Enantioselective Total Synthesis and Assignment of the Absolute Configuration of the Meroterpenoid (+)-Taondiol

Article abstract of DOI:10.1021/acs.orglett.8b00997

The first enantioselective total synthesis of (+)-taondiol, a pentacyclic marine meroterpenoid, has been achieved, which in addition to confirming the structure also established the absolute configuration of the natural product. The notable points in the synthetic route are synthesis of a highly functionalized tricyclic diterpenoid moiety starting from an enantiopure Wieland-Miescher ketone derivative in concise manner via Robinson-type annulation and an elegant hydrogen atom transfer olefin reduction followed by Lewis acid-catalyzed Friedel-Crafts reaction for one-pot C-C and C-O bond formations resulting in construction of the pentacyclic meroterpenoid skeleton.

Full text of DOI:10.1021/acs.orglett.8b00997

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis and Assignment of the Absolute
Configuration of the Meroterpenoid (+)-Taondiol
Dattatraya H. Dethe,* Samarpita Mahapatra, and Susanta Kumar Sau
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: The first enantioselective total synthesis of (+)-taondiol, a pentacyclic marine meroterpenoid, has been achieved,
which in addition to confirming the structure also established the absolute configuration of the natural product. The notable
points in the synthetic route are synthesis of a highly functionalized tricyclic diterpenoid moiety starting from an enantiopure
Wieland−Miescher ketone derivative in concise manner via Robinson-type annulation and an elegant hydrogen atom transfer
olefin reduction followed by Lewis acid-catalyzed Friedel−Crafts reaction for one-pot C−C and C−O bond formations resulting
in construction of the pentacyclic meroterpenoid skeleton.
arine algae are microorganisms that act as potential
sources of highly bioactive secondary metabolites
M
possessing different skeletal structures and varied biological
activities. These algal metabolites represent a class of
meroterpenoids owing to their core structure of the fused
polycyclic diterpene part with an aromatic ring. Stypopodium
zonale is one such marine brown algae found abundantly in the
Western Caribbean Sea. It acts as a source of various
pentacyclic algal metabolites such as stypoldione (1), stypodiol
(2), etc., which constitute a unique and interesting polycyclic
diterpene benzoquinone moiety as their backbone. The
Stypopodium family possesses an unusual spiro-o-benzoquino-
nefuran carbon skeleton. Taondiol (3) is a structural congener
of the Stypopodium family comprising a benzopyran moiety as
the only skeletal exception (Figure 1). These marine alkaloids
are known to show ichthyotoxic and cytotoxic activities.
Taondiol is known to exhibit distinct lethargic behavior and
narcosis at 10 μg/mL levels. Taondiol was isolated by Gonzalez
et al. from marine alga Taonia atomaria in 1971 where upon
extensive studies it was found to be (−)-taondiol (3).2 In the
year 1980, Fenical and his group, while continuing their
research on algal metabolites from Stypopodium zonale, also
isolated taondiol which was shown to be an optical antipode of
that previously reported by the Gonzalez group.1b Thus, it was
postulated that both the enantiomers (−)-taondiol (3) and
(+)-taondiol (4) are naturally occurring, differing in their
source of marine algae. Stypopodium zonale also constitutes
other stereoisomers of taondiol such as epitaondiol (5),3
isotaondiol (6),4 etc. Although there are a couple of reports in
the literature for the total5 synthesis and a formal6 synthesis of
Figure 1. Algal meroterpenoids.
stypoldione (1), there is only a single report directed toward
the biomimetic synthesis of DL-taondiol via acid-mediated
polyene cyclization of epoxide of the geranylgeranyl derivative
of toluquinol by Kitahara et al. in 1973.7 The major drawback
of their synthesis was the reaction yield of only 2% for the final
key polyene cyclization step. Therefore, a more efficient
method for the total synthesis of taondiol is desirable. Until
now, there were no reports on the enantioselective total
synthesis of taondiol, and hence its absolute configuration is
also unknown.
Received: March 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00997
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The biosynthesis of taondiol (4) has been proposed to occur
via tetraprenylation of homoarbutin 7 followed by deglycosy-
lation and selective epoxidation to obtain the deglycosylated
intermediate 9. The taondiol structure was obtained after
opening of the epoxide followed by polyene cyclization
(Scheme 1).8
devising an elegant route to synthesize the tricyclic ketone 13.
The synthetic sequence was commenced by a selective ketal
protection of the Wieland−Miescher ketone derivative 14 using
ethylene glycol. A Robinson-type annulation was then effected
on the bicyclic part to attain the tricyclic diterpene structure.
Thermodynamically controlled alkylation using 1-chloro-3-
pentanone/KOtBu followed by an intramolecular aldol
condensation delivered enone 1510 in 83% yield (over 2
steps). To carry forward with functionalizations on the tricyclic
compound, reductive methylation on enone 15 was carried out
using Li/NH3 and MeI to furnish ketone 16 in 80% yield. LAH
reduction on 16 followed by benzylation of the alcohol, thus
generated, provided the tricyclic benzyl compound 17 which
was further subjected to acid-mediated deketalization to
generate 18 in 90% yield. The next motive was to achieve
the desired compound 13 by reduction of the olefinic part in
18. The usual hydrogenation procedure using a H2 balloon and
Pd/C rendered reduction of olefin, but not surprisingly an
unwanted debenzylation was also observed. Hence, a different
method was foreseen to affect olefin reduction without
undergoing debenzylation. A thorough literature study revealed
Shenvi’s elegant method of hydrogen atom transfer (HAT)
using Mn catalyst and phenylsilane as an efficient route for
olefin reduction providing trans stereochemistry at the decalin
ring junction,11 which was quintessential for our total synthesis.
Henceforth, the requisite ketone 13 was attained in 80% yield
by following Shenvi’s protocol using Mn(dpm)3, TBHP, and
phenylsilane with delightfully no trace of debenzylated product.
Advancing further, α-methylation of the ketone 13 was then
carried out using LDA/MeI, followed by epimerization at the
newly generated stereocenter by treatment with NaOMe in
methanol to get the single diastereomer of 19 in 80% yield. The
penultimate step was Nozaki−Yamamoto homologation12 on
ketone 19 to obtain the unsaturated aldehyde 20 which upon
Luche reduction13 furnished the required tricyclic alcohol 11 in
57% yield (over 2 steps) (Scheme 3).
Scheme 1. Proposed Biosynthesis of Taondiol
Herein, we report the first enantioselective total synthesis of
(+)-taondiol (4), which not only confirmed the stereostructure
but also established the absolute configuration of the
meroterpenoid. A quick analysis of the taondiol skeleton
revealed a fusion of a polycyclic diterpene moiety with a
suitably substituted aromatic ring. Based on our analysis, a
synthetic strategy for (+)-taondiol (4) was envisaged to happen
via C−O cyclizaton of the intermediate 10 to form the pyran
ring. Compound 10 could be synthesized by a Friedel−Crafts
reaction9 between terpenoid 11 and quinol derivative 12
(Scheme 2). The terpenoid moiety 11, the most challenging
Scheme 2. Retrosynthetic Analysis
After acquiring the diterpene compound 11 in gram quantity,
we proceeded further toward the total synthesis of taondiol.
In our prior discussion, taondiol 4 was envisioned to be
achievable after C−O cyclization of the intermediate 10.
Therefore, to generate the intermediate 10, Lewis acid
catalyzed Friedel−Crafts reaction between the diterpene moiety
11 and quinol 12 was executed using BF3·OEt2. Unfortunately,
the coupling reaction did not happen as expected, and rather
elimination of allylic alcohol was observed as the only product.
Herein, we reasoned the failure of the Friedel−Crafts coupling
reaction might be due to inadequate nucleophilicity at the
required position on the aromatic ring. It was anticipated that
introduction of an extraneous hydroxy group onto the aromatic
ring might enhance the nucleophilicity at the required carbon.
Later, deoxygenation of the extra hydroxy group would deliver
the required pentacyclic taondiol skeleton. The considered
aromatic ring 23 with rightful substitutions was thus obtained
via sequential functionalization and deprotection on trimethox-
ybenzene 21 (Scheme 4). Therefore, the synthesis of 23 was
initiated with Vilsmeir−Haack reaction on trimethoxybenzene
21 that provided the trimethoxy benzaldehyde 22 in 80% yield.
Next, selective demethylation of 22 was performed using AlCl3
which was followed by reduction of the aldehyde group by
NaCNBH3 to render 23 in 75% yield (over 2 steps).
part of the synthesis, could be obtained from enantiopure
Wieland−Miescher ketone derivative 14 by Robinson-type
annulation followed by a few functional group transformations.
To consummate the total synthesis of (+)-taondiol (4),
synthesis of the polycyclic diterpene moiety (11) was taken as a
preliminary target. As per retrosynthetic analysis, it was
envisaged that tricyclic compound 13 could be a viable
intermediate to obtain the tricyclic terpenoid moiety 11 after
sequential functionalizations, and hence we focused majorly on
As conceptualized, to our delight, Friedel−Crafts reaction of
hydroxyquinol 23 with diterpenoid 11 using BF3·OEt2 directly
furnished a pentacyclic meroterpenoid core 24 by sequential
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DOI: 10.1021/acs.orglett.8b00997
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Tricyclic Alcohol (11)
attributed to the intramolecular hydrogen bonding between the
other hydroxy and its adjacent methoxy group that averts its
participation in the cyclization reaction. Deoxygenation of 24
was carried out by converting the hydroxy into triflate using
triflic anhydride to get the triflate 25 in 85% yield, followed by
Pd(PPh3)4-catalyzed reduction of triflate to obtain 26 in 60%
yield. The next step was demethylation of the methoxy in 26.
Unfortunately, the usual methods of demethylation by BBr3,
BCl3, and EtSH/NaH failed to provide the required
demethylated product. Gratifyingly, after a literature survey
Scheme 4. Synthesis of the Aromatic Ring
C−C and C−O bond formation in 70% yield (Scheme 5). A
notable observation of the reaction was the selective cyclization
at the olefin through the desired hydroxy group. This could be
Scheme 5. Total Synthesis of (+)-Taondiol (4)
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DOI: 10.1021/acs.orglett.8b00997
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Dethe, D. H.; Erande, R. D.; Mahapatra, S.; Das, S.; Kumar,
V. Chem. Commun. 2015, 51, 2871−2873. (b) Dethe, D. H.; Murhade,
G. M.; Dherange, B. D.; Sau, S. K. Eur. J. Org. Chem. 2017, 2017,
1143−1150. (c) Dethe, D. H.; Dherange, B. D.; Ali, S.; Parsutkar, M.
M. Org. Biomol. Chem. 2017, 15, 65−68.
(10) Dethe, D. H.; Sau, S. K. Org. Lett. 2018, 20, 632−635.
(11) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.;
Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300−1303.
(12) Taguchi, H.; Tanaka, S.; Yamamoto, H.; Nozaki, H. Tetrahedron
Lett. 1973, 14, 2465−2468.
(13) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454−
5459.
(14) Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J. X.; Yamamoto, Y.
J. Org. Chem. 2000, 65, 6179−6186.
for other methods, we achieved demethylation upon
implementing Yamamoto’s method by using B(C6F5)3 and
triethylsilane14 to get the silyl ether and then deprotection of
the silyl ether with TBAF to generate the desired demethylated
product 27. Finally, hydrogenolysis of 27 using H2 and
Pd(OH)2 delivered (+)-taondiol (4) in 58% yield (over 2
steps) whose physical and spectral data were in agreement to
those previously reported by isolation groups.1b−d,2
In conclusion, the first enantioselective total synthesis of
(+)-taondiol (4) has been achieved in 14 steps as the longest
linear sequence with 3.1% overall yield along with confirmation
of the stereostructure and absolute configuration. The key
features of the synthesis include the concise method for
attaining the polycyclic diterpene moiety from the enantiopure
Wieland−Miescher ketone derivative and the Lewis acid-
catalyzed Friedel−Crafts coupling to create a pentacyclic core
structure, which we anticipate will provide a gateway to deliver
several natural products with similar polycyclic skeleton.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00997.
Experimental procedures and spectral data for all the
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ddethe@iitk.ac.in.
ORCID
Dattatraya H. Dethe: 0000-0003-2734-210X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S. M. thanks UGC, New Delhi, and S. K. S. thanks CSIR, New
Delhi, for the award of a research fellowship. Financial support
from CSIR Project No. 02(0274)/16/EMR-II is gratefully
acknowledged.
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DOI: 10.1021/acs.orglett.8b00997
Org. Lett. XXXX, XXX, XXX−XXX