Biomimetic asymmetric total syntheses of spirooliganones A and B

Article abstract of DOI:10.1021/ol501593m

Biomimetic total syntheses of potent antiviral spirooliganones A and B were achieved with 3% and 2% yield, respectively, in 12 steps from commercially available materials. The synthetic strategy was inspired primarily by the biogenetic hypothesis and was enabled by two independent cascade events: (i) an unprecedented reaction involving aromatic Claisen rearrangement/o-quinone methide formation/hetero-Diels-Alder cycloaddition to construct the tetracyclic framework and (ii) phenol oxidative dearomatization/spirocyclization to build the spiro-fused cyclohexadienone/tetrahydrofuran moiety.

Full text of DOI:10.1021/ol501593m

Letter
pubs.acs.org/OrgLett
Biomimetic Asymmetric Total Syntheses of Spirooliganones A and B
Liyan Song, Hongliang Yao, and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
S
* Supporting Information
ABSTRACT: Biomimetic total syntheses of potent antiviral
spirooliganones A and B were achieved with 3% and 2% yield,
respectively, in 12 steps from commercially available materials.
The synthetic strategy was inspired primarily by the biogenetic
hypothesis and was enabled by two independent cascade
events: (i) an unprecedented reaction involving aromatic
Claisen rearrangement/o-quinone methide formation/hetero-
Diels−Alder cycloaddition to construct the tetracyclic framework and (ii) phenol oxidative dearomatization/spirocyclization to
build the spiro-fused cyclohexadienone/tetrahydrofuran moiety.
nfluenza virus infections continue to threaten human life as
IC50’s ranging from 3.7 to 33.3 μM, which with comparable
Ievident by a recent influenza pandemic in 2009 (H1N1/09, selectivity index (TC50/IC50) are stronger than that of the
>17,700 deaths).1 Mutations of influenza viruses would make
clinically used ribavirin. Noticeably, although its selectivity
index value was less than that of the positive control oseltamivir
(Tamiflu), spirooliganone B showed comparable activity against
influenza A with an IC50 of 5.05 μM. Therefore, spirooliga-
nones with skeletons distinct from those of all known antiviral
agents (cf., oseltamivir and zanamivir) hold great potential as
promising antiviral drugs/leads. In addition, spirooliganones A
and B displayed moderate cytotoxicity against Vero and MDCK
cells.
the current antiviral drugs/vaccines ineffective, and the deadly
mutated viruses would spread rapidly and pose a pandemic
threat. In addition to the slow vaccine development,2 antiviral
agents would provide a first line of defense and a powerful
weapon against these deadly influenza viruses.3 In the search for
new antiviral natural products, Yu4 and co-workers reported in
2013 the two structurally novel antiviral spirooliganones A and
B (Figure 1) isolated from the roots of Illicium oligandrum,
which has demonstrated a variety of antiviral activities and has
been widely used in Chinese folk medicine for treatment of
rheumatoid arthritis. In contrast to other natural products from
this species displaying no antiviral activity, spirooliganones A
and B were found to exhibit potent activity against Coxsackie
virus B3 and influenza virus A/Hanfeng/395/95 (H3N2) with
Structurally, spirooliganones A and B were reported as spiro-
isomers at C17. The 5/6/6/5/3 pentacyclic skeleton (ABCDE
rings) of spirooliganones, confirmed by the single-crystal X-ray
diffraction analysis of their benzoate derivatives, was
unprecedented in natural products. Particularly, the fashion of
ring conjunction as dioxa-spiro (AB and CD) was very unique,
which might pose significant synthetic challenges. The
combination of the potent antiviral activity and the structural
novelty prompted us to undertake synthetic studies of
spirooliganones A and B. Herein, we report a biomimetic
total synthesis of spirooliganones A and B, which were enabled
by two independent cascade reactions: (i) aromatic Claisen
rearrangement/o-quinone methide formation/hetero-Diels−
Alder cycloaddition and (ii) phenol oxidative dearomatiza-
tion/spirocyclization. It was noted that Xie and co-workers
reported the first total synthesis of spirooliganones A and B
employing a similar oxidative dearomatization/cyclization.5
Biogenetically (Figure 1), diastereomeric spirooliganones A
and B were proposed to be derived from the 5-allylbenzene-
1,2,4-triol (2) via a number of key steps including the phenol
alkylative dearomatization (prenylation, 2 → 3), 1,3-σ
migration6/epoxidation (3 → 4), 5-endo-tet cyclization via
epoxide opening7 (4 → 5) and hetero-Diels−Alder reaction8 of
o-quinone methide (8) and (−)-sabinene (7) (6 → 1a and 1b).
Received: June 3, 2014
Figure 1. Spirooliganones A and B and their biogenetic hypothesis.
© XXXX American Chemical Society
A
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Letter
It is noteworthy that the regioselective hetero-Diels−Alder
reaction of o-quinone methides,9 consistent with the natural
production of spiroisomeric spirooliganones A and B, has been
proposed in many biosyntheses of other natural products and
successfully exploited as a key synthetic strategy for biomimetic
total synthesis.10
Inspired by this biosynthetic hypothesis and previous insights
on hetero-Diels−Alder reaction of o-quinone methides,10 we
proposed a biomimetic synthetic strategy11 for spirooliganones
A and B (1a and 1b) as depicted in Scheme 1. We envisioned
single pot sequentially, which would become a highly concise
cascade reaction (13 → 12 → 11 → 10, Scheme 1). The easy
preparation of 13 from the commercially available 14 via several
known transformations encouraged us to explore this sequence
first. If successful, such cascade reaction would generate two
carbon−carbon bonds and one carbon−oxygen bond, leading
to the tetracyclic core system of spirooliganones. In addition,
both spirooliganones A and B might be produced from the
hetero-Diels−Alder cycloaddition reaction in support of their
biogenetic hypothesis.
Our synthesis (Scheme 2) began with preparation of
acetonide 15 from commercially avialable 2,6-dihydroxybenzoic
Scheme 1. Synthetic Plan for Spirooliganones A and B
Scheme 2. Synthesis of Tetracyclic Framework of
Spirooliganones A and B
that the spiro-fused AB rings of spirooliganones might arise
from the phenol oxidative dearomatization12 and simultaneous,
favorable 5-exo-trig spirocyclization13 (9 → 1, Scheme 1) at the
final stage of synthesis. This orchestration as compared with the
corresponding transformations in the biogenetic hypothesis
would minimize the manipulations of the inherently unstable
cyclohexadienone moiety14 and avoid the involvement of a
chemically unfavorable 5-endo-tet cyclization via epoxide
opening (4 → 5, Figure 1) according to Baldwin’s rule.15 In
fact, a similar phenol oxidative dearomatization/cyclization has
been proposed as a potential biosynthetic pathway for many
natural products (cf., aculeatins and amonols) and elegantly
exploited for biomimetic total synthesis.16 In light of these facts,
we speculated that spirooliganones might be biogenetically
produced via this type of processes. The structure of type 9
could be prepared in a straightforward manner from 10 in three
steps: Sharpless asymmetric dihydroxylation, phenol ortho-
allylation, and aromatic Claisen rearrangement.17 The con-
struction of the key tetracyclic framework (BCDE rings, 10)
could be achieved in a biomimetic fashion by a hetero-Diels−
Alder cycloaddition of (−)-sabinene (7) and o-quinone
methide 11. Given the fact that o-quinone methides were
unstable and commonly generated in situ by elimination of a
neutral small molecule such as H2O, HOAc, or RNMe2,10 we
proposed that the o-quinone methide 11 could arise from a
thermal aromatic Claisen rearrangement of 13 followed by
elimination of acetic acid, although such method was
unprecedented in the literature. Due to the same thermal
reaction conditions for hetero-Diels−Alder cycloaddition and
aromatic Claisen rearrangement/o-quinone methide formation,
we imagined that these two processes could be performed in a
acid (14) by using the protocol developed by Jennings.18
Palladium-catalyzed etherification19 of 15 with isobutyl-2-
methyl-3-buten-2-yl carbonate provided the ether 16 in 89%
yield as a single regioisomer. It was noted that the reaction yield
on large scale (3−10 mmol) dropped significantly to 20−55%.
Consequently, the reaction on a 1.5 mmol scale was repeated
several times to supply sufficient amount of 16 for further
elaboration. Reduction of ester 16 with LiAlH4, followed by
acylation with acetic anhydride in the presence of pyridine and
4-dimethylaminopyridine, gave the desired substrate 13 in 68%
yield over two steps. Thus, we arrived at the first key cascade
reaction. When a solution of 13 in (−)-sabinene (used as the
solvent) was heated to reflux (∼160 °C) under nitrogen
atmosphere in a sealed tube, to our delight, it cleanly produced
a 1:1 diastereomeric mixture of the desired tetracyclic core
system (10) in a remarkable 79% yield with an exclusive
regioselectivity.9,10 It was noteworthy that the tethered
trisubstituted alkene of o-quinone methide 11 did not compete
with the 1,1-disubstituted alkene of sabinene for hetero-Diels−
Alder cycloaddition in either intra- or intermolecular manner,
which was a main concern in our design phase. Mechanistically,
this novel cascade reaction was proposed to start with aromatic
Claisen rearrangement20 of 13 upon heating to provide the
hypothetic intermediate 12, followed by 1,6- or 1,4-elimination
of acetic acid21 to give o-quinone methide 11, which underwent
regioselective hetero-Diels−Alder cycloaddition with sabinene.
To the best of our knowledge, this is a new cascade reaction
and the first example recording in situ formation of o-quinone
methide from aromatic Claisen rearrangement. In addition, the
B
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Letter
successful implementation of hetero-Diels−Alder cycloaddition
of o-quinone methide and sabinene provided compelling
chemical evidence in support of the hetero-Diels−Alder
cycloaddition process in the biogenetic hypothesis of
spirooliganones.
With the key tetracyclic core (10) in hand, we directed our
attention to explore the phenol oxidative dearomatization/
spirocyclization as proposed in our synthetic plan (Scheme 1).
To this end, (−)-10 (a mixture of 10a and 10b) required to be
further elaborated to phenol 9 (Scheme 3).
in an exclusive 5-exo-trig cyclization manner to furnish the
spirooliganones A and B, respectively, as the major isolable
products in moderate yields after desilylation with HF-pyridine.
It was noted that the acetyl derivative of 19a (or 19b) led to a
lower yield, and the resulting aromatic Claisen rearrangement
adduct produced only trace amount of 1a or 1b. Nonetheless,
the successful implementation of the phenol oxidative
dearomatization/spirocyclization implied that 1a and 1b
might arise from a similar biological cyclization process in the
roots of Illicium oligandrum. All spectroscopic data of our
synthetic 1a and 1b were in well agreement with those reported
for the natural 1a and 1b.23
In conclusion, we have achieved biomimetic total syntheses
of potent antiviral spirooliganones A and B with 3% and 2%
yield, respectively, in 12 steps from commercially available
matereials. Our synthesis featured an unprecedented cascade
reaction involving aromatic Claisen rearrangement/o-quinone
methide formation/hetero-Diels−Alder cycloaddition and
phenol oxidative dearomatization/spirocyclization. In addition,
the successful implementation of hetero-Diels−Alder cyclo-
addition of o-quinone methide provided compelling chemical
evidence for the biogenetic hypothesis of spirooliganones A and
B.
Scheme 3. Completion of Total Syntheses of
Spirooliganones A and B via Phenol Oxidative
Dearomatization/Spirocyclization
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, characterizations, and copies
1
of H and 13C NMR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rtong@ust.hk.
Notes
The authors declare no competing financial interest.
First, Sharpless asymmetric dihydroxylation of the diastereo-
meric mixture of (−)-10 (10a and 10b) with AD mix-β at 0−8
°C for 4 days provided two separable diastereomers, 18a (38%
yield) and 18b (36% yield), in excellent combined yield. The
individual diastereomer (18a or 18b) was employed in the
subsequent transformations. After removal of the acetyl
protecting group of 18a and 18b, the resulting crude phenol
was alkylated with allyl bromide in the presence of K2CO3 to
give 19a and 19b, respectively, in excellent yield. Aromatic
Claisen rearrangement of 19a and 19b at 200 °C in a sealed
tube cleanly produced the desired phenol 9a and phenol 9b,
respectively, which unfortunately decomposed in the course of
phenol oxidative dearomatization with various oxidants and
solvents.22 Careful analysis of the 1H NMR spectra of the crude
products led us to discover that a characteristic aldehyde signal
was present, which might be attributed to an oxidative cleavage
of the vicinal diol. Therefore, the secondary alcohol of
individual 19a and 19b was selectively protected as triethylsilyl
ether derivative, which was used directly for aromatic Claisen
rearrangement at 200 °C to provide the desired phenol 20a and
phenol 20b, respectively, for the final phenol oxidative
dearomatization/spirocyclization. To our delight, after screen-
ing a variety of oxidants and solvents, we found that treatment
of 20a (or 20b) with PIFA in the presence of K2CO3 promoted
smoothly the phenol oxidative dearomatization/spirocyclization
ACKNOWLEDGMENTS
■
This research was financially supported by HKUST and
Research Grant Council of Hong Kong (ECS 605912 and
GRF 605113).
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