Chem. 2011, 7,
601−605. (d) Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.;
Perumal, P. T. Eur. J. Med. Chem. 2012, 51, 79−91. (e) MacDonald, J. P.;
Badillo, J. J.; Arevalo, G. E.; Silva-García, A.; Franz, A. K. ACS Comb. Sci.
2012, 14, 285−293.
(6) (a) Lu, C.; Xiao, Q.; Floreancig, P. E. Org. Lett. 2010, 12, 5112−
5115. (b) Zhang, L.; Xiao, Q.; Ma, C.; Xie, X.-Q.; Floreancig, P. E. J.
Comb. Chem. 2009, 11, 640−644. (c) Xiao, Q.; Floreancig, P. E. Org.
Lett. 2008, 10, 1139−1142.
(red dots) versus the 14,400 Maybridge compounds (gray dots)
generally indicates that our new library occupies less populated
or void regions. The corresponding 2D evaluations further
establish novelties with nine compounds (6, 7{1−2, 5−7},
10{1}, 15{5}, 17{5}) in vacant chemical space cells with the
nearest Maybridge compounds to 6 and 15{5} possessing
very low Tanimoto coefficients of 0.17 and 0.34, respectively
(Figure 6).
(7) For review of organochlorozirconocene complexes, see: Wipf, P.;
Jahn, H. Tetrahedron 1996, 40, 12853−12910.
(8) For iodination conditions, see: Castanet, A.-S.; Colobert, F.;
Broutin, P.-E. Tetrahedron Lett. 2002, 43, 5047−5048.
CONCLUSIONS
■
We have described the synthesis of a stereochemically and
structurally diverse library of spirooxindoles (37 total analogues)
using a three step nitrile hydrozirconation-acylation-cyclization
reaction cascade. These poly functional spirooxindoles were
assembled with high stereoselectivities with pivotal cyclizations
controlled by the 2-indole substitutions that were generated from
a common intermediate. Structural elaborations were provided
by a series of acylations or palladium mediated couplings. The
resulting compound library demonstrated good chemical novelty
when evaluated against the MLSMR and Maybridge compound
collections.
(9) For recent review and perspectives on Suzuki cross coupling
reactions, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−
2483. (b) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723−6737.
(c) Heravi, M. M.; Hashemi, E. Tetrahedron 2012, 68, 9145−9178.
(10) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743−8744.
(11) Mertens, A.; Muller-Beckmann, B.; Kampe, W.; Holck, J.-P.; von
̈
̈
der Saal, W. J. Med. Chem. 1987, 30, 1279−1287.
(12) (a) Pearlman, R. S.; Smith, K. M. Perspect. Drug Discovery Des.
1998, 9, 339−353. (b) Ma, C.; Lazo, J. S.; Xie, X.-Q. ACS Comb. Sci.
2011, 13, 223−231. (c) Xie, X.-Q.; Chen, J.-Z. J. Chem. Inf. Model. 2008,
48, 465−475.
(13) For additional information on this similarity method, see: Wild, D.
J.; Blankley, C. J. J. Chem. Inf. Comput. Sci. 2000, 40, 155−162.
(14) Matter, H. J. Med. Chem. 1997, 40, 1219−1229.
(15) These compounds have been submitted to the Molecular
Libraries Small Molecule Repository (MLSMR), see: http://mli.nih.
gov/mli/secondary-menu/mlscn/ml-small-molecule-repository/.
(16) For recent perspective on small molecules originating from
CMLD centers and their biological discovery/evaluations, see:
Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6699−6702.
ASSOCIATED CONTENT
* Supporting Information
Further details are given about the experimental procedures and
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: pflorean@pitt.edu (P.E.F.), mgl12@pitt.edu (M.G.L.).
■
Author Contributions
P.E.F. conceived the methodology; P.E.F., M.G.L. designed the
library strategy; S.T., K.B.H., C.L. performed the experiments;
C.F., L.W.; X.-Q.X. conducted computational analyses; M.G.L.,
P.E.F., X.-Q.X. cowrote the manuscript.
Funding
This investigation was supported by the NIH/NIGMS CMLD
program (P50GM067082) and R21HL109654.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Professor Peter Wipf for instructive discussions and
Mr. Pete Chambers and Dr. Steven Geib for LCMS/ELSD and
X-ray analyses, respectively.
349
dx.doi.org/10.1021/co4000387 | ACS Comb. Sci. 2013, 15, 344−349