Modular Synthesis of Drimane Meroterpenoids Leveraging Decarboxylative Borylation and Suzuki Coupling

Article abstract of DOI:10.1021/acs.orglett.0c03294

Drimane meroterpenoids have attracted an increasing amount of attention in the discovery of therapeutically important probes, while the laggard synthetic accessibility is a conspicuous challenge. A new paradigm merging decarboxylative borylation and Suzuki coupling was developed as a powerful platform. Key features include the mild conditions, good chemoselectivity, operational facility, scalability, and easy availability of the coupling partners. This practical strategy enables the expedient formal synthesis of a large number of natural products and rapid generation of analogues.

Full text of DOI:10.1021/acs.orglett.0c03294

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Letter
Modular Synthesis of Drimane Meroterpenoids Leveraging
Decarboxylative Borylation and Suzuki Coupling
Xia Wang, Shasha Zhang, Pengcheng Cui, and Shengkun Li*
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ABSTRACT: Drimane meroterpenoids have attracted an increasing amount of attention in the discovery of therapeutically
important probes, while the laggard synthetic accessibility is a conspicuous challenge. A new paradigm merging decarboxylative
borylation and Suzuki coupling was developed as a powerful platform. Key features include the mild conditions, good
chemoselectivity, operational facility, scalability, and easy availability of the coupling partners. This practical strategy enables the
expedient formal synthesis of a large number of natural products and rapid generation of analogues.
atural products occupied an irreplaceable role in the
discovery of therapeutically important entities due to
from a structural standpoint by assembling an sp3-hybridized
skeleton with sp2-hybridized aromatic units. Decoration on
either the aromatic ring or the drimane segment of common
scaffold 1 will lead to vast swaths of natural products (Figure
1A) possessing a wealth of bioactivities,3 including anti-HIV,
antitumor, anti-inflammatory, antiviral, antimalarial, and
antifungal potentials.
N
their unique biological profiles or uncharted chemotypes.1
Drimane (hydro)quinones (Figure 1A) make up a large family
of secondary metabolites from mixed biogenesis of polyke-
tide−terpenoid origin.2 These natural products showed a
tremendous advantage as an ideal model for drug discovery
The distinctive structure and biological importance have
promoted some synthetic efforts for these kinds of natural
products (Figure 1B,C). A majority of contributions focused
on the chiral pool approaches through the degradation of
sclareol,4 sclareolide,5 or (+)-manool6 to afford β-hydroxyl/
acetoxy aldehyde 2 or homoallylic aldehyde 3. Subsequent
nucleophilic attack by the aryl lithium reagents and
deoxidation at the C11 position will lead to product 1.
Palladium-catalyzed tandem carbene migratory insertion of a
hydrazine derivative of drimanal intermediate 2 was also
developed.7 Trifluoromethanesulfonate 4 synthesized from R-
carvone was successfully used to construct the central
framework via Stille carbonylative coupling and Michael
cyclization.8
Sclareol oxide was converted to diene 5 through Diels−
Alder cycloaddition.9 A resin-promoted Michael-type Friedel−
Crafts alkylation10 was conducted on the basis of α,β-
Received: October 1, 2020
Figure 1. Previous approaches to drimane (hydro)quinones.
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© XXXX American Chemical Society
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unsaturated ketone 6. Barton decarboxylative coupling was
realized for the efficient synthesis of yahazunol-related natural
products with homodrimanic acid 7 as a key synthon.11 Lewis
acid-catalyzed cyclization of the corresponding farnesyl
derivatives 8 was realized, recapitulating biosynthetic logic.12
Total synthesis was attempted starting from 1,3-cyclo-
hexanedione (via allylic alcohol 9).13 While such tactics can
generate certain natural products and analogues, the harsh
conditions (e.g., sensitive organometallic reagents, toxic
reagents, and a cryogenic environment), multistep, limited
scope, unstable intermediate, or poor stereofidelity impeded
the scalability and the diversity for detailed chemicobiology.
Because synthetic efforts in the discovery of functional
molecules place an emphasis on modular disconnections, a
general strategy for accessing these natural products and
mimics in a concise and divergent fashion is highly desirable.
Practical and simple methods for forging the linkage between
sp2- and sp3-hybridized carbon in drimane (hydro)quinone 1
are extremely important. An elegant demonstration of the
convenience and practicality of such a philosophy was reported
by the Baran group harnessing “borono-sclareolide” 11
(Scheme 1A).14 Inspired by the significant advances in
Scheme 2. Kumada Coupling to Drimane Meroterpenoids
substrate scope remained the glaring limitations of this system.
Extensive optimization of this Fe-catalyzed Kumada coupling
(see the Supporting Information for more details) did not give
obvious improvements.
We deprioritized the tactic described above and shifted our
attention to merging the decarboxylative borylation15a and the
Suzuki coupling.16 The drimanyl Bpin (13) was envisioned as
an advanced intermediate and was smoothly synthesized from
redox-active ester 12 with good chemoselectivity and stereo-
fidelity. This bench stable intermediate was confirmed
unambiguously by X-ray single-crystal diffraction (CCDC
2006960). Intermediate 13 was employed in the optimization
2
of Suzuki coupling with PhBr for efficiently forging the Csp −
3
Csp linkage. To our delight, a much simpler reaction mixture
compared with the Kumada coupling was achieved with the
catalytic combination of Pd2(dba)3 and RuPhos. Noteworthily,
the deprotection of the acetyl group proceeded synchronously
and desired meroterpenoid 23 with a free tertiary alcohol can
be easily isolated [46% (Table 1, entry 1)] without additional
Scheme 1. Modular Synthesis of Drimane (Hydro)Quinones
and Our Work
Table 1. Optimization of the Suzuki Coupling for the
Synthesis of Drimane Meroterpenoids
decarboxylative functionalization,15 we envisage that the
bench stable and easily accessible homodrimanic acid 7 can
be transformed into a synthetic hub for the modular and
divergent synthesis of drimane (hydro)quinones. Realization of
this hypothesis will facilitate the acquisition of manifold
drimane meroterpenoids without the previously encountered
inconvenience. Herein, we disclose the cross-talk of decarbox-
ylative borylation and Suzuki coupling as a facile tool for the
modular synthesis of drimane (hydro)quinones and mimics 14
(Scheme 1B).
Our work commenced with seeking potential “synthetic
hubs” based on the easily accessible homodrimanic acid 7 that
can be synthesized from the cheap natural product sclareol.11
With the elegant Fe-catalyzed Kumada coupling of redox-active
esters with organomagnesium reagents,15f homodrimanic acid
7 was converted to redox-active homodrimanyl-N-hydroxyph-
thalimide (NHPI) ester 12 and employed directly for the
construction of drimane meroterpenoids under the reported
conditions.15f A portfolio of drimane hydroquinone mimics can
be prepared accordingly (Scheme 2, 15−22). Though full
conversion of redox-active ester 12 was observed, the modest
yields, tedious separation (contaminated by hydrolysis of 12
and homocoupling of Grignard reagents), and the limited
manipulation. A strong synergistic effect between the
palladium species and the selected ligated ligands was
observed. The reaction became sluggish when Pd2(dba)3 was
replaced with Pd(OAc)2, PdCl2, or Pd(TFA)2 (Table 1, entry
2).
Pd2(dba)3 catalytic systems with other monodentate
Buchwald ligands diminished (Table 1, entry 6) or even
inhibited (Table 1, entry 5) the production of meroterpenoid
23. The alternative was to utilize Pd(dppf)2Cl2 as a catalyst to
B
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a
Table 2. Modular Synthesis of Drimane (Hydro)Quinones via Suzuki Coupling
a
Unless otherwise mentioned, reactions were carried out with 0.25 mmol of Ar-Br or Het-Br and 0.3 mmol of drimanyl BPin (13); yields of
b
isolated products are presented in each case. The yield was calculated on the basis of 1H NMR of the isolated inseparable mixture of the desired
product and (+)-drim-9(11)-en-8α-ol after chromatography. With 0.25 mmol of Ar-Br, 0.6 mmol of drimanyl BPin 13, 4 mol % Pd2(dba)3, 8 mol
c
% RuPhos, and 800 mol % NaOtBu.
afford a serviceable amount of the desired product (Table 1,
entry 4). No obvious products were detected with the
monodentate triphenylphosphine or the bidentate Xantphos
(Table 1, entry 5). Strong bases were necessary for this
transformation (Table 1, entries 7 and 8), and the effect of the
cationic metals is inscrutable but significant, in which Na+
demonstrated an advantageous characteristic. Enrichment of
meroterpenoid 23 benefited from the solvent screening. tert-
Butanol was identified as a superior component compared with
others, such as DMF, 2-MeTHF, ClCH2CH2Cl, etc. Other
factors were regulated routinely and are summarized in the
Supporting Information, including the ratio of the solvent
mixture, base loading, reaction time, and temperature. The
optimal conditions shown in entry 14 of Table 1 can furnish
compound 23 in 89% yield.
The established methodology proved to be general and
powerful across a range of substrates as shown in Table 2 (>45
examples). The scope with regard to the functional group
tolerance and the electronic effect was first evaluated on the
basis of the coupling with para-substituted halobenzenes (23−
34). Either electron-rich or electron-poor substituted arenes
are employed successfully as viable coupling partners. The
modest yield from the p-F-phenyl bromide can be enhanced
significantly by the employment of the iodide counterpart
(29). A small amount of (+)-drim-9(11)-en-8α-ol17 can be
detected in the coupling with the electron-withdrawing
aromatic halides. Remarkable among these examples is the
tolerance of a variety of functional groups, including ether (24
and 27), halides (28 and 29), the nitro group (31), the cyano
group (32), and ketone (34). The compatibility of these
functional groups will provide enormous opportunities for
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further pharmaceutical elaboration of meroterpenoids, which
are otherwise not so easy in Kumada coupling (vide supra).
Switching the substituents to the meta or ortho positions was
well tolerated (35−40). Interestingly, the advantageous effect
of iodides on the coupling outcomes (39 and 40) is reversed
when the fluoro substitution was changed to a methoxyl group
(37 and 38). Coupling with biphenyl bromides proceeded
smoothly with good yields (41 and 42). Fused aromatic
counterparts, including 2-bromonaphthalene, 2-bromofluor-
ene, and 9-bromophenanthrene, are also feasible, delivering
meroterpenoids 43−45, respectively, with the yields varying
from 39% to 86%. A sterically hindered 2,4,6-trimethyliodo-
benzene can also be coupled smoothly (48, 81%).
Scheme 3. Improved Synthesis of Drimanyl Bpin 13 and
Formal Synthesis of Natural Products
We next focused on the multisubstituted aromatic halides
with alkoxyl groups, from which the coupled products can
serve as versatile precursors for the expedited construction of
natural drimane hydroquinones or mimics.2,3 To our delight,
the coupling paradigm proceeded smoothly under the
optimized conditions, providing a number of yahazunol
analogues or the precursors of drimane meroterpenoids in
good to excellent yields (48−59). Interestingly, the double
coupling is amenable upon introduction of appropriate
aromatic bromides as “bridges” to access the dimeric natural
product mimics (60 and 61).
Scheme 4. Translational Diversities of Synthesized Drimane
Hydroquinone 37
The ever-present heterocyclic motifs in medicinally
important structures could also be applied. On the basis of
our previous progress in the acquisition of antifungal drimane
meroterpenoids,18 a range of heterocycles are intentionally
enlisted and tested with the aim of synthesizing unnatural
products with improved druglike properties. In addition to the
good tolerance for the electron-rich thiophene (62−64), the
electron-poor pyridine (66), quinoline (67), and isoquinoline
(68) could also be coupled with compound 13 in good yields.
The N-phenyl carbazole bromide could also be recruited
successfully in this transformation (69). Though a wide scope
of coupling partners exists, a glaring limitation was also
detected in this transformation. The tolerance of a simple
phenolic hydroxyl group (70 and 71), boronate (72), ester
(73), thiazole (76), and imidazole (77) has not yet been
realized. Attempts with aliphatic bromide (74) and the o-
bromo heterocycles (75−77) did not provide serviceable
quantities of the product.
The scalability and practicality of this process were further
enhanced by the RuCl3-catalyzed improved synthesis of
homodrimanic acid 7 (Scheme 3). Cascade oxidative
degradation of sclareol was accomplished in a short time
(3−5 h) and gave a rather simple mixture. Direct and facile
utilization of crude product 7 from scale-up transformation (10
g scale) was demonstrated to be achievable through solvent
partitioning/aqueous wash for the subsequent Steglich-type
condensation. Synthesis of drimanyl Bpin 13 can be performed
efficiently (<20 min) on a gram scale. The Suzuki coupling
proceeded in good yields under optimal conditions. The
resultant coupled products, exemplified by 50, 54, and 55,
could serve as key intermediates for the efficient trans-
formations to a wealth of natural drimane meroterpenoids
(Scheme 3).3c,11,14,19 This may open a new window to the
efficient delivery of many natural products and mimics, without
recourse for the instable and air/water sensitive organo-
metallics.
DCM will lead to the coincidence of demethylation and
rearrangement in one pot. The structurally interesting and
biologically important 6-6-6-6 ring-fused scaffold 79 was
achieved enantioselectively, and its ester 80 was unambigu-
ously determined by X-ray diffraction (CCDC 2006961). The
Lewis acid-initiated H and methyl group shifts were detected
in the treatment with SnCl4 at −78 °C, delivering a mixture of
Aureol20 analogues 83 and 84 in a combined 78% yield.
Tetrasubstituted olefin 78 and trisubstituted congeners 81 and
82 (analogues of zonarol21) can be prepared through
regioselective dehydration. In addition to the translational
potentials and diversities, it is noteworthy that the products
themselves delineated in Table 2 can be deemed as drimane
meroterpenoids or unnatural mimics. The listed examples may
be only a drop in the bucket because aromatic halides are
among the most widespread building blocks. This may foretell
an almost limitless variety of arene-flanked drimane mer-
oterpenoids, with demonstrable values to researchers in either
chemistry or biology.
In our continuing interest in the discovery of antifungal
drimane meroterpenoids,11,18 we sought to acquire the
preliminary inhibitory effect of the synthetic mimics against a
series of agriculturally important plant pathogens (see the
Supporting Information for more details). Gratifyingly, the
antifungal effects were enhanced by the introduction of either
polar substitutions (33 and 34) or heterocyclics (62−68)
compared with original models 15 and 23. This represents the
first evaluation of dysideanone22 analogues as antifungal
The promising potential with respect to other meroterpe-
noids is remarkably exemplified by the transformation of 37
(Scheme 4). Treatment of compound 37 with excess BBr3 in
D
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Author Contributions
candidates. The effect of the aromatic substituents or the
different skeleton on the antimicrobial activity suggests there
may be distinct targets or pathways involved in the observed
phenomenon.
The manuscript was written through contributions of all
authors. S.L. conceived this work. X.W. and S.Z. conducted all
experimental work and analyzed the results. P.C. helped to
prepare some intermediates. X.W. and S.L. analyzed the data
and wrote the manuscript. All authors have given approval to
the final version of the manuscript.
In summary, with the invention of the bench stable and
easily accessible drimanyl Bpin from the inexpensive natural
diterpene sclareol, a new paradigm merging decarboxylative
borylation and Suzuki coupling was developed as a powerful
platform for a large variety of drimane meroterpenoids and
non-natural mimics.23 The high degree of practicality bodes
well for the discovery of pharmaceutically important
meroterpenoids. The current facile chemistry allowed the
unprecedented antifungal evaluation of these scaffolds. Future
efforts will be devoted to an expanded library of meroterpe-
noids through this tactic for the discovery of new therapeuti-
cally important agents.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21772094 and 21977049), the
Natural Science Foundation of Jiangsu Province
(BK20191306), and the Program of Introducing Talents to
Chinese Universities (111 Program, D20023).
ASSOCIATED CONTENT
■
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https://pubs.acs.org/doi/10.1021/acs.orglett.0c03294.
Experimental procedures and characteristic data (PDF)
Accession Codes
CCDC 2006960−2006962 and 2006969−2006970 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
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Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Shengkun Li − College of Plant Protection, State & Local Joint
Engineering Research Center of Green Pesticide Invention and
Application, Nanjing Agricultural University, Nanjing 210095,
China; Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University,
Guiyang 550025, China; orcid.org/0000-0001-5458-
0811; Email: skl505@outlook.com
Authors
Xia Wang − College of Plant Protection, State & Local Joint
Engineering Research Center of Green Pesticide Invention and
Application, Nanjing Agricultural University, Nanjing 210095,
China; Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University,
Guiyang 550025, China
Shasha Zhang − College of Plant Protection, State & Local Joint
Engineering Research Center of Green Pesticide Invention and
Application, Nanjing Agricultural University, Nanjing 210095,
China
Pengcheng Cui − College of Plant Protection, State & Local
Joint Engineering Research Center of Green Pesticide Invention
and Application, Nanjing Agricultural University, Nanjing
210095, China
Complete contact information is available at:
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