A concise total synthesis of puberulic acid, a potent antimalarial agent

Article abstract of DOI:10.1039/c4cc03134b

Efficient and practical total synthesis of puberulic acid has been accomplished via 8 steps, with 54% overall yield, and only two C-C bond formations, without the introduction of oxygen atoms into the core skeleton. Construction of the tropolone framework as the key transformation was achieved by multi-tandem oxidation of the aliphatic-triol, from d-(+)-galactose as the starting material.

Full text of DOI:10.1039/c4cc03134b

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A concise total synthesis of puberulic acid,
a potent antimalarial agent†
Cite this: Chem. Commun., 2014,
50, 8715
b
Goh Sennari,a Tomoyasu Hirose,ab Masato Iwatsuki,ab Satoshi Omura* and
¯
Toshiaki Sunazuka*ab
Received 28th April 2014,
Accepted 17th May 2014
DOI: 10.1039/c4cc03134b
www.rsc.org/chemcomm
Efficient and practical total synthesis of puberulic acid has been
accomplished via 8 steps, with 54% overall yield, and only two C–C
bond formations, without the introduction of oxygen atoms into
the core skeleton. Construction of the tropolone framework as the
key transformation was achieved by multi-tandem oxidation of the
aliphatic-triol, from D-(+)-galactose as the starting material.
Malaria, which is caused by species of Plasmodium parasites, is
one of the world’s three gravest infectious diseases, and remains
a major global health problem.1 Although many antimalarial
agents have been continually developed, drug-resistant Plasmodia
rapidly and increasingly appear. Therefore, the development of
novel antimalarial drugs with new modes of action and structures
is urgently and constantly required.
Fig. 1 Structures of antimalarial troponoids.
In the course of our group’s screening programme to discover
metabolites with promise as antimalarial drugs from microorganisms,
some troponoids (Fig. 1), namely puberulic acid (1),2 stipitatic acid (2),3
and viticolins A–C (3–5), were isolated from a culture broth of
Penicillium viticola FKI-4410.4 The unique structure of a highly-
oxygenated tropolone framework, and promising antimalarial activity,
led us to pursue synthetic studies to provide clarification of detailed
structure–activity relationships. Consequently, we decided to establish
a new total synthetic route for puberulic acid (1), the compound
exhibiting the most potent antimalarial properties.
Scheme 1 Synthetic strategy for puberulic acid (1).
Total synthesis of 1 has been previously achieved by two
The unique tropolone framework, the highly-oxygenated
groups: R. B. Johns et al.5 and M. G. Banwell et al.6 In both 7-membered aromatic ring of 1, was constructed by functionally
routes, the tropolone framework was constructed by ring tolerated ring-closing metathesis (RCM)7,8 to afford the aliphatic
expansion from cyclopropanized benzene derivatives. However, 7-membered cyclic compound 6 as a key intermediate, followed
we planned a different efficient and practical total synthetic by multi-tandem oxidation of the three hydroxyl groups on 6.
route to allow for the creation of numerous analogues and Divergence to produce other naturally occurring analogues and
novel derivatives from a key synthetic intermediate (Scheme 1). novel derivatives is permitted via the enone 7, which could be
derived from stepwise oxidation of 6.
With respect to synthetic efficiency, one of the most important
a Graduate School of Infection Control Sciences, Kitasato University, Japan
tasks in synthesis planning is to envisage the production of the
b Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane,
target compound using minimal bond-forming reactions.9 In
Minato-ku, Tokyo 108-8641, Japan. E-mail: omuras@insti.kitasato-u.ac.jp,
this reaction, the target compound has a low molecular weight
sunazuka@lisci.kitasato-u.ac.jp; Fax: +81 3-5791-6340; Tel: +81 3-5791-6340
and simple planar structure which is highly-oxygenated and has
no asymmetric carbons. We envisaged that this characteristic
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc03134b
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compound could be synthesized using only two C–C bond-
forming reactions, and selected a sugar, D-(+)-galactose, as the
starting material, which contains the C–C and C–O bonds in the
backbone of the target compound. The sugar is generally useful in
chiral pool synthesis, and often utilized in the syntheses of
complex natural products as the chiral source.10 In spite of the
sugar being cheaply available, its application as a framework
source is infrequent. Therefore, in our synthetic strategy, we
proposed to utilize the structure of the common sugar without
being conscious of its three-dimensional information, allowing
maximum use of its atomic structure. Therefore, we planned to
drive the cyclization precursor 8 by a Barbier-type addition with
allyl chloride 9 to D-(+)-galactose (10).11
The iodide 11 could be accessed from 10 by a known
reaction,12 that is, protection with an acetonide group, and
subsequent Appel reaction. For the Barbier-type addition, 11
was treated with Zn in THF–H2O to generate the aldehyde
intermediate. Allyl chloride 1213 was continuously added to
the reaction mixture to produce the diene 13 as a 2.3 : 1 (6S : 6R)
separable mixture of diastereomers. Then, RCM of the diaster-
eomixture of 13 using the Grubbs 2nd catalyst (10 mol%)
afforded the cyclic diol 14 as a separable mixture in excellent
yield. The stereochemistry at the C6 position was determined
by NMR spectroscopy after the diol moiety of 14 was protected
with an acetonide group.14 After removal of the acetonide group
from the major single diastereomer (6S)-14 with p-toluene-
sulfonic acid, the key aromatization step by multi-tandem
oxidation of tetraol (6S)-15 was investigated. We expected that
if three hydroxyl groups of tetraol were oxidized, the aromatiza-
tion via tautomerization would occur immediately to give the
desired troponoid 17. However, all efforts to achieve the aroma-
tization failed under any oxidation conditions, probably because
the retro-aldol reaction occurred due to the intricate process of
oxidising of four adjacent hydroxyl groups. Additionally, it was
assumed that competition, due to the elimination of hydroxyl
groups at the b-position of the generated carbonyl group,
afforded various byproducts (Scheme 2).
Scheme 2 Multi-tandem oxidation of tetraol 15. (a) ZnCl2, H2SO4, acetone,
r.t., 97%; (b) I2, PPh3, imidazole, PhMe, 70 1C, 97%; (c) Zn, THF/H2O, then 12,
r.t., 96% (6S : 6R = 2.3: 1); (d) Grubbs 2nd catalyst (10 mol%), CH2Cl2, reflux,
97%; (e) TsOHÁH2O, MeOH, r.t., 99% (from (6S)-14).
Accordingly, oxidation of the hydroxyl group on the 7-membered
ring did not bear any fruit.15 We focused on the exocyclic primary
alcohol, and subsequently planned to oxidize the triol 18, which
could be preceded by deprotection of the PMB group (Scheme 3).
Scheme 3 Strategy for the aromatization through multi-tandem oxida-
tion of triol 18. (a) DDQ, CH2Cl2/pH 7 buffer (9 : 1), 0 1C, 94%.
On multi-tandem oxidation of the triol 18, the primary hydroxyl diols, caused decomposition of the substrate. Next, we attempted
group would be oxidized first to afford the conjugate aldehyde several activated DMSO-mediated oxidations. Although Swern
i. Oxidation of two hydroxyl groups on the 7-membered ring would oxidation, which is one of the principal methods for oxidation,
then occur to afford the tricarbonyl compound ii. Aromatization gave a complex mixture (entry 2), Parikh–Doering oxidation
would proceed via tautomerization, and subsequent proton shifts in afforded the desired compound 21, and its regioisomer,18
the intermediate iii, to give the troponoid 19.
which fortunately had a higher oxidation state than that which
Several oxidation methods (shown in Table 1) were performed. was predicted (entry 3). It was therefore hoped that oxidation
In these investigations, since the tropolone framework is known using IBS,19 which can be generated in situ from pre-MIBSK
to chelate with some metals,16 oxidants without metal catalysts with oxone, would afford the carboxylic acid, but decomposition
were specifically selected. In actuality, all compounds which was observed (entry 4). Based on these results, multi-tandem
possess the tropolone framework could not be monitored and oxidation was found to proceed only under Parikh–Doering
purified with silica gel, so the reaction was monitored with conditions to construct the desired functionalized tropolone
LC-UV,17 and purification was conducted after protection of framework.
the hydroxyl group on the tropolone framework. In entry 1, IBX
Although the desired compound was in hand, it was envi-
oxidation, which is generally useful for the oxidation of vicinal saged that aldehyde 21 and its isomer were labile during
8716 | Chem. Commun., 2014, 50, 8715--8718
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Table 1 Multi-tandem oxidation of triol 18
Entry
Conditions
Result (2 steps)
Decomp.
1
2
3
4
IBX, DMSO, r.t.
(COCl)2, DMSO, CH2Cl2, À78 1C then Et3N, À78 1C
SO3Ápyridine, DMSO, Et3N, CH2Cl2, 0 1C to r.t.
Pre-MIBSK, powdered Oxones, MeCN, 70 1C, then H2O, 70 1C
Complex mixture
21 and regioisomer:a 28% (1 : 1)b
Decomp.
a
b
Regioisomer of a-methoxy carbonyl part. Isolated yield.
This method could be applied to facilitate complete and sub-
stantial synthesis, allowing us to achieve our goal of the efficient
and practical large-scale synthesis of puberulic acid (1).
In conclusion, with D-(+)-galactose as the starting material,
the C–C and C–O backbone of the target compound was
subjected to Barbier-type addition and RCM to afford the
aliphatic-triol. The triol underwent multi-tandem oxidation
through tautomerization by Parikh–Doering oxidation to give
the desired functionalized tropolone framework. After several
conversions of the functional group, total synthesis of 1 was
accomplished via 8 steps, with 54% overall yield, and only two
C–C bond formations. Furthermore, we achieved large-scale
synthesis of puberulic acid by applying this efficient total
synthetic route. Based on our synthetic methods, comprehen-
sive synthesis of novel derivatives and structure–activity rela-
tionship studies on this class of compounds are currently in
progress.
Scheme 4 Synthesis of methyl esters 24 and 25. (a) SO3Ápyridine, DMSO,
Et3N, CH2Cl2, 0 1C to r.t.; (b) NaClO2, NaH2PO4Á2H2O, 2-methyl-2-butene,
THF/t-BuOH/H2O (1 : 1 : 1), r.t.; (c) TMSCHN2, PhH/MeOH (9 : 1), r.t., 42%
(24 : 25 = 1 : 1, 3 steps from triol 18).
We thank Dr K. Nagai and Ms. N. Sato (School of Pharmacy,
Kitasato University) for various instrumental analyses. This
work was supported by a grant from the 21st Century Center
of Excellence Program (to M. Iwatsuki), a Kitasato University
Research Grant for Young Researchers, and the Ministry of
Education, Science, Sports and Culture of Japan, through a
Grant-in-Aid for Young Scientists (B, 25860082).
purification using silica gel. Thus, we decided to proceed with
the next step without protection and purification. The multi-
tandem oxidation of triol 18, and subsequent Pinnick oxidation
afforded carboxylic acid 23, which was detected after protection
with a methyl group, and purification (Scheme 4).
Since it was found that the desired carboxylic acid 23 could be
generated by two oxidation steps, we investigated the deprotec-
tion of the acetonide group in the final step. As a result,
deprotection was clearly carried out by treatment with HBr–
AcOH6 to generate puberulic acid (1) (Scheme 5). As 1 could also
not be purified using silica gel, several purification methods were
tried, and we found that the compounds, including other tropo-
noids, could be purified using reverse-phase chromatography.
Notes and references
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Scheme 5 Synthesis of puberulic acid (1). (a) 33% HBr–AcOH, sealed
tube, 120 1C, 65% (3 steps from triol 18).
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14 See the ESI† for the reaction condition and spectroscopic data.
18 The structures of 21 and its regioisomer were determined by NOE
analysis (see the ESI† for details).
15 Although the oxidation of diols 14 was also performed, the desired 19 (a) M. Uyanik, M. Akakura and K. Ishihara, J. Am. Chem. Soc., 2009,
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8718 | Chem. Commun., 2014, 50, 8715--8718
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