Titanium(IV)-catalyzed stereoselective synthesis of spirooxindole-1-pyrrolines

Article abstract of DOI:10.1021/ol5028128

A stereoselective cyclization between alkylidene oxindoles and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (as low as 5 mol %) to afford spiro[3,3-oxindole-1-pyrrolines] in excellent yield (up to 99%) and diastereoselectivity (up to 99:1). Using a chiral scandium(III)-indapybox/BArF complex affords enantioenriched spirooxindole-1-pyrrolines where a ligand-induced reversal of diastereoselectivity is observed. This methodology is further demonstrated for the synthesis of pyrrolines from malonate alkylidene and coumarin derivatives.

Full text of DOI:10.1021/ol5028128

Letter
pubs.acs.org/OrgLett
Titanium(IV)-Catalyzed Stereoselective Synthesis of Spirooxindole-1-
pyrrolines
Joseph J. Badillo,† Carlos J. A. Ribeiro,‡ Marilyn M. Olmstead,† and Annaliese K. Franz*,†
†Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
‡Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa Av. Professor Gama Pinto, 1649-003
Lisbon, Portugal
S
* Supporting Information
ABSTRACT: A stereoselective cyclization between alkylidene
oxindoles and 5-methoxyoxazoles has been developed using
catalytic titanium(IV) chloride (as low as 5 mol %) to afford
spiro[3,3′-oxindole-1-pyrrolines] in excellent yield (up to 99%) and
diastereoselectivity (up to 99:1). Using a chiral scandium(III)−
indapybox/BArF complex affords enantioenriched spirooxindole-1-
pyrrolines where a ligand-induced reversal of diastereoselectivity is
observed. This methodology is further demonstrated for the
synthesis of pyrrolines from malonate alkylidene and coumarin
derivatives.
Scheme 1. Oxazole and Azlactone Additions to Electron-
Deficient Alkenes To Form 1-Pyrrolines
eterocyclic spirooxindoles are prevalent in natural
1
Hproducts and exhibit important biological activity.
Although methods have been reported to access nitrogen-
containing spirooxindole heterocycles, there are few one-step
transformations that provide access to 3′-nitrogen-containing
structures,2 which are found in many bioactive molecules (Figure
1).3
Figure 1. Representative biologically active spirooxindole natural
products and druglike molecules.
Our laboratory has recently shown that 5-methoxy-2-
aryloxazoles cyclize onto isatins to form spirooxindole oxazolines
in excellent yields and high diastereoselectivity.4,5 In an early
pioneering example, Suga and Ibata demonstrated that 5-
methoxy-2-aryloxazoles undergo a formal [3 + 2]-cycloaddition
with tetracyanoethylene to give 1-pyrroline derivatives (Scheme
1A).6,7 Despite these early reports, this transformation and its
application to other α,β-unsaturated systems have been
limited.8−10 Alternatively, the Toste and Wang groups have
shown that azlactones undergo a 1,3-dipolar cycloaddition with
electron-deficient alkenes to form 1-pyrrolines using gold(I) and
thiourea catalysis, respectively (Scheme 1B).11 Here, we report a
Lewis acid catalyzed method for the stereoselective synthesis of
spiro[3,3′-oxindole-1-pyrrolines] upon addition of 5-methoxy-2-
aryloxazoles to alkylidene oxindoles (Scheme 1C). We also
demonstrate this methodology for the synthesis of pyrrolines
derived from malonate alkylidenes and coumarins.
We recognized that Lewis acid activation of chelating N-
acylalkylidene 1a would provide a rigid platform for the formal [3
+ 2] cycloaddition reaction to access spirooxindoles.12 Employ-
Received: September 23, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5028128 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ing 20 mol % of titanium(IV) tetrachloride catalyzed the addition
of 5-methoxy-2-(4-methoxyphenyl)oxazole (2a) to afford spiro-
1-pyrroline 3a in 90% yield with 91:9 diastereoselectivity (Table
1, entry 2). Comparing dichloromethane and toluene demon-
With efficient conditions in hand, we proceeded to investigate
the scope of oxazole additions to α,β-unsaturated alkylidene
oxindoles (Figure 2). Ester-substituted alkylidenes work with a
Table 1. Optimization for Addition of 5-Methoxyoxazole 2a to
a
Alkylidene Oxindole 1a
b
c
entry
catalyst
none
solvent
time
5 d
dr
% yield
1
2
3
CH2Cl2
CH2Cl2
PhCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4 + 4
Ti(Oi-Pr)4
Sc(OTf)3
5
10 min
3 d
91:9
90
d
88:12
91:9
50
e
4
e,f
45 min
45 min
48 h
24 h
5 h
99
87
5
6
7
8
9
90:10
90:10
g
h
e
d
98
0
d
90:10
50:50
99
5 d
0
0
10
11
6
5 d
d
K-10
7 d
<25
a
Reactions performed with 1.5 equiv of alkylidene under argon.
Diastereomeric ratio determined using 1H NMR analysis of
b
Figure 2. Scope of spirooxindole-1-pyrrolines. Reactions run with 20
unpurified reaction mixture and reported as major plus sum of
mol % of TiCl4 and 1.5 equiv of alkylidene under argon. Diastereomeric
1
minor isomers. Diastereomers are inseparable by column chromatog-
ratio determined using H NMR analysis of the unpurified reaction
c
d
raphy. Isolated yield. Conversion determined using 1H NMR
mixture and reported as major vs sum of minor isomers. (a) Conversion
determined using 1H NMR spectroscopy. (b) Diastereoselectivity based
on purified material.
e
f
spectroscopy. Run with 5 mol % of catalyst. Run on 2.7 mmol
scale. Run with 10 mol % of 4. Significant deacylation observed.
g
h
strated that using dichloromethane is optimal; using toluene
resulted in a significant decrease in reactivity (Table 1, entry 2 vs
3). Using 5 mol % of catalyst loading maintained the high yield
and diastereoselectivity with only a minimal increase in reaction
time, even on gram scale (Table 1, entries 4 and 5). A control
experiment performed with the addition 2,6-di-tert-butyl-4-
methylpyridine (4) as a proton scavenger supports Lewis acid
activation of oxindole 1a (Table 1, entry 6), but the reduced
reaction rate suggests that protic acid may enhance catalyst
turnover. In comparison, titanium(IV) isopropoxide was
ineffective in catalyzing the reaction, and significant deacylation
was observed (Table 1, entry 7). Scandium(III) triflate also
afforded 3a with excellent yield and diastereoselectivity (Table 1,
entry 8). The relative stereochemistry of 3a was unambiguously
determined by X-ray crystallographic analysis.
Brønsted acid catalysts such as 1,3-bis(3,5-bis(trifluoro-
methyl)phenyl)thiourea (5) and phenylphosphinic acid (6)
failed to promote reactivity (Table 1, entries 9 and 10).13 We also
investigated the use of montmorillonite K-10, which was recently
shown by our group to be an effective heterogeneous catalyst for
the addition of crotylsilanes to iminoxindoles;14,15 however, K-10
provided poor catalytic activity and diastereoselectivity for this
transformation (Table 1, entry 11).
variety of 2-aryl-substituted oxazoles including 2-phenyl- and 2-
(4-bromophenyl)oxazoles 3b and 3c. Reactions with the N-Cbz-
protected and ketone-substituted alkylidenes both proceed with
excellent diastereoselectivity and yield (3d and 3e). A chelating
group on nitrogen is essential for selectivity; as expected, the N-
methyl-substituted alkylidene proceeds with low selectivity (3f).
Substitution at the 4-position of the oxazole (4-methyloxazole)
provides access to methyl-substituted spiro-1-pyrroline 3g,
containing two stereogenic quaternary centers, with high
diastereoselectivity.16 In the case of the 4-isopropyloxazole
(not shown) the isomers proved difficult to separate by column
chromatography.17 The acyl group can be readily removed to
reveal the free NH oxindole 7 using conditions with base and
hydrogen peroxide.18
We also demonstrated this methodology for the cyclization of
malonate19 8 and coumarin20,10 10 electrophiles to access
densely functionalized pyrrolines 9 and 11 (Scheme 2). The
synthesis of pyrroline 9 proceeded with high yield; however, 1
equiv of TiCl4 was required and an erosion of diastereoselectivity
was observed for this substrate (Scheme 2, eq 1).21 The synthesis
of 1-pyrroline 11 proceeds in high yield and good diaster-
eoselectivity (80:20) (Scheme 2, eq 2). The relative stereo-
B
dx.doi.org/10.1021/ol5028128 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(BArF) to promote formation of a cationic scandium complex
proved to be essential for enhancing the reaction rate in the
presence of ligand. It was notable that these conditions afford a
reversal in the diastereoinduction to afford pyrroline epi-3a (dr =
91:9) with the 4,5-syn isomer as the major product. The relative
stereochemistry of epi-3a was determined by X-ray crystallo-
graphic analysis.26 The reversal in diastereoselectivity is directly
attributed to the addition of the ligand because the Sc-catalyzed
reaction in the absence of ligand (conditions B) (Scheme 3, eq 3)
still affords 3a with high 4,5-anti diastereoselectivity.
Scheme 2. Cyclization with Malonate and Coumarin
Electrophiles
A proposed mechanism for the formation of 3 (in the absence
of a chiral ligand) is shown in Scheme 4. Lewis acid activation of
Scheme 4. Proposed Mechanism for Lewis Acid Catalyzed
Formation of 3a
chemistry of pyrroline 11 was unambiguously determined by X-
ray crystallographic analysis.
We examined several conditions for an asymmetric synthesis
of spirooxindole-1-pyrrolines (Scheme 3, eqs 1 and 2). Initial
Scheme 3. Synthesis of Enantioenriched Pyrroline epi-3a and
Ligand-Induced Reversal of Diastereoselectivity
alkylidene 1 followed by oxazole conjugate addition would give
rise to enolate-bound oxocarbenium intermediate A. Subsequent
cyclization and oxazole ring opening affords spirocycle 3.27,28
In conclusion, we have developed methodology for the
synthesis of a new class of spirocyclic oxindole 1-pyrrolines upon
cyclization of 5-alkoxy-2-aryloxazoles to alkylidene oxindoles.
This strategy forges a quaternary spirocenter with excellent levels
of stereocontrol. Using a chiral scandium(III)−indapybox/BArF
complex provides efficient access to enantioenriched spiro-1-
pyrrolines, and the addition of the ligand reverses the
diastereoselection relative to conditions performed without the
ligand for either the Sc(OTf)3 or TiCl4 catalyst. Furthermore, we
demonstrate that this methodology can be extended to other α,β-
unsaturated systems such as malonate alkylidenes and
coumarins. Efforts to optimize the enantioselectivity and control
diastereoselectivity are ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data for
all new compounds, including X-ray crystal structures for 3a, epi-
3a, and 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
attempts to induce asymmetry using a chiral Ti(IV)−(S)-BINOL
complex resulted in reduced diastereoselectivity and no
enantioselectivity (Scheme 3, eq 1).22 Using Lewis acidic metals
(e.g., Mg, Zn, and Cu) in combination with (S)-Ph-bisoxazoline
provided low yields and no enantioselectivity. Next, we
investigated several chiral Sc(III) complexes for the reaction of
5-methoxy-2-aryloxazoles with α,β-unsaturated alkylidene oxin-
doles. We have recently shown that Sc(III)−indapybox
complexes effectively catalyze nucleophilic addition and
annulation reactions with high levels of enantioselectivity.23−25
We were pleased to determine that using Sc(OTf)3, (R,S)-
indapybox, and NaBArF in toluene afforded pyrroline product in
high yield with 86:14 er (conditions A) (Scheme 3, eq 2). The
use of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: akfranz@ucdavis.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is supported by NIH/NIGMS (P41-GM0089153).
A.K.F. acknowledges 3M Corporation for a Nontenured Faculty
Award, J.J.B. acknowledges support from the NSF in the form of
a Graduate Research Fellowship, and C.J.A.R. thanks Fundaca̧ o
̃
̂
para a Ciencia e a Tecnologia (Portugal) for Fellowship SFRH/
C
dx.doi.org/10.1021/ol5028128 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) For a review on organic reactions catalyzed by clays, see: Laszlo, P.
Science 1987, 235, 1473−1477.
BD/69258/2010. Julia Jennings (UCD) is acknowledged for
technical assistance.
(16) Using the 5-methoxy-2-(4-methoxyphenyl)-4-methyloxazole
provided a complex mixture of regio- and diastereomers; however, the
major product was readily separable by column chromatography.
(17) Disubstituted alkylidene oxindoles such as diethyl 2-(1-acetyl-2-
oxoindolin-3-ylidene)malonate) and 2-(1-acetyl-2-oxoindolin-3-yli-
dene)malononitrile were determined to be unreactive. Both (E)-2-(1-
acetyl-2-oxoindolin-3-ylidene)acetonitrile and (E)-1-acetyl-3-benzyli-
deneindolin-2-one proceed with little or no selectivity.
(18) See the Supporting Information for standard deprotection
conditions.
(19) For examples of Lewis acid activated π-nucleophile additions to
alkylidene maolonates, see: (a) Liu, Y.; Shang, D.; Zhou, X.; Liu, X.;
Feng, X. Chem.Eur. J. 2009, 15, 2055−2058. (b) Wu, J.; Wang, D.;
Wu, F.; Wan, B. J. Org. Chem. 2013, 78, 5611−5617.
(20) For examples of asymmetric conjugate additions to coumarins,
see: (a) Teichert, J. F.; Feringa, B. L. Chem. Commun. 2011, 47, 2679−
2681. (b) Kuang, Y.; Liu, X.; Chang, L.; Wang, M.; Lin, L.; Feng, X. Org.
Lett. 2011, 13, 3814−3817.
(21) The reaction was sluggish using 20 mol % of TiCl4, and the
oxazole is prone to decomposition upon extended exposure to Lewis
acids.
REFERENCES
■
(1) For recent reviews on spirooxindoles see: (a) Badillo, J. J.; Hanhan,
N. V.; Franz, A. K. Curr. Opin. Drug Discovery Devel. 2010, 13, 758−776.
(b) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012,
10, 5165−5181. (c) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F. ACS
Catal. 2014, 743−762.
(2) For the synthesis of 3′-N-spirooxindole derivatives, see:
(a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748−8758. (b) Viswambharan, B.; Selvakumar, K.; Madhavan, S.;
Shanmugam, P. Org. Lett. 2010, 12, 2108−2111. (c) Chen, X.-H.; Wei,
Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131,
13819−13825. (d) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella,
M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat.
̈
Chem. 2010, 2, 735−740. (e) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Zhang,
F.; Wang, R. Angew. Chem., Int. Ed. 2011, 9124−9127. (f) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209−2219.
(3) For examples of biologically active 3′-N-containing spirooxindoles,
see: (a) Zhao, Y.; Liu, L.; Sun, W.; Lu, J.; McEachern, D.; Li, X.; Yu, S.;
Bernard, D.; Ochsenbein, P.; Ferey, V.; Carry, J.-C.; Deschamps, J. R.;
Sun, D.; Wang, S. J. Am. Chem. Soc. 2013, 135, 7223−7234. (b) 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, 3432−3435. (c) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron
1996, 52, 12651−12666. (d) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.;
Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J. Am. Chem. Soc.
2005, 127, 10130−10131.
(22) For examples of asymmetric Lewis acid−BINOL-derived catalysts
for the addition of oxazoles to carbonyl compounds, see: (a) Suga, H.;
Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040−7047. (b) Suga, H.; Shi,
X.; Ibata, T. J. Org. Chem. 1993, 58, 7397−7405.
(23) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz,
A. K. Angew. Chem., Int. Ed. 2010, 49, 744−747.
(24) Gutierrez, E. G.; Wong, C. J.; Sahin, A. H.; Franz, A. K. Org. Lett.
2011, 13, 5754−5757.
(4) Badillo, J. J.; Arevalo, G. E.; Fettinger, J. C.; Franz, A. K. Org. Lett.
2011, 13, 418−421.
(25) Ball-Jones, R. N.; Badillo, J. J.; Tran, T. T.; Franz, A. K. Angew.
Chem., Int. Ed. 2014, 53, 9462−9465.
(5) For additional studies reguarding the addition of oxazoles to
carbonyl compounds, see: (a) Suga, H.; Shi, X.; Fujieda, H.; Ibata, T.
Tetrahedron Lett. 1991, 32, 6911−6914. (b) Suga, H.; Fujieda, H.;
Hirotsu, Y.; Ibata, T. J. Org. Chem. 1994, 59, 3359−3364. (c) Yu, Z.-X.;
Wu, Y.-D. J. Org. Chem. 2003, 68, 421−432. (d) Evans, D. A.; Janey, J.
M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40,
1884−1888. For the synthesis of 5-methoxy-2-(4-methoxyphenyl)
oxazoles, see: (e) Mitchell, J. M.; Shaw, J. T. Angew. Chem., Int. Ed. 2006,
45, 1722−1726. (f) Li, P.; Evans, C. D.; Wu, Y.; Cao, B.; Hamel, E.;
Joulli, M. M. J. Am. Chem. Soc. 2008, 130, 2351−2364.
(26) The absolute stereochemistry of the major enantiomer for epi-3a
was assigned by analogy based on the selectivity observed for the
addition of allylsilanes to alkylidenes (see ref 25) to be 3S,4′R,5′S.
CCDC 1006412−1006414 contain the supplementary crystallographic
data. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(27) An alternative mechanism involving a Diels−Alder adduct
followed by ring opening could also be operable (see ref 7).
(28) See the Supporting Information for a proposed rationale to
explain the ligand-induced reversal of diastereoselectivity.
(6) Ibata, T.; Isogami, Y.; Nakawa, H.; Tamura, H.; Suga, H.; Shi, X.;
Fujieda, H. Bull. Chem. Soc. Jpn. 1992, 65, 1771−1778.
(7) Ibata, T.; Isogami, Y.; Nakano, S.; Nakawa, H.; Tamura, H. J. Chem.
Soc., Chem. Commun. 1986, 1692−1693.
(8) Reddy, P. V.; Bhat, S. V. Tetrahedron Lett. 1997, 38, 9039−9042.
(9) Hassner, A.; Fischer, B. Tetrahedron 1989, 45, 3535−3546.
(10) For an example of a cycloaddition between 1,3-oxazolium-5-olate
and coumarin, see: Cordaro, M.; Grassi, G.; Risitano, F.; Scala, A.
Tetrahedron 2010, 66, 2713−2717.
(11) (a) For the addition of azlactones to electron-deficient alkenes to
form 1-pyrrolines see: Melhado, A. D.; Amarante, G. W.; Wang, Z. J.;
Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 3517−3527. (b)
For a complementary chiral thiourea-catalyzed 1,3-dipolar cycloaddition
between azlactones and alkylidene oxindoles, see: Sun, W.; Zhu, G.; Wu,
C.; Li, G.; Hong, L.; Wang, R. Angew. Chem., Int. Ed. 2013, 52, 8633−
8637. For recent reviews on the use of azlactones as 1,3-dipoles, see:
(c) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432−
1440. (d) Piperno, A.; Scala, A.; Risitano, F.; Scala, G. Cur. Org. Chem.
2014, 18, 2691−2710.
(12) For examples of Lewis acid activation of chealating substrates, see:
Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am.
Chem. Soc. 2007, 129, 10029−10041.
(13) For reviews on Brønsted acid and small molecule hydrogen-
bonding catalysis, see: (a) Terada, M. Synthesis 2010, 1929−1982.
(b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713−5743.
(14) MacDonald, J. P.; Shupe, B. H.; Schreiber, J. D.; Franz, A. K.
Chem. Commun. 2013, 50, 5242−5244.
D
dx.doi.org/10.1021/ol5028128 | Org. Lett. XXXX, XXX, XXX−XXX