Total synthesis and configurational validation of (+)-violapyrone C

Article abstract of DOI:10.1002/ejoc.201402524

Gold(I)-catalyzed intramolecular 6-endo-dig cyclization of tert-butyl ynoates afforded α-pyrone cores of violapyrones. Moreover, this reaction was successfully applied to the stereospecific syntheses of (+)- and (-)-violapyrone C, which allowed the absolute configuration of natural (+)-violapyrone C to be assigned by comparison of the optical rotations. This first total synthesis, which proceeded in 22% yield over 10 steps from (S)-(-)-2-methylbutanol, features silver(I) oxide promoted monobenzylation of 1,4-butanediol, Wittig olefination, Claisen condensation, Corey-Fuchs reaction, and gold(I)-catalyzed α-pyrone synthesis. Copyright

Full text of DOI:10.1002/ejoc.201402524

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Date: 16-06-14 10:35:24
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402524
Total Synthesis and Configurational Validation of (+)-Violapyrone C
Jong Seok Lee,*[a,b] Junho Shin,[a,c] Hee Jae Shin,[a,b] Hwa-Sun Lee,[a] Yeon-Ju Lee,[a,b]
Hyi-Seung Lee,[a,b] and Hoshik Won[c]
Keywords: Total synthesis / Natural products / Oxygen heterocycles / Gold / Wittig reactions
Gold(I)-catalyzed intramolecular 6-endo-dig cyclization of
tert-butyl ynoates afforded α-pyrone cores of violapyrones.
Moreover, this reaction was successfully applied to the
stereospecific syntheses of (+)- and (–)-violapyrone C, which
allowed the absolute configuration of natural (+)-violapyr-
one C to be assigned by comparison of the optical rotations.
This first total synthesis, which proceeded in 22% yield over
10 steps from (S)-(–)-2-methylbutanol, features silver(I) oxide
promoted monobenzylation of 1,4-butanediol, Wittig ole-
fination, Claisen condensation, Corey–Fuchs reaction, and
gold(I)-catalyzed α-pyrone synthesis.
Introduction
Violapyrones constitute a family of nine 3,4,6-trisubsti-
tuted α-pyrone derivatives first reported by Huang and co-
workers (Figure 1).[1] These chemical entities were isolated
from the fermentation broth of Streptomyces violascens
(YIM100525) obtained from Hylobates hoolock feces.[1]
Very recently, (+)-violapyrone C along with the two new
members violapyrones H and I were identified in our labo-
ratory from the mass culture of actinomycete Streptomyces
sp. 112CH148 associated with crown-of-thorns starfish,
Acanthaster planci, collected from Chuuk, Micronesia.[2]
Although violapyrones contain relatively simple alkyl
chains at the C6 position of the core α-pyrone scaffold, the
absolute configuration at C11 of violapyrone C (1) has yet
to be validated. In addition to moderate antibacterial activi-
ties originally reported by Huang and co-workers,[1] viola-
pyrone C showed cytotoxicity against a panel of six human
tumor cell lines.[2a] Moreover, in an assay with the use of
HCT116 human colon cancer cells stably expressing a lucif-
Figure 1. Violapyrones.
study. Herein, we report the gold(I)-catalyzed efficient syn-
thesis of the α-pyrone skeleton and its application to the
total synthesis and configurational validation of (+)-viola-
pyrone C.
erase reporter construct under the control of a hypoxia re- Results and Discussion
sponse element (HCT116-HRE-Luc), it was revealed that
Although protocols for α-pyrone synthesis by 6-endo-dig
(+)-violapyrone C has inhibitory effect on the HIF (hyp-
oxia-inducible factor) pathway, which is related to tumor
progression, invasion, and metastasis.[2b] Therefore, ensuing
material supply is in urgent need for further biomedical
intramolecular cyclization are already known, either unde-
sirable extra steps (e.g., hydrolysis) or harsh reaction condi-
tions are required.[3] Owing to its alkynophilic character
and high functional group compatibility, in addition to its
many other advantages, gold as a catalyst has been at the
center of rapid development over the past decade.[4,5] Re-
cently, the successful application of (SPhos)AuNTf2 (SPhos
= 2-dicyclohexylphosphino-2Ј,6Ј-dimethoxybiphenyl, Tf =
trifluoromethylsulfonyl) to the synthesis of 4-hyroxy-2-pyr-
ones under exceptionally mild conditions was reported.[3a]
We imagined that treatment of β-keto esters with an appro-
priate catalyst would form α-pyrones. In our retrosynthetic
analysis of violapyrone C (Scheme 1), the key step is the
gold-catalyzed 6-endo-dig cyclization of β-keto ester 17 to
[a] Marine Natural Products Chemistry Laboratory,
Korea Institute of Ocean Science & Technology (KIOST),
Ansan, Republic of Korea
E-mail: jslee@kiost.ac
http://eng.kiost.ac/kordi_eng/main/
[b] Department of Marine Biotechnology, Korea University of
Science and Technology,
Republic of Korea
[c] Department of Chemistry and Applied Chemistry, Hanyang
University,
Ansan, Republic of Korea
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402524.
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J. S. Lee et al.
SHORT COMMUNICATION
form the α-pyrone core leading to violapyrone C. To access Table 1. Screening of the reaction conditions.[a]
the key intermediate, β-keto ester 17, it is necessary to intro-
duce an ester group directly to propargylic intermediate 16
through the acetylide anion, followed by Claisen condensa-
tion. Further analysis suggested that installation of a CϵC
bond to intermediate 16 could be achieved by Corey–Fuchs
reaction of aldehyde 14a, which in turn would be prepared
by Wittig olefination between phosphonium iodide salt 10
and aldehyde 12. In principle, these two Wittig reagents
would be accessible in a few steps from (S)-(–)-2-methyl-1-
butanol (9) and 1,4-butanediol (11, Scheme 1).
Entry
Cat. (10 mol-%) Solvent
Conv. [%][b]
AcOH/MeNO2 (4:1) 11
AcOH/MeNO2 (4:1) 34
1[c]
2[c]
3[c]
4[c]
5[c]
PdCl3
Ag2CO3
InCl3
Sc(OTf)3
AuCl3
AcOH/MeNO2 (4:1) trace
AcOH/MeNO2 (4:1) trace
AcOH/MeNO2 (4:1) 23
6[d]
7[d]
8[d]
9[f]
8[e]
8[e]
8[e]
8[e]
8[e]
toluene
CH2Cl2
THF
91
86
82
AcOH/MeCN (4:1)
100 (69)[g]
10[f]
AcOH/MeNO2 (4:1) 100 (73)[g]
[a] The reactions were performed under a N2 atmosphere at room
temperature. [b] Determined by 1H NMR spectroscopy. [c] Reac-
tion quenched after 44 h. [d] Reaction quenched after 20 h.
[e]
[Bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)-
gold(I) (2:1) toluene adduct was used. [f] Reaction was complete in
15 h. [g] The value in parentheses indicates the yield of the isolated
product.
was prepared by silver(I) oxide promoted monobenzylation
of readily available 1,4-butanediol (11) in the presence of
Ag2O and benzyl bromide in CH2Cl2 to afford primary
alcohol 11a (not shown, 83% yield);[9] this was followed by
Scheme 1. Retrosynthetic analysis of violapyrone C.
To prove the concept, an inseparable mixture of β-keto
ester 5 and tautomer 6 was applied as a model system for
this transformation (Table 1).[6] Although preliminary test
reactions with various transition-metal catalysts suffered
from low conversion efficiency and poor yields, as evaluated
1
by H NMR spectroscopy (Table 1, entries 1–5), significant
catalytic conversions were noticed in reactions with gold(I)
catalyst 8 {[bis(trifluoromethanesulfonyl)imidate](triphenyl-
phosphine)gold(I) (2:1) toluene adduct} (Table 1, entries 6–
8). Further investigation in a 4:1 mixture of AcOH/MeCN
at room temperature provided 7 in 69% yield (Table 1, en-
try 9). Moreover, if MeNO2 was used instead of MeCN, the
reaction improved and gave desired 7 in 73% yield (Table 1,
entry 10).
Consequently, the above reaction was considered to be
applicable to the synthesis of violapyrone C. Our synthesis
began with transformation of readily available (S)-(–)-2-
methyl-1-butanol (9) into corresponding iodide 9a (not
shown) by using imidazole, iodine, and triphenylphosphine
in CH2Cl2 (83% yield, Scheme 2).[7] Subsequent treatment
of iodide 9a with triphenylphosphine in toluene at reflux
furnished desired phosphonium iodide 10 in 82% yield
(Scheme 2).[8] The coupling partner of phosphonium iodide
10 in the ensuing Wittig olefination, that is, aldehyde 12, Scheme 2. Synthesis of terminal alkyne 16.
2
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Total Synthesis and Configurational Validation of (+)-Violapyrone C
Swern oxidation with trifluoroacetic anhydride (TFAA) and
DMSO (83% yield, Scheme 2).[10] Wittig olefination be-
tween phosphonium iodide 10 and aldehyde 12 by using n-
butyllithium provided desired olefin 13 (E/Z = 2.3:1) in
77% yield (Scheme 2).[8]
Notably, if olefin 13 was subjected to hydrogenation con-
ditions in the presence of a palladium catalyst, reduction of
the C=C bond and deprotection of the benzyl group were
concurrently triggered to afford primary alcohol 14 in 97%
yield (Scheme 2). Swern oxidation of primary alcohol 14
with DMSO, TFAA, and N,N-diisopropylethylamine (DI-
PEA) provided corresponding aldehyde 14a (not shown).[10]
Corey–Fuchs reaction for the one-carbon homologation
of aldehyde 14a to corresponding terminal alkyne 16 was
accomplished by homologation to dibromoolefin 15 with
carbon tetrabromide and triphenylphosphine in CH2Cl2
(65% overall), followed by sequential lithium–halogen ex-
change with n-butyllithium and elimination (96% yield,
Scheme 2).[11]
With propargylic intermediate 16 in hand, our attention
was now directed towards installation of the β-keto ester
moiety in key intermediate 17. Introduction of an ester
group to terminal alkyne 16 was successfully achieved by
generation of the acetylic anion by using n-butyllithium and
subsequent treatment with methyl chloroformate to provide
corresponding methyl ynoate 16a (not shown).[12] As pre-
cedented in the model system (for 5 and 6), Claisen conden-
sation with LDA (lithium diisopropylamide) and tert-butyl
propionate afforded an inseparable mixture of desired β-
keto ester 17 along with tautomer 18 in a 1:1 ratio (86%
yield, Scheme 3).[3a] We were now poised to complete the
synthesis by gold-catalyzed 6-endo-dig intramolecular cycli-
zation. Thus, treatment of a mixture of 17 and 18 from the
above reaction with catalyst 8 in MeNO2 provided 1 in 81%
yield (Scheme 3).
Scheme 3. Completion of the total synthesis.
yne 21 was accomplished by treatment of terminal alkyne
21 with n-butyllithium and methyl chloroformate to provide
corresponding ynoate 22 in 95% yield (Scheme 4). Comple-
tion of 2 relied on Claisen condensation of ynoate 22 by
using LDA and tert-butyl propionate to afford β-keto ester
19, which was followed by formation of the α-pyrone by
using gold(I) catalyst 8 (10 mol-%) in MeNO2 to provide
desired enantiomer 2 in 52% yield over two steps
(Scheme 4).
With synthetic samples of 1 (22% yield overall) and 2
(27% yield overall) in hand, we were able to assign the ab-
solute configuration of (+)-violapyrone C. As expected, the
1H NMR and 13C NMR spectra of the two synthetic sam-
ples were indistinguishable to those of natural (+)-viola-
pyrone C obtained from actinomycete Streptomyces sp.
112CH148. Ultimately, the optical rotations of these three
compounds were compared [natural violapyrone C: [α]D
=
+50.0 (c = 0.1, MeOH); compound 1: [α]D = +49.0 (c =
0.1, MeOH); compound 2: [α]D = –53.0 (c = 0.1, MeOH)]
to confirm that synthetic 1 was (+)-violapyrone C and 2
was its enantiomer (Figure 2).[13]
In parallel to the synthesis of 1, the synthesis of the
enantiomer of 1 was sought to validate the absolute config-
uration of (+)-violapyrone C. Thus, Swern oxidation of pri-
mary alcohol 19 provided aldehyde 19a (not shown). Sim-
ilar to the previously described synthesis, transformation of
aldehyde 19a (not shown) into corresponding terminal alk-
yne 21 was achieved by Corey–Fuchs reaction (Scheme 4).
Conclusions
In conclusion, we described the efficient first total syn-
Introduction of an ester functional group to terminal alk- thesis of (+)-violapyrone C and its enantiomer. The synthe-
Scheme 4. Synthesis of (–)-violapyrone C.
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J. S. Lee et al.
SHORT COMMUNICATION
6.6 Hz, 3 H), 0.82–0.85 ppm (t, J = 7.4 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): δ = 138.9, 137.0, 136.97, 128.5, 127.92, 127.88,
127.82, 127.81, 127.7, 73.10, 73.07, 70.1, 70.0, 38.6, 33.5, 30.4, 30.2,
30.1, 29.9, 29.3, 24.3, 21.2, 20.6, 12.2, 12.0 ppm. HRMS (ESI):
calcd. for C16H23O [M – H]– 231.1749; found 231.1768.
(S)-6-Methyloctan-1-ol (14): A mixture of olefin 13 (656.0 mg,
2.82 mmol) and 10% Pd/C (27.0 mg, 9.0 mol-%) was stirred under
an atmosphere of hydrogen at 50 °C for 45 h. Upon completion of
the reaction, the catalyst was removed by filtration through a pad
of Celite, and the filter cake was washed with CH2Cl2. The filtrate
was concentrated in vacuo. The crude residue was purified by flash
column chromatography (EtOAc/n-hexane = 1:20 to 1:5) to give 14
(395.9 mg, 2.74 mmol, 97%). 1H NMR (500 MHz, CDCl3): δ =
3.60–3.62 (t, J = 6.6 Hz, 2 H), 1.52–1.57 (m, 2 H), 1.22–1.32 (m, 7
H), 1.06–1.12 (m, 2 H), 0.81–0.84 (t, J = 7.5 Hz, 3 H), 0.81–
0.83 ppm (d, J = 7.8 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ =
63.3, 36.8, 34.5, 33.0, 29.7, 27.1, 26.3, 19.4, 11.6 ppm. HRMS
(ESI): calcd. for C9H20O [M]+ 144.1514; found 144.0677.
Figure 2. Optical rotations (in MeOH) of synthetic compounds 1
and 2 and natural violapyrone C.
sis route features the silver(I) oxide promoted monobenzyl-
ation of 1,4-butanediol, Wittig olefination, Claisen conden-
sation, Corey–Fuchs reaction, and the gold-catalyzed syn-
thesis of α-pyrone by 6-endo-dig cyclization. Furthermore,
our total synthesis of (+)-violapyrone C confirms the struc-
ture and absolute configuration of natural (+)-viola-
pyrone C.
(S)-1,1-Dibromo-7-methylnon-1-ene
(15):
TFAA
(427.3 µL,
3.07 mmol, 3.0 equiv.) was added dropwise to a solution of DMSO
(436.6 µL, 6.15 mmol, 6.0 equiv.) in CH2Cl2 at –78 °C. After stir-
ring at –78 °C for 10 min, a solution of 14 (147.7 mg, 1.02 mmol)
in CH2Cl2 (4.0 mL) was added dropwise. The resultant cloudy mix-
ture was stirred at –78 °C for 1 h. DIPEA (892.4 µL, 5.12 mmol,
5.0 equiv.) was added slowly, and the mixture was warmed to room
temperature for 2 h. The mixture was diluted with EtOAc and
quenched with H2O. The organic layer was washed with brine,
dried with Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash column chromatography (EtOAc/n-
hexane = 1:40) to give 14a (123.5 mg, 0.87 mmol, 85%). A solution
of carbon tetrabromide (575.9 mg, 1.74 mmol, 2.0 equiv.) in
CH2Cl2 was stirred at room temperature, and the solution was
cooled in an ice bath. Triphenylphosphine (911.0 mg, 3.47 mmol,
4.0 equiv.) was added at 0 °C, and the mixture was stirred for 1 h.
A solution of 14a (123.5 mg, 0.87 mmol) in CH2Cl2 (1.0 mL) was
added to this mixture. The solution was warmed to room tempera-
ture and stirred for 18 h. The mixture was diluted with CH2Cl2 and
quenched with H2O. The organic layer was washed with brine,
dried with Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash column chromatography (100% pent-
ane) to give 15 (200.5 mg, 0.67 mmol, 65% over 2 steps). 1H NMR
(500 MHz, CDCl3): δ = 6.35–6.38 (t, J = 7.0 Hz, 1 H), 2.05–0.10
(q, 2 H), 1.38–1.39 (m, 2 H), 1.25–1.30 (m, 5 H), 1.07–1.13 (m, 2
H), 0.83–0.85 (t, J = 7.2 Hz, 3 H), 0.83–0.84 ppm (d, J = 6.8 Hz,
3 H). 13C NMR (125 MHz, CDCl3): δ = 139.1, 88.7, 36.5, 34.5,
33.3, 29.7, 28.4, 26.8, 19.4, 11.6 ppm. HRMS (ESI): calcd. for
C10H19Br2 [M + H]+ 296.9853; found 296.9890.
Experimental Section
General: All reactions were performed under an atmosphere of ni-
trogen unless otherwise indicated. Anhydrous dichloromethane
(CH2Cl2), toluene, acetonitrile (MeCN), dimethyl sulfoxide
(DMSO), nitromethane (MeNO2), and tetrahydrofuran (THF)
were directly used from commercial sources. The concentration of
nBuLi was titrated by using (–)-menthol and 1,10-phenanthroline.
All other reagents were used without further purification. All
workup, wash, and chromatographic solvents were distilled. So-
dium sulfate (Na2SO4) was anhydrous. Thin-layer chromatography
(TLC) was used to monitor the progress of the reactions by cospot-
ting with the starting materials. p-Anisaldehyde (1350 mL absolute
ethanol, 50 mL concentrated H2SO4, 37 mL p-anisaldehyde) was
utilized as a common TLC visualizing solution. Flash chromato-
graphic purifications were performed by using silica gel (230–
400 mesh). The 1H NMR and 13C NMR spectroscopic data were
recorded with a Varian 500-NMR in [D1]chloroform as the solvent
and are described in parts per million (ppm) from residual chloro-
form [δ =7.24 (for 1H) and 77.23 ppm (for 13C)]. Mass spectra were
performed by using a Surveyor MSQ Benchtop LC–MS (Thermo
Finnigan) and a 6128 Quadrupole LC–MS (Agilent Technologies)
in KIOST.
(S)-{[(6-Methyloct-4-en-1-yl)oxy]methyl}benzene (13): A mixture of
phosphonium iodide 10 (2.3 g, 5.00 mmol) and THF was cooled to
0 °C, and a solution of nBuLi (1.85 m in hexanes, 2.7 mL,
5.00 mmol) was added. After the mixture was stirred at room tem-
perature for 30 min, a solution of aldehyde 12 (1.2 g, 6.50 mmol,
1.3 equiv.) in THF (5.0 mL) was added at 0 °C. The reaction mix-
ture was stirred at room temperature for 1 h, saturated aqueous
NH4Cl was added, and the resulting mixture was extracted with
pentane, dried with Na2SO4, filtered, and concentrated in vacuo.
The crude residue was purified by flash column chromatography
(S)-7-Methylnon-1-yne (16): Dibromoolefin 15 (755.5 mg,
2.53 mmol) was dissolved in THF under an atmosphere of N2 and
cooled to –78 °C. The solution was treated with nBuLi (1.85 m in
hexanes, 5.9 mL, 10.90 mmol) and then stirred. After 1 h, the mix-
ture was warmed to room temperature and stirred. After 3 h, the
mixture was treated with H2O, extracted with pentane, dried with
Na2SO4, filtered, and concentrated in vacuo. The crude residue was
purified by flash column chromatography (100% pentane) to give
1
16 (337.3 mg, 2.44 mmol, 96%). H NMR (500 MHz, CDCl3): δ =
(CH2Cl2/pentane = 5:95 to 15:85) to give 13 [892.1 mg, 3.84 mmol, 2.15–2.18 (dt, J = 7.2 Hz, 2 H), 1.91–1.92 (t, J = 2.7 Hz, 1 H),
77%; 2.3:1 mixture of (E)/(Z) isomers]. 1H NMR (500 MHz,
CDCl3): δ = 7.33–7.34 (d, J = 4.1 Hz, 4 H), 7.26–7.29 (m, 1 H),
5.29–5.34 (m, 1 H), 5.11–5.16 (t, J = 10.3 Hz, 1 H), 4.50 (s, 2 H),
3.47–3.49 (t, J = 6.5 Hz, 2 H), 2.33–2.36 (m, 1 H), 2.07–2.16 (m, 2
H), 1.65–1.71 (m, 2 H), 1.17–1.35 (m, 2 H), 0.92–0.93 (d, J =
1.46–1.53 (m, 2 H), 1.25–1.44 (m, 5 H), 1.06–1.14 (m, 2 H), 0.82–
0.85 (t, J = 6.8 Hz, 3 H), 0.82–0.84 ppm (d, J = 6.4 Hz, 3 H). 13C
NMR (125 MHz, CDCl3): δ = 85.0, 68.3, 36.2, 34.5, 29.7, 29.0,
26.5, 19.4, 18.6, 11.6 ppm. HRMS (ESI): calcd. for C10H17 [M –
H]– 137.1330; found 137.1341.
4
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Total Synthesis and Configurational Validation of (+)-Violapyrone C
[2] a) H. J. Shin, H.-S. Lee, J. S. Lee, J. Shin, M. A. Lee, H.-S. Lee,
Y.-J. Lee, J. Yun, J. S. Kang, Mar. Drugs 2014, 12, 3283–3291;
b) unpublished results.
(10S)-tert-Butyl 2,10-Dimethyl-3-oxododec-4-ynoate (17): nBuLi
(1.85 m in hexanes, 142.6 µL, 0.2638 mmol) was added to a cold
solution (–78 °C) of terminal alkyne 16 (22.8 mg, 0.16 mmol) in
THF under an atmosphere of N2. The resulting mixture was stirred
for 40 min and methyl chloroformate was added. The mixture was
allowed to warm to room temperature. The mixture was diluted
with diethyl ether and quenched with H2O. The organic layer was
dried with Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash column chromatography (EtOAc/n-
hexane = 1:30) to give 16a (31.3 mg, 0.16 mmol, quantitative). tert-
Butyl propionate (59.7 µL, 0.39 mmol, 3.0 equiv.) was added drop-
wise to a stirred solution of LDA (2.0 m in THF, 1.31 mmol,
10.0 equiv.) at –78 °C. The mixture was stirred at this temperature
for 30 min before 16a (25.8 mg, 0.13 mmol) was slowly introduced;
stirring was continued at –78 °C for 2 h. The mixture was diluted
with diethyl ether and quenched with saturated aqueous solution
of NH4Cl. The organic layer was dried with Na2SO4, filtered, and
concentrated in vacuo. The crude residue was purified by flash col-
umn chromatography (EtOAc/n-hexane = 1:35) to give 17 (34.3 mg,
[3] a) W. Chaładaj, M. Cobet, A. Fürstner, Angew. Chem. Int. Ed.
2012, 51, 6929–6933; Angew. Chem. 2012, 124, 7035–7039; b)
F. Bellina, D. Ciucci, R. Rossi, P. Vergamini, Tetrahedron 2000,
56, 2533–2545; c) B. Legouin, E. Marchal, P. Uriac, P. Weghe,
L. Toupet, P. Weghe, Tetrahedron 2007, 63, 9979–9990; d) R. C.
Larock, L. W. Harrison, J. Am. Chem. Soc. 1984, 106, 4218–
4227; e) T. Honda, H. Morita, M. Rudyanto, Y. Tomizawa,
Org. Lett. 2008, 10, 1921–1922; f) J.-H. Li, Y. Liang, Y.-X. Xie,
Synthesis 2007, 3, 400–406; g) T. Honda, K. Kobayashi, M.
Rudyanto, Heterocycles 2009, 79, 753–764; h) B. Godoi, S. Pin-
ton, A. Speranca, G. Zeni, D. F. Back, P. H. Menezes, J. Org.
Chem. 2011, 76, 6789–6797; i) M. Ackermann, J.
De Buck Becker, R. Doepp, A. S. K. Hashmi, C. Lothschuetz,
F. Rominger, M. Rudolph, C. Scholz, Adv. Synth. Catal. 2012,
354, 133–147; j) T. Sakamoto, A.-N. Masayuki, Y. S. Kondo,
H. Yamanaka, Chem. Pharm. Bull. 1986, 34, 2754–2759; k) H.
Seo, M. E. Jun, K. H. Ahn, O. A. Egorova, K.-H. Lee, K.-T.
Kim, Org. Lett. 2012, 14, 5062–5065; l) P. Fiedler, A. Kolla-
rovic, D. Saman, I. G. Stara, I. Stary, F. Teply, Tetrahedron
1998, 54, 11209–11234; m) F. Bellina, R. Rossi, L. Mannina,
Tetrahedron Lett. 1998, 39, 3017–3020; n) I. Wetzel, F. Bracher,
J. Z. Krauss, Z. Naturforsch. B 2009, 64, 313–318; o) M. Alami,
J.-D. Brion, A. Hamze, G. Le Bras, P.-B. Le Calvez, S. Messa-
oudi, O. Provot, Synthesis 2008, 10, 1607–1611; p) W. Ajana,
M. Alvarez, L. Feliu, J. A. Joule, Tetrahedron 1998, 54, 4405–
4412; q) D. J. Burton, Y. Wang, J. Org. Chem. 2006, 71, 3859–
3862; r) B. Y.-W. Man, A. Knuhtsen, M. J. Page, B. A. Mes-
serle, Polyhedron 2013, 61, 248–252; s) I. D. Ivanchikova, G. E.
Usubalieva, P. V. Schastnev, A. A. Moroz, M. S. Shvartsberg,
Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1992,
41, 1672–1679; t) P. T. Perumal, C. Praveen, A. Ayyanar, Bi-
oorg. Med. Chem. Lett. 2011, 21, 4170–4173.
1
0.12 mmol, 86% over 2 steps). H NMR (500 MHz, CDCl3): δ =
12.27 (s, 1 H), 3.40–3.44 (q, 1 H), 2.39–2.41 (t, J = 7.0 Hz, 2 H),
2.34–2.37 (t, J = 7.1 Hz, 2 H), 1.81 (s, 3 H), 1.55 (m), 1.48 (s, 9 H),
1.45 (s, 9 H), 1.25–1.32 (m), 1.07–1.12 (m), 0.82–0.85 (t, J = 7.0 Hz,
6 H), 0.82–0.84 ppm (d, J = 6.6 Hz, 6 H). 13C NMR (125 MHz,
CDCl3): δ = 183.8, 173.2, 169.0, 152.1, 104.5, 100.1, 96.8, 82.0,
81.9, 79.7, 75.3, 56.1, 49.9, 36.2, 36.1, 34.5, 34.4, 29.624, 29.617,
28.6 28.4, 28.32, 28.27, 28.22, 28.19, 28.17, 28.09, 28.0, 26.6, 26.6,
19.7, 19.4, 19.34, 19.26, 14.0, 13.6, 13.0, 11.6 ppm. HRMS (ESI):
calcd. for C18H29O3 [M – H]– 293.2117; found 293.2127.
(S)-4-Hydroxy-3-methyl-6-(5-methylheptyl)-2H-pyran-2-one (1): A
solution of gold(I) catalyst 8 (9.2 mg, 0.01 mmol, 10.0 mol-%) and
17 (34.3 mg, 0.12 mmol) in MeNO2/AcOH (4:1) was stirred for 20 h
at room temperature. The mixture was diluted with EtOAc and
quenched with a saturated aqueous solution of NaHCO3. The or-
ganic layer was washed with brine, dried with Na2SO4, filtered,
and concentrated in vacuo. The crude residue was purified by flash
column chromatography (EtOAc/n-hexane = 1:4 to 1:2) to give 1
(22.5 mg, 0.09 mmol, 81%). 1H NMR (500 MHz, CD3OD): δ =
5.99 (s, 1 H), 2.47 (t, J = 7.6 Hz, 2 H), 1.85 (s, 3 H), 1.62 (m, 2 H),
1.36 (m, 2 H), 1.33 (m, 2 H), 1.32 (m, 1 H), 1.15 (m, 2 H), 0.87 (t,
J = 7.0 Hz, 3 H), 0.87 ppm (d, J = 6.5 Hz, 3 H). 13C NMR
(125 MHz, CD3OD): δ = 169.3, 168.2, 165.0, 101.3, 99.0, 37.5, 35.7,
34.4, 30.7, 28.4, 27.6, 19.7, 11.9, 8.4 ppm. HRMS (ESI): calcd. for
C14H22O3 [M]– 238.1569; found 238.1564.
[4] For recent reviews on gold-catalyzed reactions, see: a) Z. Li, C.
Brouwer, C. He, Chem. Rev. 2008, 108, 3239–3265; b) A.
Corma, A. Leyva-Pérez, M. J. Sabater, Chem. Rev. 2011, 111,
1657–1712; c) M. Rudolph, A. Hashmi, K. Stephen, Chem.
Soc. Rev. 2012, 41, 2448–2462; d) S. F. Kirsch, Synthesis 2008,
3183; e) T. de Haro, C. Nevado, Synthesis 2011, 2530.
[5] a) T. Luo, S. L. Schreiber, Angew. Chem. Int. Ed. 2007, 46,
8250–8253; Angew. Chem. 2007, 119, 8398–8401; b) T. Luo, M.
Dai, S.-L. Zheng, S. L. Schreiber, Org. Lett. 2011, 13, 2834–
2836.
[6] For the preparation of ynoates 5 and 6, see the Supporting
Information.
[7] D. Noutsias, G. Vassilikogiannakis, Org. Lett. 2012, 14, 3565–
3567.
[8] Z. Yang, X. Jin, M. Guaciaro, B. F. Molino, J. Org. Chem.
2012, 77, 3191–3196.
[9] A. Bouzide, G. Sauve, Tetrahedron Lett. 1997, 38, 5945–5948.
[10] J. S. Lee, P. L. Fuchs, J. Am. Chem. Soc. 2005, 127, 13122–
13123.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and copies of
1
the H NMR and 13C NMR spectra for all new compounds.
[11] a) E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–
3772; b) N. G. Angelo, P. S. Arora, J. Am. Chem. Soc. 2005,
127, 17134–17135.
Acknowledgments
[12] a) D. A. Rooke, E. M. Ferreira, Angew. Chem. Int. Ed. 2012,
51, 3225–3230; Angew. Chem. 2012, 124, 3279–3284; b) R. C.
Livingston, B. M. Trost, J. Am. Chem. Soc. 2008, 130, 11970–
11978.
This work was partially supported by the Korea Institute of Ocean
Science and Technology (grant numbers PE98986, PE99214,
PE99273) and the Ministry of Oceans and Fisheries, Republic of
Korea (grant number PM57561).
[13] For a comparison of the 1H NMR and 13C NMR spectra of
synthetic 1 and 2 and natural violapyrone C, see: Table S2 in
the Supporting Information.
[1] J. Zhang, Y. Jiang, Y. Cao, J. Liu, D. Zheng, X. Chen, L. Han,
Received: May 1, 2014
Published Online: ᭿
C. Jiang, X. Huang, J. Nat. Prod. 2013, 76, 2126–2130.
Eur. J. Org. Chem. 0000, 0–0
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5

Job/Unit: O42524
/KAP1
Date: 16-06-14 10:35:24
Pages: 6
J. S. Lee et al.
SHORT COMMUNICATION
Total Synthesis
J. S. Lee,* J. Shin, H. J. Shin, H.-S. Lee,
Y.-J. Lee, H.-S. Lee, H. Won ........... 1–6
Total Synthesis and Configurational Vali-
dation of (+)-Violapyrone C
The total synthesis of (+)-violapyrone C is
accomplished through gold(I)-catalyzed 6-
endo-dig cyclization, silver(I) oxide pro-
moted monobenzylation, Wittig olefin-
ation, and Corey–Fuchs reaction [22%
yield over 10 steps from readily available
(S)-(–)-2-methylbutanol]. The absolute
configuration of natural (+)-violapyrone C
is determined; Tf = trifluoromethylsulf-
onyl.
Keywords: Total synthesis / Natural prod-
ucts / Oxygen heterocycles / Gold / Wittig
reactions
6
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Eur. J. Org. Chem. 0000, 0–0