Asymmetric pericyclic cascade approach to spirocyclic oxindoles

Article abstract of DOI:10.1021/ol300982f

The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of enantioselectivity (90-99% ee) via a pericyclic cascade process.

Full text of DOI:10.1021/ol300982f

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2762–2765
Asymmetric Pericyclic Cascade Approach
to Spirocyclic Oxindoles
ꢀꢁ ꢀ
Edward Richmond, Nicolas Duguet, Alexandra M. Z. Slawin, Tomas Lebl, and
Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh,
St. Andrews, KY16 9ST, U.K.
ads10@st-andrews.ac.uk
Received April 16, 2012
ABSTRACT
The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of
enantioselectivity (90ꢀ99% ee) via a pericyclic cascade process.
Spirocyclic oxindoles are an important structural motif
central to a variety of both natural products1 and phar-
maceutically relevant materials.2 Synthetic routes to 3,3-
disubstituted oxindoles bearing a spiro-heterocyclic frame-
work (such as 3,30-pyrrolidines) are relatively common.3
However, routes that access 3,3-spirocarbocyclic oxi-
ndoles, especially asymmetric strategies, are relatively
less explored, with the alkaloid natural product gelsemine
providing a major impetus for synthetic exploration.4
Prominent examples of approaches toward spirocarbocyc-
lic oxindoles include Lewis acid mediated cyclizations,5
adaptations of classic Fischer indole chemistry and other
[3,3]-sigmatropic rearrangements,6 radical cyclizations,7
catalytic asymmetric domino/tandem processes,8 as well
as transition-metal- and organo-catalyzed asymmetric
cycloadditions,9 among others.10 Overman’s extensive
(5) (a) England, D. B.; Merey, G.; Padwa, A. Org. Lett. 2007, 9, 3805–
3807. (b) Gorokhovic, I.; Neuville, L.; Zhu, J. Org. Lett. 2011, 13, 5536–
5539.
(6) (a) Mao, Z.; Baldwin, S. W. Org. Lett. 2004, 6, 2425–2428. (b) Liu,
K. G.; Robichaud, A. J. Tetrahedron Lett. 2007, 48, 461–463.
(7) (a) Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.;
Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943–
6944. (b) Dutton, K. J.; Steel, R. W.; Tasker, A. S.; Popsavin, V.;
Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 765–766.
(8) (a) Miyamoto, H.; Okawa, Y.; Nakazaki, A; Kobayashi, S.
Angew. Chem., Int. Ed. 2006, 45, 2274–2277. (b) Bencivenni, G.; Wu,
L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli,
G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200–7203. (c) Jiang,
K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.;Eur. J. 2010, 16,
2852–2856. (d) Lan, Y.-B.; Zhao, H.; Liu, Z.-M.; Liu, G.-G.; Tao, J.-C.;
Wang, X.-W. Org. Lett. 2011, 13, 4866–4869. (e) Wang, L.-L.; Peng, L.;
Bai, J. F.; Jia, L. N.; Luo, X.-Y.; Huang, Q.-C.; Xu, X.-Y.; Wang, L.-X.
Chem. Commun. 2011, 47, 5593–5595.
(9) (a) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396–12397. (b) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12,
1008–1011. (c) Tan, B.; Hernandez-Torres, G.; Barbas, C. F., III. J. Am.
Chem. Soc. 2011, 133, 12354–12357.
(10) (a) Wenkert, E.; Liu, S. Synthesis 1992, 323. (b) Feldman, K. S.;
Karatjas, A. G. Org. Lett. 2006, 8, 4137–4140. (c) Pettersson, M.;
Knueppel, D.; Martin, S. F. Org. Lett. 2007, 9, 4623–4626. (d) Richter,
J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.; Llamas, T.; Pohjakallio,
A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17938–17954.
(1) For a review, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209–2219. For selected papers, see: (b) Fischer, C.;
Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000, 83, 1175–1181. (c)
Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002, 124, 14826–
14827. (d) Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42,
694–696.
(2) (a) Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 2003, 59,
4615–4622. (b) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella,
M.; Schuermann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H.
Nature Chem. 2010, 2, 735–740.
(3) For a review, see: (a) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748–8758. For select recent strategies, see: (b)
Lakshmaiah, G.; Kawabata, T.; Shang, M.; Fuji, K. J. Org. Chem. 1999,
64, 1699–1704. (c) Kumar, U. K. S.; Ila, H.; Junjappa, H. Org. Lett.
2001, 3, 4193–4196. (d) Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti,
M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447–8453. (e) Trost, B. M.;
Brennan, M. K. Org. Lett. 2006, 8, 2027–2030. (f) Castaldi, M. P.;
Troast, D. M.; Porco, J. A., Jr. Org. Lett. 2009, 11, 3362–3365. (g)
Zhang, Y.; Panek, J. S. Org. Lett. 2009, 11, 3366–3369. (h) Cao, Y.;
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(4) For a review of strategies toward syntheses of gelsemine, see: Lin, H.;
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r
10.1021/ol300982f
Published on Web 05/14/2012
2012 American Chemical Society

intramolecular Heck studies have been used to great effect
in the synthesis of both gelsemine11 and spirotryprostatin
B,12 and epitomize the principal strategies employed in
construction of these motifs. Much attention is now fo-
cused upon asymmetric variants of these reactions.13
We have previously developed an asymmetric route
to 3,3-oxindoles (up to 91% ee) through treatment of
isolable alkylarylketenes with Garner’s aldehyde derived N-
arylnitrones.14 A computational rationale and optimization
of the observed stereoselectivity in this process, consistent
with a pericyclic cascade comprising a [3 þ 2]-cycloaddition
followed by [3,3]-sigmatropic rearrangement, has been
reported.15 Herein, we apply this methodology to the
synthesis of a range of achiral and chiral 3,3-spirocarbocyc-
lic oxindoles, while demonstrating the robustness of this
process by using ketenes prepared in situ (Figure 1).
Figure 3. Synthesis of 3,3-spirocyclic oxindoles.
Scheme 1. Asymmetric Spirooxindole Formation and Molecu-
lar Representation of X-ray Structure of 22
Figure 1. Proposed synthesis of spirocyclic oxindoles.
Initial proof of concept studies used zinc-mediated
reduction of acyl bromide 1 to access pentamethyleneke-
tene 2 in situ,16 with addition of nitrone 3 giving oxindole 6
in 65% yield. Following this procedure, 5-substituted
oxindoles 7 and 8 were prepared in 48 and 56% yield,
respectively, from the corresponding 4-substituted N-ar-
ylnitrones (Figure 2).
Further investigations used the known, stable hexa-
methyleneketene 1217 in combination with a range of
N-arylnitrones. In an optimized procedure, treatment of
(12) Overman, L. E.; Rosen, M. D. Tetrahedron 2010, 66, 6514–6525.
(13) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6477–6487. (b) Overman, L. E.; Watson,
D. A. J. Org. Chem. 2006, 71, 2587–2599.
(14) Duguet, N.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2009, 11,
3858–3861.
€
(15) C-elebi-Olc-um, N.; Lam, Y.-h.; Richmond, E.; Ling, K. B.;
Smith, A. D.; Houk, K. N. Angew. Chem., Int. Ed. 2011, 50, 11478–
11482.
€
Figure 2. Initial proof of concept study.
(16) Allen, A. D.; Tidwell, T. T. J. Am. Chem. Soc. 1987, 109, 2774–
2780.
(11) Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.;
Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054–18065.
(17) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578–
1579.
Org. Lett., Vol. 14, No. 11, 2012
2763

Figure 5. Proposed mechanism and rationalization of
stereocontrol.
cyclization. However, the use of more forcing acidic con-
ditions as a workup step (6 M HCl) ensured complete
imine hydrolysis and cyclization to the desired oxindole
(Scheme 1). In an optimized process, treatment of nitrone
19 with ketene 20 gave, after aqueous workup, the desired
asymmetric oxindole 22 in 91% yield and 98% ee
(Scheme 1), with spectroscopic data in agreement with
that previously reported for the racemate by Padwa.5a The
absolute configuration within (S)-22 was confirmed by
single-crystal X-ray diffraction,20 with the observed sense
ofasymmetricinduction consistentwithour previouswork
using simple disubstituted alkylarylketenes.14
Having demonstrated in our initial studies that crude
solutions of ketene are tolerated in this reaction process,
the generality of this asymmetric process was investigated
by treatment of a series of TIPBS-substituted N-arylni-
trones 24ꢀ28 with in situ prepared carbocyclic alkyl-
arylketenes. The desired ketenes were prepared via
Figure 4. Asymmetric spirocyclic oxindole synthesis; scope.
nitrone 3 with ketene 12 gave oxindole 13 in 79% isolated
yield. Similar levels of reactivity were observed with a
range of substituted N-arylnitrones incorporating both
electron-donating and -withdrawing 4-substituents, as well
as 2-substitution, giving selectively the respective 5- and
7-substituted oxindoles 14ꢀ18 that were isolated in good
to excellent yields (68ꢀ92%) (Figure 3).
An asymmetric spirocyclic oxindole synthesis was next
investigated using TIPBS = 2,4,6-triisopropylbenzenesul-
fonyl nitrone 19 and known, isolable ketene 20.18 In
preliminary studies, low yields of the oxindole 22 were
obtained, withintermediate imino acid21(99:1dr) isolated
as the major component of the crude reaction mixture.19
In contrast to our previous studies,14 spirocyclic imino acid
21 is stable to mild acidic hydrolysis and concomitant
(20) Crystallographic data for 22 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 871574.
(21) A one-pot preparation was also investigated; however, in the
presence of base, the nitrone and acid chloride form, through a re-
arrangement process, the amide rather than the ketene. For further
details, see: Heine, H. W.; Zibuck, R.; VandenHeuvel, W. J. A. J. Am.
Chem. Soc. 1982, 104, 3691–3694.
(18) Hodous, B. L.; Ruble, C. J.; Fu., G. C. J. Am. Chem. Soc. 1999,
121, 2637–2638.
(19) See the Supporting Information for full characterization data of
intermediate 21.
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Org. Lett., Vol. 14, No. 11, 2012

dehydrohalogenation of the corresponding acid chloride
with Me2NEt, readily synthesized from the requisite tetra-
lone in a scalable, multigram procedure (see the Supporting
Information), and were used as crude solutions in THF after
stereodefined cyclic intermediate 39. Subsequent [3,3]-sig-
matropic rearrangement yields further intermediate 40 that
undergoes rearomatization and tautomerization to yield
imino acid precursor 41. Acidic hydrolysis and cyclization
then yields the oxindole with excellent levels of enantiocon-
trol and also regenerates chiral aldehyde 23 (Figure 5).23
In conclusion, we have extended the scope of this chiral
auxiliary approach to the asymmetric synthesis of spirocyc-
lic oxindoles (up to 99% ee). This methodology is robust,
tolerating in situ generated crude ketene solutions without
the need for their isolation, improving the versatility of this
process and avoiding the need for ketene purification by
distillation. Further extensions of this methodology includ-
ing the development of a catalytic version of this transfor-
mation and applications in natural product synthesis are
ongoing and will be reported in due course.
filtration of Me2NEt HCl.21 This process is tolerant of
3
2- and 4-substitution within the N-aryl unit of the chiral
nitrone, allowing selective access to the corresponding 5- and
7-substituted oxindoles 29ꢀ38 that were isolated in good
yield (48ꢀ97%) and excellent ee (90ꢀ99%) (Figure 4).22
In congruence with the previous mechanistic elucidation
of this transformation,15 the observed asymmetry can be
rationalized through initial enantioselective [3 þ 2] cycload-
dition of nitrone across the ketene CdO bond, with pre-
ferential anti-addition with respect to the aryl portion of the
ketene. Facial selectivity in this cycloaddition is governed by
1,3-allylic strain in the nitrone chiral auxiliary, generating
Acknowledgment. We thank the Royal Society for a
University Research Fellowship (A.D.S.), The Lever-
hulme Trust (N.D.), and Cancer Research UK (E.R.) for
funding and the EPSRC mass spectrometry facility.
(22) The absolute configurations of 29ꢀ38 were assigned by analogy
to that established for oxindole 22.
(23) To demonstrate the recyclability of TIPBS nitrone 19, the
following representative experiment was performed. TIPBS nitrone 19
(0.075 g, 0.154 mmol) and ketene 20 (0.029 g, 0.185 mmol) gave, under
standard reaction conditions (see the Supporting Information; general
procedure F), oxindole 22 (0.035 g) in 90% yield and 98% ee with chiral
aldehyde 23 (0.045 g) recovered in 74% yield. Aldehyde 23 (0.045 g,
0.114 mmol) was then treated with PhNHOH (0.015 g, 0.137 mmol),
regenerating nitrone 19 (0.055 g) in 99% yield after trituration with
petroleum ether. The regenerated TIPBS nitrone 19 (0.050 g, 0.103
mmol) and ketene 20 (0.020 g, 0.123 mmol) gave oxindole 22 (0.012 g) in
46% yield and 91% ee with chiral aldehyde 23 (0.025 g) once more
recovered in 61% yield.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and HPLC data for all pro-
ducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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