Electrochemical and photochemical approaches for the synthesis of the C28–C38 fragment of okadaic acid

Article abstract of DOI:10.1016/j.tet.2019.02.060

Okadaic acid, a potent and selective inhibitor of Protein Phosphatases 1 and 2A (PP1 and PP2A), is widely used as a probe for various biochemical processes. We describe herein two innovative methods for the synthesis of the terminal C28–C38 fragment of the natural polyether. Suárez photochemical oxidative cyclization and electrochemical oxidation of malonates to their ketals equivalents have been successfully applied for the assembly of the key spiroketal core.

Full text of DOI:10.1016/j.tet.2019.02.060

Accepted Manuscript
Electrochemical and photochemical approaches for the synthesis of the C28–C38
fragment of okadaic acid
Simon Dochain, Jean-Boris Nshimyumuremyi, Damien F. Dewez, Jean-François
Body, Benjamin Elias, Michael L. Singleton, István E. Markó
PII:
S0040-4020(19)30240-6
https://doi.org/10.1016/j.tet.2019.02.060
TET 30183
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 December 2018
Revised Date: 22 February 2019
Accepted Date: 25 February 2019
Please cite this article as: Dochain S, Nshimyumuremyi J-B, Dewez DF, Body Jean-Franç, Elias B,
Singleton ML, Markó IstváE, Electrochemical and photochemical approaches for the synthesis of the
C28–C38 fragment of okadaic acid, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.02.060.
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Electrochemical and photochemical
approaches for the synthesis of the C28-C38
fragment of okadaic acid.
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Simon Dochain, Jean-Boris Nshimyumuremyi, Damien F. Dewez, Jean-François Body, Benjamin Elias,
Michael L. Singleton and István E. Markó
Université catholique de Louvain UCLouvain, Institute of condensed matter and nanosciences (IMCN), MOST, Place Louis Pasteur 1/L4.01.02, 1348
Louvain-la-Neuve, Belgium

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Tetrahedron
journal homepage: www.elsevier.com
Electrochemical and photochemical approaches for the synthesis of the C28-C38
fragment of okadaic acid.
Simon Dochain, Jean-Boris Nshimyumuremyi,# Damien F. Dewez,# Jean-François Body, Benjamin Elias,
Michael L. Singleton* and István E. Markó1
Université catholique de Louvain (UCLouvain), Institute of condensed matter and nanosciences (IMCN), MOST, Place Louis Pasteur 1/L4.01.02, 1348 Louvain-
la-Neuve, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Okadaic acid, a potent and selective inhibitor of Protein Phosphatases 1 and 2A (PP1 and
PP2A), is widely used as a probe for various biochemical processes. We describe herein two
innovative methods for the synthesis of the terminal C28-C38 fragment of the natural polyether.
Suárez photochemical oxidative cyclization and electrochemical oxidation of malonates to their
ketals equivalents have been successfully applied for the assembly of the key spiroketal core.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Electrochemical oxidation
Suárez photochemical oxidation
Spiroketal
Okadaic acid
Natural product
———
*
Corresponding author. E-mail address: m.singleton@uclouvain.be (M.L. Singleton).
# These authors contributed equally
1
Deceased

2
Tetrahedron
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Figure 1: Structure of the marine toxin okadaic acid
Its reactivity with the different protein phosphatases, together
with a range of biological activities, including tumor-promoting
activity6 and ability to induce apoptosis,7 attracted the attention of
the synthetic community to this challenging target. To date, three
independent total syntheses have been reported,8 along with the
synthesis of natural and non-natural analogues9 and some
fragment studies.10 However, continuous improvement of the
synthesis is still required to reach OA in an efficient, greener and
shorter way.
Structure activity relationship (SAR) studies have shown that
the terminal C28-C38 hydrophobic part of the polyether is
particularly important for the phosphatase inhibition reactivity.11
Previous syntheses of this fragment have relied largely on the
formation of keto-diols and their acid catalyzed ketalization
generating the spiroketal center.8-10 While this approach allows
the target spiroketal to be obtained in an efficient and even
sometimes short manner, new methods that can improve atom
economy and allow simple modification of the structure can
facilitate the synthesis of new derivatives of OA, and more
generally spiroketals.
Herein, two innovative approaches for the synthesis of the
terminal C28-C38 fragment of OA starting from homoallylic
alcohol 4, scheme 1, are described which give access to
spiroketal alcohol 9, an intermediate used in previous syntheses
of OA.8,9 The first involves the construction of the spiroketal
moiety through sequential tetrahydropyran formation using a
modified Taddei-Ricci protocol12 followed by a hydrogen atom
transfer through the photochemical oxidative conditions
described by Suárez.13 The second route relies on an original
method developed in the Markó group for the electrochemical
oxidation of malonates into ketals.14
2. Results and Discussion
The starting point of both routes is the homoallylic alcohol 4,
obtained in four steps from commercial (S)-Roche ester 2
through a diastereoselective crotylstannation developed by Keck
(Scheme 1).10g, 15 This central building block possess all the chiral
centers of the fragment with the exception of the
thermodynamically controlled spiroketal center and can be
obtained with both excellent dia- and enantioselectivity.
1. Introduction
Okadaic acid (OA 1, Figure 1), a complex natural polyether, is
the leading member of the family of toxins that cause diarrheic
shellfish poisoning.1 It was originally isolated from the marine
sponges Halichondria okadai and Halichondria melanodocia2
and subsequently identified as being produced by the marine
dinoflagellates Prorocentrum lima and Dinophysis fortii3 which
accumulated in the sponges through filter feeding.3b OA has been
shown to be a potent and selective inhibitor of serine/threonine
protein phosphatases 1 and 2A (IC50 of 3.4 and 0.07 nM
respectively).4 Thus, it is a valuable and widely used tool in
biochemical studies involving these enzymes.5
Scheme 1: Reagents and conditions: a) TBDPSCl, Et3N, DMAP, DCM, RT,
quant. b) DIBAL-H, DCM, -78 °C to RT, 88%. c) DMP, DCM, RT, 85%. d)
Crotyltributylstananne, BF3.OEt2, Et2O, -100 to -78 °C, 83%, e.r.; d.r. > 98:2.
2.1 Photochemical route
The first approach expands on a method described by the
Markó group involving
cyclization step using HgO/I2.10a This method allowed direct
synthesis of spiroketal center starting from model
tetrahydropyran system. The excellent efficiency of this approach
a
key photochemical oxidative
a
a

3
notwithstanding, removal of the toxic reagents and harsh
conditions would offer a significant improvement.
2.2 Electrochemical route
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Over the last decades, organic electrochemistry has regained
attention in the field of synthetic organic methods.19 Classical
chemical reducing or oxidizing agents are being replaced by
electric current as an inexpensive and inherently safe reagent.
Suárez and co-workers have reported a photochemical method
that allowed them to obtain a variety of spiroketals. Their
approach makes use of (diacetoxyiodo)benzene (BAIB)/I2 and
involves the generation of an alkoxy radical followed by an
intramolecular 1,6-hydrogen atom transfer (1,6-HAT).13 This
intramolecular HAT allows for the functionalization of diverse
tetrahydropyrans and avoids the use of mercury reagents. Using
this idea, a new method was envisaged involving the construction
of the spiroketal moiety through sequential tetrahydropyran
formation via a modified Taddei-Ricci12 protocol followed by a
hydrogen atom transfer through the photochemical oxidative
conditions described by Suárez. This method allows for the
formation of the spiroketal moiety of the C28-C38 fragment
without using the classical keto-diol approach.
Recently, investigations in the Markó group on radical
generation under electrolytic conditions20 and on the Kolbe-type
reaction of monocarboxylic acids21 led to the development of a
method to perform the electrolysis of malonic acids to their ketal
equivalent under mild conditions.14 This method allows for the
umpolung-like facile assembly of unsymmetrical ketones or
ketals with relatively good yields (Scheme 3). Furthermore, the
presence of free alcohols on the R1 or R2 chains of malonic acid
derivatives could permit the intramolecular capture of the
carbocation intermediate and hence the formation of spiroketal
equivalents such as the terminal fragment of okadaic acid. This
approach can constitute therefore a second route to spiroketal 9.
The synthesis of the target molecule started with the
incorporation of the five carbons corresponding to the second
ring of the spiroketal onto alcohol 4 through the formation of the
THP-ketal 5 with excellent yield. This ketal 5 was then
transformed to the tetrahydropyran 6 according to the modified
Taddei-Ricci conditions formerly developed for the synthesis of a
model fragment of okadaic acid.10a The reaction is described to
occur by the addition of titanium tetrachloride allowing the
opening of the ketal with formation of the corresponding
oxonium. This intermediate is subsequently attacked by the
terminal alkene with the help of a chloride ion, leading to
tetrahydropyran 6 in very good yield and with excellent
diastereoselectivity (Scheme 2).16 Removal of the chlorine atom
through TTMSS/AIBN mediated reduction led then to THP
alcohol 7, which is well suited for the photochemical cyclization.
Scheme 3: Electrochemical oxidative decarboxylation of malonic acid
derivatives
With this idea in mind, chiral alcohol 4 was converted into the
corresponding bromide 12, through initial protection of the
alcohol as its acetate derivative 10, followed by a two-step 9-
BBN hydroboration/Appel bromination of the terminal alkene to
give primary bromide 12 (Scheme 4). This alkylbromide,
corresponding to the backbone of the substituted THP ring of the
terminal fragment of OA 1, was then connected to di-tert-butyl
malonate to yield the malonate 13. Finally, deprotonation of 13
with sodium hydride and alkylation with iodobutyl acetate
furnished the adduct 14, containing all the carbons of the full
skeleton of the target molecule.
Addition of BAIB and iodine to 7 under UV light gave
spiroketal 8 as a single diastereomer with a good yield of 61%.
As described by Suárez,13c this reaction should proceed through
generation of the alkoxy radical which can undergo a 1,6-HAT to
generate a radical on the THP ring. Its further oxidation to the
oxonium permits the intramolecular attack of the alcohol to form
the thermodynamic spiroketal. Final deprotection of the alcohol
lead to the C28-C38 fragment 9 of OA in only five steps from 4.
Comparison of the spectroscopic data and optical rotation with
the literature confirmed the relative and absolute configuration of
9.17
Scheme 2: Reagents and conditions: a) DHP, CSA cat., DCM, -20 °C, 95%.
b) TiCl4, DCM, -100 °C, 89%, d.r. = 95:5. c) TTMSS, AIBN, Tol, 110 °C,
65%. d) BAIB, I2, hν, cyclohexane, 40 °C, 61%, d.r. >20:1. e) TBAF, THF,
RT, 89%.
This very short assembly of the target molecule, requiring only
five steps from the known alcohol 4, represents the shortest
access to date to the key intermediate 9. It highlights also the
great application of the Suárez photochemical oxidation
conditions for the synthesis of complex spiroketals,18 in particular
because of the excellent atom economy and also because these
conditions avoid the toxic reagents (HgO, CCl4) used previously.
Furthermore, it is the only example, except from the gold
catalyzed spiroketalization of Forsyth,10j that does not use the
keto-diol approach to reach the C28-C38 fragment of OA.
Scheme 4: Reagents and conditions: a) Ac2O, DMAP cat., py, RT, 92%. b)
i. 9-BBN, THF, 0 °C to RT; ii. NaH2BO4, H2O, RT, >95%. c) CBr4, PPh3,
DCM, 0 °C to RT, >95%. d) di-tert-butyl malonate, NaH, THF, 0 °C to RT
then 12, THF, 70 °C, 93%. e) NaH, THF, RT to 70 °C then 4-iodobutyl
acetate, THF, 70 °C, 93%. f) TBAF, THF, 0 °C then Ac2O, DMAP cat., RT,
93%. g) i. TFA, DCM, RT then ii. NH3, MeOH, quant. h) i. Undivided cell,

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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and Kem W., Springer-Verlag, Berlin Heidelberg, 2009.
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.
Toxicon 2007; 49:1.
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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.
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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.
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Kolbe and related reactions. In Encyclopedia of Applied

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Electrochemistry; Kreysa, G., Ota, K.-i., Savinell, R., Eds.;
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Springer: New York, 2014; pp 1151−1159. For some other
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22. As mentioned in reference 14a, the malonic acid can be either
isolated as so and electrolyzed in MeOH with 2 equivalents of
NH3 or isolated as the ammonium salt and electrolyzed as so in
MeOH. The choice of one method to the other depends on the ease
of the isolation of the acid. For 16, the compound is more easily
isolated as the ammonium salt.
23. Practical information on method and apparatus is presented in the
supporting information.