Unified Approach to Furan Natural Products via Phosphine-Palladium Catalysis

Article abstract of DOI:10.1002/anie.202015232

Polyalkyl furans are widespread in nature, often performing important biological roles. Despite a plethora of methods for the synthesis of tetrasubstituted furans, the construction of tetraalkyl furans remains non-trivial. The prevalence of alkyl groups in bioactive furan natural products, combined with the desirable bioactivities of tetraalkyl furans, calls for a general synthetic protocol for polyalkyl furans. This paper describes a Michael–Heck approach, using sequential phosphine-palladium catalysis, for the preparation of various polyalkyl furans from readily available precursors. The versatility of this method is illustrated by the total syntheses of nine distinct polyalkylated furan natural products belonging to different classes, namely the furanoterpenes rosefuran, sesquirosefuran, and mikanifuran; the marine natural products plakorsins A, B, and D and plakorsin D methyl ester; and the furan fatty acids 3D5 and hydromumiamicin.

Full text of DOI:10.1002/anie.202015232

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8874–8881
International Edition:
German Edition:
doi.org/10.1002/anie.202015232
doi.org/10.1002/ange.202015232
Homogeneous Catalysis
Unified Approach to Furan Natural Products via Phosphine-Palladium
Catalysis
Violet Yijang Chen and Ohyun Kwon*
Abstract: Polyalkyl furans are widespread in nature, often
performing important biological roles. Despite a plethora of
methods for the synthesis of tetrasubstituted furans, the
construction of tetraalkyl furans remains non-trivial. The
prevalence of alkyl groups in bioactive furan natural products,
combined with the desirable bioactivities of tetraalkyl furans,
calls for a general synthetic protocol for polyalkyl furans. This
paper describes a Michael–Heck approach, using sequential
phosphine-palladium catalysis, for the preparation of various
polyalkyl furans from readily available precursors. The
versatility of this method is illustrated by the total syntheses
of nine distinct polyalkylated furan natural products belonging
to different classes, namely the furanoterpenes rosefuran,
sesquirosefuran, and mikanifuran; the marine natural products
plakorsins A, B, and D and plakorsin D methyl ester; and the
furan fatty acids 3D5 and hydromumiamicin.
Scheme 1. Examples of polyalkyl furan natural products and reaction
design.
Introduction
Furan is a structural motif in a wide variety of bioactive
natural products,[1] pharmaceuticals,[2] and useful intermedi-
ates in organic synthesis.[3] Polyalkyl furans, in particular,
feature prominently in bioactive natural products (Sche-
me 1A), including the galerucella pheromone;[4] calicogor-
gins A–C;[1d] furan fatty acids (F-acids),[5] potent antioxidants
and radical scavengers that protect polyunsaturated fatty
acids from lipid peroxidation; rosefuran,[6] the fragrant
component of highly prized rose oil; and plakorsins D[7] and
B,[8] cytotoxic F-acid derivatives isolated from the marine
sponge P. simplex.
Although C2/C5-functionalization of furans can be ach-
ieved quite readily through metalation or electrophilic
aromatic substitution,[9] the regioselective construction of
highly functionalized furans poses a challenge. Among myriad
methods available for the syntheses of tetrasubstituted furans,
the overwhelming majority provide carbonyl-,[10] thioalkyl-,[11]
halo-,[12] amino- and aryl-substituted[13] furans, but very few
enable direct access to the tetraalkyl furans[14] that feature
prominently in biologically important compounds (e.g., the F-
acids). Notably, none of the three known syntheses of
tetraalkyl furans[14] have, to the best of knowledge, ever
provided furans with four non-identical alkyl substituents.
Given the prevalence and desirable bioactivities of polyalkyl
furans and the relative paucity of aryl substituents in furan-
containing natural products,[15] it would be useful to have the
ability to prepare polyalkyl furans efficiently.
(Z)-3-Halo-2-propen-1-ols are versatile substrates that
can be obtained rapidly and stereoselectively from readily
available propargyl alcohols and alkynoates through hydro/
carbometalation-iodinolysis and hydroiodination-reduction
sequences, respectively.[16] Having both hydroxyl and vinyl
halide functionalities, we have found that they can be
integrated seamlessly into sequential phosphine-palladium
catalysis, wherein initially the OH group undergoes phos-
phine-catalyzed (E)-selective Michael addition to activated
alkynes to give vinyl ether intermediates,[17a–c] which then
undergo sequential Heck cyclization and spontaneous aro-
matization to give highly substituted furans (Scheme 1B).
The phosphine organocatalyst for the Michael addition acts as
a ligand in the Heck reaction. The resulting (alkoxycarbony-
l)alkyl side chain can then be transformed into other func-
tional groups and homologated.[18–20] Using appropriately
substituted (Z)-b-halo allylic alcohols, this approach becomes
a general method for the synthesis of various bioactive
polyalkyl furans from readily accessible precursors.
[*] V. Y. Chen, O. Kwon
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095-1659 (USA)
E-mail: ohyun@chem.ucla.edu
Results and Discussion
Our investigation of the Michael–Heck reaction began
with optimization of the Michael addition between the b-
iodoallylic alcohol 1m and methyl propiolate (Supporting
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.202015232.
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Information, Table S1). The more nucleophilic PBu3 was
Because conditions A worked well for the preparation of
superior to PPh3 at accelerating the Michael reaction, while
nonpolar solvents were preferred over polar ones, delivering
the Michael adduct in 96% yield. Next, we examined the
Heck reaction using the optimized conditions for the Michael
addition (Supporting Information, Table S2). A screen of
various bases revealed that Et3N containing 1% water was
optimal (Supporting Information, Table S3).[21] Toluene and
MeCN were superior to dioxane as solvents, and PdII catalysts
outperformed Pd0 species. The presence of the phase-transfer
agent tetrabutylammonium chloride (TBAC) was essential.[22]
Thus, the use of non-anhydrous Et3N and catalytic Pd(OAc)2
in MeCN provided the furan 3m in 97% yield [Eq. (1)].
furans containing at least one electron-withdrawing group, we
attempted to make the Michael acceptor more electron-
deficient (Supporting Information, Scheme S5), but detected
no product and obtained copious amounts of polymerized
Michael acceptor.[17c] Intrigued by Fuꢀs report on the use of
air-stable trialkylphosphonium salts for various cross-cou-
plings of deactivated aryl chlorides and bromides,[24] we
adapted those conditions for our Michael–Heck reaction
[Eq. (2)].
Using P(t-Bu)3HBF4 along with Cy2NMe as the base, we
prepared trialkyl furans with fused cycloalkyl (3z) and linear
alkyl (3cc, 3dd, 3ee, 3hh) substituents in moderate to good
yields. Plakorsin D methyl ester,[7] a polyketide isolated from
the marine sponge P. simplex, was obtained in 64% yield.
Significantly, the medicinally relevant CF3 group was com-
patible, furnishing the furan 3aa in good yield.[25,26] While
these conditions failed for the synthesis of tetraalkyl furans,
a slight increase in the reaction temperature to 1108C (from
908C for conditions B) and the use of Pd2(dba)3 as a catalyst
enabled the preparation of tetraalkyl furans in good yields
[Eq. (3)].
With these optimized conditions in hand, we explored the
substrate scope of the Michael–Heck reaction (Table 1).
Under conditions A, we obtained the 2-substituted furan 3a
in 94% yield. These conditions were also compatible with
both C3-alkyl and -aryl groups, delivering the 2,3-disubsti-
tuted furans 3a–3k in good yields (53–90%). Elevated
temperatures were required in the cases of the bulky 3-
isopropyl- and 3-tert-butyl-substituted furans 3c and 3d
(conditions A1). Notably, potentially reactive allyl and prenyl
groups were inert to the Heck conditions, delivering 3e and
3 f, respectively, in good yields. While both electron-donating
and -withdrawing substituents on the C3-phenyl ring were
tolerated, the reaction was sensitive to steric effects, with meta
substituents (3j, 3k) giving substantially lower yields than
para (3h, 3i) ones. A similar trend occurred among the 2,4-
disubstituted furans, where C2-phenyl compounds containing
para electron-withdrawing (3o) and -donating (3p) groups
outperformed an ortho-substituted one (3n). While both C4-
alkyl (3l) and -aryl (3m) groups were compatible, the use of 3-
butyn-2-one (3l’, 3m’) and ethynyl phenyl ketone (3m’’) in
place of methyl propiolate required slow addition of the
alkyne (conditions A2) to prevent rapid polymerization of the
Michael acceptor under phosphine catalysis. The ease with
which the starting (Z)-3-halo-2-propen-1-ol could be func-
tionalized enabled facile access to both 2,3- and 2,4-function-
alized furans, which are difficult to obtain regioselectively
when using conventional methods.[23] The standard conditions
A were also applicable for the synthesis of 2,5-disubstituted
furans, where C5-alkyl (3q, 3r), -cycloalkyl (3s, 3t), and -aryl
(3v–3x) groups were all incorporated. No opening of the
cyclopropyl ring (3s) occurred, and both bulky cyclohexyl
(3t) and 1-naphthyl (3x) groups were compatible. Plakorsi-
n A,[8a] an F-acid derivative from the marine sponge P.
simplex, was obtained in 86% yield.
Whereas the presence of a C3-aryl unit led to a slightly
diminished yield (3ii), tetraalkyl furans with either fused
cycloalkyl (3kk) or linear alkyl (3jj, 3ll) groups were
prepared in good yields. In the cases of 3z and 3kk, we used
a vinyl bromide substrate, further highlighting the versatility
of this method. Finally, furans substituted with four different
alkyl groups (3mm, 3nn) could be prepared in good yields. To
the best of your knowledge, this methodology is the first ever
reported of result in the synthesis of furans bearing four
different alkyl substituents. Among the more than 90 reports
describing the syntheses of tetrasubstituted furans, only three
have been amenable to the preparation of tetraalkyl furans,[14]
and none of them to the synthesis of furans presenting four
different alkyl groups. The compatibility of silyl ether groups
is also significant, suggesting potential application of this
method towards total synthesis of complex furan natural
products.
We turned our attention to the preparation of tri- and
tetrasubstituted furans. While conditions A1 delivered the
aryl-containing trisubstituted furans 3y, 3bb, and 3gg in good
yields, they failed for di- or trialkyl-substituted substrates.
Having demonstrated the wide substrate scope of the
Michael–Heck reaction, we explored its applications in the
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Table 1: Substrate scope of the Michael–Heck reaction.[a,b]
[a] All reactions were performed under Ar using anhydrous solvents. [b] Isolated yields after flash-column chromatography. [c] X=Br.
total syntheses of bioactive furans (Scheme 2A). Hydrolysis
of plakorsin A produced plakorsin B, known to exhibit strong
cytotoxicity against colon carcinoma (COLO-250) cells and
weak activity against nasopharyngeal carcinoma (KB-16)
cells.[8a] Previous approaches to plakorsins A and B have
included Lewis acid-mediated 5-endo-dig cyclization of 3-
alkyne-1,2-diols,[27] sequential functionalization of furan
through lithiation/alkylation,[28] and electrophilic aromatic
substitution of methyl 2-furylacetate[29] and 2-cyanomethyl-
furan,[29b,30] the latter of which suffered from highly variable
yields (23–92%). On the other hand, our Michael–Heck
approach reliably furnished plakorsin A from methyl propio-
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Scheme 2. Applications of products of Michael–Heck reactions to total syntheses of bioactive furan natural products Reaction conditions:
a) LiAlH4, Et2O, 08C, 15 min. b) PPh3, I2, imidazole, THF, rt, 15 min. c) KCN, acetone/water, reflux, 16 h. d) PPh3, neat, 1 h, 80–858C.
late in 62% yield over three steps. Hydrolysis of plakorsin D
methyl ester furnished plakorsin D-its first total synthesis.[31a]
Next, we moved on to the synthesis of 2,3-disubstituted
furanoterpenes (Scheme 2B). Reduction of the ester group of
the furan 3b produced an alcohol intermediate,[32] which we
transformed to a halide. Surprisingly, the bromide was
unstable,[33] but the iodide proved to be robust and was
converted smoothly to the phosphonium iodide 4 when using
PPh3 as the reaction solvent.[34] A subsequent Wittig reaction
under Bodenꢀs conditions[35] furnished rosefuran in 97%
yield. To prevent complications resulting from lithiation of
the free C5 position of 4, we chose KOtBu as the base. We
used the same approach for the syntheses of sesquirosefur-
an[36] and mikanifuran.[37] In these cases, excess ketone and
high reaction concentrations were necessary to prevent the
formation of 3-methyl-2-vinylfuran as a side product (pre-
sumably resulting from E2 elimination of 4).[38] Under these
conditions, we obtained sesquirosefuran in 96% yield as
a mixture of E/Z isomers. Despite efforts to selectively obtain
the E-isomer,[39] the inherent Z-selectivity of Wittig reactions
with unstabilized ylides resulted in a mixture of isomers.[40] We
also used these conditions to prepare mikanifuran in 56%
yield as a mixture of E/Z isomers. In addition to being used in
fragrances and spices, rosefuran is also a female sex pher-
omone in the acarid mite, Caloglyphus sp., capable of
triggering sexual excitation at less than 100 ng.[6a,b] While
mikanifuran has no known biological activity, sesquirosefuran
displays significant cytotoxicity against HeLa cells in vivo.[36]
The commercial importance and biological activity of rose-
furan has inspired several ingenious syntheses of it and
related furanoterpenes. These strategies can be classified into
alkylation, transition metal-catalyzed methods, functionaliza-
tion of cyclic precursors, and cyclization of linear precur-
sors.[41]
For the total synthesis of 3D5, a unique F-acid found in
the soft corals S. glaucum and S. gemmatun (Scheme 2C), we
employed a sequence of reduction, Appel reaction, and
cyanation of the furan 3ll to produce the nitrile 5, which
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underwent hydrolysis in 98% yield to give the F-acid.[42]
Similarly, the furan 3cc was converted into the nitrile 6,
which was hydrolyzed in 98% yield to produce hydromumia-
micin,[43] an F-acid derivative in the actinomycete strain
Mumia sp. YSP-2-79 with antimicrobial and antioxidant
activity. While several syntheses have been reported of F-
acids featuring long carboxyalkyl chains, our present total
syntheses are the first for F-acids having a three-carbon
carboxyalkyl chain.[44] While many efficient methods are
available for the syntheses of 2,3-disubstituted furanoter-
penes, F-acids, and their derivatives, only this present
approach is applicable to the preparation of all three types
of natural products.
lished, examples involving tertiary alcohols are extremely
rare and often involve the use of more reactive PMe3.[46] We
found, however, that employing PMe3 resulted in the rapid
polymerization of methyl propiolate. Tejedorꢀs insightful
report on Lewis base-catalyzed addition of primary, secon-
dary, and tertiary alcohols onto alkyl propiolates suggested
that the increased basicity of a tertiary alcohol, as well as the
decreased nucleophilicity of the corresponding tertiary alk-
oxide, made it unable to compete with the dimerization or
polymerization of alkyl propiolates in the presence of amines
or phosphine catalysts.[17c] To remedy this quandary, we
positioned a pKa-lowering CF3-substituent onto the tertiary
alcohol.[47] To our delight, we obtained the Michael adduct 8
from 1g’ in 84% yield. Having verified the feasibility of the
DABCO-catalyzed Michael addition of acidic tertiary alco-
hols onto methyl propiolate, we then subjected 1g’ to the
Heck conditions. Gratifyingly, the small amount of methyl
To verify the reaction mechanism, we isolated the putative
Michael adduct (E)-alkoxyacrylate[45] intermediate 7 and
subjected it to the optimized Heck conditions, obtaining the
furan 3g, albeit in slightly diminished yield when compared
with the one-pot procedure [Eq. (4)]. The nascent Michael– propiolate dimer[48] formed did not interfere with the Heck
Heck adduct 2-furanylideneacetate 3g’ was also prepared
when using the tertiary alcohol 1g’ [Eq. (5)]. Notably, only
(Z)-2-[furan-2(5H)-ylidene]acetate 3g’ was isolated in 68%
yield, supporting the occurrence of stereospecific syn-inser-
tion and syn-elimination during the Heck process (see below).
While the phosphine-catalyzed Michael addition of primary
and secondary alcohols onto alkyl propiolates is well estab-
reaction, and the (Z)-2-[furan-2(5H)-ylidene]acetate 3g’ was
isolated in 68% yield. NOE correlations between the
electron-deficient vinyl proton and the ortho phenyl protons
confirmed the (Z)-geometry of 3g’.
The observations described above underpin the following
mechanism for our Michael–Heck reaction (Scheme 3B).
Initially, tributylphosphine adds onto the electron-deficient
Scheme 3. Mechanistic investigations.
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8. Subsequent oxidative addition of the Pd0 complex leads to
D, which undergoes syn-carbopalladation to produce the
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À
dihydrofuran intermediate E. After rotation about the C C
single bond, the resulting intermediate F undergoes stereo-
specific syn-b-hydride elimination to generate (Z)-2-[furan-
2(5H)-ylidene]acetate G, which spontaneously undergoes
aromatization to give the desired furan products when one
of the C5 substituents is a hydrogen atom.
Conclusion
We have developed a Michael–Heck protocol for the
versatile synthesis of furans of various substitution patterns
from (Z)-3-halo-2-propen-1-ols and propiolates. Notably, this
method produced, for the first time, furans substituted with
four different alkyl groups. The C2-carboxymethyl group
derived from the propiolate can then be used conveniently as
a handle for further transformations. We have demonstrated
the applicability of this new protocol through total syntheses
of the P. simplex marine sponge natural products plakorsin-
s A, B, and D and plakorsin D methyl ester; the furanoter-
penes rosefuran, sesquirosefuran, and mikanifuran; and the
F-acids 3D5 and hydromumiamicin. Employing (Z)-b-halo
allylic alcohols, which are readily available, this method offers
a general entry to the direct and regioselective syntheses of F-
acids and other biologically important polyalkyl furans.
Acknowledgements
Financial support for this study was provided by the NIH
(R01GM071779). We thank Dr. Yi Chiao Fan for his initial
studies into furan synthesis based on the Michael–Heck
process.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: furan natural products ·furan synthesis ·
Heck reaction ·Michael addition ·phosphine–
palladium catalysis
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[31] a) Although plakorsin D methyl ester has not been prepared
de novo, it, along with another furanylidene P. simplex natural
product, has been demonstrated to arise from the FeCl3-
mediated rearrangement of the cyclic endoperoxide analogue
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Supporting Information for a full list of previous syntheses.
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[44] In addition to the strategies used for the preparation of plakorsin
natural products and 2,3-disubstituted furanoterpenes, rear-
rangements of cyclic endoperoxides (Ref. [31b]) and catalytic
isomerization of cyclic epoxyalkynols have also been reported
for the synthesis of 11 M5 and its methyl ester. Other syntheses
include lithiation/alkylation of 3-iodofurans; Sonogashira and
Negishi couplings of methyl 4,5-dibromofurano-2-carboxylate;
electrophilic aromatic substitution of methyl 3-methyl-2-furo-
ate; and reduction/iodination/reduction of 3-ethoxycarbonylfur-
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syntheses.
[45] The coupling constants (J) for the vinyl protons of methyl (Z)-b-
alkoxyacrylates range from 6.7 to 7.2 Hz, in contrast to values of
approximately 12 Hz for corresponding E isomers. For examples,
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[29] a) Ref. [8a]; b) Ref [8d]; c) Ref [8e].
[30] Ref [8c].
[46] Examples of PMe3-catalyzed addition of tertiary alcohols onto
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8880 www.angewandte.org
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Angewandte
Research Articles
Chemie
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[47] While an alkynyl group would lower the pKa of a tertiary alcohol
by approximately 2 units, replacing one of the methyl groups in
tert-butanol by a CF3 group would lower the pKa from 17 to 12.6
(a change of 4.4 units). See Ref. [17c].
[48] DABCO is known to quantitatively dimerize methyl propiolate
to (E)-hex-2-en-4-ynedioic acid dimethyl ester: a) Y. Matsuya,
Manuscript received: November 14, 2020
Revised manuscript received: January 12, 2021
Accepted manuscript online: February 2, 2021
Version of record online: March 8, 2021
Angew. Chem. Int. Ed. 2021, 60, 8874 –8881
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8881