Biomimetic Synthesis of Meroterpenoids by Dearomatization-Driven Polycyclization

Article abstract of DOI:10.1002/anie.201910710

A biomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)-derived meroterpenoid scaffolds has yet to be reported despite great interest from the chemistry and biomedical research communities. A concise synthetic route with the poten

Full text of DOI:10.1002/anie.201910710

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201910710
Biomimetic Synthesis
Biomimetic Synthesis of Meroterpenoids by Dearomatization-Driven
Polycyclization
Zachary Powers, Adam Scharf, Andrea Cheng, Feng Yang, Martin Himmelbauer,
Takaaki Mitsuhashi, Lena Barra, Yoshimasa Taniguchi, Takashi Kikuchi, Makoto Fujita,
Ikuro Abe, and John A. Porco, Jr.*
Abstract: A biomimetic route to farnesyl pyrophosphate and
dimethyl orsellinic acid (DMOA)-derived meroterpenoid
scaffolds has yet to be reported despite great interest from the
chemistry and biomedical research communities. A concise
synthetic route with the potential to access DMOA-derived
meroterpenoids is highly desirable to create a library of related
compounds. Herein, we report novel dearomatization method-
ology followed by polyene cyclization to access DMOA-
derived meroterpenoid frameworks in six steps from commer-
cially available starting materials. Furthermore, several farne-
syl alkene substrates were used to generate structurally novel,
DMOA-derived meroterpenoid derivatives. DFT calculations
combined with experimentation provided a rationale for the
observed thermodynamic distribution of polycyclization prod-
ucts.
M
eroterpenoids derived from 3,5-dimethylorsellinic acid
(DMOA) and farnesol pyrophosphate (FPP) comprise an
extensive family of natural products containing a wide array
of structural diversity and biological activity (Figure 1a).[1]
Over 100 congeners have been isolated and characterized,
including tropolactone D (1),[2] berkeleyone A (2) (anti-
inflammatory activity),[3] preterretonin A (3),[4] asperterpe-
ne A (4) (a potent BACE-1 inhibitor),[5] terretonins (anti-
microbial),[6] austins,[7] andrastins,[8] preandiloid A (5),[9] and
Figure 1. a) Representative DMOA-derived meroterpenoid natural
[*] Z. Powers, Dr. A. Scharf, A. Cheng, F. Yang, Dr. M. Himmelbauer,
Prof. Dr. J. A. Porco, Jr.
products. b) Biosyntheses of the DMOA-derived meroterpenoids.
anditomin (6).[10] Despite the promising therapeutic potential
of this family, many compounds remain untested or the
biological assays are limited in scope, largely due to the small
quantities of natural samples available via isolation methods.
Although recent elegant syntheses of the DMOA-derived
meroterpenoid family members berkeleyone A (2) and select
andrastin/terretonin congeners have been reported by the
Maimone and Newhouse laboratories,[11] a general biomim-
etic strategy to access the majority of DMOA/FPP natural
product family remains elusive.
Studies on the biosyntheses of DMOA-derived meroter-
penoids by the Abe laboratory[1,4,9,10,12] reveal, remarkably,
that the broad spectrum of structural diversity exhibited
within the natural product family is the result of divergent
pathways from a common intermediate, 10 (Figure 1b) and its
stereoisomers.[1] For example, enzymatic pathways for natural
products berkeleyone A (2) and preterrotonin A (3) have
been rigorously established (Figure 1b).[4,12a,b] In these
sequences, DMOA (7) is first dearomatized with farnesyl
Department of Chemistry, Center for Molecular Discovery (BU-
CMD), Boston University
590 Commonwealth Avenue, Boston, Massachusetts 02215 (USA)
E-mail: porco@bu.edu
T. Mitsuhashi, Dr. I. Abe
Graduate School of Pharmaceutical Sciences, The University of Tokyo
7-3-1 Hongo, Bunkyoku, Tokyo 113-0033 (Japan)
Y. Taniguchi
Central Laboratories for Key Technologies, Kirin Holdings Co. Ltd.
1-13-5, Fukuura Kanazawaku, Yokohama-shi, Kanagawa 236-0004
(Japan)
T. Kikuchi
Rigaku Corporation
3-9-12 Matsubaracho, Akishima-shi, Tokyo 196-8666 (Japan)
M. Fujita
Department of Applied Chemistry, Graduate School of Engineering,
The University of Tokyo
7-3-1 Hongo, Bunkyoku, Tokyo 113-8656 (Japan)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201910710.
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pyrophosphate (8) and the resultant enzymatic intermediate 9
is methylated and subsequently epoxidized at the 10,11-
trisubstituted alkene. Consequently, the dearomatized inter-
mediate 10 is then accepted as a substrate by the terpene
cyclase enzymes AusL and Trt1 which mediate cascade
polycyclizations to form tetracylic products berkeleyone A
(2) and preterrotonin A (3) via cationic intermediate 11.
Thus, a biomimetic route is highly desirable to create
a platform to generate numerous FPP/DMOA-derived mer-
oterpenoids through a single and direct synthetic route.
Considering the biosynthetic pathway, we devised a syn-
thetic scheme to access the key dearomatized substrate 14
which contains 10 as well as its stereoisomers (Figure 2).
Scheme 1. Ester-to-acid functional group conversion alters alkylative
dearomatization regioselectivity.
LiHMDS in THF (08C) followed by reaction with farnesyl
bromide 16 led to highly selective dearomative alkylation of
15 at the C3-position to afford 17 in 50% yield. Alkylation of
unsaturated carboxylic acids is known to occur at the (g)
position under basic conditions.[19] We considered whether the
carboxylic acid 7 could undergo a similar C5, g-selective
alkylation. In the event, deprotonation of 7 with LiHMDS in
THF to afford a lithium trianion[20] followed by alkylation
with farnesyl mesylate 18 afforded only the desired regioiso-
mer 19 in 45% yield. The structure of 19 was identical to
a natural sample of farnesyl DMOA isolated in the Abe
laboratory.[12a] Moreover, additional experiments were con-
ducted with cinnamyl and phenyl propargyl mesylate to
extend the C5-alkylative dearomatization methodology to
non-farnesyl electrophiles (Scheme 2).[21]
Our rationale for the alkylative dearomatization selectiv-
ity of methyl ester 15 vs. acid 7 is shown in Figure 3.
Deprotonation of 15 with LiHMDS may afford the dienolate
intermediate 20 which undergoes (a)-alkylation with 16 to
afford the C3-dearomatized product 17. The change in
dearomatization selectivity of DMOA 7 is believed to arise
via formation of the proposed dienediolate [19] intermediate 21
(Figure 3). (g)-Alkylation of 7 with farnesyl electrophile 18
leads to the C5-dearomatized product 19. After experimen-
tation,[21] it was hypothesized that an aggregated species[22] is
likely responsible for the regioselective dearomatization
Figure 2. Biomimetic approach to access DMOA-derived meroterpe-
noids.
Intermediate 14 may be derived from dearomatization of
DMOA (7) or derivatives 12 with an appropriate farnesyl
electrophile 13 and serves as a gateway intermediate to access
FPP/DMOA-derived meroterpenoids. However, achieving
this site-selective dearomatization has proved extremely
difficult to date using established base-mediated acylphlor-
oglucinol dearomatization methodology.[13] A major chal-
lenge in our biomimetic approach lies in the ability to achieve
C5-selective alkylative dearomatization of substrates 12 and
suppress etherification of the phenols. Alkylative dearoma-
tization of orsellinic acid derivatives has been achieved
previously, but typically on C3 (cf. Figure 2).[13f] Following
dearomatization, we propose that cationic epoxy-diene poly-
[14]
cyclization
of 14 may be utilized to generate tetracyclic
meroterpenoid products. Termination of the polyene cycliza-
tion is possible by either C-[11b,15] or O-cyclization[16] of the
dearomatized enol moiety to produce asperterpene and
preandiloid A-type scaffolds, respectively. To the best of our
knowledge, this is the first report wherein the terminating
group in a polyene cyclization is a pendant, dearomatized
moiety. This unique terminating group provides a novel
research area in the field of polyene cyclizations. Here, we
report the first biomimetic approach to FPP/DMOA-derived
meroterpenoids via novel dearomatization methodology
followed by polycyclization that we term dearomatization-
driven polycyclization (DDP). Tetracyclic meroterpenoids
are constructed in six steps from commercially available
materials (longest linear sequence) and allow access to the
family of FFP/DMOA-derived meroterpenoids.
In our initial studies, we evaluated dearomative farnesy-
lation of dimethyl atratate (DMOA methyl ester)[18] 15 under
basic conditions[13d,h,i] (Scheme 1). Deprotonation of 15 with
Scheme 2. C5-dearomatization of 7 with cinnamyl and propargyl elec-
trophiles.
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acid methyl ester (25) was isolated and characterized as
a 1:1 mixture of diastereomers in 27% yield (2 steps).
Polyene cyclization has been found to be an expedient
approach to quickly generate complex carbocyclic struc-
tures.[14,17,23] Literature reports[16b,24] have also shown that the
traditional chair–chair transition state can be altered to
a chair–boat assembly based on suitable modification of the
polyene fragment or terminating group. Our experimental
results revealed that the dearomatized intermediate 25 was
highly prone to rearomatization under acidic conditions to
afford DMOA methyl ester 15.[21] After considerable exper-
imentation, we found that alkyl aluminum-based Lewis acids
(e.g. Et2AlCl, EtAlCl2, and MeAlCl2) were the only initiators
that could perform the polyene cascade cyclization to afford
fully cyclized tetracyclic meroterpenoids. Ultimately, we
found that a mixed Lewis acid combination of 2:1 EtAl-
Cl2:Et2AlCl as a mediator afforded the best results.[17,23c] After
cyclization of substrate 25 was complete, two fully cyclized
compounds 26 and 27 were isolated (Scheme 3). Both
compounds are derived from different diastereomers of
dearomatized intermediate 25 and from the corresponding
Stork–Eschenmoser[25] chair–chair transition states (Fig-
ure 4a). The C-cyclized compound 27 contains the (8,9)-epi-
Figure 3. Rationale for C5 vs. C3 dearomatization.
outcome for 7. The reaction was optimal at a concentration of
50 mm; use of higher or lower concentrations had a delete-
rious effect on the yield of 19. We also discovered that the
presence of salts and additives (e.g. LiCl, HMPA) led to
a pronounced reduction in the yield of 19. An improved yield
of 19 was realized with use of an excess of DMOA trianion at
50 mm and a dilute (10 mm) concentration of 18. By using an
excess of DMOA trianion, the lithium mesylate salt concen-
tration was effectively lowered, thereby allowing for an
increase in the selectivity towards C5-dearomatization.
After dearomatization method development, we con-
ducted a related dearomatization of 7 under basic conditions
using (2E,6E)-10,11-epoxyfarnesyl mesylate (24) as electro-
phile (Scheme 3). After reaction completion, esterification of
the crude product with TMS-diazomethane to access 25 was
performed without isolation of the carboxylic acid. In
particular, the intermediate acid proved to be incompatible
with the epoxide on the farnesyl fragment leading to
degradation when isolation was attempted.[21] The newly
formed
(2E,6E)-10,11-epoxyfarnesyl-5-dimethylorsellinic
Figure 4. Product predictions based on Stork–Eschenmoser configura-
tions.
asperterpene skeleton and the O-cyclized product 26 contains
the (8,9)-epi-tropolactone D skeleton (cf. Figure 1a). The
structures of 26 and 27 were determined by 2D NMR analysis
and compound 26 was fully confirmed by X-ray crystallog-
raphy[26] using the crystalline sponge (CS) method which has
been successfully used to determine structures of non-
crystalline terpenoids.[27]
We hypothesized that if a (2Z,6E)-(10,11)-epoxyfarnesyl-
5-dimethylorsellinic acid methyl ester (29) substrate variant
was used, the opposite stereochemistry[28] at C9 should be
obtained based on Stork–Eschenmoser configurations (cf.
Figure 4b). The synthesis of 29 also employed alkylative
dearomatization of the lithium trianion derived from DMOA
Scheme 3. Dearomatization and polyene cyclization of (2E,6E)-10,11-
epoxyfarnesyl-5-DMOA methyl ester (25).
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7 with (2Z,6E)-10,11)-epoxyfarnesyl mesylate (28) and was
found to require a lower temperature (À158C) (Scheme 4). It
is apparent that the (2Z)-alkene geometry of substrate 29
generates a more readily rearomatized substrate leading to
elimination on the farnesyl chain.
Schemes 3 and 4). DFT analysis of the products (B3LYP-
D3(BJ)/6-31G**)[29] showed that the isomers have a range of
relative energies. In each case, the lower energy terminating
group (O vs. C) is produced as the isolated product, except for
substrate 39 (S,S diasteromer of 29) which results in produc-
tion of both O- and C-cyclized products 31 and 32 (vide infra
Figure 6). We note that all products generated from chemical
cyclizations obey the Stork–Eschenmoser hypothesis (cf.
Figure 4) wherein the conformation of the product is adopted
by the substrate prior to polycyclization.[25]
Scheme 4. Dearomatization and polyene cyclization of (2Z,6E)-(10,11)-
epoxyfarnesyl-5-DMOA methyl ester (29).
(2Z,6E)-(10,11)-Epoxyfarnesyl-5-dimethylorsellinic acid
methyl ester substrate (29) (1:1 mixture of diastereomers)
was then exposed to polyene cyclization conditions using
EtAlCl2/Et2AlCl (2:1). Three fully cyclized compounds were
isolated which are all derived from Stork–Eschenmoser-type
transition states (cf. Figure 4b) and bearing the opposite
stereochemistry at C9 as expected. Meroterpenoid 30, an 8-
epi-preandiloid A type framework (cf. Figure 1a), is the only
compound derived from the (3S,12R) diastereomer of 29.
Both O- and C-cyclized products 31 and 32 are derived from
the same (3S, 12S) diastereomer of 29. The structure of 30 was
determined by 2D NMR analysis and the structures of both 31
and 32 (the latter as the derived p-bromobenzoate derivative)
were determined by X-ray crystal structure analysis
(Figure 5).[26]
Of the possible eight fully cyclized structures that may be
produced with Stork–Eschenmoser configurations, only five
structures were generated from chemical polycyclization (cf.
Figure 6. B3LYP-D3(BJ)/6-31-G** relative energy (kcalmolÀ1) levels for
fully cyclized products.
Based on analysis of the product energies (Figure 6), we
considered whether O-cyclized products such as 31 may
undergo [1,3] O-to-C rearrangement.[30] Indeed, when 31 was
stirred in neat formic acid,[13d] a mixture of 31 and 32 was
observed, confirming [1,3] shift reactivity (Scheme 5). This
result demonstrates that thermodynamic equilibration to an
energetically favored cyclization product such as 32 may
occur. On the other hand, subjection of O-cyclized product 30
to acidic conditions[21] did not produce cyclized products such
as 38 which has a correspondingly high relative DFT energy.
In conclusion, we have successfully demonstrated regio-
selective, biomimetic C5-dearomatization of 3,5-dimethylor-
sellinic acid (DMOA) with farnesyl derivatives and other
Figure 5. X-ray crystal structures of DMOA-derived meroterpenoids 31
and 32 (p-Br benzoate).
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polycyclization (DDP) of the key dearomatized epoxyfarne-
syl-5-dimethylorsellinic acid methyl ester scaffolds was con-
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Acknowledgements
We thank the National Institutes of Health (R35 GM-118173,
J.A.P., Jr.) and a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan (JSPS KAKENHI Grant Number
JP16H06443, I.A.). A.C. is supported by a grant from the
Arnold and Mabel Beckman Scholars Program at Boston
University. We thank Dr. Jeffrey Bacon (Boston University)
and Dr. Samantha MacMillan (Cornell University) for X-ray
crystal structure analyses and Dr. Norman Lee (Boston
University) for high-resolution mass spectra. NMR (CHE-
0619339) and MS (CHE-0443618) facilities at Boston Uni-
versity are supported by the NSF. Research at the BU-CMD
was supported by NIH grant GM-067041. We thank Saishuai
Wen, Dr. Wenhan Zhang, and Sloane OꢀNeill for helpful
discussions and manuscript edits. We also thank Dr. James
McNeely and Manav Kumar for helpful discussions regarding
computation.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: 3,5-dimethylorsellinic acid · biosynthesis ·
dearomatization · meroterpenoids · polyene cyclization
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Manuscript received: August 21, 2019
Version of record online: && &&, &&&&
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Communications
Biomimetic Synthesis
Z. Powers, A. Scharf, A. Cheng, F. Yang,
M. Himmelbauer, T. Mitsuhashi, L. Barra,
Y. Taniguchi, T. Kikuchi, M. Fujita, I. Abe,
J. A. Porco*
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Regioselective dearomatization of 3,5-
dimethylorsellinic acid (DMOA) provides
rapid access to a key dearomatized
intermediate in the biosynthetic pathway
of DMOA-derived meroterpenoids. This
intermediate undergoes polycyclization
under Lewis acid mediation to provide
meroterpenoid scaffolds. Several struc-
turally novel meroterpenoids were
obtained by termination via either C- or
O-cyclization.
Biomimetic Synthesis of Meroterpenoids
by Dearomatization-Driven
Polycyclization
Angew. Chem. Int. Ed. 2019, 58, 1 – 7
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!