A Construction of α-Alkenyl Lactones via Reduction Radical Cascade Reaction of Allyl Alcohols and Acetylenic Acids

Article abstract of DOI:10.1021/acs.orglett.0c02973

An iron-catalyzed cascade reaction of radical reduction of allyl alcohols and acetylenic acids to construct polysubstituted α-alkenyl lactones has been developed. In this paper, various allyl alcohols can form allyl ester intermediates and are further transformed into alkyl radicals, which form products through intramolecular reflex-Michael addition. In addition, this method can be used to prepare spirocycloalkenyl lactones. Interestingly, this protocol can be used to synthesize the skeleton structure of natural products. Moreover, the product can be further transformed into a β-methylene tetrahydrofuran and tetrahydrofuran diene.

Full text of DOI:10.1021/acs.orglett.0c02973

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Letter
A Construction of α‑Alkenyl Lactones via Reduction Radical Cascade
Reaction of Allyl Alcohols and Acetylenic Acids
Hua Zhang, Guo-Min Zhang, Shuai He, Zhi-Chuan Shi, Xiao-Mei Zhang, and Ji-Yu Wang*
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ABSTRACT: An iron-catalyzed cascade reaction of radical reduction of allyl alcohols and acetylenic acids to construct
polysubstituted α-alkenyl lactones has been developed. In this paper, various allyl alcohols can form allyl ester intermediates and are
further transformed into alkyl radicals, which form products through intramolecular reflex-Michael addition. In addition, this method
can be used to prepare spirocycloalkenyl lactones. Interestingly, this protocol can be used to synthesize the skeleton structure of
natural products. Moreover, the product can be further transformed into a β-methylene tetrahydrofuran and tetrahydrofuran diene.
prepare α-alkenyl lactones, Hoffmann2 and Reiser3 have
α-Alkenyl lactones are a class of compounds with synthetic
reviewed related work. There are also a few traditional
methods for synthesizing α-alkenyl lactones, such as the use
of strong bases to enolize γ-butyrolactones via aldol,4
Mannich,5 or Wittig6 reactions to synthesize α-alkenyl
butyrolactones. The direct lactonization of chain alkenyl esters
to produce α-alkenyl butyrolactones has also been extensively
studied by organic chemists.7 In addition, the preparation of α-
alkenyl butyrolactones by the Dreiding−Schmidt organo-
metallic approach has been widely reported.8 Of course,
other metal-promoted approaches have also been used to
prepare α-alkenyl butyrolactones.9 It is also a very important
method to prepare complex α-alkenyl butyrolactones from
simple α-alkenyl butyrolactones.10 In recent years, the
preparation of α-alkenyl butyrolactones by free-radical
cyclization has also been shown to be a very practical
method.11 Finally, other methods are occasionally used to
prepare α-alkenyl butyrolactones.12 Although there are many
methods for synthesizing α-alkenyl lactones, it is still worth
challenges and biological activities in nature, such as
costunolide, parthenolide, piperphilippinin IV, septuplinolide,
and xanthatin (Scheme 1). Since the first α-alkenyl lactone
isolated in 1891, more than 4000 α-alkenyl lactones have been
isolated from natural products.1
Therefore, the preparation of α-alkenyl lactones by a
convenient and fast method has always been the goal of
efforts of organic chemists. Early scientists used biosynthesis to
Scheme 1. Biological Compounds Containing α-Alkenyl
Lactone Skeletons
Received: September 6, 2020
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© XXXX American Chemical Society
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A

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a b
,
studying to use simple starting materials to construct α-alkenyl
lactones conveniently and quickly.
Table 1. Exploration of Reaction Conditions
The construction of carbon−carbon bonds has always been
an important research direction in the field of organic
chemistry. In recent years, transition-metal-catalyzed free-
radical hydrogen functionalization of olefins was found to be
an effective method for constructing carbon−carbon bonds
and carbon−hetero bonds.13 Currently, there are many reasons
why iron is the most widely used catalyst. The content of iron
in the earth’s crust is second only to aluminum. The great
appeal of iron catalysts is attributed to their low price, low
toxicity, and environmental friendliness.14 At present, the iron-
catalyzed free-radical reduction cross-coupling reaction showed
its extraordinary significance in organic chemistry and was a
powerful means of constructing C−C bonds, C−N bonds, and
C−X (X = F, Cl, S) bonds. In particular, Boger used iron
oxalate as a catalyst to develop the hydrofluorination reaction
of unactivated olefins.15 Baran reported Fe-catalyzed practical
reductive olefin coupling between nonactivated olefins and
various electron-accepting olefins.16 The Cui team also studied
the reductive coupling of nonactivated olefins.17 Pronin used
the cascade reaction of reducing free radicals for the synthesis
of (−)-nodulisporic acid C and paxilline indole diterpenes.18
Previously, our research group reported the reductive olefin
coupling of chromones as an acceptor olefin, and then we
developed the free radical reduction cascade reaction of
maleimides and allyl alcohols.19 Although there have been
many reports of reductive cross-coupling, there are still a few
reports of free-radical reductive cascade reactions.
yield (%)
entry
catalyst
reductant solvent
T (°C)
3a
50
0
trace
28
trace
50
81
4a
1
2
3
4
5
6
7
8
Fe(acac)3
Fe(ox)3·6H2O
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
PhSiH3
PhSiH3
Ph2SiH2
NaBH4
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
EtOH
EtOH
EtOH
EtOH
THF
MeOH
EtOH
EtOH
EtOH
60
60
60
60
60
60
75
0
0
0
0
0
0
0
0
0
100 (seal)
75
72
20
c
9
a
Reaction conditions: 2a (0.6 mmol), 1a (0.2 mmol), reductant (2
equiv), catalyst (30 mol %), solvent (1 mL), 4 h. Yield refers to
b
c
isolated product. Fe(acac)3 (10 mol %) was used.
we only obtained a trace amount of product (entry 3). When
NaBH4 was used as a reducing agent, α-alkenyl butyrolactone
could be obtained in a lower yield (entry 4). When THF was
used as the solvent for this reaction, only trace amounts of
product can be obtained (entry 5). The reaction yield in
methanol was about the same as ethanol (entry 6). To our
surprise, when the reaction temperature increased to 75 °C,
the yield of 3a could impressively increase to 81% (entry 7).
Unfortunately when the reaction temperature continued to
increase to 100 °C (seal), the yield of 3a decreased slightly
(entry 8). We also tried to reduce the catalyst loading to 10%,
but the yield of the reaction was greatly reduced (entry 9).
According to the conditions obtained by optimization, we
would explore the substrate adaptability of this transformation
(Scheme 3). Therefore, different types of allyl alcohols would
be included in our scope of examination. In addition, the X-
single crystal diffraction pattern proved that the reaction was a
reduction radical cascade reaction. Interestingly, cyclohex-1-en-
1-ylmethanol and cyclopent-1-en-1-ylmethanol could prepare
spirocycloalkenyl lactones in good to excellent yields (3b−3c).
When alkyl chain allyl alcohols were used in this reaction, α-
alkenyl butyrolactones could be obtained in moderate yields
(3d−3e). When the 1-position of allyl alcohols was connected
to substituted benzene, both the electron-withdrawing and
electron-donating substituents could deliver fully substituted
α-alkenyl lactones smoothly in moderate yields (3f−3h). The
electronic properties had no influence on the reaction.
Moreover, 1-(prop-1-en-2-yl)cyclopentan-1-ol and 1-(prop-1-
en-2-yl)cyclohexan-1-ol were also well applicable in this
protocol to deliver the fully substituted spirocycloalkenyl
lactones in moderate yields (3i,3j). The (E)-3-methylpent-3-
en-2-ol could be engaged in this process to afford the product
in a moderate yield (3k). The exciting thing was that when
cyclohept-2-en-1-ol and 2-methylenecycloheptan-1-ol were
applied to the protocol, seven-membered cyclic alkenyl
lactones could be obtained smoothly (3l,3m). The lactones
were the backbone structure of natural product xanthatin.1f−h
Gratifyingly, 3-methylbut-2-en-1-ol could deliver alkenyl
valerolactone in excellent yield (3n, 92%). Furthermore, 4-
methylpent-3-en-2-ol and 4-methyl-2-(p-tolyl)pent-4-en-2-ol
were used, and the α-alkenyl valerolactone could also be
At present, there have been reports in the literature that
acetylenic acids and alcohols can be esterified under Lewis acid
catalysis.20 Cui’s team has reported the free-radical debromi-
nation coupling reaction of brominated alkynes and olefins
(Scheme 2A).21 In addition, phenylpropynoic acid can
Scheme 2. Hydrogen Functionalization of Alkyne
undergo reflex-Michael addition reaction with free radicals.22
We inferred that acetylenic acids and allyl alcohols can be
esterified under the catalysis of Fe(acac)3 to form allyl ester
intermediates. The intermediates were then closed by
intramolecular radical reflex-Michael addition to form
products. Therefore, we developed an inexpensive iron-
catalyzed radical cascade reaction to synthesize α-alkenyl
lactones through esterification/radical reflex-Michael addition.
We started our research under various conditions with
phenylpropynoic acid (1a) and 2-methylallyl alcohol (2a) as
reactants. (Table 1, see the Supporting Information for
detailed data). Initially, we attempted the conditions of
Baran16 to carry out this reaction. Fortunately, the α-alkenyl
lactone was obtained in a moderate yield (entry 1). In
addition, iron oxalate15 did not catalyze the reaction (entry 2).
What’s more, when another reductant like Ph2SiH2 was used,
B
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a,b
reaction. For example, for the 4-substituted phenylpropioic
acids, both electron-donating and electron-withdrawing
substituents could obtain products smoothly in good to
excellent yields (3q−3v), such as fluoro, chloro, bromo,
phenyl, methyl, and methoxy. In general, the reactivity of
electron-withdrawing substituents was better than that of
electron-donating substituents. It might be that the electron-
withdrawing group reduced the electron cloud density at the α
position of phenylpropynoic acid, making the attack of the free
radical more effective. When the position of the substituent on
benzene changed, the products could be obtained in moderate
yields (3w−3x). Furthermore, the disubstituted phenyl group
was also compatible with this reaction (3y). Interestingly, the
heterocyclic substituted acetylenic acids also had good
compatibility with this reaction, and the products could be
obtained in a moderate to good yield (3z−3ab). Additionally,
a naphthalene ring could be introduced at the α position of the
alkenyl lactone (3ac). Regrettably, we tried alkyl substituents
to carry out this reaction, but none of the alkenyl lactones were
obtained.
Scheme 3. Substrate Scope of Allyl Alcohols
In order to explore the potential application value of this
method, after the reaction was scaled up to 10 mmol, the
product was still obtained with an isolated yield of 76%
(Scheme 5A). β-Methylene tetrahydrofuran is a structural
Scheme 5. Scale-up Reaction and Synthetic Application
a
Reaction conditions: 2 (0.9 mmol), 1a (0.3 mmol), PhSiH3 (2
b
equiv), Fe(acac)3 (0.3 equiv), EtOH (0.2 M), 75 °C, 4 h. Isolated
yields. The reaction time was 24 h. The dr was determined by H
NMR spectrum.
c
d
1
formed, albeit in moderate yield (3o,3p). This phenomenon
indicated that the steric hindrance on the allyl alcohol oxygen
would reduce the yield of the reaction.
Next, we discuss the effect of the change of the acetylenic
acid substituent on the reaction (Scheme 4). We found that
various acetylenic acids showed good compatibility with this
a,b
Scheme 4. Substrate Scope of Acetylenic Acids
motif of some marine products and has a very important
application value.23 In addition, the method for synthesizing β-
methylene tetrahydrofuran was less developed.24 However, the
development of a convenient and practical method to
synthesize β-methylene tetrahydrofuran still faces many
difficulties. Therefore, the derivatization of α-alkenyl butyr-
olactone into β-methylene tetrahydrofuran proved its potential
application value (Scheme 5B). α-Alkenyl butyrolactone could
be reduced to 3-benzylidene-2,2-dimethylbutane-1,4-diol, and
3-benzylidene-2,2-dimethylbutane-1,4-diol could be refluxed in
perchloric acid to obtain β-methylene tetrahydrofuran (6a) in
a moderate yield.24b In addition, the addition of α-alkenyl
butyrolactone and bromine could form a quaternary carbon
bromine center (Scheme 5C). Interestingly, hard nucleophiles
could attack the carbonyl group of alkenyl lactones to form
hemiacetal intermediates 8a, and 8a dehydrated under Lewis
acid catalysis to form tetrahydrofuran diene 9a25 (Scheme 5D).
a
Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Fe(acac)3 (0.3
b
equiv), PhSiH3 (2 equiv), EtOH (0.2 M), 75 °C, 4 h. Isolated yields.
C
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The strategy will provide precursor molecules for the synthesis
of polysubstituted benzotetrahydrofurans.
In order to explore the reaction process of this reaction, we
conducted a series of control experiments (Scheme 6). When
the expected product could be obtained in a moderate yield.
This process showed that there was a transesterification
process between ethyl 3-phenylpropiolate (4a) and allyl
alcohol (2a). In addition, when deuterated ethanol was used
to replace the solvent of the reaction, the reaction could
proceed smoothly, but 80% of 3aD was obtained. This
phenomenon indicated that most of the protons in the reaction
come from the solvent. It might be that ethanol acted as a
solvent for this reaction, which made the anionic intermediate
more likely to collide with ethanol.
Scheme 6. Control Experiments
Based on control experiments and literature descrip-
tions,16−19 we proposed a possible reaction process in Scheme
7. Initially, iron catalyst, phenylsilane, and ethanol worked
Scheme 7. Proposed Mechanism
together to form ferrohydrogen species (A). Meanwhile, the
esterification reaction of acetylenic acid and alcohol formed
intermediates 4 and 5.20 Intermediates 4 and 5 were in
dynamic equilibrium and as intermediate 5 was consumed,
intermediate 4 was continuously transformed into intermediate
5. The iron hydride species (A) and the donor olefin 5
underwent hydrogen atom transfer to form a free-radical
intermediate C, and the free-radical intermediate C rapidly
underwent an intramolecular reflex-Michael addition reaction
to give a free-radical addition product D. Then the single-
electron transfer between FeIILn and D delivered E, which was
protonated to α-alkenyl butyrolactone. Then intermediate D
and FeIILn underwent single-electron transfer to form
intermediate E. Intermediate E took protons from the alcohol
to form a product.
In summary, an iron-catalyzed acetylenic acid and allyl
alcohol radical reduction tandem reaction to prepare α-alkenyl
lactones was developed. This process not only has mild
conditions and broad substrate adaptability but also reveals the
tandem reaction of radical reduction of acetylenic acid, which
provides a new method for the synthesis of α-alkenyl lactones,
spiro α-alkenyl lactones, and cyclic α-alkenyl lactone. Mean-
while, the α-alkenyl butyrolactone can be further converted to
a β-methylene tetrahydrofuran. In the future, in order to
explore the potential application value of α-alkenyl lactone, we
will test their biological activity.
Fe(acac)3 was not added in the reaction, only the starting
material was detected in the system. It shows that Fe(III)
catalyst had a vital role in this process. Interestingly, when 2a
was used as solvent to perform the reaction without
phenylsilane, we were able to successfully prepare intermediate
5a. Under standard conditions, the free-radical scavenger
(TEMPO) was added to the reaction, and no product was
detected in the reaction system. When intermediate 5a was
added to the TEMPO reaction under standard conditions, no
α-alkenyl butyrolactone 3a was still formed. It revealed that the
reaction underwent a free-radical process. Moreover, under
standard conditions, intermediate 5a could obtain 3a in a
lower yield (16%), and this result was consistent with the
reaction result of 1 equiv of allyl alcohol under standard
conditions (18%). Phenylpropynic acid reacted with ((2-
methylallyl)oxy)benzene (2q) under the standard conditions,
resulting in recovery of the starting material. This phenomenon
indicated that the process did not first form the C−C bond. In
addition, under standard conditions, the reaction was carried
out using 1a and 2a without silane. Compounds 4a and 5a
were detected, and the ratio was 10:1 (Supporting
Information). When ethyl 3-phenylpropiolate (4a) and allyl
alcohol (2a) were carried out under the standard conditions,
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02973.
All experimental procedures, single crystal data analysis,
NMR spectra data, characterization data, HPLC
spectrum (PDF)
D
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Accession Codes
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Syntheses of Xanthanolides. Angew. Chem., Int. Ed. 2017, 56, 16323−
16327.
CCDC 2022014 contains 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.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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̈
AUTHOR INFORMATION
Corresponding Author
■
Ji-Yu Wang − Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. China;
orcid.org/0000-0002-0681-4836; Email: jiyuwang@
cioc.ac.cn
̈
Eriolangin. Angew. Chem., Int. Ed. 2004, 43, 5991−5994. (c) Merten,
J.; Hennig, A.; Schwab, P.; Frohlich, R.; Tokalov, S. V.; Gutzeit, H.
̈
O.; Metz, P. A. Concise Sultone Route to Highly Oxygenated 1,10-
seco-Eudesmanolides-Enantioselective Total Synthesis of the Anti-
leukemic Sesquiterpene Lactones(−)-Eriolanin and (−)-Eriolangin.
Eur. J. Org. Chem. 2006, 2006, 1144−1161. (d) Dai, M.; Danishefsky,
S. J. The Total Synthesis of Spirotenuipesines A and B. J. Am. Chem.
Soc. 2007, 129, 3498−3499. (e) Tada, M.; Yamada, H.; Kanamori, A.;
Chiba, K. Total synthesis of three eudesman-12,8-olides, ( )-iso-
alantolactone, ( )-dihydrocallitrisin and ( )-septuplinolide; structure
revision of septuplinolide. J. Chem. Soc., Perkin Trans. 1 1993, 2, 239−
247. (f) Yokoe, H.; Yoshida, M.; Shishido, K. Total synthesis of
(−)-xanthatin. Tetrahedron Lett. 2008, 49, 3504−3506.
Authors
Hua Zhang − Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Guo-Min Zhang − Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. China;
University of Chinese Academy of Sciences, Beijing 100049, P.
R. China
Shuai He − Southwest Minzu University, Chengdu 610041, P. R.
China
Zhi-Chuan Shi − Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. China;
University of Chinese Academy of Sciences, Beijing 100049, P.
R. China; Southwest Minzu University, Chengdu 610041, P. R.
China
(5) (a) Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse,
B.; Reiser, O. Enantioselective Synthesis of Arglabin. Angew. Chem.,
Int. Ed. 2007, 46, 6361−6363. (b) Nakamura, T.; Tsuboi, K.; Oshida,
M.; Nomura, T.; Nakazaki, A.; Kobayashi, S. Total Synthesis of
(−)-Diversifolin. Tetrahedron Lett. 2009, 50, 2835−2839. (c) Taber,
D. F.; Song, Y. Specific C-C Bond Construction by Remote C-H
Activation: Synthesis of (−)-trans-Cembranolide. J. Org. Chem. 1997,
62, 6603−6607. (d) Murta, M. M.; de Azevedo, M. B. M.; Greene, A.
E. An Improved Procedure for α-Methylenation of Lactones. Synth.
Synth. Commun. 1993, 23, 495−503. (e) Frankowski, K. J.; Golden, J.
Xiao-Mei Zhang − Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. China
Complete contact information is available at:
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́
E.; Zeng, Y.; Lei, Y.; Aube, J. Syntheses of the Stemona Alkaloids
( )-Stenine, ( )-Neostenine, and ( )-13-Epineostenine Using a
Stereodivergent Diels−Alder/Azido-Schmidt Reaction. J. Am. Chem.
Soc. 2008, 130, 6018−6024.
Notes
The authors declare no competing financial interest.
(6) (a) Miyake, T.; Uda, K.; Kinoshita, M.; Fujii, M.; Akita, H.
Concise Syntheses of Coronarin A, Coronarin E, Austrochaparol and
Pacovatinin A. Chem. Pharm. Bull. 2008, 56, 398−403. (b) Edwards,
M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Scott, M. S.; Taylor, R. J.
K. The Telescoped Intramolecular Michael/Olefination (TIMO)
Approach to α-Alkylidene-γ-butyrolactones: Synthesis of (+)-Paeoni-
lactone B. Angew. Chem. 2008, 120, 1961−1963. (c) Edwards, M. G.;
Kenworthy, M. N.; Kitson, R. R. A.; Perry, A.; Scott, M. S.;
Whitwood, A. C.; Taylor, R. J. K. The Preparation of α-Alkylidene-γ-
Butyrolactones Using a Telescoped Intramolecular Michael/Olefina-
tion (TIMO) Sequence: Synthesis of (+)-Paeonilactone B. Eur. J. Org.
Chem. 2008, 2008, 4769−4783.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the CAS “Light of
West China” Program and the Applied Basic Research
Programs of Sichuan Province, China (No. 20YYJC0492).
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