Dinuclear zinc catalyzed asymmetric spirannulation reaction: An umpolung strategy for formation of α-alkylated-α-hydroxyoxindoles

Article abstract of DOI:10.1021/ol300577y

A highly diastereo- and enantioselective formal [3 + 2] cycloaddition of α,β-unsaturated esters and 3-hydroxyoxindoles catalyzed by a dinuclear zinc-ProPhenol complex is reported. The stereoselective Michael additions of 3-hydroxyoxindoles and the subsequent transesterifications afford spirocyclic δ-lactones.

Full text of DOI:10.1021/ol300577y

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2446–2449
Dinuclear Zinc Catalyzed Asymmetric
Spirannulation Reaction: An Umpolung
Strategy for Formation of r-Alkylated-r-
Hydroxyoxindoles
Barry M. Trost* and Keiichi Hirano
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received March 7, 2012
ABSTRACT
A highly diastereo- and enantioselective formal [3 þ 2] cycloaddition of r,β-unsaturated esters and 3-hydroxyoxindoles catalyzed by a dinuclear
zinc-ProPhenol complex is reported. The stereoselective Michael additions of 3-hydroxyoxindoles and the subsequent transesterifications afford
spirocyclic δ-lactones.
Given that 3,3-disubstituted oxindoles are a common
structural motif found in many natural products,1 there
has been an intense interest in the development of catalytic
stereoselective methods for their preparation.2 Of particular
Scheme 1. Nucleophilic Approach to R-Alkylated-R-Hydro-
xyoxindoles
interest are processes that construct an oxygen-containing
€
stereocenter at the 3-position. Kundig has reported the
installation of such ethers and the corresponding amines
via an intramolecular R-arylation3 and has also demon-
strated the synthesis of 3-hydroxyoxindoles via the intra-
molecular arylpalladation of ketoamides;4 a subsequent
(1) (a) Suzuki, H.; Morita, H.; Shiro, M.; Kobayashi, J. Tetrahedron
2004, 60, 2489. (b) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.;
Ukon, R.; Ogawa, A. Tetrahedron 2004, 60, 3493. (c) Marti, C.; Carreira,
E. M. Eur. J. Org. Chem. 2003, 2209. (d) Hibino, S.; Choshi, T. Nat.
report by Shibasaki and Kanai rendered this process
enantioselective.5 Lewis acid catalyzed hydroxylation of
3-substituted oxindolesusing Davis’soxaziridinealsogives
access to this class of molecules,6 as does the enantioselec-
tive addition of organometallic reagents,7ꢀ10 enolates,11
ꢀ
ꢀ
Prod. Rep. 2002, 19, 148. (e) Frechard, A.; Fabre, N.; Pean, C.; Montaut,
ꢀ
S.; Fauvel, M.-T.; Rollin, P.; Fouraste, I. Tetrahedron Lett. 2001, 42,
9015. (f) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.;
Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990.
(g) Rasmussen, H. B.; MacLeod, J. K. J. Nat. Prod. 1997, 60, 1152. (h)
Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.; Komiyama, K.;
Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783. (i) Balk-Bindseil, W.;
Helmke, E.; Weyland, H.; Laatsch, H. Liebigs Ann. 1995, 1291.
(2) For recent review, see: Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381.
(5) Yin, L.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2011,
50, 7620.
(6) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488. For an organocata-
lytic enantioselective addition of oxindoles to nitrosobenzne, see: Bui,
T.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc. 2010, 132,
5574.
€
(3) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kundig,
E. P. Chem. Commun. 2008, 4040.
€
(4) Jia, Y.-X.; Katayev, D.; Kundig, E. P. Chem. Commun. 2010, 46,
130.
(7) Addition of Me2Zn: Funabashi, K.; Jachmann, M.; Kanai, M.;
Shibasaki, M. Angew. Chem., Int. Ed. 2003, 42, 5489.
r
10.1021/ol300577y
Published on Web 04/30/2012
2012 American Chemical Society

and electron-rich heterocycles to the corresponding
isatins.10a,12
zinc-ProPhenol-catalyzedasymmetrictandem Michael ad-
ditionꢀtransesterification process that employs 3-hydro-
xyoxindoles as nucleophiles.
We wondered whether 3-hydroxyoxindole 1, an isatinic
anion equivalent, might undergo stereoselective addition
to electrophiles to afford 3-hydroxy-3-alkyloxindoles via a
formal umpolung13 strategy, providing a new approach to
highly functionalized 3-hydroxyoxindoles14 (Scheme 1).
Since the first synthesis of 115 there have been only a few
reports of its use in alkylation reactions.16 Moreover, there
are only a few direct catalytic highly enantioselective reac-
tions using R-disubstituted R-oxycarbonyl compounds,17
although the use of hydroxymethyl ketone derivatives
have been well studied.17e,f,18,19,20c Herein we report a
Scheme 2. Dinuclear Zinc-ProPhenol Complex-Catalyzed
Tandem Michael AdditionꢀTransesterification
(8) Addition of boronic acid derivatives: (a) Liu, Z.; Gu, P.; Shi, M.;
McDowell, P.; Li, G. Org. Lett. 2011, 13, 2314. (b) Shintani, R.; Takatsu, K.;
Hayashi, T. Chem. Commun. 2010, 46, 6822. (c) Lai, H.; Huang, Z; Wu, Q.;
Qin, Y. J. Org. Chem. 2009, 74, 283. (d) Toullec, P. Y.; Japt, R. B. C.; Vries,
J. G.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2006,8, 2715. (e) Shintani, R.;
Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353.
(9) Addition of aryl and alkenylsilanes: Tomita, D.; Yamatsugu, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946.
Our studies commenced with the evaluation of several
Michael acceptors for the desired process (Scheme 2).20
Cinnamoylpyrrole (4) and the corresponding indole 5 were
cleanly converted to spirocyclic oxindole 2a21 in excellent
yields with moderate diastereo- and enantioselectivities.
Attenuating the reactivity of the Michael acceptor by
employing methyl cinnamate (6) significantly increased
the enantioselectivity to 95% ee. In this case, open chain
product 3 was also isolated in 19% yield and 97% ee as a
single diastereomer. The corresponding phenyl ester based
Michael acceptor 7 afforded 2a exclusively in excellent
yield, 9.2:1 dr, and 96% ee. Subsequent variation of the
reaction temperature, solvent, metal, ligand, and substrate
did not improve upon this initial lead (Table 1, entry 1).
Lowering the reaction temperature to rt slightly decreased
the diastereoselectivity without affecting the enantioselec-
tivity (entry 2), but lowering the reaction concentration
significantly decreased the diastereoselectivity (entry 3).
The catalyst prepared in THF provided the desired prod-
uct in comparable enantioselectivity, albeit in lower yield
and diastereoselectivity (entry 4). When THF was em-
ployed as the solvent, 2a was obtained in 98% ee but with
modest diastereoselectivity (entry 5). The reaction was
sluggish in toluene and dichloromethane, presumably
due to poor solubility of 1a in either of these solvents
(entries 6 and 7). However, in both cases 1a was obtained
as a single diastereomer and with excellent enantioselec-
tivity. The analogous dinuclear magnesium catalyst22
furnished the desired product in only 51% ee and 2.3:1
(10) Allylation: (a) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.;
Fettinger, J. C.; Franz, A. K. Angew. Chem. Int. Ed. 2010, 49, 744.
(b) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed. 2009,
48, 6313. (c) Qiao, X.-C.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2009, 20, 1254. (d) Kitajima, M.; Mori, I.; Arai, K.;
Kogure, N.; Takayama, H. Tetrahedron Lett. 2006, 47, 3199.
(11) (a) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Adv. Synth.
Catal. 2010, 352, 1621. (b) Itoh, T; Ishikawa, H.; Hayashi, Y. Org. Lett.
2009, 11, 3854. (c) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru, T. Chem.;Eur. J. 2008, 14, 8079. (d) Malkov, A. V.;
ꢀꢁ
ꢀ
Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.; Pluhackova,
ꢁ
ꢀ
K.; Kocovsky, P. Org. Lett. 2007, 9, 5473. (e) Chen, J.-R.; Liu, X.-P.;
Zhu, X.-Y.; Li, L.; Qiao, Y.-F.; Zhang, J.-M.; Xiao, W.-J. Tetrahedron
2007, 63, 10437. (f) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.;
Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418.
(12) Deng, J.; Zhang, S.; Ding, P.; Jiang, H.; Wang, W.; Li, J. Adv.
Synth. Catal. 2010, 352, 833.
(13) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(14) During review of our manuscript, we found a similar report
using 3-hydroxyoxindoles as nucleophiles: Bergonzini, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2012, 51, 971.
(15) Michaelis, A. Chem. Ber. 1897, 30, 2809.
(16) (a) Hallmann, G. Chem. Ber. 1962, 95, 1138. (b) Hellmann, H.;
ꢀ
Hallmann, G.; Lingens, F. Chem. Ber. 1953, 86, 1346. (c) Stolle, R.;
Merkle, M. J. Prakt. Chem. 1934, 139, 329.
(17) (a) Misaki, T.; Kawano, K.; Sugimura, T. J. Am. Chem. Soc.
2011, 133, 5695. (b) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am.
Chem. Soc. 2011, 133, 5695. (c) Hynes, P. S.; Stranges, D.; Stupple, P. A.;
Guarna, A.; Dixon, D. J. Org. Lett. 2007, 9, 2107. (d) Trost, B. M.;
Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004, 126, 1944. (e) Harada,
S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 2582. (f) Kumagai, N.; Matsunaga, S.; Kinoshita,
T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 2169.
(18) Pioneering organocatalytic approaches: (a) Enders, D.; Grondal,
C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005, 44, 4079.
(b) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077.
(c) Notz, W.; Watanabe, S.; Chowdari, N. S.; Zhong, G.; Betancort, J. M.;
Tanaka, F.; Barbas, C. F., III. Adv. Synth. Catal. 2004, 346, 1131. (d) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827.
(19) Multimetallic catalysis: (a) Matsunaga, S.; Sugita, M.; Yamagiwa,
N.; Handa, S.; Yamaguchi, A.; Shibasaki, M. Bull. Chem. Soc. Jpn.
2006, 79, 1906. (b) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M.
Tetrahedron Lett. 2006, 47, 3985. (c) Harada, S.; Handa, S.; Matsunaga,
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365. (d) Sugita, M.;
Yamaguchi, A.; Yamagiwa, N.; Handa, S.; Matsunaga, S.; Shibasaki,
M. Org. Lett. 2005, 7, 5339. (e) Matsunaga, S.; Yoshida, T.; Morimoto,
H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777. (f)
Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 4712. (g) Yoshikawa, N.; Suzuki, T.; Shibasaki, M.
J. Org. Chem. 2002, 67, 2556. (h) Trost, B. M.; Ito, H.; Silcoff, E.
J. Am. Chem. Soc. 2001, 123, 3367. (i) Yoshikawa, N.; Kumagai, N.;
Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2466.
(20) For examples of asymmetric conjugate addition reactions using
ProPhenol, see: (a) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.;
Wang, R. Org. Lett. 2010, 12, 1880. (b) Zhao, D.; Yuan, Y.; Chan,
A. S. C.; Wang, R. Chem.;Eur. J. 2009, 15, 2738. (c) Trost, B. M.;
Hisaindee, S. Org. Lett. 2006, 8, 6003. (d) Trost, B. M.; Hitce, J. S. J. Am.
€
Chem. Soc. 2009, 131, 4572. (e) Trost, B. M.; Muller, C. J. Am. Chem.
Soc. 2008, 130, 2438.
(21) Nair reported the racemic synthesis of 2a and related compounds
via the NHC-catalyzed conjugate umpolung of cinnamaldehydes in com-
bination with isatins: Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.;
Suresh, E. Org. Lett. 2006, 8, 507. During preparation of this manuscript,
the enantioselective variant of this reaction appeared in the literature: Sun,
L.-H.; Shen, L.-T.; Ye, S. Chem. Commun. 2011, 47, 10136.
Org. Lett., Vol. 14, No. 10, 2012
2447

dr(entry8). Replacing the phenyl substituentsof the ligand
with 1-naphthyl groups (L2) gave a racemic product with
the reversed sense of diastereoselection (entry 9), whereas
the ligand with 2-naphthyl groups (L3) provided 2a in 95%
ee but only 5.6:1 dr (entry 10). Interestingly, the Z-phenyl
cinnamate gave 2a in <10% yield and with poor stereo-
selectivity (entry 11).
2h). Acceptors containing heteroaromatic rings were ob-
tained with excellent ee’s (2iꢀ2k), as was ferrocene-
containing oxindole 2l, although in the latter case the yield
was modest, likely due to low solubility of the correspond-
ing ester. Use of R,β,γ,δ-unsaturated esters yielded the 1,4-
addition product exclusively, and the products were ob-
tained with excellent ee’s (2m and 2n). An ynenoate can
also be employed as an acceptor with a modest decrease in
enantioinduction (2o). Alkyl substitution of the acceptor is
also tolerated. The moderately sterically encumbered cyclo-
propyl group decreased the reaction conversion and 2p
was isolated in only 38% yield, but the smaller methyl
group gave 2q in 67% yield. Phenyl acrylate is also a
competent substrate, providing unsubstituted δ-lactone
2r. In addition to various acceptors, other nitrogen pro-
tecting groups on 3-hydroxyoxindole, such as allyl, meth-
oxymethyl, benzyl, and para-methoxybenzyl, perform well
in the desired reaction (2sꢀ2v).
Table 1. Selected Optimization Experimentsa
variation from the
standard conditionsb
yield
[%]c
ee
[%]e
entry
drd
1
none
89
9.2:1 96
2
rt instead of 40 °C
(92) 8.5:1 96
(98) 4.4:1 94
(71) 4.7:1 94
(94) 3.6:1 98
(20) >19:1 94
(41) >19:1 96
(54) 2.3:1 51
3f
4f
5f
6f
7f
8f
9f
10f
11
0.35 M instead of 0.60 M
THF instead of toluene
THF instead of CH3CN
toluene instead of CH3CN
CH2Cl2 instead of CH3CN
Bu2Mg instead of Et2Zn
L2 instead of L1
Scheme 3. Enantioselective Spirooxindole Formationa
(37) 1:1.8
0
L3 instead of L1
(86) 5.6:1 ꢀ95g
(Z)-phenyl cinnamate instead of 7
8
1.1:1 39
a All reactions run on a 0.25 mmol scale. b The dinuclear zinc catalyst
(0.0125 mmol, 5 mol %) prepared in toluene (0.13 mL) was injected to a
mixture of (E)-cinnamaldehyde (0.25 mmol) and (E)-phenyl cinnamate
(0.0127 mmol) in toluene (0.29 mL). The resulting mixture was stirred at
40 °C for 24 h. See Supporting Information for details. c Yields in par-
entheses were determined by 1H NMR relative to mesitylene as an internal
standard. d Determined by 1H NMR of the crude mixture. e Determined by
chiral HPLC analysis. f Reactions run at rt. g Opposite enantiomer.
With optimized conditions in hand, we evaluated the
scope of this reaction (Scheme 3). Substitution at the C4-
position of the aromatic group of the Michael acceptor is
well-tolerated, although the level of diastereoinduction is
somewhat dependent on its electronic properties (2bꢀ2d).
While the electron-donating 4-methoxy acceptor afforded
2b with 13.0:1 dr and 95% ee, the electron-withdrawing
4-chloro- (inductive) and 4-cyano (mesomeric) acceptors
gave the corresponding products with excellent ee but only
modest diastereoinduction. The 3,5-dimethoxy and 3,5-
dibromo substrates were converted to products 2e and 2f,
respectively, with moderate dr’s and high ee’s. The abso-
lute configuration was established unequivocally by single
crystal X-ray analysis of 2f to be (R,R) (Figure 1). Ortho-
substitution of the aromatic ring is also possible (2g and
a All reactions run on a 0.25 mmol scale. bIsolated yield. cDetermined by
1H NMR of the crude mixture. dDetermined by chiral HPLC. e24 h. fThe
absolute configuration was unambiguously determined to be (R,R) by the
X-ray analysis. See Figure 1 and Supporting Information for details.
The catalystisinvolvedinboththe Michael addition and
the subsequent transesterification23 (Scheme 4). When the
racemic uncyclized methyl ester rac-3 was subjected to the
(22) (a) Trost, B. M.; Malhotra, S.; Koschker, P.; Ellerbrock, P.
J. Am. Chem. Soc. 2012, 134, 2075. (b) Trost, B. M.; Malhotra, S.; Fried,
B. A. J. Am. Chem. Soc. 2009, 131, 1674.
(23) (a) Trost, B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S.
Chem.;Eur. J. 2008, 14, 7648. (b) Trost, B. M.; Mino, T. J. Am. Chem.
Soc. 2003, 125, 2410.
2448
Org. Lett., Vol. 14, No. 10, 2012

Scheme 5. Proposed Catalytic Cycle and Mode of Stereoinduction
Figure 1. Single crystal X-ray diffraction analysis of 2f.
reaction conditions, 2a was obtained in 80% yield in the
racemic form. The open-chained product 3 was isolated in
17% yield with 11% ee. This result indicates that the
stereochemistry of 3 is not recognized by the catalyst during
cyclization. Additionally, there might be the retro-Michael
reactionꢀrecombination process to induce some enantio-
selectivity. However, no formation of 2a was observed in
the absence of the dinuclear zinc ProPhenol complex.
zinc-ProPhenol-catalyzed tandem Michael additionꢀ
transesterification. This process represents a rare report
of 3-hydroxyoxindoles as an isatinic anion equivalent in a
catalytic enantioselective reaction, and the spirocylic oxi-
ndole products are the highly versatile synthetic building
block to provide various 3-alkyl-3-hydroxy-substitued
oxindoles. This underutilized compound24 provides a
new way of synthesizing oxindoles bearing a tertiary
alcohol at the stereogenic 3-position, and further efforts
on this topic are currently underway and will be reported
in due course.
Scheme 4. Zinc-ProPhenol Complex Is Necessary for the
Transesterification
Acknowledgment. We thank the National Science Foun-
dation for their support of our programs, and the post-
doctoral fellowships by the Uehara Memorial Foundation
(for the first 6 months) and JSPS-Postdoctoral Research
Fellowship (for the following period) to K.H. are gratefully
acknowledged. Prof. Allen Oliver (University of Notre
Dame) is gratefully acknowledged for XRD analysis.
Our proposed catalytic cycle is described in Scheme 5.
The first, 3-hydroxyoxindole is deprotonated by an ethyl-
zinc species to give I. Phenyl cinnamate then coordinates
the less hindered zinc atom (marked in red) to form II.
CꢀC bond formation to III followed by tautomerization
gives IV. This complex undergoes intramolecular transes-
terification to release the spirocyclic oxindole and regen-
erate the zinc phenoxide species that deprotonates another
equivalent of 3-hydroxyoxindole.
Supporting Information Available. Experimental pro-
cedures, characterization of the products, and crystal-
lographic data (CIF) for 2f. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a highly stereo-
selective synthesis of spirocyclic oxindoles via a dinuclear
(24) 3-Hydroxy-1-methylindolin-2-ones are sensitive to oxidation to
form the corresponding isatins.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2449