Complete transfer of chirality in an intramolecular, thermal [2 + 2] cycloaddition of allene-ynes to form non-racemic spirooxindoles

Article abstract of DOI:10.3762/bjoc.7.70

A thermal [2 + 2] cycloaddition reaction of allene-ynes has been used to transform chiral non-racemic allenyl oxindoles into chiral non-racemic spirooxindoles containing an alkylidene cyclobutene moiety. The enantiomeric excesses were determined by chiral lanthanide shift NMR analysis and the transfer of chiral information from the allene to the spirooxindole was found to be greater than 95%.

Full text of DOI:10.3762/bjoc.7.70

Complete transfer of chirality in an intramolecular,
thermal [2 + 2] cycloaddition of allene-ynes
to form non-racemic spirooxindoles
Kay M. Brummond* and Joshua M. Osbourn
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 601–605.
University of Pittsburgh, Department of Chemistry, Chevron Science
Center, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
doi:10.3762/bjoc.7.70
Received: 23 March 2011
Accepted: 26 April 2011
Published: 12 May 2011
Email:
Kay M. Brummond* - kbrummon@pitt.edu
* Corresponding author
This article is part of the Thematic Series "Allene chemistry".
Editor-in-Chief: J. Clayden
Keywords:
alkylidene cyclobutene; allene; allenyloxindole; chiral lanthanide shift
reagent; chiral transfer
© 2011 Brummond and Osbourn; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A thermal [2 + 2] cycloaddition reaction of allene-ynes has been used to transform chiral non-racemic allenyl oxindoles into chiral
non-racemic spirooxindoles containing an alkylidene cyclobutene moiety. The enantiomeric excesses were determined by chiral
lanthanide shift NMR analysis and the transfer of chiral information from the allene to the spirooxindole was found to be greater
than 95%.
Introduction
The [2 + 2] cycloaddition reaction of allenes and alkynes A isonitrile (3), we became interested in the synthesis of chiral
provides rapid entry into synthetically challenging alkylidene non-racemic spirooxindoles for application to natural product
cyclobutene ring systems. We, along with others, have demon- synthesis [5-7]. Herein, we disclose preliminary results demon-
strated the intramolecular variant of this reaction under thermal strating a complete transfer of chiral information from a chiral
conditions [1,2]. This thermally forbidden process is believed to non-racemic allene-yne to form an enantiomerically enriched
proceed via a biradical intermediate mechanism, a conclusion spirooxindole in a [2 + 2] cycloaddition reaction.
supported by both computational and experimental studies [3].
Recently, the scope of this method has been expanded to the Findings
synthesis of spirooxindole-containing skeletons 2 in a two-step This study commenced with the preparation of the enantiopure
one-pot process from propargyl acetates 1 [4] (Scheme 1). propargyl acetate 7 [8]. Treatment of racemic propargyl alcohol
Inspired by this rapid entry into the molecularly complex 4 with the (R)-acid chloride 5, DMAP, and pyridine resulted in
substructure 2, and the structural similarity to welwitindolinone propargyl ester 6 as a separable 4:1 mixture of diastereomers.
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Beilstein J. Org. Chem. 2011, 7, 601–605.
Scheme 1: Conversion of propargyl acetate 1 to spirooxindole 2 containing the core framework of welwitindolinone A isonitrile (3).
Scheme 2: Preparation of enantiopure propargyl acetate 7 (R = Ac).
Saponification of the major diastereomer of 6, followed by Next, the focus turned to the conversion of enantiomerically
acylation provided the propargyl acetate 7 in quantitative yield enriched propargyl acetate 7 to an enantiomerically enriched
(Scheme 2).
allene 8. It has been previously shown that delivery of an alkyl
group from an organocuprate in an SN2’ fashion occurs with
The enantiomeric purity of propargyl acetate 7 was determined retention of chiral information in the resulting allene [9]; thus
based on treatment of the compound with the chiral shift we began by screening cuprate conditions to form the desired
reagent (+)-Eu(hfc)3. Figure 1 shows the 1H NMR of the allenyloxindole 8 (Table 1). In order to generate the allene, we
racemic as well as the enantiomerically enriched propargyl examined various leaving groups (OMs, OMe, OAc), solvents
acetate upon treatment with the chiral shift reagent. Treating (THF, Et2O), and cuprates (lower and higher order
racemic acetate 7 with the chiral shift reagent enabled resolu- cyanocuprates). The reaction incorporating a mesylate as a
tion of the resulting diastereomeric complexes, which was evi- leaving group was problematic due to substrate instability
denced by the resonances for the aromatic proton labeled Ha in issues, even at low temperatures (Table 1, entry 1) and the
the spectrum shown below. The spectrum of racemic acetate 7 substrates containing –OMe and –OAc leaving groups were
contains two doublets at δ 7.54 and 7.52, while the spectrum of unreactive toward the lower order cuprates (Table 1, entries
enantiomerically enriched 7 shows only a single doublet at δ 2–5). The optimal conditions were found using the propargylic
7.54. Based on this result, the enantiomeric excess of enan- acetate and the higher order cuprate, t-Bu2Cu(CN)Li2 at −78 °C
tiomerically enriched acetate 7 is greater than 95%.
which gave compound 8 (R’ = tert-butyl) in 49% yield (Table 1,
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Beilstein J. Org. Chem. 2011, 7, 601–605.
entry 6). As a prelude to this proposed synthetic route, our
attempts to thermally rearrange the chiral non-racemic
propargyl acetate to form an enantiomerically enriched allenyl
acetate followed by tandem [2 + 2] cycloaddition to provide
directly a structure resembling compound 2, gave the racemic
spirooxindole product. This finding will be discussed in detail
in a full account of this work.
To examine the chiral transfer from the propargylic acetate 7 to
the allenyloxindole 8, a chiral 1H NMR shift analysis was
performed using (+)-Eu(hfc)3. The NMR spectra of the racemic
compound 8 as well as the enantiomerically enriched com-
pound 8 are shown in Figure 2. In the case of the racemic com-
pound, the resonances for the tert-butyl groups of the diastereo-
meric complexes are split into two distinct signals in the pres-
ence of the shift reagent; one singlet at δ 1.23 ppm and a second
singlet at δ 1.20 ppm. The enantiomerically enriched com-
pound 8 shows one singlet, corresponding to the resonance for
the tert-butyl group at δ 1.22 ppm; thus the enantiomeric excess
of allenyloxindole 8 is greater than 95%.
With the enantiomerically enriched allene-yne 8 in hand, we
were poised to test the transfer of chiral information under
thermal [2 + 2] reaction conditions. Irradiation of 8 in
o-dichlorobenzene with microwaves for 5 min at 225 °C
provided the desired spirooxindole 9 in 44% yield (Scheme 3).
Despite the somewhat low yield, the reaction is clean as judged
by TLC with the exception of some baseline material.
Figure 1: Chiral NMR shift analysis of propargyl acetate 7.
Table 1: Screening conditions for the formation of allenyloxindole 8.
Entry
R
Solvent
Temp
Cuprate
R’
Yield
1
2
3
4
5
6
Ms
Me
Ac
Ac
Ac
Ac
THF
Et2O
Et2O
THF
Et2O
THF
−45 °C
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
t-BuCu(CN)Li
Me
Me
Me
Me
t-Bu
0%a
0%b
0%b
0%c
0%b
49%d
0 to 35 °C
0 °C
−78 °C to rt
−78 °C
−78 °C
t-Bu2Cu(CN)Li2 t-Bu
aComplete decomposition of the mesylate (generated in situ) was observed prior to cuprate addition. bComplete recovery of starting material.
cStarting material was recovered in addition to the deacylation product. dThe product of a second addition of the tert-butyl group to the central carbon
of the allene was also isolated in 21% yield.
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Beilstein J. Org. Chem. 2011, 7, 601–605.
Figure 2: Chiral NMR shift analysis of allenyloxindole 8.
Figure 3: Chiral NMR shift analysis of spirooxindole 9.
Spirooxindole 9 was purified by column chromatography and Our working hypothesis for the mechanism for transfer of chiral
the transfer of chiral information was determined using chiral information from the allene to the spirooxindole-containing
1H NMR shift analysis.
cyclobutene is that the reaction still proceeds through the ther-
mally generated biradical intermediate, but the tert-butyl group
hinders rotation around the carbon–carbon bond as shown in
Figure 4, thus slowing racemization of the resulting radical
containing carbon. This hypothesis is supported by a report by
Pasto, where transfer of chiral information was incomplete in a
thermal, intermolecular [2 + 2] cycloaddition reaction between
2,3-pentadiene and methyl propiolate [10].
Scheme 3: Microwave irradiation of allenyloxindole 8.
Spirooxindole 9 was treated with 0.75 equiv of (+)-Eu(hfc)3 in
CDCl3. The resulting diastereomeric complexes were resolved
based upon the resonances at δ 3.98 and δ 3.87 ppm, which are
peaks that correspond to the methyl in the MOM group on the
oxindole nitrogen. For the enantiomerically enriched com-
pound 9, only a single resonance is observed at δ 4.05 ppm in
Figure 4: Thermally generated biradical intermediate 10.
the presence of the chiral shift reagent. Based on this analysis, In summary, there are only a few general methods to prepare
the product was formed with greater than 95% enantiomeric carbocyclic spirooxindoles non-racemically [11-14]; we have
excess (Figure 3).
demonstrated the first thermal, intramolecular [2 + 2] cycload-
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Beilstein J. Org. Chem. 2011, 7, 601–605.
dition reaction of an allene-yne that generates a chiral non-
racemic spirooxindole from a chiral non-racemic allene.
Furthermore, this reaction could also be applicable in the
enantioselective synthesis of natural products that contain a
spirooxindole core, such as welwitindolinone A isonitrile. We
are currently working to expand the scope of this chirality
transfer to other allenyl systems possessing less bulky and/or
traceless groups.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
Supporting Information
(http://www.beilstein-journals.org/bjoc)
Supporting Information File 1
General methods, experimental and spectral data for all
new compounds.
The definitive version of this article is the electronic one
which can be found at:
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-70-S1.pdf]
doi:10.3762/bjoc.7.70
Acknowledgements
Generous support from the National Science Foundation is
gratefully acknowledged (NSF 0910597).
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