Modular Synthesis of Functionalized Butenolides by Oxidative Furan Fragmentation

Article abstract of DOI:10.1002/ejoc.201901613

The development of new chemical transformations to simplify the synthesis of valuable building blocks is a challenging task in organic chemistry and has been the focus of considerable research effort. Here we report a chemical transformation that enables

Full text of DOI:10.1002/ejoc.201901613

DOI: 10.1002/ejoc.201901613
Full Paper
YourJOC Talents | Very Important Paper |
Modular Synthesis of Functionalized Butenolides by Oxidative
Furan Fragmentation**
Jiajing Bao,[a][‡] Hailong Tian,[a][‡] Peicheng Yang,[a] Jiachen Deng,[a] and Jinghan Gui*[a]
Abstract: The development of new chemical transformations diated radical fragmentation in the presence of Cu(OAc)2 or var-
to simplify the synthesis of valuable building blocks is a chal- ious radical trapping reagents to afford butenolides bearing a
lenging task in organic chemistry and has been the focus of wide variety of appended remote functional groups, including
considerable research effort. Here we report a chemical trans- olefins, halides, azides, and aldehydes. The practical utility of
formation that enables the facile and modular synthesis of syn- this transformation is demonstrated by easy diversification of
thetically challenging yet biologically important functionalized the products by means of cross-coupling reactions and, most
butenolides from easily accessible furans. Specifically, Diels–Al- importantly, by its ability to simplify the syntheses of known
der reactions between furans and singlet oxygen generate ver- building blocks of eight biologically active natural products.
satile hydroperoxide intermediates, which undergo iron(II)-me-
ever, these approaches generally suffer from two limitations:
they require lengthy and tedious manipulations, and they lack
Introduction
modularity: that is, each structural motif is synthesized by a
completely different synthetic strategy. Therefore, the develop-
Butenolides are a class of five-membered-ring unsaturated lact- ment of a concise and modular approach to functionalized
ones that are present in a wide variety of compounds such as butenolides from simple and readily available starting materials
food additives, agrochemicals, pharmaceuticals, and biologically would be highly desirable.
active natural products. Examples include vitamin C (ascorbic
acid, 1, Figure 1a), which is an essential nutrient found in vari-
ous foods and is used as a dietary supplement to prevent and
treat scurvy; 3-methyl-2H-furo[2,3-c]pyran-2-one (2), which is
isolated from plant-derived smoke and promotes germination
of the seeds of agricultural weeds;[1] and clavilactone A (3)[2]
and pyranicin (4),[3] natural products that exhibit antifungal,
antibacterial, pesticidal, immunosuppressive, and antitumor ac-
tivities, among others. Compounds 3 and 4 could potentially
be accessed convergently via a fragment-coupling strategy in-
volving butenolides with appended remote functional groups
as key coupling partners. The various conventional approaches
for constructing butenolides have been reviewed[4] and include
ring-closing metathesis of unsaturated esters,[3f] intermolecular
alkylation of α-sulfenyl γ-lactones,[5] intermolecular aldol reac-
tions[6] and Pd-catalyzed carbonylation of vinyl iodides.[7] How-
One powerful strategy for rapidly generating molecular com-
plexity is carbon–carbon (C–C) bond fragmentation.[8] This strat-
egy has found numerous applications in natural product syn-
thesis[9] and materials science[10] and has drawn considerable
attention from synthetic chemists over the years.[11] Classic ex-
amples include the Grob[12] and Eschenmoser–Tanabe[13] frag-
mentations, dating back to the 1950s, for the expedient synthe-
sis of alkenes and alkynes (Figure 1b). In addition to ionic frag-
mentation,[14] radical fragmentation is also widely used.[15] Ex-
amples pertinent to this study include the seminal work on
iron-mediated decomposition reactions of hydroperoxides
reported by Kochi,[16] and Schreiber.[17] In these reactions, the
O–O bond of the hydroperoxide is cleaved in the presence of
an iron(II) salt to give an alkoxy radical, which undergoes ꢀ-
fragmentation to generate an alkyl radical. Subsequent oxid-
ation of the alkyl radical by a copper(II) salt furnishes the alkene
product.[16,18] Although this strategy is exceptionally powerful
for oxidative cleavage of ketones, removal of an isopropenyl
group,[11c,19] and macrolide synthesis,[20] it has rarely been used
for selective fragmentation of feedstock chemicals (such as
furans) to provide efficient, direct access to high-value-added
compounds.
[‡] These authors contributed equally to this work.
[a] CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center
for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032, China
E-mail: guijh@sioc.ac.cn
http://guigroup.sioc.ac.cn
[**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.26434/chemrxiv.8874455.v1).
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901613.
Because furans are inexpensive, readily available, and highly
reactive, they are versatile synthons and have frequently been
used to access a wide array of valuable building blocks.[21] Typi-
cal transformations of furans include Diels–Alder reactions to
afford butenolides and 1,4-diketones, Achmatowicz reactions to
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Figure 1. Overview of butenolides, bond-fragmentation strategies, and transformations of furans.
furnish pyranones and pyridones, and Mukaiyama aldol reac- process would be the conversion of furans to synthetically chal-
tions to form butenolides (Figure 1c). Despite the frequent ap- lenging yet biologically important butenolides simply by using
plication of these classic transformations in natural product syn- singlet oxygen and an inexpensive iron(II) salt. Herein we dis-
thesis and medicinal chemistry, the use of furans to rapidly gen- close the development of just such a process: specifically, we
erate molecular complexity via C–C bond fragmentation has report that oxidative fragmentation of furans provides rapid,
rarely been reported.[22] Given the easy accessibility of furans, modular access to functionalized butenolides bearing a broad
the development of a method for oxidizing the furan ring while range of appended remote functional groups, including olefins,
concurrently cleaving the adjacent C–C bond to generate func- halides, azides, and aldehydes (Figure 1d). Furthermore, we
tionalized butenolides would be highly appealing (Figure 1c). show that these remote functional groups can undergo various
The endoperoxide produced by a Diels–Alder reaction between bond-forming reactions, significantly expanding the chemical
a furan and singlet oxygen[23] is expected to form a hydroperox- space of accessible butenolides. Most importantly, we demon-
ide in MeOH,[24] which we speculated could then decompose strate that although the fragmentation of peroxides via Fe/Cu
in the presence of an iron(II) species to give a functionalized salts is known from the work of Kochi and applied to the syn-
butenolide via radical fragmentation. The net outcome of this thesis by Schreiber in the early 1980s, its application to hydro-
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peroxyfurans is a tremendously useful approach from the point C2-hydroxyethyl or -aryl group, afforded products bearing a re-
of view of creating rapid structural diversity from simple start- mote isopropenyl group (19i–k). Substrates with a C3-hydroxy-
ing materials.[25] Examples include butenolides 12–16, which
bear diverse remote functional groups and were concisely pre-
pared in a modular fashion from a single starting material (furan
11, Figure 1e).
alkyl, -amidylalkyl, -phenyl, or -allyl group (17l–o) were also
compatible with the reaction conditions. However, because of
the low solubility of furans 17n and 17o in MeOH, petroleum
ether was used as a co-solvent. Gratifyingly, substrates with an
endo- or exocyclic double bond or a free hydroxyl group on
the cycloalkyl ring were also tolerated: 17p–r and 17s gave
dienes 19p–r and allylic alcohol 19s, respectively.
Results and Discussion
It should be mentioned that in all the examples mentioned
above, hydroperoxide fragmentation generated a primary alkyl
radical, which in turn gave rise to a terminal olefin after being
oxidized by Cu(OAc)2. Accordingly, in the reactions of substrates
17t–v, radical fragmentation of the corresponding hydroperox-
ides (18t–v) could conceivably generate secondary or tertiary
alkyl radicals, which could lead to a mixture of terminal and
internal olefin products after oxidation. Indeed, when these
substrates were subjected to the standard conditions, a 2:1 to
4:1 mixture favoring the terminal-olefin products was obtained.
Therefore, to increase the regioselectivity of these reactions, we
used TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) instead of
Cu(OAc)2 to trap the alkyl radicals, which afforded butenolides
with a remote TEMPO group. Subsequent removal of the
TEMPO group[26] by means of microwave heating gave desired
We began our studies by carrying out experiments aimed at
optimizing the reaction conditions for oxidative furan fragmen-
tation. Using cyclohexane-fused furan 17a as a model substrate,
we evaluated various iron and copper salts, solvents, and tem-
peratures (Table S1, Supporting Information) in reactions to
form butenolide 19a, which has a terminal olefin group. Photo-
oxidation of 17a with singlet oxygen in MeOH gave hydroper-
oxide 18a in nearly quantitative yield, and optimization experi-
ments revealed that subsequent hydroperoxide fragmentation
in the presence of iron(II) lactate (1.2 equiv.) and Cu(OAc)2
(1.2 equiv.) in 3:1 DMSO/H2O at room temperature afforded de-
sired product 19a in 91 % isolated yield. With the optimized
conditions in hand, we set out to examine the substrate scope
of the reaction (Table 1). Cycloalkane-fused furans with various
ring sizes (17b–e, n = 2, 3, 7, and 10, respectively) delivered
desired butenolides 19b–e in 69–83 % yields. In addition, products 19t–v in good yields with high regioselectivities. No-
furans with a C2-alkyl or -hydroxyalkyl substituent (17f–h) tably, the use of this two-step procedure for dihydrocarvone-
proved to be viable substrates, giving rise to 19f–h in good derived furan 17v yielded terminal olefin 19v as the sole prod-
yields. Menthofuran-derived substrates 17i–k, which have a
uct.
Jiajing Bao received his B. S. degree in chemistry in 2016 from Soochow University. He then received his M.S. degree in organic chemistry in 2019
from Shanghai Institute of Organic Chemistry (SIOC) under the guidance of Prof. Jinghan Gui. In the fall of 2019, he bagan to pursue his
Ph.D research in natural product synthesis in Prof. Jinghan Gui's group.
Hailong Tian received his B. S. degree in Shanghai Normal University in 2016. In the same year, He joined Prof. Jinghan Gui′s research group as a
research associate to study the efficient synthesis of complex steroids and triterpenoid natural products.
Peicheng Yang received his B. S. degree from Changzhou University in 2016. In 2017, he joined Prof. Jinghan Gui's group at SIOC to pursue his
M. S. Research in methodology development.
Jiachen Deng received his B. S. degree from East China University of Science and Technology in 2015. In 2016, he joined Prof. Jinghan Gui's group
at SIOC to pursue his Ph.D research in natural product synthesis.
Jinghan Gui received his B.S. degree from Anhui Normal University in 2007. After completing his PhD at SIOC with Prof. Weisheng Tian in 2012, he
went on to pursue his postdoctoral research with Prof. Phil S. Baran at The Scripps Research Institute in February 2013. In March 2016, he moved
back to SIOC to begin his independent research career. His current research interests focus on the synthesis of complex, biologically active natural
products and on the development of novel synthetic methods with practical applications in drug discovery.
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Table 1. Synthesis of butenolides with an appended remote olefin group.[a]
[a] Reaction conditions: 17 (0.1–1 mmol), MB (1 mol %), MeOH, O2, hv, 0 °C, 30 min, then iron(II) lactate (1.2 equiv.), Cu(OAc)2 (1.2 equiv.), DMSO/H2O (3/1),
r.t., 0.5 h. Isolated yields are shown. [b] Iron(II) lactate (1.5 equiv.), Cu(OAc)2 (1.5 equiv.). [c] MeOH/petroleum ether (4:1) was used instead of MeOH. [d] Iron(II)
lactate (1.2 equiv.), TEMPO (1.5 equiv.), MeOH, r.t., 0.5 h, then DCB/iPr2NH (10:1), 200 °C (MW), 5 h. [e] Ratios of terminal olefin to internal olefin. Abbreviations:
MB = methylene blue, DMSO = dimethyl sulfoxide, TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, DCB = 1,2-dichlorobenzene.
Compared with the species generated by ionic fragmenta- As expected, addition of TEMPO to the reaction mixture deliv-
tion, alkyl radical intermediates generated by radical fragmenta- ered 20f in 78 % yield. Interestingly, alkyl radical 21 could be
tion are more versatile, and they can be intercepted by a variety intercepted by O2 to generate a mixture of aldehyde 20g and
of functional groups, thereby providing rapid, divergent access alcohol 20h in the presence of PhSiH3. The aldehyde or the
to underexplored chemical space by means of radical function- alcohol could be obtained selectively by subjecting the frag-
alization. Having synthesized butenolides with an appended re- mentation reaction mixture to Dess–Martin oxidation condi-
mote olefin group, we next turned our attention to trapping tions or to NaBH4 reduction conditions, respectively. In addition
alkyl radical intermediate 21 (Table 2) with various radical cou- to C–O bond formation, C–S and C–Se bond formation could
pling partners. This turned out to be nontrivial and necessitated be accomplished by employing Ph2S2 and Ph2Se2 as radical ac-
considerable effort to optimize the reaction conditions. In gen- ceptors to obtain 20i and 20j, respectively. We were pleased to
eral, either of two iron salts (iron(II) lactate or FeSO4) and one find that we could introduce difluoromethylthio and trifluoro-
of three solvent systems (MeOH, DMSO/H2O or CH3CN/H2O) methylthio groups by trapping 21 with PhSO2SCF2H[28] and
[29]
provided the best results. Specifically, after photo-oxidation of PhSO2SCF3;
this transformation can be expected to find
17a, the addition of FeSO4 and n-dodecyl mercaptan (a numerous applications in medicinal chemistry owing to the
hydrogen atom donor) led to the isolation of reduced buteno- change of molecular lipophilicity induced by introduction of
lide 20a in 90 % yield. Remarkably, this reaction was complete these groups. Furthermore, butenolides with a thiocyano group
within 25 s, as indicated by a color change (a photographic or an azide group (20m and 20n) were generated by reaction
[30]
description is given on page S11 of Supporting Information). with freshly prepared Cu(SCN)2 and Cu(N3)2.
Alternatively,
Gratifyingly, the use of 3:1 DMSO/D2O[27] resulted in selective 20o could be obtained via C–N bond formation when di-tert-
deuteration at the terminal position, giving 20b in 72 % yield butyl azodicarboxylate was used as the acceptor.
with 88 % deuterium incorporation.
Next, we evaluated the use of this radical fragmentation–
Halogenation reactions proceeded smoothly to give chloride functionalization cascade for C–C bond formation, which was
20c, bromide 20d, and iodide 20e in moderate to good yields. much more difficult than carbon–heteroatom bond formation.
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Table 2. Synthesis of butenolides with various appended remote functional groups.[a]
[a] Reaction conditions: 17a (0.1 or 0.3 mmol), MB (1 mol %), MeOH, O2 (1 atm), hv, 0 °C, 30 min, then iron(II) salt (1.2–2.5 equiv.), radical trapping reagent
(1.2–3 equiv.), solvent, r.t., 0.5 h. Isolated yields are shown. [b] The reaction was completed in 25 s as indicated by a color change. [c] Cu(OAc)2 (1.5 equiv.)
and LiOAc (3 equiv.) were added. Abbreviations: NBS = N-bromosuccinimide, NIS = N-iodosuccinimide, DMP = Dess–Martin periodinane, DBAD = di-tert-butyl
azodicarboxylate, Ts = p-toluenesulfonyl.
For example, a Giese-type reaction with ethyl vinyl ketone 22 tween butenolide 19a and 22 in the presence of Hoveyda–
as the radical acceptor gave only a low yield (ca. 20 %) of de- Grubbs II catalyst furnished desired product (E)-25 in 95 % yield
sired product 20p, along with major by-products arising from (Scheme 1a). Alternatively, 19a could react with 22 under
oligomerization of the vinyl ketone. Extensive optimization Baran's reductive olefin-coupling conditions[32] to give rise to
studies revealed that using Cu(OAc)2 and LiOAc as additives and 26 in 66 % yield. A B-alkyl Suzuki–Miyaura cross-coupling reac-
employing a reverse addition procedure (adding hydroperoxide tion,[25,33] a classic tool for total synthesis, between 19a and 27
to the reaction mixture) improved the yield of 20p to 48 %. afforded hydroarylated product 28 in 51 % yield. We also car-
Butenolide 20q, which has a remote acrylate ester group, was ried out some transformations of bromo-substituted butenolide
obtained in 53 % yield by reaction with 23 under the same 20d. Although bromides are well-known to undergo SN2 substi-
conditions. Finally, radical alkynylation and cyanation pro- tution, pioneering work by Fu and co-workers demonstrated
ceeded in moderate yields when sulfone 24 and tosyl cyanide that they are also ideal electrophiles for a range of transition-
(commercially available), respectively, were used to trap the rad- metal-catalyzed cross-coupling reactions to form C–C bonds.[34]
ical intermediate.
We found that palladium-catalyzed Suzuki[35] and Negishi[36]
cross-coupling reactions of 20d under Fu's conditions led to
excellent yields of desired cross-coupling products 30 and 32,
respectively (Scheme 1b).
This oxidative furan fragmentation reaction provides facile,
modular access to functionalized butenolides with various ap-
pended remote functional groups, including olefins, halides, al-
dehydes, and azides. To demonstrate its broad utility for organic
Organoboron compounds, which can be easily accessed by
synthesis, we were interested in connecting these butenolides means of olefin hydroboration, are versatile substrates for a
with other partners via fragment-coupling reactions wide array of transformations, including Suzuki coupling reac-
(Scheme 1), aiming to: 1) further expand the chemical space of tions, Zweifel olefination reactions,[37] lithiation-borylation
accessible butenolides; and 2) facilitate its application in natural chemistry[38] and conjunctive cross-coupling reactions.[39] For
product synthesis. Olefins are among the most versatile func- instance, borate 33, which was synthesized via iridium-cata-
tional groups in organic chemistry, and we explored some of lyzed hydroboration[40] of 19a, smoothly underwent Zweifel
the numerous methods available for their diverse transforma- olefination to give two-carbon-extended olefin 34 in 71 % yield
tions. For example, an olefin cross-metathesis reaction[31] be- (Scheme 1c). Sulfones are also valuable functionalities that can
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Scheme 1. Fragment-coupling reactions of functionalized butenolides. Yields of isolated products are shown. Abbreviations: acac = acetylacetonyl, 9-BBN =
9-borabicyclo[3.3.1]nonane, Cy = cyclohexyl, dba = dibenzylideneacetone, Cyp = cyclopentyl, PT = 1-phenyl-1H-tetrazol-5-yl, LDA = lithium diisopropylamide.
be used for Ramberg–Bäcklund reactions, Julia olefination reac- butenolide 42, which has a terminal iodide. Copper-catalyzed
tions, and radical cross-coupling reactions.[41] We found that a alkyl–alkyl cross-coupling[46] followed by in situ hydrolysis fur-
Julia–Kocienski olefination reaction between 1-phenyl-1H- nished 44 in 44 % yield, thus completing its synthesis in only
tetrazol-5-yl sulfone 35 (prepared from 20d in two steps) and two steps from 17d.
benzaldehyde delivered olefin 36 in 51 % yield (Scheme 1d).
Azides are widely used not only for generating amines but also
for aza-Wittig reactions and click chemistry.[42] Treatment of
azide 20n with phenylacetylene in the presence of catalytic
CuSO4 gave rise to 1,2,3-triazole 38 in excellent yield
(Scheme 1e).[43] Lastly, because aldehydes are known to be use-
ful for generating C–C bonds via nucleophilic addition reac-
tions, olefination reactions, and so on, we subjected aldehyde
20g to Horner–Wadsworth–Emmons olefination conditions and
Takai–Utimoto olefination conditions and obtained good yields
of desired unsaturated ester 40 and vinyl iodide 41, respectively
(Scheme 1f).
Next, we turned our attention to the annonaceous aceto-
genins, a large family of polyketide natural products found in
Annonaceae species, with more than 400 family members hav-
ing been isolated so far.[47] Structurally, these compounds are
characterized by an unbranched 32- or 34-carbon chain bearing
some oxygenated functional groups (e.g., hydroxyl, ketone, ep-
oxide, tetrahydrofuran, tetrahydropyran) and a terminal γ-but-
enolide. Annonaceous acetogenins exhibit a wide array of bio-
logical activities, including antiparasitic, pesticidal, antifeedant,
antimicrobial, immunosuppressive and antitumor activities, and
have therefore attracted substantial attention from the chemis-
try community.[48] Although considerable progress has been
To further illustrate the power of this new transformation, made in the synthesis of the butenolide fragments, the re-
we present eight examples in which its use simplified the syn- ported routes generally suffer from being long and inefficient,
thesis of a natural product (44) or known building blocks for and they lack modularity. For example, structurally similar
natural products (12–16, 59, 63) (Scheme 2). The first synthetic butenolides 12–16 (Scheme 2b–d), which are known synthetic
target was gorgonian lipid 44, which was isolated as a race- intermediates of acetogenins pyranicin (4),[3f] 10-hydroxy-
mate[44] and belongs to a class of anti-inflammatory fatty acid asimicin (68),[49] muricatetrocin C (67),[6a] mucocin (66),[50] and
γ-hydroxybutenolides.[45] The reported five-step procedure for asimicin (69),[7a] respectively, were previously prepared in 10–
its synthesis involves alkylation of a lithiated silyloxyfuran as the 16 steps from four distinct starting materials via four completely
key step. In contrast, our synthesis commenced with an oxid- different sequences. In sharp contrast, the protocol we have
ative fragmentation reaction of known furan 17d (Scheme 2a). described herein enabled concise, divergent and modular syn-
Addition of N-iodosuccinimide to the reaction mixture afforded theses of all five of these intermediates from a single starting
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Scheme 2. Synthesis simplification enabled by oxidative furan fragmentation. Yields of isolated products are shown. Abbreviations: NMP = N-methyl-2-
pyrrolidinone, PMB = para-methoxybenzyl, TBS = tert-butyldimethylsilyl, MOM = methoxymethyl, m-CPBA = meta-chloroperbenzoic acid, DMDO = dimethyl
dioxirane, CBS = Corey-Bakshi-Shibata reagent.
material (furan 11) and more importantly, via a single strategy:
Our syntheses started with the preparation of enantio-
oxidative furan fragmentation (as shown in Table 1 and Table 2) enriched furan 11 via cyclization of known alkynyl ketone 45,
followed by fragment coupling (as shown in Scheme 1).
followed by Noyori reduction (93 % ee) (Scheme 2b). After pro-
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tection of the hydroxyl group with a PMB group, reaction under analysis. We have illustrated that readily available furans, which
our standard conditions delivered desired olefinic butenolide have traditionally been employed as surrogates for a number
47 in 62 % yield. Basic hydrolysis and subsequent reduction of four-carbon building blocks, can undergo selective fragmen-
produced 12 in 75 % yield. Alternatively, protection of the tation to deliver valuable building blocks that are otherwise
hydroxyl group of 11 with a TBS group, followed by oxidative difficult or tedious to prepare. Moreover, we have shown that a
furan fragmentation (iron(II)lactate, TEMPO) and basic reduc- variety of butenolides with diverse structural features can be
tion, delivered a diastereomeric mixture of butenolide 52 expediently synthesized by means of a modular strategy involv-
(Scheme 2c). This TEMPO adduct was then oxidized by m-CPBA ing oxidative furan fragmentation and subsequent cross-cou-
to afford desired aldehyde 15,[51] which was subjected to Takai pling reactions.
olefination to give vinyl iodide 14 in 79 % yield. If the hydroxyl
group of 11 was protected with a MOM group instead of a TBS
Acknowledgments
group, vinyl iodide 13 could be easily obtained via the same
sequence. Moreover, butenolide 16, which has a long terminal-
olefin side chain, could be accessed from furan 48 in three steps
via oxidative fragmentation (iron(II) lactate, N-iodosuccinimide),
nickel-catalyzed alkyl–alkyl cross-coupling (under Knochel's
conditions)[52] and subsequent reduction (Scheme 2d). In a sim-
ilar manner, vinyl iodide 59, a known synthetic intermediate of
asiminocin 70,[5a] could be prepared via oxidative fragmenta-
tion, Takai olefination and reduction in three steps from known
furan 56 (Scheme 2e). Notably, the previously reported ap-
proach to 59 required eight steps.
Financial support was provided by the “Shanghai Rising-Star
Plan” (Grant No. 17QA1405100), the “Thousand Youth Talents
Plan”, the Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDB20000000), CAS Key Labo-
ratory of Synthetic Chemistry of Natural Substances, and Shang-
hai Institute of Organic Chemistry. We thank Prof. Qilong Shen
(SIOC) for providing PhSO2SCF3 and PhSO2SCF2H and Prof.
Liang Yin (SIOC) for providing access to chiral HPLC instrument.
Keywords: Butenolides · Oxygen heterocycles · Radical
reactions · Singlet oxygen · Synthetic methods
Finally, we prepared compound 63, an intermediate in the
synthesis of clavilactone A (3), which belongs to a family of
natural products with antifungal and antibacterial activities, as
well as potent inhibitory activities against Ret/ptc1 and epider-
mal growth factor receptor tyrosine kinases (Scheme 2f).[2d] The
previous approach to 63 required seven steps, with a relay ring-
closing metathesis reaction as the key step. Our synthetic se-
quence commenced with the preparation of C2-aryl furan 61 by
means of Sonogashira coupling, epoxidation and Au-catalyzed
cyclization. Furan 61 was subjected to the standard fragmenta-
tion condition and then ketal reduction, which furnished 63 in
five steps from commercially available 60.
It should be pointed out that one unsolved problem with
the above-described syntheses is the nonstereoselective reduc-
tion of the ketal moiety, which led to a diastereomeric mixture
of the butenolide product. To provide a proof-of-principle solu-
tion to this problem, we used ketal 19d as a model substrate
and converted it to γ-keto ester 64 in two steps. Gratifyingly,
subsequent Corey-Bakshi-Shibata reduction[53] of 64 gave rise
to butenolide 65 in good yield with good enantioselectivity
(Scheme 2g).
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Conclusions
In summary, we have developed a practical and efficient strat-
egy to access underexplored functionalized butenolides from
readily accessible furans via photo-oxidation with singlet oxy-
gen and subsequent iron(II)-mediated radical fragmentation.
The key aspects of this strategy are as follows: 1) it features
mild reaction conditions, inexpensive reagents and operational
simplicity; 2) it allows for precise and divergent installation of
remote functional groups (such as olefins, halides, aldehydes,
alcohols, and azides) at a position distal to the butenolide moi-
ety; 3) it has a broad substrate scope and generates diverse
products; and 4) it has great potential to simplify retrosynthetic
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Received: November 4, 2019
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YourJOC Talents
J. Bao, H. Tian, P. Yang, J. Deng,
J. Gui* ................................................. 1–10
Modular Synthesis of Functionalized
Butenolides by Oxidative Furan
Fragmentation**
An oxidative furan fragmentation reac- The practical utility of this transforma-
tion is described, which provides facile tion is demonstrated by its ability to
and modular access to butenolides simplify the syntheses of known build-
bearing a wide variety of appended re- ing blocks of eight biologically active
mote functional groups, including natural products.
olefins, halides, azides and aldehydes.
DOI: 10.1002/ejoc.201901613
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