4
Tetrahedron
ACCEPTED MANUSCRIPT
Cgr/Cgr, 50 mA, MeOH, RT; ii. K2CO3, MeOH, RT; iii. HCl 1M, RT, 61%,
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The next step of the reaction requires the t-Bu deprotection of
the malonate group. This can be accomplished directly on 14
using freshly sublimed AlCl3. However, as formation of HCl can
lead to the removal of the TBDPS group, exchange of the silyl
protecting group for the corresponding acetate 15 was performed
to increase the reproducibility of this step. Malonic acid
ammonium salt 16 was then obtained quantitatively using
trifluoroacetic acid followed by treatment with ammonia.22
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Finally, the electrochemical oxidation of malonic acid 16 to its
dimethoxyketal derivative was conducted in an undivided cell
using graphite electrodes and under a constant current of 50
mA.23 The reaction was monitored by TLC and stopped when
complete conversion was observed. In situ saponification of the
three acetates using potassium carbonate in methanol followed by
an acidification of the reaction medium gave the final spiroketal
9 with 61% yield.
7. Aune T, Larsen S, Aasen JAB, Rehmann N, Satake M, Hess P.
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From the same intermediate 4 used in the photochemical
route, eight steps were needed to reach the same spiroketal
adduct 9 with excellent yields over all the synthesis. Using this
electrochemical umpolung approach, the assembly of a broad
range of spiroketals could be envisaged, avoiding the use of a
classical dithiane central building block. Hence, this could allow
facile variation of each cycle of the spiroketal, independently,
aiding in additional SAR studies of okadaic acid. Furthermore,
the very mild, metal-free and eco-friendly electrochemical
conditions of the final step make this approach an excellent
candidate for further application and development in total
synthesis.
3. Conclusion
In conclusion, we have developed two innovative and concise
synthetic entries to the C28−C38 fragment of okadaic acid by
exploiting
green
photochemical
and
electrochemical
methodologies for the construction of the spiroketal unit. Our
synthetic strategies allow for rapid assembly of complex
spiroketals in high yield with longest linear sequences from
commercially available material of nine and twelve steps for the
photochemical and electrochemical approaches respectively.
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4. Supplementary Material
1
Supplementary material (experimental procedures, H and 13C
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2015; 17 :4690. (b) Ma X, Dewez DF, Du L, Luo X, Markó IE,
Lam K. J. Org. Chem. 2018; 83 :12044.
NMR data for the described compounds) associated with this
article can be found, in the online version, at XXX.
15. Keck GE, Abbott DE. Tetrahedron Lett. 1984; 25:1883.
16. A postulated transition state to explain the stereochemistry of the
tetrahydropyran could be found in reference 10a.
Acknowledgments
17. Optical rotation values described for compound 9 are 25[α]D +69 (c
1.55, CHCl3)8b, 20[α]D +67 (c 0.75, CHCl3)10g and 24[α]D +92.2 (c
1.00, CHCl3)10k as ours is 20[α]D +74.2 (c 1.39, CHCl3). Listing of
This paper is dedicated to the memory of Professor István E.
Markó. Financial support from the Fonds de la Recherche
Scientifique (FRS-FNRS) via the Fonds pour la formation à la
Recherche dans l’Industrie et dans l’Agriculture (FRIA
fellowship for SD, JBN, DFD, and JFB), and the Université
catholique de Louvain are gratefully acknowledged.
1
the previous H and 13C NMR spectral data can be found in the
supporting information.
18. For a review on the synthesis of natural products containing
spiroketals via intramolecular hydrogen abstraction see : Sperry J,
Liu YC, Brimble MA. Org. Biomol. Chem. 2010; 8:29.
19. (a) Navarro M. Curr. Opin. Electrochem. 2017; 2:43. (b) Yan M,
Kawamata Y, Baran PS. Chem. Rev. 2017; 117:13230. (c) Wiebe
A, Gieshoff T, Möhle S, Rodrigo E, Zirbes M, Waldvogel SR.
Angew. Chem. Int. Ed. 2018; 57:5594.
References and notes
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21. (a) For recent review on Kolbe reaction, see: Markó I.E., Chellé F.
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