Stereoselective synthesis of five-membered spirooxindoles through Tomita zipper cyclization

Article abstract of DOI:10.1021/ol4020305

Functionalized five-membered spirooxindoles were furnished in good yields and excellent stereoselectivities by using an effective Tomita zipper cyclization (TZC) reaction through organophosphine catalysis.

Full text of DOI:10.1021/ol4020305

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Stereoselective Synthesis
of Five-Membered Spirooxindoles
through Tomita Zipper Cyclization
D. B. Ramachary,* Chintalapudi Venkaiah, and Patoju M. Krishna
Catalysis Laboratory, School of Chemistry, University of Hyderabad,
Central University (PO), Hyderabad 500 046, India
ramsc@uohyd.ernet.in; ramchary.db@gmail.com
Received July 19, 2013
ABSTRACT
Functionalized five-membered spirooxindoles were furnished in good yields and excellent stereoselectivities by using an effective Tomita zipper
cyclization (TZC) reaction through organophosphine catalysis.
Natural and unnatural compounds containing a spir-
ooxindole as a core structure display vast biological
activities.1 Although many synthetic methods have been
developed for the selective synthesis of spirooxindoles, but
their high-yielding synthesis with multiple stereocenters
and a spiro-quaternary carbon is a still demanding task.2
Notably, existing stereoselective catalytic syntheses of
substituted five-membered spirooxindoles from simple
substrates and catalysts are very few.3,4 Therefore, the
development of a catalytic stereoselective protocol for
the direct synthesis of functionalized five-membered spir-
ooxindoles is a significant challenge.
In 2013, we have discovered an aminoenyne catalysis for
the synthesis of six-membered spirooxindoles with a qua-
ternary C-3 chiral center.5a Meanwhile, it was realized that
substituted five-membered spirooxindoles also displayed in
a number of biologically active natural products (Figure 1),1
but their stereoselective synthesis with suitable functional
groups remains a great challenge for synthetic chemists.
Only a few reactions are known to achieve this goal.3,4
To attempt this synthetic goal, we aimed to design an
organophosphine-catalyzed zipper cyclization that would
involve a reaction between two simple starting materials.
Providing the recent discovery of in situ generated
(Z)-4-(tributylphosphonio)buta-1,3-dien-2-olate as a no-
vel mild nucleophile in the intramolecular Tomita zipper
cyclization (eq 1) and Fu cyclization reactions (eq 2) for the
(1) (a) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.; Steyn, P. S.
J. Chem. Soc., Perkin Trans. 1 1979, 1751. (b) Polonsky, J. M.; Merrien,
M. A.; Prange, T.; Pascard, C. J. Chem. Soc., Chem. Commun. 1980, 601.
(c) Greshock, T. J.; Grubbs, A. W.; Jiao, P.; Wicklow, D. T.; Gloer, J. B.;
Williams, R. M. Angew. Chem., Int. Ed. 2008, 47, 3573. (d) Mugishima,
T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.; Kawabata, J.;
Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem. 2005, 70, 9430.
(2) For reviews on spirooxindole synthesis, see: (a) Honga, L.; Wang,
R. Adv. Synth. Catal. 2013, 355, 1023. (b) Dalpozzo, R.; Bartolib, G.;
Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247. (c) Singh, G. S.; Desta,
Z. Y. Chem. Rev. 2012, 112, 6104. For the original papers, see: (d)
Tessier, J. D.; O’Bryan, E. A.; Schroeder, T. B. H.; Cohen, D. T.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 4963. (e) Jiang, X.; Cao,
Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am. Chem. Soc. 2010, 132,
15328.
(3) (a) Albertshofer, K.; Tan, B.; Barbas, C. F., III. Org. Lett. 2012,
14, 1834. (b) Sun, W.; Zhu, G.; Wu, C.; Hong, L.; Wang, R. Chem.;Eur.
J. 2012, 18, 6737. (c) Tan, B.; Candeias, N. R.; Barbas, C. F., III. Nat.
Chem. 2011, 3, 473. (d) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew.
Chem., Int. Ed. 2011, 50, 7837. (e) Tan, B.; Candeias, N. R.; Barbas,
C. F., III. J. Am. Chem. Soc. 2011, 133, 4672. (f) Deng, H.-P.; Wei, Y.;
Shi, M. Org. Lett. 2011, 13, 3348. (g) Voituriez, A.; Pinto, N.; Neel, M.;
Retailleau, R.; Marinetti, A. Chem.;Eur. J. 2010, 16, 12541.
(4) (a) Tan, B.; Zeng, X.; Leong, W. W. Y.; Shi, Z.; Barbas, C. F., III;
Zhong, G. Chem.;Eur. J. 2012, 18, 63. (b) Shi, F.; Tao, Z.-L.; Luo,
S.-W.; Tu, S.-J.; Gong, L.-Z. Chem.;Eur. J. 2012, 18, 6885. (c)
Bergonzini, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 971.
(d) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Zhang, F.; Wang, R. Angew.
Chem., Int. Ed. 2011, 50, 9124. (e) Chen, X.-H.; Wei, Q.; Luo, S.-W.;
Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819.
(5) (a) Ramachary, D. B.; Venkaiah, Ch.; Madhavachary, R. Org.
Lett. 2013, 15, 3042. (b) Ramachary, D. B.; Reddy, G. B.; Mondal, R.
Tetrahedron Lett. 2007, 48, 7618.
r
10.1021/ol4020305
XXXX American Chemical Society

Table 1. Reaction Preliminary Optimizationa
solvent
catalyst
(mol %)
time yield (%)b yield (%)b
entry (0.2 M)
(h)
(E)-4aa
(Z)-4aa
Figure 1. Bioactive natural products containing the spirooxin-
dole core structure.
1
DCE
DCE
DCE
THF
DCE
DCE
DCE
DCE
DCM
3a: Ph3P
12
8
55
55
40
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5
2c
3
3a
carbocycles synthesis,6e,h we realized that the intermolecu-
lar zipper cyclization between unmodified ynones 1 and
3-alkylideneindolin-2-ones 2 would yield the desired five-
membered spirooxindoles in a highly stereoselective man-
ner (eq 3, Scheme 1). As intermolecular Tomita zipper
cyclization (TZC) is not known for carbocycle synthesis,6
herein, we present the novel organocatalytic TZC be-
tween 1 and 2 that would provide the functionalized five-
membered spirooxindole 4 or 5 in good yield with high
selectivity (Scheme 1).
3b: Ph2EtP
96
72
24
36
60
16
60
48
60
48
4
3c: n-Bu3P
5
3d: (p-FC6H4)3P
85
75
75
55
70
70
45
40
ꢀ
6d
7e
8f
9
3d
3d
3d
3d
5
5
5
5
10
11
12
13
14
CHCl3 3d
CH3CN 3d
5
ꢀ
ꢀ
ꢀ
ꢀ
THF
DCE
DCE
3d
3e: (p-OMeC6H4)3P 72
3f: HMPT 72
_
a Reactions were carried out in solvent (0.2 M) with 2 equiv of 1a
relative to the 2a (0.2 mmol) in the presence of 20 mol % of catalyst 3.
b Yield refers to the column-purified product. c 3.0 equiv of 1a were used.
d Catalyst 3d was taken as 10 mol %. e Catalyst 3d was taken as 5 mol %.
f Reaction performed at 60 °C.
Scheme 1. Design for the Five-Membered Spirooxindoles
Synthesis through Tomita Zipper Cyclization (TZC)
product 5aa. Surprisingly, the same reaction with Ph2EtP
3b as the catalyst at 25 °C for 96 h furnished the spiroox-
indole (E)-4aa in only 40% yield, but there is no reaction
with well-known n-Bu3P 3c as the catalyst at 25 °C for 72 h
in THF (Table 1, entries 3ꢀ4). The same reaction with
(p-FC6H4)3P 3d as the catalyst at 25 °C for 24 h in DCE
furnished (E)-4aa in 85% yield with a 17:1 E/Z ratio
(Table 1, entry 5). After thorough investigation of the
3d-catalyzed TZC reaction, we found that the solvent,
catalyst loading, and temperature have a significant effect
on the yields and E/Z ratio (Table 1, entries 6ꢀ12). Sur-
prisingly, there is no TZC reaction observed under the
catalysis of electron rich phosphine catalysts 3e and 3f
(Table 1, entries 13ꢀ14). In the final optimization, TZC
reaction of 1a and 2a through 3d catalysis in DCE at 25 °C
for 24 h furnished the spirooxindole (E)-4aa in 85% yield
with 89% E-selectivity (Table 1, entry 5).
We commenced our studies by evaluating the TZC
reaction between ynone 1a and olefin 2a using Ph3P 3a
as the catalyst in DCE at 25 °C (Table 1, entry 1). We
found that the reaction proceeded to furnish the (E)-4aa in
55% yield with >99% E-selectivity without formation of
Table 2. N-Substitution Effect on the TZC Reaction of 1a with
2bꢀe under the 3d Catalysis in DCE at 25 °C
entry
Pg
time (h) yield (%)a (E)-4 yield (%)a (Z)-4
1
2
3
4
2b: H
16
24
16
16
60 (E-4ab)
50 (E-4ac)
50 (E-4ad)
51 (E-4ae)
<5 (Z-4ab)
<5 (Z-4ac)
ꢀ (Z-4ad)
ꢀ (Z-4ae)
(6) (a) Lian, Z.; Wei, Y.; Shi, M. Tetrahedron 2012, 68, 2401. (b)
Yang, L.; Xie, P.; Li, E.; Li, X.; Huang, Y.; Chen, R. Org. Biomol. Chem.
2012, 10, 7628. (c) Lian, Z.; Shi, M. Org. Biomol. Chem. 2012, 10, 8048.
(d) Lian, Z.; Shi, M. Eur. J. Org. Chem. 2012, 581. (e) Wilson, J. E.; Sun,
J.; Fu, G. C. Angew. Chem., Int. Ed. 2010, 49, 161. (f) Meng, L.-G.; Cai,
P.; Guo, Q.; Xue, S. J. Org. Chem. 2008, 73, 8491. (g) Methot, J. L.;
Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (h) Kuroda, H.;
Tomita, I.; Endo, T. Org. Lett. 2003, 5, 129.
2c: Me
2d: COCH3
2e: Boc
a Yield refers to the column-purified product.
B
Org. Lett., Vol. XX, No. XX, XXXX

We further demonstrated the electronic factor of
N-substitution of the designed TZC reaction (Table 2).
Reaction of 1a with N-H olefin 2b under the catalysis of 3d
in DCE at 25 °C for 16 h furnished (E)-4ab in 60% yield
with >85% E-selectivity (Table 2, entry 1). In a similar
manner, TZC reaction of 1a with N-Me olefin 2c under 3d
catalysis for 24 h furnished (E)-4ac in 50% yield with
>82% E-selectivity (Table 2, entry 2). Surprisingly, TZC
reaction between 1a and N-Ac or N-Boc olefins 2d/2e
under 3d catalysis for 16 h furnished (E)-4ad and (E)-4ae
in 50/51% yield with >99% E-selectivity, respectively
(Table 2, entries 3ꢀ4). This result clearly shows that the
single directional electrophilicity of olefin 2 is crucial to
achieving high yields and selectivity in the designed TZC
reaction.
To gain further insight into the electronic factors in
TZC, we explored the treatment of different olefins 2fꢀp
with ynone 1a under 3d catalysis to furnish product 4 or 5
(Table 3). Reaction of olefin 2f with 1a under the 3d or 3a
catalysis furnished the product 4af in moderate yields and
E/Z ratio, but the same reaction under 3e catalysis gave 4af
in good yield with 2:1 E/Z ratio (Table 3, entries 1, 2).
Olefin 2g gave the product 4ag in good yields with poor dr
and a very good E/Z ratio under3a or 3d catalysis (Table 3,
entries 3, 4). Surprisingly, treatment of olefin 2h with 1a
under 3a, 3d, or 3e catalysis furnished the product 5ah in
poor yield, but the same reaction with olefin 2i furnished
the product (E)-5ai in 50% yield with 4:1 dr (Table 3,
entries 5, 6). Reaction of 2j with 1a under 3d or 3e catalysis
furnished the product 5aj in poor yields, but the same
reaction under 3a catalysis gave the (E)-5aj in 70% yield
with 6:1 dr (Table 3, entries 7, 8). In a similar manner,
spirooxindoles (E)-5akꢀap were obtained in good yields
and excellent dr’s with a variety of olefins containing
neutral and halogenated 2kꢀ2p from the TZC reaction
(Table 3, entries 9ꢀ14).
After realizing the electronic factors of olefins, we
further explored the scope of the 3d-catalyzed TZC reac-
tion by developing diversity-oriented stereoselective syn-
thesis of spirooxindoles 4 through the reaction of ynones
1aꢀj with olefins 2a and 2qꢀu (Table 4). The spirooxin-
doles 4 were obtained in good yields, excellent dr’s, and
E/Z ratios with a variety of olefins containing neutral and
halogenated 2a, 2qꢀu and ynones containing a neutral,
electron-donating, halogenated, R0-branched aliphatic
group and heteroatom substituted 1aꢀ1j from the stereo-
selective TZC reaction (Table 4). In this work, treatment of
the unmodified ynones 1aꢀj with catalyst 3a or 3d gave the
in situ catalytic species (Z)-4-(triarylphosphonio)buta-1,3-
dien-2-olates as interesting mild nucleophiles, which are
used in a TZC reaction to furnish the spirooxindoles
4baꢀau with up to >89% E-selectivity and 10:1 dr in
good yields (Table 4). The structure and stereochemistry of
the products 4 and 5 were confirmed by NMR analysis and
also finally confirmed by X-ray structure analysis on 5an
and 4ar as shown in Figures S1 and S2 (Supporting
Information (SI)).7
With applications in mind, we explored the utiliza-
tion of compounds 4 in the synthesis of functionalized
spiranes 6ꢀ7 via simple cascade reductions. Reduction of
Table 3. Scope of the TZC Reaction with Other Olefins
Table 4. Designed TZC Reaction with Other Ynones
T
yieldaꢀc
(%)
entry
olefin 2
catalyst 3 time (h) yielda (%) drb,c
entry
ynone 1
olefin 2
(h)
1
2
3
4
5
1b: R2, R1 = 4-MeC6H4, H
1c: R2, R1 = 4-MeOC6H4, H
2a: Fg = H
2a
1d: R2, R1 = 4-MOMOC6H4, H 2a
36 65 (4ba)
72 66 (4ca)
48 60 (4da)
24 65 (4ea)
36 65 (4fa)
48 66 (4ga)e
48 78 (4ha)f
48 64 (4ia)
12 60 (4ja)h
24 60 (4aq)
48 60 (4ar)
36 60 (4as)
24 60 (4at)
1d 2f: R1, R2 = CO2Et
2d 2f: R1, R2 = CO2Et
3a or 3d
3e
2g: R1, R2 = CN, CO2Et 3a
72
72
24
36
72
24
48
72
24
24
12
12
12
12
40 (4af)
60 (4af)
ꢀ
ꢀ
3
4
5
6
7
8
9
60 (4ag) 1.3:1
75 (4ag) 1.3:1
<10 (5ah) ꢀ
1e: R2, R1 = 4-FC6H4, H
1f: R2, R1 = 4-CIC6H4, H
2a
2a
2a
2a
2a
2a
2g: R1, R2 = CN, CO2Et 3d
2h: R1 = Ph
3e
3a
3a
3d or 3e
3a
3a
3a
3a
3a
6d 1g: R2, R1 = Ph, Me
2i: R1 = CO2Me
2j: R1 = CO2Et
2j: R1 = CO2Et
50 (5ai) 4:1
70 (5aj) 6:1
7
1h: R2, R1 = Ph, Et
8d 1i: R2, R1 = 2-Thiophenyl, H
9g 1j: R2, R1 = Ph, OMOM
10 1a: R2, R1 = Ph, H
11 1a
<10 (5aj)
ꢀ
2k: R1 = CO2 Bu
70 (5ak) 6:1
60 (5al) 9:1
55 (5am) 9:1
50 (5an) 17:1
50 (5ao) 17:1
50 (5ap) 9:1
t
2q: Fg = 5-F
2r: Fg = 5-CI
2s: Fg = 5-Br
2t: Fg = 5-I
10 21; Fg = 5-F
11 2m: Fg = 5-Cl
12 2n: Fg = 5-Br
13 2o: Fg = 5-I
12 1a
13 1a
14 1a
2u: Fg = 5,7-Me2 36 80 (4au)
14 2p: Fg = 5,7-Me2
3a
a Yield refers to the column-purified product. b dr determined by 1H
NMR analysis. c In all entries, <5% of Z-isomer is formed. d Reaction
were carried out at 60 °C. e dr was 10:1. f dr was 8:1. g 3:1 ratio of E/Z
isomers is formed. h dr was 2:1.
a Yield refers to the column-purified product. b dr determined by 1H
NMR analysis. c In all entries, <5% of Z-isomer is formed except in
entries 1 and 2. d 2:1 ratio of E/Z isomers are formed.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Synthetic Applications of Spirooxindoles
Scheme 3. Reaction Mechanism
spirooxindoles (E)-4ga and (E)-4ha with 1.5 equiv of
NaBH4 in dry CH3OH at 0ꢀ25 °C for 1.0 h furnished
the double (olefin and carbonyl) reduced alcohols 6ga and
6ha in each 30% yield with >99:1 dr, accompanied by
unexpected bicyclic imines 7ga and 7ha each in 30% yield
with >99:1 dr, respectively (Scheme 2). Interestingly, di-
astereomerically pure alcohols 6 and bicyclic imines 7 were
separated through column chromatography. The structure
and stereochemistry of products 6 and 7 were confirmed
by NMR analysis and also finally confirmed by X-ray
structure analysis on 7ga as shown in Figure S3 (SI).7
The most possible reaction pathway is shown in Scheme 3
based on the controlled experiments. A zwitterionic in-
termediate 8a is produced by the Michael addition of
the triarylphosphine catalyst 3 with ynones 1, which
further undergoes an intramolecular proton migration
from the inner methylene to produce catalytic (Z)-
4-(triarylphosphonio)buta-1,3-dien-2-olates 8b.6h For the
first time, the regioselective formation of zwitterionic
intermediate 8a was confirmed by 31P NMR analysis and
also online monitoring through HRMS analysis of the
reaction between 1a and 3a (Scheme S1 and Figure S4,
SI-I). Although supplementary studies are needed to se-
curely elucidate the stereoselective formation of two kinds
of cyclization products 4 and 5 from 2aꢀu with 8b, the
reaction proceeds in a stepwise manner between in situ
generated 8b with olefins 2aꢀu (Scheme 3). A nucleophilic
attack of the resulting enolate 8b to the olefins 2aꢀg
and 2qꢀu produces carbanion species 9, which further
undergoes an intramolecular cyclization to furnish the
phosphorane 10. Charge migration followed by triar-
ylphosphine 3 elimination of intermediate 10 produces
the final product 4. In a similar manner, products 5 are
generated from the intermediates 11 and 12 through the
treatment of in situ enolate 8b with olefins 2hꢀp. The
reaction rate and diastereoselective product distribution
of 4 and 5 through a TZC is completely based on the olefin
π-electron distribution, which is controlled by the cyclic
amide, N-substitution and olefin, aryl substitutions as
shown in Tables 1ꢀ4. The reactivity of in situ generated
species 8 from 1 with 3a will be high compared to 3d or 3e
due to their self-stabilization, which is reflected on the
reaction with less reactive olefins 2iꢀp (Table 3). Based on
the control experiments and crystal structure studies, we
can rationalize the observed high regio- and stereoselectiv-
ity of the TZC reaction is due to the in situ formation of
(Z,Z)-enolate 8b as the major isomer and also the strong
electrostatic attraction, CHꢀπ interactions between 8b
and 2. Surprisingly, treatment of ynone 1a with olefin 2a
under the diisopropylethylamine catalysis furnished the
unexpected spiro[indoline-3,40-pyran]-2-one 13aa in 45%
yield and product 4aa in <5% yield, which highlights the
importance of phosphine catalysis for the zipper cycliza-
tion (eq S1, SI-I).8
In summary, we have developed a versatile zipper cycliza-
tion protocol for the stereoselective synthesis of substituted
five-membered spirooxindoles 4and 5from acyclic precursors
by using a commanding but mostly less explored cata-
lytic in situ generated species of (Z)-4-(triarylphosphonio)
buta-1,3-dien-2-olates (8b) reactivity discovered by Tomita.6h
The products of the TZC reaction 4were transformed into the
highly functionalized drug-like molecules 6ꢀ7 with >99:1 dr.
Future studies from this group will continue to explore the
scope of novel methods of catalytic 8b reactivity furnished by
chiral phosphines with unmodified ynones.
Acknowledgment. This work was made possible by a
grant from the DST, New Delhi. C.V. and P.M.K. thanks
CSIR, New Delhi for their research fellowship.
Supporting Information Available. Experimental pro-
cedures, compound characterization, X-ray crystal struc-
tures, and analytical data (1H NMR, 13C NMR, and
HRMS) for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7) CCDC-949984 for 5an, CCDC-949985 for 4ar, and CCDC-
949986 for 7ga contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(8) For the treatment of ynones with secondary amines, see: (a)
Ramachary, D. B.; Venkaiah, Ch.; Krishna, P. M. Chem. Commun.
2012, 48, 2252. (b) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett.
2006, 8, 5417.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX