Kojic acid and maltol: The “Transformers” in organic synthesis

Article abstract of DOI:10.1016/j.cclet.2020.06.034

The deconstructive reorganization strategy for the synthesis of benzene-containing products from the kojic acid- and maltol-derived alkynes has been recently reported. In this strategy, kojic acid and maltol are analogous to the “Transformers”, which can

Full text of DOI:10.1016/j.cclet.2020.06.034

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Kojic acid and maltol: The “Transformers” in organic synthesis
Jianqiang Chena, Lingwei Wua, Jie Wua,b,
*
a
School of Pharmaceutical and Materials Engineering &Institute for Advanced Studies, Taizhou University, Taizhou 318000, China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Available online xxx
The deconstructive reorganization strategy for the synthesis of benzene-containing products from the
kojic acid- and maltol-derived alkynes has been recently reported. In this strategy, kojic acid and maltol
are analogous to the “Transformers”, which can transform into benzofurans and benzaldehydes via
annulation reactions. Under the synthetic standpoint, this deconstructive reorganization strategy
features high atom economy, innate scalability and functional group tolerance. In the near future, we
believe that this unique method will be widely investigated and other novel transformations of kojic acid
and maltol will be discovered.
Keywords:
Kojic acids
Maltols
Rearrangement
Deconstructive reorganization
Benzofurans
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Rearrangement manipulations of compounds are widely found
in the chemical transformations taking place both in scientific
laboratories and nature [1,2]. In particular, scientists have studied
the rearrangement properties of molecules bearing unsaturated
bonds, such as carbonyl- and alkynyl-containing compounds, for
decades [2]. If applied appropriately, synthetic chemists may
synthesize the complex natural products from simple substrates.
In fact, reconstruction manipulations possess many benefits over
traditional general transformations, such as innate scalability, high
atom economy, functional group tolerance and high degree of
regioselectivity and stereoselectivity [1,2].
Pyrone moiety is widely found in the core structure of organic
synthetic intermediates, natural products and bioactive com-
pounds [3]. For example, the kojic acid and maltol which have been
extensively investigated and numerous transformations have been
described in organic synthesis [3–5]. Traditionally, Kojic acid and
maltol have been widely used in [5 + 2] cycloaddition reactions,
during which seven-membered rings can be formed in a single
step [4]. Maltol-type [5 + 2] cycloaddition reactions involve the
formation of an oxidopyrylium zwitterion as the reactive
intermediate. As shown in Scheme 1a, the main body structure
of substrates can also be found in the products in these
transformations [5]. Additionally, a bridging oxygen atom can be
formed during the process. The related examples of the inter- and
intramolecular [5 + 2] cycloaddition reactions occur upon
treatment of zwitterionic intermediates with unsaturated car-
bon-carbon double bonds.
In pyrone-based rearrangement, kojic acids and maltols are
commonly used as substrates to generate benzofurans and
benzaldehydes. As shown in Scheme 1b, compared with [5 + 2]
cycloaddition reactions, the deconstructive reorganization strate-
gies are general description of the bond-breaking reactions of CÀÀO
bonds and the construction of benzofurans or benzaldehydes in a
single step.
The cascade Claisen rearrangement of the pyrone-containing
substrates, such as maltol propargyl ether 1, was reported
(Scheme 2) [6]. In this case, the thermal [3,3]-sigmatropic
rearrangement of maltol propargyl ether 1 to the corresponding
1,5-ene-allene intermediate 4 occurred under the high tempera-
ture. And then, the intermediate 4 was subjected to a second
Claisen rearrangement to provide the aldehyde 5 that was
converted to the key intermediate 6 after the keto-enol tautome-
rization. The 1,6-Michael addition of intermediate 6 was achieved
by treatment with an alkene 2 and the resulting 7 could be
transformed to the intermediate 8 after Friedel-Crafts alkylation.
Finally, the generated species 8 underwent intramolecular 1,5-
hydrogen transfer reaction to give the final product. In this
transformation, the maltol moiety was taken apart and then
reorganized into a benzene ring bearing an aldehyde group.
Preparation of polysubstituted salicylaldehydes by this cut-
and-sew strategy was described (Scheme 3) [7]. Under the similar
reaction conditions, Zhu and co-workers utilized an intramolecular
double Claisen rearrangement for the efficient construction of the
p-quinone-methide framework 12 which was similar to interme-
diate 6. Subsequently, the vinyl ether, trimethoxybenzene and
* Corresponding author at: School of Pharmaceutical and Materials Engineering
&Institute for Advanced Studies, Taizhou University, Taizhou 318000, China.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
https://doi.org/10.1016/j.cclet.2020.06.034
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: J. Chen, et al., Kojic acid and maltol: The “Transformers” in organic synthesis, Chin. Chem. Lett. (2020), https://
doi.org/10.1016/j.cclet.2020.06.034

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Scheme 1. Pyrone-based transformations.
Scheme 2. Cascade Claisen rearrangement of the pyrone-containing substrates: general strategy, mechanism and selected scope of the products.
benzylthiol could be used as nucleophiles to trap the intermediate
12 leading to the final products.
It is well-known that keto alkynes can undergo cyclization to
form isomeric products [2a]. This deconstructive reorganization
strategy was demonstrated for the synthesis of benzofuran-
containing products from the kojic acid- and maltol-derived
alkynes (Scheme 4) [8]. In this case, activation of the carbon-
carbon triple bond with the indium salt generated a p-complex 15,
Please cite this article in press as: J. Chen, et al., Kojic acid and maltol: The “Transformers” in organic synthesis, Chin. Chem. Lett. (2020), https://
doi.org/10.1016/j.cclet.2020.06.034

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3
Scheme 3. Preparation of polysubstituted salicylaldehydes by the cut-and-sew strategy: general strategy, mechanism, and selected scope of the products.
Scheme 4. Substrate scope for the cycloisomerization of kojic acid- and maltol-derived alkynes: general strategy, mechanism and selected scope of the products.
which could undergo the 5-endo-dig cyclization to provide the
pyrylium 17. The highly activated intermediate 17 could be
hydrolyzed to the stabilized 1,5-dicarbonyl compound 18, which
would then convert to ketol 19 through the intramolecular
aldol cyclization. The generated intermediate 19 underwent
dehydration and aromatization giving rise to the dihydroxylated
benzofuran 14. As the six-carbon synthons, the kojic acid and
maltol moieties of the substrates were deconstructed and then
reorganized into the hydroxylated benzene rings. At the beginning,
kojic acid-derived alkynes with a hydroxyl group were readily
converted to the corresponding C5, C6-dihydroxyl benzofurans
using In(OTf)3 as the alkynophilic catalyst. Under the same reaction
Please cite this article in press as: J. Chen, et al., Kojic acid and maltol: The “Transformers” in organic synthesis, Chin. Chem. Lett. (2020), https://
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Scheme 5. Total synthesis of benzofuran-containing natural products.
conditions, other reactants could be converted into the corre-
sponding C6-substituted, C5, C6-disubstituted and C4, C5, C6-
trisubstituted benzofurans. As a result, four kinds of substituted
benzofurans were synthesized with kojic acid-derived alkynes as
the starting materials. Encouraged by the positive results described
above, other substituted benzofurans could be prepared under the
conditions when maltol derivatives were used as the substrates.
Likewise, maltol-derived alkynes could also be easily transformed
into the C4-substituted and C4, C5-disubstituted benzofurans
bearing an unprotected hydroxyl group in good yields.
The hydroxylated benzofuran moiety is widely found in the
structure of drug candidates and natural products [9]. This
deconstructive reorganization strategy mentioned above would
be useful for the synthesis of natural products containing the
benzofuran moiety. In the past, the major challenge was how to
construct the substituents at different positions of the benzofuran
scaffold. Now, this challenge can be solved with this new strategy.
Treatment of kojic acid- and maltol-derived alkynes under
the general reaction conditions provided the hydroxylated
benzofurans, which were subsequently subjected to derivatization
with different reagents providing diverse hydroxylated benzo-
furan-containing natural products. To confirm the practicability
of this methodology, various benzofuran-containing natural
products, such as Cuspidan B, Alfafuran, Coumestrol and Witti-
furan E, were synthesized (Scheme 5) [8].
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (Nos. 21871053 and 21532001) and the Leading Innovative
and Entrepreneur Team Introduction Program of Zhejiang
(No. 2019R01005) is gratefully acknowledged.
References
[1] (a) Z.M. Chen, X.M. Zhang, Y.Q. Tu, Chem. Soc. Rev. 44 (2015) 5220–5245;
(b) J.B. Sweeney, Chem. Soc. Rev. 38 (2009) 1027–1038;
(c) R.A. Fernandes, P. Kattanguru, S.P. Gholap, D.A. Chaudhari, Org. Biomol.
Chem. 15 (2017) 2672–2710;
(d) Z.L. Song, C.A. Fan, Y.Q. Tu, Chem. Rev. 111 (2011) 7523–7556;
(e) C. Wang, X. Huang, X. Liu, et al., Chin. Chem. Lett. 31 (2020) 677–680;
(f) W. Li, L. Shu, Q. Wang, G. Li, Y. Shan, Chin. J. Org. Chem. 39 (2019) 1976–1982;
(g) F. Wang, J. Wang, Y. Zhang, J. Yang, Chin. Chem. Lett. 31 (2020) 677–680;
(h) C.X. He, Z.B. Jiang, H.Q. Cui, D.L. Yin, Chin. Chem. Lett. 27 (2016) 1036–1039;
(i) X. Wu, J. Lei, Z.L. Song, Chin. Chem. Lett. 22 (2011) 306–309.
[2] (a) L. Chen, K. Chen, S. Zhu, Chem 4 (2018) 1208–1262;
(b) A.V. Gulevich, A.S. Dudnik, N. Chernyak, V. Gevorgyan, Chem. Rev. 113 (2013)
3084–3213;
(c) H. Wang, Y. Kuang, J. Wu, Asian J. Org. Chem. 1 (2012) 302–312;
(d) A.L.S. Kumari, A.S. Reddy, K.C.K. Swamy, Org. Biomol. Chem. 14 (2016) 6651–
6671;
In summary, the highlighted reports demonstrate the unique
application of deconstructive reorganization strategy to unlock
new reactivity in organic synthesis. This strategy is general
description of the intramolecular bond-breaking reactions of
several old bonds and the construction of several new bonds in one
step. With this novel method, the main body structure of kojic
acids and maltols, as a five- or six-carbon synthon, was taken apart
and then reorganized into a benzene ring bearing an unprotected
hydroxyl group, and a series of benzofuran-containing natural
products have been constructed. In this strategy, kojic acid and
maltol are analogous to the “Transformers” which are characters in
Marvel comics. Under the synthetic standpoint, this deconstructive
reorganization strategy features high atom economy, innate
scalability and functional group tolerance. In the near future, we
believe that this unique method will be widely investigated and
other novel transformations of kojic acid and maltol will be
discovered.
(e) L. Yang, L. Wei, J.P. Wan, Chem. Commun. 54 (2018) 7475–7478;
(f) F. Peng, Q. Zhao, W. Huang, et al., Green Chem. 21 (2019) 6179–6186.
[3] (a) C.F. Zhu, S. Battah, X. Kong, et al., Bioorg. Med. Chem. Lett. 25 (2015) 558–561;
(b) Q. Zhang, N.P. Bottingz, C. Kay, Chem. Commun. 47 (2011) 10596–10598;
(c) M.A. Telpoukhovskaia, B.O. Patrick, C. Rodríguez-Rodríguez, C. Orvig, Bioorg.
Med. Chem. Lett. 26 (2016) 1624–1628;
(d) P.A. Wender, N. Buschmann, N.B. Cardin, et al., Nat. Chem. 3 (2011) 615–619.
[4] (a) K.E.O. Ylijoki, J.M. Stryker, Chem. Rev. 113 (2013) 2244–2266;
(b) M.E. Garst, B.J. McBride, J.G. Douglass III, Tetrahedron Lett. 24 (1983) 1675–
1678.
[5] G. Mei, H. Yuan, Y. Gu, et al., Angew. Chem. Int. Ed. 53 (2014) 11051–11055.
[6] T. Cao, Y. Kong, K. Luo, L. Chen, S. Zhu, Angew. Chem. Int. Ed. 57 (2018) 8702–
8707.
[7] T. Cao, L. Chen, S. Zhu, Org. Lett. 21 (2019) 90–94.
[8] (a) L. Zhang, T. Cao, H. Jiang, S. Zhu, Angew. Chem. Int. Ed. 59 (2020) 4670–4677;
(b) Z. Guan, H. Zhu, Chin. J. Org. Chem. 40 (2020) 1398–1399.
[9] (a) N.T.T. Thuy, J.E. Lee, H.M. Yoo, N. Cho, J. Nat. Prod. 82 (2019) 3025–3032;
(b) N. Al-Maharik, Nat. Prod. Rep. 36 (2019) 1156–1195;
(c) A. Zafar, S. Singh, I. Naseem, Food Chem. Toxicol. 99 (2017) 149–161.
Please cite this article in press as: J. Chen, et al., Kojic acid and maltol: The “Transformers” in organic synthesis, Chin. Chem. Lett. (2020), https://
doi.org/10.1016/j.cclet.2020.06.034