Protecting-Group-Free Total Synthesis of Chatenaytrienin-2

Article abstract of DOI:10.1021/acs.joc.9b01952

An efficient seven-step, protecting-group-free first total synthesis of chatenaytrienin-2 based on ring-closing metathesis and C(sp)-C(sp³) Sonogashira coupling with a 36.5% overall yield has been described. The ready availability of starting m

Full text of DOI:10.1021/acs.joc.9b01952

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A Protecting-Group-Free Total Synthesis of Chatenaytrienin-2
Rupesh A Kunkalkar, and Rodney Agustinho Fernandes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01952 • Publication Date (Web): 01 Sep 2019
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The Journal of Organic Chemistry
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A Protecting-Group-Free Total Synthesis of Chatenaytrienin-2
Rupesh A. Kunkalkar and Rodney A. Fernandes*
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Department of Chemistry, Indian Institute of Technology Bombay, Powai Mumbai 400076, Maharashtra, India
Supporting Information Placeholder
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ABSTRACT: An efficient 7 step, protecting-group-free first total synthesis of chatenaytrienin-2 based on ring-closing metath-
esis and C(sp)-C(sp3) Sonogashira coupling with 36.5% overall yield has been described. The ready availability of starting
materials and key Wittig olefination, ring-closing metathesis, Lindlar reduction and C(sp)-C(sp3)coupling makes this strategy
applicable for the synthesis of various unbranched polyene-natural products having the 1,5,9,n-(Z)-configured double bonds.
synthesis of unbranched 1,5,9,n-polyenes.10 With our con-
Annonaceous acetogenins solely found in the genera of the
archaic plant family called as Annonaceae, are a group of
fatty acid type natural products.1,2 Many natural products
belonging to this group have been isolated, characterized
and shown to possess interesting and important bioactivi-
ties,1,3 significantly the antitumor effects and growth inhibi-
tory action against multidrug-resistant cancer cells.4 Struc-
turally, acetogenins have a very long alkyl chain usually
ranging from 32 to 34 carbon atoms substituted by oxygen-
ated groups, usually tetrahydrofuran (THF) ring, epoxide or
hydroxyl groups. These long chain compounds are mainly
terminated by an α,β-unsaturated-γ-methyl-γ-lactone at
one end and a methyl group on the other. The number of
THF rings and the stereochemistry, both have a profound
effect on the biological activities; e.g. adjacent bis-THF
groups in membranacin,5,6 leads to a highly potent tumour
growth inhibitor.
tinued interest in the synthesis of γ-lactone and butenolide
natural products11 and also our recent synthesis of (+)-mu-
ricadienin,11a we became interested in the synthesis of
chatenaytrienin-2 (1b). Herein, we disclose an efficient pro-
tecting-group-free first total synthesis of chatenaytrienin-2
based on C(sp)-C(sp3) Sonogashira coupling and ring-clos-
ing metathesis (RCM) as key steps.
The first acetogenin without a THF ring was isolated in
1990 containing epoxy-ene units, which gave the idea of
natural occurrence of bis-unsaturated precursors, mu-
ricadienin, muridienins and chatenaytrienins.7 This led to
the assumption of biosynthetic pathways for THF contain-
ing acetogenins, where these THF heterocycles originate
from 1,5 and 1,5,9,n polyenes. The majority of these natural
products feature exclusively (Z)-configured double bonds
like in muricadienin, muridienins and chatenaytrienins.7b It
is proposed that muricadienin might be a precursor for both
the acetogenins cis- and trans-solamins.8 Many acyclic poly-
ene acetogenins have been isolated from the same plant as
their oxidized and cyclized THF forms.1b,9 In 1998, Cave et
al. isolated chatenaytrienins, the polyenes (1,5,9 trienes) as
a mixture of chatenaytrienin-1 (1a) and -2 (1b), and chate-
naytrienin-3 (1c) and -4 (1d) (Figure 1).7b In 2016, Stark
and Adrian executed the first total synthesis of chatenaytri-
enin-4 (1d) by an iterative strategy for the stereodivergent
Figure 1. Chatenaytrienins-1, -2, -3 and -4 (1a-d).
Retrosynthetically, C(sp)-C(sp3) Sonogashira coupling
and Lindlar reduction were planned from precursors, ene-
diyne 2 and bromobutenolide 3, to lead to 1b as shown in
Scheme 1. The ene-diyne 2 can be easily prepared using al-
dehyde from 4 by Wittig olefination. Alkylation of 6 would
give 4. Esterification of acid 5 with chiral homoallyl alcohol
and ring-closing metathesis (RCM) will give 3. Compound 5
can be prepared from 10-bromodecan-1-ol (7) through ox-
idation and -methylenation. The chatenaytrienins 1a-d
have the common (Z,Z,Z)-1,5,9-triene system and the termi-
nal butenolide moiety. The difference lies in the spacers be-
tween the olefin bond and the butenolide unit and also the
terminal alkyl chain. The synthetic strategy adopted here is
quite flexible in that compound 7 could be of different car-
bon chain length. Also the alkylhalo compound for
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alkylation of 6 can be varied. Thus, the strategy can eventu-
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-methelenic acid 5 in 73% yield over three steps. Acid 5
was then esterified with the chiral alcohol 9 under Steglich
conditions,14 which afforded ester 11 in 91% yield. Com-
pound 11 on ring-closing metathesis using the Grubbs-II
catalyst (20 mol%) delivered 3 in 88% yield, similar to our
earlier report.11a However, when Hoveyda−Grubbs-II cata-
lyst was used, the bromobutenolide 3 was obtained in 93%
yield, requiring 10 mol% of the catalyst.
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ally lead to the synthesis of all chatenaytrienins.
Scheme 1. Retrosynthesis of chatenaytrienin-2 (1b)
The ene-diyne 2 was prepared as shown in Scheme 3. Al-
kylation of commercially available compound 6 with 1-bro-
mododecane provided the alkynol 4 in 84% yield. The Wit-
tig salt 12 was prepared from the same compound 6, by first
converting alcohol to iodide and then reaction with tri-
phenylphosphine. Further oxidation of alcohol 4 to alde-
hyde and reaction with the ylide from 12 resulted in the
ene-diyne 2 in 76% yield over two steps (E/Z = 5:95, by
NMR). The strategy demonstrates the dual use of alkyne 6
to obtain both, the alcohol 4 and also the Wittig salt 12.
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Scheme 3. Synthesis of ene-diyne 2
The synthesis of 1b began with the preparation of bromo-
butenolide 3 as shown in Scheme 2. Styryl methyl ketone 8
was prepared on gram scale in 98% yield by Wittig olefina-
tion between benzaldehyde and 1-(triphenylphosphoranyl-
idene)-2-propanone.12 Compound 8 was reduced following
literature procedure reported by Corey to afford 9 in 95%
yield and 97% ee.13 Oxidation of 10-bromodecan-1-ol (7)
using Dess−Martin periodinane to the corresponding alde-
hyde and subsequent Mannich condensation with formalde-
hyde furnished -methelenic aldehyde 10. Further oxida-
tion of aldehyde 10 under Pinnick conditions provided
The completion of the total synthesis of 1b was accom-
plished as shown in Scheme 4. The key C(sp)-C(sp3) So-
nogashira coupling15 between ene-diyne 2 and bromobu-
tenolide 3 was executed using previously optimized So-
nogashira coupling conditions in our muricadienin synthe-
sis.11a Thus, the reaction of 2 with 3 using [PdCl(allyl)]2 (2.5
mol%) and ligand 13 (5 mol%) in the presence of CuI (7.5
mol%) as additive and Cs2CO3 (1.4 equiv) as base in
Et2O/DMF (2:1) as solvent at 45 C furnished the coupled
product 14. Compound 14 however was not stable enough
to be characterized. Surprisingly, we observed the presence
of only one olefinic proton in the 1H NMR (excluding the bu-
tenolide proton). Similarly, the 13C NMR showed the pres-
ence of only three peaks for the olefinic carbons though
there should be 4 carbons corresponding to two olefin
bonds (including the butenolide bond).16 Hence we consid-
ered using the crude product for the next step of Lindlar re-
duction. Thus, after the coupling of compound 2 with 3, the
reaction mixture was filtered through a small pad of Celite-
silica gel and the pad washed with EtOAc/petroleum ether
(19:1). The filtrate was concentrated and the residue was
subjected to Lindlar reduction using Pd/CaCO3 and quino-
line under H2 (3 atm) to provide cleanly chatenaytrienin-2
(1b) in 59% overall yield from 3. Chatenaytrienin-2 (1b)
Scheme 2. Synthesis of bromobutenolide 3
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and chatenaytrienin-4 (1d) have the same core units,
and the CDCl3 peak at  = 77.00 ppm (t) for carbon NMR. IR
spectra were obtained on an FT-IR spectrometer by evapo-
rating compounds dissolved in CHCl3 on CsCl pellete. HRMS
(ESI-TOF) spectra were recorded using positive elec-
trospray ionization by the TOF method. Optical rotations
were measured with a Rudolph polarimeter using the so-
dium D line (589 nm).
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(1,5,9)-triene and the butenolide. The difference lies in the
chain lengths of the terminal alkyl group and the spacer be-
tween the double bond and the butenolide. Thus, the part
1
spectra (both H and 13C NMR) of 1b completely coincides
with that of 1d10 (see spectra in Supporting Information for
comparison). The isolation paper7b for chatenaytrienins
have not characterized these molecules fully as they were
obtained as mixtures of 1a + 1b and then 1c + 1d. Thus, the
total synthesis gains significance in these natural product
synthesis and biological evaluation.
(S,E)-4-Phenylbut-3-en-2-ol (9).13 To a solution of (E)-4-
phenylbut-3-en-2-one 8 (50 mg, 0.342 mmol, azeotropically
dried with toluene) in toluene (0.5 mL) was added (S)-(−)-
2-butyl-CBS-oxazaborolidine (CBS reagent, 0.2M in toluene,
0.26 mL, 0.052 mmol, 15 mol%) at –78 C and subsequently
catecholborane (62.4 mg, 0.52 mmol) was then added di-
rectly into the rapidly stirred heterogeneous reaction mix-
ture and the mixture was allowed to stir for 20 h at –78 C.
It was then quenched with MeOH (1 mL) and the solution
was warmed gradually to 25 C. Volatiles were evaporated
and the residue was dissolved in EtOAc (10 mL). The or-
ganic layer was washed with brine (2 × 5 mL), dried
(Na2SO4), and concentrated. The residue was purified by sil-
ica gel column chromatography with petroleum
ether/EtOAc (4:1) as an eluent to provide alcohol 9 (48.1
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Scheme 4. Completion of the total synthesis of chate-
naytrienin-2 (1b)
25
mg, 95%, 97% ee) as colorless oil. [α]D = −30.1 (c = 2.0,
CHCl3), lit.17 [α]D25 = −29.2 (c = 2, CHCl3); IR (CHCl3) υmax
=
3389, 3371, 3023, 2967, 2926, 2890, 1657, 1493, 1448,
1410, 1360, 1304, 1142, 1061, 1029, 966, 937, 876, 753,
692 cm–1; 1H NMR (400 MHz, CDCl3) δ = 7.41−7.36 (m, 2H),
7.32 (td, J = 6.2, 1.5 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 6.57 (d, J
= 16.0 Hz, 1H), 6.27 (dd, J = 15.9, 6.4 Hz, 1H), 4.50 (quint., J
= 6.4 Hz, 1H), 1.70 (br s, 1H), 1.38 (d, J = 6.3 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ = 136.6, 133.5, 129.4,
128.6, 127.6, 126.4, 68.9, 23.4 ppm. HRMS (ESI-TOF) m/z:
[M + K]+ Calcd for C10H12OK 187.0520; Found: 187.0519.
10-Bromo-2-methylenedecanoic acid (5). To a solution of
10-bromodecan-1-ol 7 (237.2 mg, 1.0 mmol) in dry CH2Cl2
(15 mL) was added Dess–Martin periodinane (636.2 mg, 1.5
mmol, 1.5 equiv) in portions at 0 C and the reaction mix-
ture allowed to stir for 2 h at room temperature. It was then
treated with sat. aq. solutions of Na2S2O3·5H2O (3 mL) and
NaHCO3 (3 mL) and stirred for 20 min. The solution was ex-
tracted with CH2Cl2 (3  20 mL). The combined organic lay-
ers were washed with water, brine, dried (Na2SO4) and con-
centrated to afford the desired aldehyde (253 mg) that was
taken for the next step without further purification.
To the solution of the crude aldehyde (253 mg) in CH2Cl2
(8 mL) were added pyrrolidine (14.2 mg, 0.2 mmol, 0.20
equiv) and propionic acid (14.8 mg, 0.2 mmol, 0.20 equiv).
The mixture was stirred for 5 min at 0 °C and then 37% aq.
formaldehyde (0.24 mL, 3.0 mmol, 3.0 equiv) was added
dropwise and the mixture stirred for 6 h at room tempera-
ture. CH2Cl2 (20 mL) was added and the organic layer sepa-
rated and washed with water, brine, dried (Na2SO4) and
concentrated to afford 10-bromo-2-methylenedecanal 10
(269 mg), which was directly taken for the next step.
In summary, in this paper we have executed an efficient,
convergent and protecting-group-free first total synthesis
of chatenaytrienin-2 (1b) using ring-closing metathesis,
(Z)-selective Wittig olefination, C(sp)-C(sp3) Sonogashira
coupling, and Lindlar reduction as key steps. The synthesis
is completed in 7 linear steps from 7 with 36.5% overall
yield. The strategy is flexible that the synthesis of other
chatenaytrienins can be achieved by varying the alkyl chain
carbons in the materials used.
EXPERIMENTAL SECTION
General information. Solvents were dried by using
standard procedures. Thin-layer chromatography was per-
formed on EM 250 Kieselgel 60 F254 silica gel plates. The
spots were visualized by staining with KMnO4 or by using a
UV lamp. 1H-NMR and 13C-NMR were recorded with a spec-
trometer operating at 400 or 500 and 100 or 125 MHz for
proton and carbon nuclei, respectively. The chemical shifts
are based on the CHCl3 peak at  = 7.26 ppm for proton NMR
To a solution of crude 10 (269 mg) in t-BuOH (6 mL) was
sequentially added cyclohexene (411 mg, 5.0 mmol, 5
equiv), a solution of NaClO2 (136 mg, 1.5 mmol, 1.5 equiv)
and NaH2PO4·2H2O (214 mg, 1.2 mmol, 1.2 equiv) in H2O (6
mL) at 10 C. The pale-yellow reaction mixture was stirred
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25.1, 19.2 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
Page 4 of 6
for 4 h at room temperature. The solution was extracted
with EtOAc (3  25 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated.
The residue was purified by silica gel column chromatog-
raphy with petroleum ether/EtOAc (7:3) as an eluent to af-
ford 5 (192.1 mg, 73% over three steps) as a sticky solid. IR
(CHCl3) υmax = 2928, 2855, 1696, 1627, 1439, 1282, 1212,
1161, 949, 917, 758, 733, 648, 566 cm-1. 1H NMR (400 MHz,
CDCl3) δ = 6.28 (d, J = 1.1 Hz, 1H), 5.64 (d, J = 2.0 Hz, 1H),
3.40 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 7.7 Hz, 2H), 1.85 (quint., J
= 6.9 Hz, 2H), 1.55–1.37 (m, 4H), 1.35–1.26 (m, 6H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ = 172.6, 140.2, 126.9, 34.0,
32.8, 31.4, 29.2, 29.0, 28.6, 28.3, 28.1 ppm; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C11H20 BrO2 263.0641; Found
263.0643.
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3
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5
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C13H21BrO2Na 311.0617; Found 311.0613.
Heptadec-4-yn-1-ol (4). To a stirred solution of 4-pentyn-
1-ol 6 (841 mg, 10 mmol, 2.0 equiv) in dry THF (20 mL) and
HMPA (6 mL) was added dropwise n-BuLi (13.8 ml, 1.6M,
22 mmol, 4.4 equiv) at −78 C. The reaction mixture was
then stirred for 30 min at same temperature. To this mix-
ture was added dropwise 1-bromododecane (1.246 g, 5
mmol, 1.0 equiv) dissolved in THF (5 mL). The reaction mix-
ture was then stirred for 12 h and then quenched with sat.
aq. solution of NH4Cl (20 mL). The solution was extracted
with Et2O (3  30 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated.
The residue was purified by silica gel column chromatog-
raphy with petroleum ether/EtOAc (9:1) as an eluent to
give heptadec-4-yn-1-ol 48 (1.060 g, 84%) as sticky white
solid. IR (CHCl3) υmax = 3428, 2982, 2211, 1613, 1510, 1497,
1467, 1370, 1315, 1229, 1152, 1123, 1025, 909, 821, 783,
750, 631 cm-1; 1H NMR (400 MHz, CDCl3) δ = 3.73 (t, J = 6.1
Hz, 2H), 2.26 (tt, J = 6.9, 2.5 Hz, 2H), 2.11 (tt, J = 7.1, 2.9 Hz,
2H), 1.72 (quint., J = 6.4 Hz, 2H), 1.45 (quint., J = 7.7 Hz, 2H),
1.37–1.20 (m, 18H), 0.86 (t, J = 6.7 Hz, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ = 81.1, 79.2, 62.0, 31.9, 31.6, 29.63,
29.60, 29.5, 29.3, 29.1, 29.0, 28.9, 22.6, 18.7, 15.4, 14.1 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H33O 253.2526;
Found 253.2527.
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(S,E)-4-Phenylbut-3-en-2-yl 10-bromo-2-methylenedecano-
ate (11). To a stirred solution of 5 (40 mg, 0.152 mmol, 1.0
equiv) in dry CH2Cl2 (2 mL) were added N,N’-dicyclohexyl-
carbodiimide (DCC, 37.6 mg, 0.182 mmol, 1.2 equiv) and
DMAP (5.6 mg, 0.046 mmol, 0.3 equiv) at 0 C. The mixture
was stirred for 10 min and then a solution of (S,E)-4-phenyl-
but-3-en-2-ol 9 (45 mg, 0.304 mmol, 2.0 equiv) in dry CH2Cl2
(1 mL) was added dropwise at 0 C. The reaction mixture
was stirred for an additional 5 h at room temperature. It
was then filtered through a cotton plug and the plug washed
with CH2Cl2 (5 mL). The filtrate was washed with water,
brine, dried (Na2SO4) and concentrated under vacuum. The
residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (20:1) as an eluent to afford
Pent-4-yn-1-yltriphenylphosphonium iodide (12). To a so-
lution of 4-pentyn-1-ol 6 (1.0 g, 11.89 mmol) in dry CH2Cl2
(20 mL) were added sequentially PPh3 (3.743 g, 14.27
mmol, 1.2 equiv), imidazole (0.971 g, 14.27 mmol, 1.2
equiv) and iodine (3.622 g, 14.27 mmol, 1.2 equiv) at 0 C.
The reaction mixture was stirred for 4 h at room tempera-
ture. It was then treated with sat. aq. solution of
25
11 (54.4 mg, 91%) as colorless oil. [α]D = –25.1 (c = 1.3,
CHCl3); IR (CHCl3) υmax = 2930, 2856, 1715, 1627, 1449,
1303, 1170, 1144, 1041, 965, 946, 812, 749, 693, 648 cm-1;
1H NMR (500 MHz, CDCl3) δ = 7.38 (d, J = 7.2 Hz, 2H), 7.31
(d, J = 7.3 Hz, 2H ), 7.26−7.22 (m, 1H), 6.62 (d, J = 16.0 Hz,
1H), 6.22 (dd, J = 6.7, 16.0 Hz, 1H), 6.16 (d, J = 1.3 Hz, 1H),
5.64–5.55 (m, 1H), 5.52 (d, J = 1.3 Hz, 1H), 3.39 (t, J = 6.9 Hz,
2H), 2.31 (t, J = 7.7 Hz, 2H), 1.83 (quint, J = 7.1 Hz, 2H), 1.51–
1.38 (m, 7H), 1.35–1.28 (m, 6H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ = 166.6, 141.3, 136.4, 131.4, 128.9, 128.6,
127.9, 126.6, 124.3, 71.1, 34.0, 32.8, 31.8, 29.2, 29.1, 28.7,
28.4, 28.1, 20.4 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C21H29BrO2Na 415.1243; Found 415.1248.
(S)-3-(3-Bromooctyl)-5-methylfuran-2(5H)-one (3). To a
stirred and degassed solution of ester 11 (50 mg, 0.127
mmol) in dry CH2Cl2 (10 mL) was added Hoveyda−Grubbs
second-generation catalyst (8.0 mg, 0.0127 mmol, 10
mol%) at room temperature and the mixture was refluxed
for 30 h. The mixture was then cooled and filtered through
a small pad of silica gel and the filtrate was concentrated un-
der vacuum. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (5:1) as an
eluent to provide bromobutenolide 3 (34.2 mg, 93%) as col-
orless semi-solid. [α]D25 = +16.3 (c = 0.7, CHCl3); IR (CHCl3)
νmax = 2926, 2857, 1756, 1456, 1320, 1202, 1122, 1076,
1025, 953, 861, 760 cm−1; 1H NMR (500 MHz, CDCl3) δ = 6.98
(d, J = 1.4 Hz, 1H), 4.99 (qd, J = 6.8, 1.7 Hz, 1H), 3.40 (t, J =
6.9 Hz, 2H), 2.28–2.22 (m, 2H), 1.84 (quint., J = 6.9 Hz, 2H),
1.54 (quint., J = 7.7 Hz, 2H), 1.44–1.38 (m, 5H), 1.36–1.29
(m, 6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 173.9,
148.9, 134.2, 77.4, 34.0, 32.7, 29.04, 29.00, 28.6, 28.0, 27.3,
.
Na2S2O3 5H2O (15 mL) and stirred for further 10 min. The
organic layer was separated and the aqueous layer ex-
tracted with CH2Cl2 (2  20 mL). The combined organic lay-
ers were washed with water, brine, dried (Na2SO4) and con-
centrated to half its volume and then passed through a small
silica gel column (10 cm) and washed with petroleum ether
(50 mL). The filtrate was concentrated until 5-10 mL of pe-
troleum ether remained (concentrations of fractions was
done at low temperature and pressure considering the vol-
atility of iodoalkyne). To this was added PPh3 (3.743 g,
14.27 mmol, 1.2 equiv) and benzene (20 mL). The mixture
was refluxed for 10 h. The phosphonium salt 12 precipi-
tated out as white solid. The mixture was concentrated and
the phosphonium salt formed was washed with dry THF (3
 10 mL) under nitrogen atmosphere (to remove excess
PPh3), vacuum dried and was used directly for next reaction
(5.42 g).
(Z)-Docosa-5-en-1,9-diyne (2). To a solution of heptadec-4-
yn-1-ol 4 (252.4 mg, 1 mmol, 1.0 equiv) in CH2Cl2 (5 mL)
was added Dess–Martin periodinane (636.2 mg, 1.5 mmol,
1.5 equiv) in portions at 0 C and the reaction mixture was
allowed to stir for 4 h at room temperature. It was then
treated with sat. aq. solution of Na2S2O3·5H2O (3 mL) and
NaHCO3 (3 mL) and stirred for 20 min. The solution was ex-
tracted with CH2Cl2 (3  20 mL). The combined organic lay-
ers were washed with water, brine, dried (Na2SO4) and
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The Journal of Organic Chemistry
concentrated to afford the corresponding aldehyde (231
mg) that was used for next step directly.
129.06, 77.4, 31.9, 29.7, 29.68, 29.6, 29.56, 29.4, 29.35,
29.32, 29.3, 29.25, 29.2, 27.4, 27.39, 27.36, 27.3, 27.2, 25.2,
22.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C35H61O2
513.4666; Found 513.4666.
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2
3
4
5
6
7
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To a solution of pent-4-yn-1-yltriphenylphosphonium io-
dide 12 (502 mg, 1.1 mmol, 1.1 equiv) in dry THF (10 mL)
under nitrogen atmosphere was added NaHMDS (1.1 mL,
1M solution in THF, 1.1 mmol, 1.1 equiv) drop wise at –78
°C and stirred for 1 h. To the orange colored suspension,
pre-dissolved solution of crude heptadec-4-ynal (231 mg)
in THF (10 mL) was added drop wise. After 12 h, the reac-
tion mixture was quenched with sat. aq. solution of NH4Cl.
The solution was extracted with EtOAc (3  20 mL). The
combined organic layers were washed with water, brine,
dried (Na2SO4) and concentrated. The residue was purified
by silica gel column chromatography with petroleum ether
as an eluent to afford (Z)-docosa-5-en-1,9-diyne 2 (228.4
mg, 76%) as colorless oil. IR (CHCl3) υmax = 3010, 2926,
2854, 2318, 2253, 1464, 1380, 1319, 1122, 1087, 1027, 910,
766, 732, 649 cm-1; 1H NMR (500 MHz, CDCl3) δ = 5.56−5.44
(m, 2H), 2.34−2.17 (m, 8H), 2.13 (tt, J = 7.1, 2.2 Hz, 2H), 1.95
(t, J = 2.6 Hz, 1H), 1.47 (quint., J = 6.9 Hz, 2H), 1.37−1.23 (m,
18H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) δ = 129.8, 128.6, 84.1, 80.7, 79.5, 68.4, 31.9, 29.7,
29.6, 29.55, 29.3, 29.2, 29.1, 28.9, 27.1, 26.4, 22.7, 19.1, 18.8,
18.7, 14.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H37O 317.2839; Found 317.2842.
Chatenaytrienin-2 (1b). To a solution of 1,3-bis(1-adaman-
thyl)benzimidazolium chloride 13 (2.3 mg, 0.0055 mmol, 5
mol%), CuI (1.57 mg, 0.0083 mmol, 7.5 mol%), [PdCl(π-al-
lyl)]2 (1.0 mg, 0.0028 mmol, 2.5 mol %), and Cs2CO3 (50.5
mg, 0.1548 mmol, 1.4 equiv) in a mixture of dry Et2O/DMF
(2:1, 1.0 mL) in a sealed tube was added a solution of ene-
diyne 2 (59.8 mg, 0.199 mmol, 1.8 equiv) in a mixture of dry
Et2O and DMF (0.5 mL) followed by the solution of bromo-
lactone 3 (32 mg, 0.1106 mmol, 1.0 equiv) in a mixture of
dry Et2O and DMF (0.5 mL). The tube was then sealed with
a teflon lined cap and the reaction mixture was stirred vig-
orously at 45 °C for 20 h. The crude reaction mixture was
filtered through a small pad of Celite-silica gel and the pad
washed using petroleum ether/EtOAc (19:1) as an eluent.
The filtrate was concentrated under vacuum to afford 14
(78 mg) that was used in next reaction.
To the solution of 14 (78 mg) in absolute MeOH (2 mL)
was added Lindlar catalyst Pd/CaCO3 (26.1 mg of 5% Pd on
CaCO3 poisoned with lead) and quinoline (21.4 mg, 0.166
mmol, 1.5 equiv). The reaction mixture was stirred under H2
(3 atm) for 3 h at 40 C. After complete consumption of the
starting material, the crude reaction mixture was filtered
through a small pad of Celite-silica gel and the filtrate con-
centrated. The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (19:1) as an
eluent to afford 1b (33.5 mg, 59% over two steps) as a col-
orless waxy solid. []D25 = +15.8 (c = 0.5, CHCl3); IR (CHCl3)
νmax = 3007, 2925, 2853, 1759, 1654, 1464, 1376, 1318,
1217, 1200, 1119, 1073, 1027, 968, 858, 757, 722, 665 cm-
1; 1H NMR (500 MHz, CDCl3) δ = 6.97 (d, J = 1.4 Hz, 1H), 5.44–
5.33 (m, 6H), 4.99 (qd, J = 6.8, 1.6 Hz, 1H), 2.26 (t, J= 7.9 Hz,
2H), 2.14–2.05 (m, 8H), 2.05–1.97 (m, 4H), 1.54 (quint., J =
7.5 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.34–1.24 (m, 30H), 0.88
(t, J = 6.9 Hz, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ =
173.9, 148.8, 134.3, 130.4, 130.3, 129.63, 129.6, 129.1,
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
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1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: rfernand@chem.iitb.ac.in
ORCID
Rodney A. Fernandes: 0000-0001-8888-0927
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank SERB New Delhi, Grant No. EMR/2017/000499 for
financial support. RAK thank the University Grants Commis-
sion of India (UGC) for research fellowship.
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