Butenolide synthesis from functionalized cyclopropenones

Article abstract of DOI:10.1021/acs.orglett.9b03298

A general method to synthesize substituted butenolides from hydroxymethylcyclopropenones is reported. Functionalized cyclopropenones undergo ring-opening reactions with catalytic amounts of phosphine, forming reactive ketene ylides. These intermediates can be trapped by pendant hydroxy groups to afford target butenolide scaffolds. The reaction proceeds efficiently in diverse solvents and with low catalyst loadings. Importantly, the cyclization is tolerant of a broad range of functional groups, yielding a variety of α- and γ-substituted butenolides.

Full text of DOI:10.1021/acs.orglett.9b03298

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Butenolide Synthesis from Functionalized Cyclopropenones
Sean S. Nguyen,†,# Andrew J. Ferreira,†,# Zane G. Long,† Tyler K. Heiss,† Robert S. Dorn,†
R. David Row,† and Jennifer A. Prescher*,†,‡,§
‡
§
†Departments of Chemistry, Molecular Biology & Biochemistry, and Pharmaceutical Sciences, University of California, Irvine,
California 92697, United States
S
* Supporting Information
ABSTRACT: A general method to synthesize substituted
butenolides from hydroxymethylcyclopropenones is reported.
Functionalized cyclopropenones undergo ring-opening reactions
with catalytic amounts of phosphine, forming reactive ketene
ylides. These intermediates can be trapped by pendant hydroxy
groups to afford target butenolide scaffolds. The reaction
proceeds efficiently in diverse solvents and with low catalyst
loadings. Importantly, the cyclization is tolerant of a broad range of functional groups, yielding a variety of α- and γ-substituted
butenolides.
utenolides are found in a variety of natural product scaffolds
More general methods to build butenolides are therefore
needed.
B
and possess desirable bioactive properties.1 For example,
linderalactone (Figure 1A) can protect hepatocytes from
Cyclopropenones (CpOs) are attractive synthons for
butenolide formation. These microcycles map readily onto the
target structures and are easily accessible from alkyne
precursors.10 CpOs have only recently been exploited for
lactone synthesis, though.11−13 The groups of Lin and Sun
developed methods to convert symmetric CpOs to function-
alized butenolides (Figures 1B and 1C). Both transformations
proceed via intermolecular 1,2-addition of carbonyl groups into
the CpO scaffold, followed by ring opening. The resulting vinyl
anion intermediates subsequently cyclize to deliver the desired
lactones. While robust, both methods require electron-rich
carbonyl fragments. The vinyl anion intermediates are also not
compatible with a range of functional groups, limiting the scope
of these chemistries. Furthermore, the intermolecular nature of
the reactions can present regioselectivity challenges when
unsymmetrical CpOs are employed.
We hypothesized that an intramolecular reaction could
convert CpOs to functionalized butenolides and potentially
broaden the scope of accessible products. Toward this end, we
drew inspiration from our previous work on bioorthogonal
CpOs.14,15 These motifs undergo conjugate addition reactions
with bioorthogonal phosphines, producing ketene-ylide inter-
mediates upon ring fragmentation.16 The electrophiles can be
readily trapped by pendant nucleophiles on the phosphine
(Figure 2A) to afford covalent adducts. We surmised that
pendant nucleophiles on the CpOrather than the phos-
phinecould also trap the ketene (Figure 2B). If the
nucleophile was part of a hydroxymethyl tether, the products
would comprise lactones. Subsequent ylide protonation and
phosphine elimination could ultimately deliver functionalized
butenolides. Since the proposed method involves bioorthogonal
Figure 1. (A) Butenolides (blue) are common motifs in bioactive
natural products. Recent work by (B) Lin and (C) Sun featured
intermolecular reactions between CpOs and carbonyls to generate
functionalized butenolides.
oxidative damage.2 Other butenolides, including (−)-incrusto-
porin, are potent inhibitors of pathogenic fungi.3 These and
related scaffolds4 have inspired chemists to develop efficient
syntheses of α,β-unsaturated lactones. While several methods
now exist,5−9 most are limited in terms of substitution pattern,
functional group tolerance, or starting material accessibility.
Received: September 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Butenolide Cyclization
b
entry phosphine (mol %)
solvent
time
conversion (%)
1
2
3
4
5
6
7
8
9
PTA (100)
PTA (10)
CyDPP (5)
P(o-tolyl)3 (5)
PPh3 (100)
PPh3 (100)
PPh3 (5)
PPh3 (100)
PPh3 (5)
PPh3 (10)
PPh3 (5)
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
DMSO-d6
DMSO-d6
C6D6
10 min
2 h
>95
67
90
2.5 h
2.5 h
10 min
22 h
24 h
1 h
24 h
1.5 h
2.5 h
0
>95
>95
16
>95
94
C6D6
CD3OD
CD3OD
10
11
>95
>95
a
Reaction conditions: CpO (15 μmol), TMS-acetylene (3 μmol),
b
solvent (600 μL). NMR conversion, calculated from integral ratios
between starting CpO and butenolide product.
Figure 2. CpOs react with phosphines to reveal ketene ylides. These
intermediates can be trapped with (A) pendant nucleophiles on
bioorthogonal phosphines or (B) hydroxy group nucleophiles on CpO
scaffolds. In the latter case, phosphine addition at C2 affords
butenolides (top). Phosphine addition at C3 could provide undesired
β-lactones (bottom).
nucleophilic to add into the CpO core but be reasonably air
stable. When CpO 1a was treated with tri(o-tolyl)phosphine,
though, no conversion to butenolide 2a was observed (entry 4).
No butenolide was formed even with longer reaction times or
elevated temperatures (Table S1 and Figures S14−S15). The
increased steric bulk surrounding the phosphine likely precluded
efficient conjugate addition. Indeed, this phosphine is rarely
used in Michael-type reactions and is primarily employed as a
metal ligand.21−23
We next tested a less sterically encumbered reagent,
triphenylphosphine (PPh3). PPh3 is commercially available,
inexpensive, and bench stable, making it attractive for methods
development. When 1a was treated with stoichiometric amounts
of PPh3 in CD3OD, rapid conversion to butenolide 2a was
observed (entry 5). Efficient cyclization occurred even at
reduced catalyst loadings (entries 10 and 11) with no evidence
of intermolecular solvent trapping. In the realm of phosphine
organocatalysis, few reactions feature catalyst loadings below 10
mol %, and even fewer use air-stable, commercially available
reagents.24 We were surprised that low catalyst loadings afforded
rapid butenolide formation, considering the diminished
nucleophilicity of PPh3. We hypothesized that the polar protic
solvent accelerated the reaction via hydrogen-bond activation of
the starting CpO. Similar observations were made when CpOs
were tuned for bioorthogonal ligation.15 When the cyclizations
were performed in DMSO-d6 or C6D6, longer reaction times or
stoichiometric amounts of PPh3 were required for full
conversion (entries 6−9).
We aimed to test the optimized reaction conditions with a
variety of hydroxymethyl CpOs. Such probes can be readily
accessed via appropriately functionalized alkynes.10 We thus
prepared a variety of alkyl- and aryl-substituted alkynes via
acetylide addition to formaldehyde or Sonogashira cross-
coupling reactions, respectively (Scheme S1). Each alkyne also
comprised a THP-protected hydroxymethyl tether. The alkyne
products were subjected to difluorocarbene, a reagent generated
in situ via the conditions of Olah25 (Scheme 1). The resulting
difluorocyclopropenes were then hydrolyzed and deprotected to
furnish the desired hydroxymethyl CpOs (1a−u, Scheme 1).
The carbene insertion and hydrolysis sequence was not
compatible with alkynes bearing nitrogen heterocycles, and
reagents, it would likely be compatible with a variety of
functional groups. The proximity of the hydroxy group on the
CpO tether would also promote intramolecular cyclization,
outcompeting any exogenous nucleophile in the trapping step.15
The regioselectivity of the proposed reaction was further
considered. Phosphine addition at C2 (i.e., the carbon bearing
the hydroxymethyl tether) would likely provide the desired
products. However, phosphine addition at C3 could give
undesired β-lactones. Cyclization en route to the β-lactone (4-
exo-dig) is disfavored according to Baldwin’s rules, but notable
examples exist.17−19 We reasoned that butenolide formation
could still predominate in the reaction, even if phosphine
attacked C3. Ketene-ylide formation is reversible in the absence
of trapping nucleophiles,14,20 and cyclization en route to the β-
lactone would likely be slower than the reverse reaction to
reform the CpO. Thus, the reaction could funnel to a butenolide
product, regardless of the initial site of phosphine addition.
To examine the overall strategy, model CpO 1a was
synthesized and treated with a panel of phosphines. The
reactions were performed in various solvents and monitored
1
using H NMR spectroscopy (Tables 1 and S1, Figures S1−
S15). 1,3,5-Triaza-7-phosphaadamantane (PTA) was initially
selected due to its potent reactivity and unique stability in protic
solvents. When combined stoichiometrically with 1a, PTA
afforded rapid conversion to the desired butenolide (entry 1).
The reaction slowed significantly when the catalyst loading was
reduced to 10 mol % (entry 2). Notably, no intermolecular
solvent trapping was observed even with longer reaction times.
Sluggish reactivity was not general to all alkyl-substituted
phosphines. When 1a was treated with cyclohexyldiphenylphos-
phine (CyDPP), rapid formation of 2a was observed even at low
catalyst loadings (entry 3).
Anticipating that alkyl phosphines would be prone to
oxidation and thus less general, we further investigated
triarylphosphines. We were particularly drawn to tri(o-tolyl)-
phosphine, as this reagent would likely be sufficiently
B
DOI: 10.1021/acs.orglett.9b03298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 1. Diverse Butenolides were Synthesized from Substituted CpOs
a
b
c
d
e
Reaction conditions: CpO (1 equiv), PPh3 (5 mol %), methanol (0.25 M). Isolated yields. 10 mol % of PPh3. 20 mol % of PPh3. C6H6 (0.25
M) was used.
attempts to isolate the corresponding CpOs resulted in
decomposition. These results are in stark contrast to
heterocyclic alkenes, which undergo robust difluorocarbene
insertion.26,27
cannot provide β-substituted butenolides, such scaffolds are
readily accessible postcyclization. Cycloadditions28,29 and Heck
couplings30 can be used in this regard, along with several other
methods.31,32 Notably, functionalized butenolides can also serve
as gateways to butyrolactones33−36 and other interesting
scaffolds.37,38
Our collective results demonstrate that butenolides are
favored in the hydroxymethyl CpO-phosphine reaction. All
but one of the cyclizations proceeded with no competing β-
lactone formation. Such side products were observed only when
CpO 1m was subjected to low catalyst loadings in methanol
(Figures 3A and S16). The gem-dimethyl groups on 1m likely
promoted phosphine addition to the more accessible C3
position and accelerated β-lactone cyclization to provide
3a,b.39 An appreciable amount of product 2m was still formed
under these challenging conditions, though, supporting the
original hypothesis that butenolide formation can predominate,
despite the potential for competing pathways.
The panel of hydroxymethyl-tethered CpOs was subjected to
butenolide formation conditions (Scheme 1). As anticipated,
the cyclization was tolerant of a broad range of functional
groups. α-Alkyl-substituted CpOs (2a−d), including branched
(2b) and cyclic (2c) substrates, were efficiently converted. The
reaction also proceeded in the presence of competing
nucleophiles (2d), albeit with lower yields. α-Aryl-substituted
CpOs also generated butenolides in the presence of PPh3. Both
electron-donating (2e−2l) and electron-withdrawing (2p−2u)
groups were examined, along with thiophene heterocycles (2l).
Notably, robust product formation was observed even in the
presence of electrophilic esters (2t) and cyano groups (2q). The
reaction was also tolerant of different substitution patterns on
the aryl ring (2f−2j and 2s).
The CpO-phosphine reaction further enabled access to more
highly substituted butenolides. As noted above, the cyclization is
tolerant of numerous α-substituents (Scheme 1). These groups
are positioned away from the ketene and thus minimally
interfere with trapping. Additional substituents on the
hydroxymethyl tether provided access to α,γ-disubstituted
butenolides (2m−2o). Compound 2n, in particular, comprises
the α,γ-substitution pattern present in incrustoporin (Figure
1A) and related natural products. While the CpO reaction
We carried out additional experiments to examine the
propensity for hydroxymethyl CpOs to form butenolides. The
observed product distributions likely reflect the faster rate of
five- versus four-membered ring cyclization following ketene
formation (Figure 2B). An alternative explanation is that
phosphine attack is favored at C2. To investigate these
possibilities, we devised a competitive trapping experiment
with diol 1d. This compound comprises two hydroxy group
tethers and is capable of cyclizing to five- or six-membered rings,
C
DOI: 10.1021/acs.orglett.9b03298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jpresche@uci.edu.
ORCID
Sean S. Nguyen: 0000-0002-1801-5521
Jennifer A. Prescher: 0000-0002-9250-4702
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Figure 3. Mechanistic studies involving butenolide formation. (A)
Upon phosphine treatment, CpO 1m formed β-lactone products 3a,b.
The additional steric bulk at C2 likely disfavored phosphine addition.
(B) δ-Lactone 5 was not observed when diol-CpO 1d was treated with
PPh3. This reaction produced a mixture of γ-lactones (4a,b), in addition
to the desired butenolide 2d. For (A),(B), percent conversion values
(from NMR analyses) are reported.
Author Contributions
#S.S.N. and A.J.F. contributed equally.
Notes
The authors declare no competing financial interest.
depending on the ketene formed. We anticipated that 1d would
provide a mixture of γ- and δ-lactones upon phosphine
treatment, as the steric environments around C2 and C3 are
similar and unlikely to bias phosphine addition. Additionally,
five- or six-membered ring formation (postketene generation)
should be similarly facile. When diol 1d was treated with PPh3, a
mixture of γ-lactones was observed, in addition to butenolide 2d
(Figure S17). No δ-lactone (5) formed, though, to our surprise
(Figures 3B and S17). The ketene en route to 4 was capable of
forming and cyclizing, as demonstrated with a CpO probe
outfitted with a single hydroxyethyl tether (Figure S18). These
data suggest that phosphine addition to C2 could be preferred
when CpOs are functionalized with hydroxymethyl appendages.
The exact mechanism is the subject of ongoing work, but the
tether could promote internal hydrogen-bond activation,
preorganizing the CpO for C2 attack.
In conclusion, we developed a method to prepare substituted
butenolides using bioorthogonal reagents: hydroxymethyl-
tethered cyclopropenones and aryl phosphines. This method
features mild reaction conditions and low catalyst loadings and
can produce a variety of targets. The reaction exhibits wide
functional group tolerance, typical of biocompatible reagents.
The reported transformation is complementary to existing
methods that furnish α,γ-substituted butenolides40−49 but is
potentially more generalizable. Importantly, the requisite
hydroxymethyl CpOs can be derived from propargyl alcohols,
widely used and available materials in organic synthesis. We
further anticipate that CpOs and other bioorthogonal reagents
will continue to inspire the development of useful method-
ologies.
ACKNOWLEDGMENTS
■
This work was supported by the U.S. National Institutes of
Health (R01 GM126226 to J.A.P.) and the Alfred P. Sloan
Foundation (J.A.P.). A.J.F. was supported by a George Hewitt
Medical Research Postdoctoral Fellowship. We thank the Dong,
Blum, Heyduk, Nowick, and Chamberlin laboratories for
providing reagents and equipment. We also thank Philip
Dennison (UCI) for assistance with NMR experiments, Felix
Grun (UCI), Jasper Ostrom (UCI), and Benjamin Katz (UCI)
̈
for assistance with mass spectrometry experiments, and Dan
Huh (UCI) and Joseph Ziller (UCI) for assistance with X-ray
crystallography experiments. Last, we thank members of the
Prescher laboratory for manuscript edits and helpful discussions.
REFERENCES
■
(1) Karuppiah, V.; Sun, W.; Li, Z. Chapter 13: Natural Products of
Actinobacteria Derived from Marine Organisms. Stud. Nat. Prod. Chem.
2016, 48, 417−446.
(2) Gan, L.-S.; Zheng, Y.-L.; Mo, J.-X.; Liu, X.; Li, X.-H.; Zhou, C.-X.
Sesquiterpene Lactones from the Root Tubers of Lindera aggregata. J.
Nat. Prod. 2009, 72, 1497−1501.
(3) Lu, A.; Wang, J.; Liu, T.; Han, J.; Li, Y.; Su, M.; Chen, J.; Zhang, H.;
Wang, L.; Wang, Q. Small Changes Result in Large Differences:
Discovery of (−)-Incrustoporin Derivatives as Novel Antiviral and
Antifungal Agents. J. Agric. Food Chem. 2014, 62, 8799−8807.
(4) Hou, Y.; Shi, T.; Yang, Y.; Fan, X.; Chen, J.; Cao, F.; Wang, Z.
Asymmetric Total Syntheses and Biological Studies of Tuber-
ostemoamide and Sessilifoliamide A. Org. Lett. 2019, 21, 2952−2956.
(5) Rao, Y. S. Chemistry of Butenolides. Chem. Rev. 1964, 64, 353−
388.
(6) Rao, Y. S. Recent advances in the chemistry of unsaturated
lactones. Chem. Rev. 1976, 76, 625−694.
ASSOCIATED CONTENT
* Supporting Information
■
(7) Knight, D. W. Synthetic approaches to butenolides. Contemp. Org.
Synth. 1994, 1, 287−315.
S
(8) Carter, N. B.; Nadany, A. E.; Sweeney, J. B. Recent developments
in the synthesis of furan-2(5H)-ones. J. Chem. Soc., Perkin Trans. 1
2002, 2324−2342.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03298.
Experimental details and spectroscopic data for new
compounds (PDF)
́
(9) Mao, B.; Fananas-Mastral, M.; Feringa, B. L. Catalytic Asymmetric
̃
Synthesis of Butenolides and Butyrolactones. Chem. Rev. 2017, 117,
10502−10566.
Accession Codes
(10) Komatsu, K.; Kitagawa, T. Cyclopropenylium Cations, Cyclo-
propenones, and Heteroanalogues−Recent Advances. Chem. Rev.
2003, 103, 1371−1427.
CCDC 1913684 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 Cambridge
(11) Li, X.; Han, C.; Yao, H.; Lin, A. Organocatalyzed [3 + 2]
Annulation of Cyclopropenones and β-Ketoesters: An Approach to
D
DOI: 10.1021/acs.orglett.9b03298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Substituted Butenolides with a Quaternary Center. Org. Lett. 2017, 19,
778−781.
(32) Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. Total
Syntheses of (+)-Secosyrins 1 and 2 and (+)-Syributins 1 and 2. J. Org.
Chem. 1997, 62, 8095−8103.
(12) Ren, J.-T.; Wang, J.-X.; Tian, H.; Xu, J.-L.; Hu, H.; Aslam, M.;
Sun, M. Ag(I)-Catalyzed [3 + 2]-Annulation of Cyclopropenones and
Formamides via C−C Bond Cleavage. Org. Lett. 2018, 20, 6636−6639.
(13) Xu, J.; Cao, J.; Fang, C.; Lu, T.; Du, D. Organocatalytic C−C
bond activation of cyclopropenones for ring-opening formal [3 + 2]
cycloaddition with isatins. Org. Chem. Front. 2017, 4, 560−564.
(14) Shih, H.-W.; Prescher, J. A. A Bioorthogonal Ligation of
Cyclopropenones Mediated by Triarylphosphines. J. Am. Chem. Soc.
2015, 137, 10036−10039.
(33) Feringa, B. L.; de Lange, B. Asymmetric 1,4-Additions to 5-
Alkoxy-2(5H)-furanones. An Efficient Synthesis of (R)- and (S)-3,4-
Epoxy-1-butanol. Tetrahedron 1988, 44, 7213−7222.
(34) de Lange, B.; van Bolhuis, F.; Feringa, B. L. Asymmetric 1,4-
additions to 5-alkoxy-2(5H)-furanones enantioselective synthesis and
absolute configuration determination of β-amino-γ-butyrolactones and
amino diols. Tetrahedron 1989, 45, 6799−6818.
(35) Sweidan, A.; Chollet-Krugler, M.; van de Weghe, P.; Chokr, A.;
Tomasi, S.; Bonnaure-Mallet, M.; Bousarghin, L. Design, synthesis and
biological evaluation of potential antibacterial butyrolactones. Bioorg.
Med. Chem. 2016, 24, 5823−5833.
(36) Goldfogel, M. J.; Roberts, C. C.; Manan, R. S.; Meek, S. J.
Diastereoselective Synthesis of γ-Substituted 2-Butenolides via (CDC)-
Rh-Catalyzed Intermolecular Hydroalkylation of Dienes with Silylox-
yfurans. Org. Lett. 2017, 19, 90−93.
(37) Chu, C. K.; Beach, J. W.; Ullas, G. V.; Kosugi, Y. An efficient total
synthesis of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2’,3′-
dideoxyuridine (AZDDU, CS-87) from D-mannitol. Tetrahedron Lett.
1988, 29, 5349−5352.
(38) Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.; Coffen, D. L.
Synthesis of the Dideoxynucleosides ddC and CNT from Glutamic
Acid, Ribonolactone, and Pyrimidine Bases. J. Org. Chem. 1988, 53,
4780−4786.
(39) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. CXIX.The
formation and stability of spiro-compounds. Part I. spiro-Compounds
from cyclohexane. J. Chem. Soc., Trans. 1915, 107, 1080−1106.
(40) Cowell, A.; Stille, J. K. Synthesis of Lactones by the Palladium-
Catalyzed Carbonylation of Halo Alcohols. J. Am. Chem. Soc. 1980, 102,
4193−4198.
(41) Buchwald, S. L.; Fang, Q.; King, S. M. A new method for the
preparation of 3,5-disubstituted butenolides. Tetrahedron Lett. 1988,
29, 3445−3448.
(42) DeShong, P.; Sidler, D. R.; Rybczynski, P. J.; Slough, G. A.;
Rheingold, A. L. A general method for the preparation of carbonyl
compounds and butenolides from organomanganese pentacarbonyl
complexes. J. Am. Chem. Soc. 1988, 110, 2575−2585.
(43) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L.; Santi, C.
Selenium Catalysed Conversion of β,γ-Unsaturated Acids into
Butenolides. Synlett 1993, 1993, 798−800.
(44) Yoneda, E.; Zhang, S.-W.; Zhou, D.-Y.; Onitsuka, K.; Takahashi,
S. Ruthenium-Catalyzed Cyclocarbonylation of Allenyl Alcohols and
Amines: Selective Synthesis of Lactones and Lactams. J. Org. Chem.
2003, 68, 8571−8576.
(45) Oh, C. H.; Park, S. J.; Ryu, J. H.; Gupta, A. K. Regioselective Pd-
catalyzed alkylative lactonizations of 4-hydroxy-2-alkynecarboxylates
with organoboronic acids. Tetrahedron Lett. 2004, 45, 7039−7042.
(46) Kang, J.-E.; Lee, E.-S.; Park, S.-I.; Shin, S. Gold-catalyzed
cyclization of tert-butyl allenoate: general synthesis of 2,4-function-
alized butenolides. Tetrahedron Lett. 2005, 46, 7431−7433.
(47) Takii, K.; Kanbayashi, N.; Onitsuka, K. Modular synthesis of
optically active lactones by Ru-catalyzed asymmetric allylic carbox-
ylation and ring-closing metathesis reaction. Chem. Commun. 2012, 48,
3872−3874.
(15) Row, R. D.; Shih, H.-W.; Alexander, A. T.; Mehl, R. A.; Prescher,
J. A. Cyclopropenones for Metabolic Targeting and Sequential
Bioorthogonal Labeling. J. Am. Chem. Soc. 2017, 139, 7370−7375.
(16) Hamada, A.; Takizawa, T. Synthesis of phosphorane having
ketene group at α-position. Tetrahedron Lett. 1972, 13, 1849−1850.
(17) Cooke, M. P., Jr. Metal-Halogen Exchange-Initiated Intra-
molecular Conjugate Addition Reactions of Conjugated Acetylenic
Esters. J. Org. Chem. 1993, 58, 6833−6837.
(18) Cooke, M. P., Jr. Boron-Activation of Acetylenes to Nucleophilic
Addition Reactions. J. Org. Chem. 1994, 59, 2930−2931.
(19) Alabugin, I. V.; Gilmore, K.; Manoharan, M. Rules for Anionic
and Radical Ring Closure of Alkynes. J. Am. Chem. Soc. 2011, 133,
12608−12623.
(20) Wei, Y.; Zhao, W.-T.; Yang, Y.-L.; Zhang, Z.; Shi, M. Allenic
Esters from Cyclopropenones by Lewis Base Catalysis: Substrate
Scope, the Asymmetric Variant from the Dynamic Kinetic Asymmetric
Transformation, and Mechanistic Studies. ChemCatChem 2015, 7,
3340−3349.
(21) Ziegler, C. B., Jr.; Heck, R. F. Palladium-catalyzed vinylic
substitution with highly activated aryl halides. J. Org. Chem. 1978, 43,
2941−2946.
(22) Hartwig, J. F. Transition Metal Catalyzed Synthesis of
Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope
and Mechanism. Angew. Chem., Int. Ed. 1998, 37, 2046−2067.
(23) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Rational
Development of Practical Catalysts for Aromatic Carbon−Nitrogen
Bond Formation. Acc. Chem. Res. 1998, 31, 805−818.
(24) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Phosphine
Organocatalysis. Chem. Rev. 2018, 118, 10049−10293.
(25) Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.;
Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Synthesis of gem-
Difluorinated Cyclopropanes and Cyclopropenes: Trifluoromethyl-
trimethylsilane as a Difluorocarbene Source. Angew. Chem., Int. Ed.
2011, 50, 7153−7157.
(26) Zhou, J.; Campbell-Conroy, E. L.; Silina, A.; Uy, J.; Pierre, F.;
Hurley, D. J.; Hilgraf, N.; Frieman, B. A.; DeNinno, M. P. Synthesis of
Fused Bicyclic Piperidines: Potential Bioactive Templates for
Medicinal Chemistry. J. Org. Chem. 2015, 80, 70−79.
(27) Nosik, P. S.; Ryabukhin, S. V.; Pashko, M. O.; Grabchuk, G. P.;
Grygorenko, O. O.; Volochnyuk, D. M. Synthesis of 1-hetaryl-2,2-
difluorocyclopropane-derived building blocks: The case of pyrazoles. J.
Fluorine Chem. 2019, 217, 80−89.
(28) Hanessian, S.; Murray, P. J. Stereochemical control of nature’s
biosynthetic pathways: A general strategy for the synthesis of
polypropionate-derived structural units from a single chiral progenitor.
Tetrahedron 1987, 43, 5055−5072.
(29) Boukouvalas, J.; Maltais, F.; Lachance, N. Furanolate-Based
Strategy for Sequential 2,3,4-Trisubstitution of Butenolide: Total
Synthesis of Nostoclides I and II. Tetrahedron Lett. 1994, 35, 7897−
7900.
(30) Khoobi, M.; Alipour, M.; Zarei, S.; Jafarpour, F.; Shafiee, A. A
facile route to flavone and neoflavone backbones via a regioselective
palladium catalyzed oxidative Heck reaction. Chem. Commun. 2012, 48,
2985−2987.
(48) Matsushita, K.; Komori, T.; Oi, S.; Inoue, Y. Carbonylation of
Tertiary Propargylic Alcohols Catalyzed by a Cationic Palladium(II)
Complex: Synthesis of 2(5H)-Furanones. Tetrahedron Lett. 1994, 35,
5889−5890.
(49) Yu, W.-Y.; Alper, H. Palladium-Catalyzed Cyclocarbonylation of
Terminal and Internal Alkynols to 2(5H)-Furanones. J. Org. Chem.
1997, 62, 5684−5687.
(31) Almirante, N.; Cerri, A. Synthesis of Digitoxigenin from 3β-
[(tert-Butyldimethylsilyl)oxy]-17α-iodo-5β-androstan-14β-ol via 17β
Stereoselective Free-Radical Introduction of γ-Butyrolactone Moiety. J.
Org. Chem. 1997, 62, 3402−3404.
E
DOI: 10.1021/acs.orglett.9b03298
Org. Lett. XXXX, XXX, XXX−XXX