Organic Letters
Letter
acylic α-substituted acrolein, fumarate, or isobutylidene
malonate unit. Expected products were commonly obtained in
moderate to excellent yields as a single diastereomer, indicating
that the methodology is synthetically practicable.
Table 3. Diels−Alder Adducts Derived from Ketone-
dienolates
More importantly, many are structurally unambiguously
identified by X-ray analysis, lending substantial evidence to
Diels−Alder chemistry claimed for this novel [4 + 2] annulation.
For example, products 15 (89%) and 25 (90%),13 formed
exclusively in high yields as a single stereoisomer, are considered
to be typically governed by the ortho and endo addition rule with
complete face selectivity via effectively shielding the gem-
dimethyl side of verbenone. Product 30 (84%),13 containing
four contiguous stereogenic centers precisely predicted by the
ortho and endo rule, also provides strong support for a concerted
Diels−Alder approach. Encouragingly, when starting α-
aldehyde β-methyl alkenones allow both γ and γ′ sites to
undergo deprotonation, the desired aldehyde-dienolate prod-
ucts are still constantly formed in good to excellent yields (77−
96%) as seen in 12−14, 17, 18, 23, 26, 27, 29−33, and 35−37,
with the exception of 18 (53%) in a moderate yield, presumably
because of the obstruction of the transannular strain in medium
rings. Nevertheless, when products 31 (85%) and 35 (79%)
were isolated, the corresponding ketone-dienolate adducts 31a
identified in 8% and 10% yield, indicating that cisoid dienolates
through enolization of γ′ protons could also be formed and
captured by certain active dienophiles such as N-phenylmaleic
imide. A single diastereomer 21 (84%) obtained exclusively also
supports that a concerted approach should be adopted as both
cisoid and transoid dienolates were generated during the
reaction. Indeed, the highly conserved configuration of the
dienophile during the transformation into the corresponding
product is hard to explain if a two-step Michael−Aldol addition
is thought to be a preferred pathway.
a
Reactions were performed in THF (0.2 M) with Na2CO3 (1.2 equiv)
b
c
under N2. Reaction was carried out in a sealed tube. 2.0 equiv of
dienophile was used instead. The relative configuration was
determined by a single-crystal X-ray analysis.
d
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures and spectroscopic data for all
Accession Codes
To further confirm whether ketone-dienolate D−A adducts
are synthetically useful and general, a series of α-aldehyde
cycloalkenones, containing only γ′ protons, or α-ester cyclo-
alkenones, containing γ and/or γ′ protons, were designed in
order to generate merely the ketone-type cisoid dienolate.
Results are listed in Table 3. As predicted by a concerted endo-
addition approach, all products 38−46 were obtained with high
regio- and stereoselectivity in good to high yields (71∼95%).17
Products 38−41, produced at higher temperature (100 °C) than
their α-aldehyde counterparts 42−46 (66 °C), are somewhat
contradictory because dienolates containing a weaker electron-
withdrawing ester group should be more reactive in terms of
inductive effects. These reverse outcomes might result from the
steric hindrance caused by the ester group during cycloaddition.
In conclusion, unprecedented anionic Diels−Alder chemistry
of highly electron-deficient cross-conjugated vinylogous systems
has been newly developed, in which the cyclic sodium dienolate
ion pairs, generated in situ in the presence of a weak sodium base
in THF, are highly thermally stable and operationally simple to
play the role of electron-rich dienes during reactions. Products
thus obtained contain multiple contiguous chiral centers, whose
stereochemical arrangements could be accurately predicted by
the ortho and endo rule, thus strongly supporting a concerted [4
+ 2] cycloaddition rather than a consecutive Michael−Aldol
type annulation.
the supplementary crystallographic data for this paper. These
or by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
AUTHOR INFORMATION
Corresponding Author
■
Kak-Shan Shia − Institute of Biotechnology and Pharmaceutical
Research, National Health Research Institutes, 35053 Taiwan,
Author
Jing-Kai Huang − Institute of Biotechnology and
Pharmaceutical Research, National Health Research
Institutes, 35053 Taiwan, R.O.C.
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
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Org. Lett. 2021, 23, 5709−5713