A Catalytic Asymmetric Protecting-Group-Free Total Synthesis of (4 S,5 S)-4,8-Dihydroxy-3,4-dihydrovernoniyne and Its Enantiomer

Article abstract of DOI:10.1021/acs.joc.9b02461

A catalytic asymmetric second generation synthesis of (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne has been completed employing the asymmetric dihydroxylation strategy. Further, a four-step protecting-group-free synthesis of the natural product and its enantiomer has been achieved through the modified Knoevenagel reaction, asymmetric dihydroxylation, and Cadiot-Chodkiewicz coupling. The protecting-group-free synthesis is completed in four steps and 41% overall yield.

Full text of DOI:10.1021/acs.joc.9b02461

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Article
A Catalytic Asymmetric Protecting-Group-Free Total Synthesis of
(4S,5S)-4,8-Dihydroxy-3,4-dihydrovernoniyne and its Enantiomer
GUJJULA V RAMAKRISHNA, and Rodney Agustinho Fernandes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02461 • Publication Date (Web): 18 Sep 2019
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The Journal of Organic Chemistry
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A Catalytic Asymmetric Protecting-Group-Free Total Synthe-
sis of (4S,5S)-4,8-Dihydroxy-3,4-dihydrovernoniyne and its
Enantiomer
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Gujjula V. Ramakrishna and Rodney A. Fernandes*
Department of Chemistry, Indian Institute of Technology Bombay, Powai Mumbai 400076, Maharashtra, India
Supporting Information Placeholder
ABSTRACT: A catalytic asymmetric second generation synthesis of (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne has been
completed employing the asymmetric dihydroxylation strategy. Further, a four step protecting-group-free synthesis of the
natural product and its enantiomer has been achieved through modified Knoevenagel reaction, asymmetric dihydroxylation
and Cadiot−Chodkiewicz coupling. The protecting-group-free synthesis is completed in 4 steps and 41% overall yield.
INTRODUCTION
mannitol) leading to the revision in the structure of the nat-
ural product, to have the (4S,5S) absolute configuration. The
presence of -hydroxy--lactone moiety in this natural
product caught our attention and we recently completed
the total synthesis of all stereoisomers through chiral pool
chemistry and confirmed the natural product to have the
(4S,5S) configuration.11 The synthesis was based on an effi-
cient conversion of L-mannonic--lactone or D-glucono--
lactone to either enantiomer of -vinyl--hydroxy--lactone,
hetero-atom directed Wacker oxidation, Seyferth−Gilbert
reaction and Cadiot−Chodkiewicz coupling. Considering the
C4/C5 relative configuration in the natural product to be
syn, we envisioned the same to be derived through catalytic
asymmetric dihydroxylation of a trans---unsaturated es-
ter.
Natural products containing conjugated carbon-carbon tri-
ple bonds display diverse biological activities such as anti-
bacterial, antitumor, anti-inflammatory, antiparasitic, in-
secticidal, antiviral and other cytotoxic activities.1 Polyacet-
ylene natural products are isolated from various sources.2
Many of these tend to decompose being reactive and rela-
tively unstable when exposed to pH variations, light and ox-
idative conditions.3 Various coupling strategies have been
used toward the synthesis of polyacetylene bonds in natural
products, like Glaser−Hay,4 Sonogashira5 and Ca-
diot−Chodkiewicz6 coupling being quite popular. Catalysis
in asymmetric synthesis of natural products have gained
significance due to various environment and economic con-
cerns.7 Similarly, the protecting-group-free synthesis ena-
bles step-economy in a total synthesis. Over the past few
decades, many natural products have been synthesized
without relying on the use of protecting groups, displaying
the potential for future course of natural product syntheses
with improved economy and efficiency.8 In this paper, we
describe a catalytic asymmetric second generation synthe-
sis of (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne (1b,
Figure 1), a triyne natural product, the structure of which
has been revised through total synthesis. Biavatti and co-
workers9 isolated this triyne natural product along with
other related molecules from the leaves of Vernonia scorpi-
oides (Asteraceae). Their structures were deduced by MS
analysis and 1D and 2D NMR spectroscopy. Recently, Moha-
patra et al.10 accomplished the first asymmetric total syn-
thesis of (4S,5R)-1a and (4S,5S)-4,8-dihydroxy-3,4-dihy-
drovernoniyne (1b) (using the chiral pool material D-
Figure 1. The triyne natural product 1a, revised structure
1b and its enantiomer.
The retrosynthetic analysis for 1b based on asymmetric
dihydroxylation is depicted in Scheme 1. Our initial focus
was to synthesize the intermediate 3 from which the final
molecule has been synthesized by us in two steps.11 The al-
kyne 3 can be obtained through homologation of aldehyde
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Scheme 2. Catalytic Asymmetric Total Synthesis of
Page 2 of 7
from 4 after debenzylation. The latter was planned through
catalytic asymmetric dihydroxylation of trans---unsatu-
rated ester 5, which in turn can easily be prepared through
modified Knoevenagel condensation using the requisite al-
dehyde.
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(4S,5S)-4,8-Dihydroxy-3,4-dihydrovernoniyne (1b)
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Scheme 1. Retrosynthetic Analysis for (4S,5S)-4,8-Dihy-
droxy-3,4-dihydrovernoniyne (1b)
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RESULT AND DISCUSSION
The forward synthesis commenced from benzyl pro-
tected 1,4-diol6 (Scheme 2). Oxidation of 6 to aldehyde and
modified Knoevenagel reaction12 with half ester of malonic
acid delivered the trans-,-unsaturated ester 5 (,- v/s
,-unsaturated = 6.5:1) in 65% yield from 6. Further, the
catalytic asymmetric dihydroxylation of 5 using the (DHQ)2-
PHAL ligand provided the β-hydroxy--lactone 8 in 70%
yield and 99% ee.13 The latter was free from undesired
,-dihydroxylated compound 9 isolated in 10.2% yield
arising from ,-unsaturated olefin (present in 5) at this
stage. Protection of the free hydroxyl group of 8 as TBS
ether 4 in 75% yield, and further debenzylation gave 10 in
94% yield. Oxidation of alcohol 10 with PCC to the corre-
sponding aldehyde followed by alkynylation using Sey-
ferth−Gilbert reagent Z14 proceeded optimally to give the al-
kyne 3 in 54% yield (over two steps from 10). The use of
Ohira−Bestmann reagent gave 3 in lower yield (43%). The
required bromodiyne partner 2 was prepared in two steps
from propargyl alcohol 11, by first coupling with TMS acet-
ylene under Glaser−Hay conditions4 and then one-step de-
silylative bromination.15 This two step sequence provided 2
in 69% overall yield. Further, coupling of alkyne 3 with
bromo-alkyne 2 under Cadiot−Chodkiewicz conditions6
(CuCl, NH2OH.HCl, n-BuNH2), and deprotection of TBS ether
furnished (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne
(1b) in 69% overall yield from 3.11 Compound 1b had opti-
cal rotation []D25 −14.8 (c 0.78, EtOH) in comparison to our
We envisioned that the oxidation of 4-pentyne-1-ol to the
aldehyde, followed by modified Knoevenagel reaction
would the give the trans-,-unsaturated--alkyne-ester
12, which on catalytic asymmetric dihydroxylation would
give the -(prop-2-yne-1-yl)-β-hydroxy--lactone 13 di-
rectly (Scheme 3). This strategy appeared promising, con-
sidering a protecting-group-free approach being possible to
synthesize 1b and its enantiomer in a short four step se-
quence. This synthesis will be highly efficient and step-eco-
nomic.
The commercially available 4-pentyne-1-ol (14, Sigma Al-
drich, approx. $7/g) was oxidized to the aldehyde under
Swern oxidation conditions and subsequent modified
Knoevenagel reaction12 using half ester of malonic acid fur-
nished the trans-,-unsaturated--alkyne-ester 12 in 67%
yield from 14 (,- v/s ,-unsaturated = 6.8:1, Scheme 3).
The ensuing stereodivergent catalytic asymmetric dihy-
droxylation of 12 using (DHQ)2-PHAL or (DHQD)2-PHAL lig-
ands provided -(prop-2-yne-1-yl)-β-hydroxy--lactone 13
and ent-13, efficiently in 75% and 76% yields, respectively.
We also isolated the minor diols 15 (9.4%) and ent-15
(9.6%) arising from the dihydroxylation of the correspond-
ing ,-unsaturated ester compound present, in each case,
respectively. Compounds 13 and ent-13 were obtained in
93% ee and 94% ee, respectively.16 Finally, the efficient
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earlier work,11 []D −17.6 (c 0.83, EtOH) and the natural
isolate9 as []D25 −2.16 (c 0.74, EtOH). Spectral data was well
in agreement with the literature data.10 While compound 6
is prepared from 1,4-butane diol in 81% yield (see Experi-
mental Section), the catalytic asymmetric dihydroxylation-
based synthesis of 1b was completed in 10 steps from 1,4-
butanediol in overall yield of 9.7%.
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The Journal of Organic Chemistry
coupling of 13 or ent-13, each with bromodiyne 2, under
EXPERIMENTAL SECTION
Cadiot−Chodkiewicz conditions6 furnished (4S,5S)-4,8-di-
hydroxy-3,4-dihydrovernoniyne (1b, 82%) and ent-1b
(81%) in a protecting-group-free synthesis. The spectral
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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 CDCl3 peak at  = 7.26 ppm for proton NMR
and the CDCl3 peak at  = 77.00 ppm (t) for carbon NMR and
acetone-d6 peak at 29.92 (s) in carbon NMR. IR spectra were
obtained on an FT-IR spectrometer by evaporating com-
pounds dissolved in CHCl3 on CsCl pellete or by preparing
KBr pellets for solids. HRMS (ESI-TOF) spectra were rec-
orded using positive electrospray ionization by the TOF
method.
4-Benzyloxy-butan-1-ol (6).13b To a suspension of NaH
(843.3 mg, 60% in mineral oil, 21.08 mmol, 1.0 equiv) in dry
THF (30 mL) was added dropwise butane-1,4-diol (1.9 g,
21.08 mmol) at 0 °C. After complete addition, the mixture
was stirred for 30 min and benzyl bromide (3.0 g, 17.54
mmol, 0.832 equiv) was added dropwise. Then a catalytic
amount of tetra-butylammonium iodide was added and the
reaction mixture was allowed to warm to room tempera-
ture and was stirred for 3 h. The reaction was quenched
with sat. aq. NH4Cl, and the solution extracted with EtOAc (2
 20 mL). The combined organic layers were washed with
brine, dried (Na2SO4) and concentrated. The residue was
purified by silica gel column chromatography using petro-
leum ether/EtOAc (4:1) as eluent to give 6 (3.08 g, 81%) as
colorless oil. IR (CHCl3): νmax = 3419, 3030, 2937, 2871,
1638, 1496, 1454, 1364, 1204, 1087, 1072, 955, 740, 699,
608 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.35−7.26 (m, 5H),
4.52 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 3.52 (t, J = 5.8 Hz, 2H),
2.35 (br s, 1H), 1.74−1.64 (m, 4H) ppm; 13C{1H} NMR (125
MHz, CDCl3): δ = 138.1, 128.4, 127.7, 127.6, 73.0, 70.3, 62.5,
30.0, 26.5 ppm.
25
and analytical data of 1b, []D −14.6 (c 0.73, EtOH) and
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ent-1b, []D +15.1 (c 0.75, EtOH) matched well with that
reported in the literature.10,11 The four step sequence was
completed in a promising 41% overall yield for both enan-
tiomers from 14.
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Scheme 3. Catalytic Asymmetric Protecting-Group-Free
Total Synthesis of (4S,5S)-4,8-Dihydroxy-3,4-dihydrov-
ernoniyne (1b) and its Enantiomer ent-1b
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Methyl (E)-6-(benzyloxy)hex-3-enoate (5).13b,c To a solu-
tion of alcohol 6 (1.0 g, 5.54 mmol) in CH2Cl2 (20 mL) was
added PCC (1.8 g, 8.32 mmol, 1.5 equiv) at 0 C. The result-
ing mixture was stirred at 0 C for 3 h. The mixture was then
filtered through a pad of Celite and silica gel and the pad
washed with CH2Cl2. The filtrate was concentrated to give
the crude aldehyde that was used for the next step.
To the above aldehyde (1.0 g) was added mono methyl
malonate (654 mg, 5.54 mmol, 1.0 equiv) followed by Et3N
(0.74 mL, 5.54 mmol, 1.0 equiv). The reaction mixture was
stirred at 90 C for 18 h. It was then cooled to room temper-
ature and concentrated. The residue was purified by silica
gel column chromatography using petroleum ether/EtOAc
(9:1) as eluent to give ester 5 (0.844 g, 65%, ,- v/s ,-
unsaturated = 6.5:1 by 1H NMR) as colorless oil. IR (CHCl3):
νmax = 3020, 2966, 2932, 1736, 1481, 1366, 1103, 1027, 968,
736, 693 cm-1; 1H NMR (400 MHz, CDCl3): δ = 7.35−7.26 (m,
5H), 5.63−5.59 (m, 2H), 4.51 (s, 2H), 3.6 (s, 3H), 3.52−3.49
(dd, J = 13.5, 6.7 Hz, 2H ), 3.05 (d, J = 5.8 Hz, 2H), 2.39−2.29
(m, 2H); 13C{1H} NMR (100 MHz, CHCl3): δ = 172.4, 138.4,
131.0, 128.3, 127.6, 127.5, 123.6, 72.9, 69.6, 51.8, 37.9, 32.9
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H18O3Na
257.1148; Found 257.1145.
CONCLUSION
In summary, in this paper we have accomplished the cat-
alytic asymmetric second generation total synthesis of
(4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne (1b) em-
ploying modified Knoevenagel reaction, catalytic asymmet-
ric dihydroxylation, Seyferth−Gilbert alkyne formation and
Cadiot−Chodkiewicz coupling. Also, a promising protecting-
group-free four step synthesis of both enantiomers of the
natural product 1b has been completed based on modified
Knoevenagel reaction, asymmetric dihydroxylation and Ca-
diot−Chodkiewicz coupling in an overall yield of 41%.
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(4S,5S)-5-(2-Benzyloxyethyl)-4-hydroxydihydrofuran-
the mixture stirred for 10 min, followed by addition of tert-
butyldimethylsilylchloride (717.5 mg, 4.76 mmol, 1.5
equiv) and 4-(N,N-dimethylamino)pyridine (77.5 mg, 0.634
mmol, 0.2 equiv). After stirring for 24 h at room tempera-
ture, the reaction was quenched by addition of sat. aq. NH4Cl
solution (50 mL) and then diluted with CH2Cl2 (50 mL). The
layers were separated, and the aqueous layer extracted
with CH2Cl2 (3  50 mL). The combined organic extracts
were dried (Na2SO4) and concentrated. The residue was pu-
rified by silica gel column chromatography using petroleum
ether/EtOAc (4:1) as eluent to give silyl ether 4 (834 mg,
75%) as colorless oil. [α]D25 ‒34.4 (c 1.2, CHCl3); IR (CHCl3):
νmax= 2930, 2857, 1777, 1471, 1362, 1258, 1205, 1164,
2(3H)-one (8)13b,c and Methyl (2R,3S)-6-benzyloxy-2,3-dihy-
droxhexanoate (9). To a mixture of K3Fe(CN)6 (2.107 g, 6.40
mmol, 3.0 equiv), K2CO3 (884.5 mg, 6.40 mmol, 3.0 equiv),
(DHQ)2-PHAL (16.4 mg, 0.021 mmol, 1 mol%) in t-BuOH-
1
2
3
4
5
6
7
8
.
H2O (1:1, 40 mL) cooled at 0 C was added K2OsO4 2H2O (4.7
mg, 0.0128 mmol, 0.6 mol%) followed by methane sulfona-
mide (191 mg, 2.01 mmol, 1.0 equiv). After stirring for 5 min
at 0 C, the olefin 5 (500 mg, 2.134 mmol) was added in one
portion. The reaction mixture was stirred at 0 C for 24 h
and then quenched with solid Na2SO3 (1.0 g). Stirring was
continued for an additional 45 min and the solution was ex-
tracted with EtOAc (2  30 mL). The combined organic lay-
ers were washed with brine, dried (Na2SO4) and concen-
trated. The residue was purified by silica gel column chro-
matography using petroleum ether/EtOAc (3:2) as eluent to
give methyl (2R,3S)-6-benzyloxy-2,3-dihydroxhexanoate 9
(58.4 mg, 10.2 %) as colorless oil. Further elution provided
the lactone 8 (353 mg, 70%) as white solid.
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1
1096, 1026, 908, 838, 778, 700 cm-1; H NMR (400 MHz,
CDCl3): δ = 7.36−7.32 (m, 5H), 4.62 (d, J = 9.2 Hz, 1H), 4.50
(q, J = 11.7 Hz, 2H), 4.38 (s, 1H), 3.65 (dd, J = 7.2, 4.7 Hz, 2H),
2.73 (dd, J = 17.2, 4.9 Hz, 1H), 2.42 (d, J = 17.1 Hz, 1H),
2.14−2.03 (m, 1H), 1.95−1.87 (m, 1H), 0.87 (s, 9H), 0.06 (s,
3H), 0.04 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CHCl3): δ =
175.4, 138.1, 128.4, 127.7, 127.67, 81.9, 73.2, 69.7, 66.4,
39.8, 29.5, 25.6, 17.9, ‒4.7, ‒5.2 ppm; HRMS (ESI-TOF) m/z:
Data for 9: [α]D25 ‒7.8 (c 1.0, CHCl3); IR (CHCl3): νmax= 3505,
3284, 2955, 2928, 2854, 1740, 1647, 1449, 1363, 1285,
1219, 1127, 1093, 1019, 700, 668, 627; 1H NMR (500 MHz,
CDCl3): δ = 7.38–7.24 (m, 5H), 4.51 (s, 2H), 4.09 (d, J = 2.0
Hz, 1H), 3.95–3.91 (m, 1H), 3.81 (s, 3H), 3.53 (dt, J = 12.0,
6.1 Hz, 2H), 1.83–1.71 (m, 4H); 13C{1H} NMR (125 MHz,
CHCl3): δ = 173.9, 138.0, 128.4, 127.7, 127.67, 73.5, 73.1,
72.3, 70.1, 52.7, 31.1, 26.2 ppm; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C14H20O5Na 291.1203; Found 291.1207.
[M
+
Na]+ Calcd for C19H30O4SiNa 373.1806; Found
373.1805.
(4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(2-hydroxy-
ethyl)dihydrofuran-2(3H)-one (10). To a stirred solution of
4 (500 mg, 1.426 mmol) in EtOAc (20 mL) was added Pd-C
(10%, 15 mg) and the mixture stirred at room temperature
under H2 (balloon). After stirring for 12 h at room tempera-
ture, the mixture was filtered through Celite pad and the
pad washed with EtOAc. The filtrate was concentrated and
the residue purified by silica gel column chromatography
using petroleum ether/EtOAc (3:2) as eluent to afford 10
(349 mg, 94%) as colorless solid. M.p. 55‒59 C; [α]D25 –36.3
(c 2.0, CHCl3); IR (CHCl3): νmax= 3432, 2952, 2933, 2884,
2858, 1768, 1638, 1472, 1388, 1294, 1257, 1164, 1092,
1063, 957, 938, 878, 839, 777, 675 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 4.60 (dt, J = 9.6, 3.6 Hz, 1H), 4.42 (t, J = 3.8 Hz,
1H), 3.78 (dd, J = 6.8, 4.9 Hz, 2H), 2.74 (dd, J = 17.3, 5.1 Hz,
1H), 2.56 (s, 1H), 2.40 (d, J = 17.2 Hz, 1H), 2.07−1.98 (m, 1H),
1.84−1.76 (m, 1H), 0.85 (s, 9H), 0.04 (s, 6H) ppm; 13C{1H}
NMR (100 MHz, CHCl3): δ = 175.7, 82.2, 69.8, 58.9, 39.7,
31.8, 25.5, 17.9, –4.8, –5.2 ppm; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C12H24O4SiNa 283.1336; Found 283.1333.
25
Data for 8: M.p. 76−77 C, [α]D ‒41.4 (c 2.5, CHCl3), lit.13c
22
[α]D ‒42.2 (c 2.68, CHCl3); IR (CHCl3): νmax = 3403, 3037,
2961, 2941, 2892, 2862, 1763, 1453, 1346, 1318, 1295,
1233, 1201, 1177, 1128, 1067, 1002, 959, 901, 796, 751,
700, 666, 610, 531 cm-1; 1H NMR (400 MHz, CDCl3): δ =
7.38−7.28 (m, 5H), 4.57−4.49 (m, 2H), 4.46−4.41 (m, 2H),
3.74−3.69 (m, 1H), 3.57−3.52 (m, 1H), 2.75 (dd, J = 17.8, 5.6
Hz, 1H), 2.53 (d, J = 17.9 Hz, 1H), 2.30−2.26 (m, 1H),
2.24−2.12 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CHCl3): δ =
175.6, 136.9, 128.6, 128.2, 127.9, 83.7, 73.8, 68.6, 66.0, 37.9,
28.5 ppm; HRMS (ESI-TOF) m/z: [M + K]+ Calcd for
C13H16O4K 275.0680; Found 275.0682. The enantiomeric
excess of 8 was determined by converting it into its OTBDPS
ether 8 using TBDPS-Cl and by following a similar proce-
dure as described for compound 4. Reaction of 8 (20 mg,
0.084 mmol) using TBDPS-Cl (34.7 mg, 0.126 mmol, 1.5
25
equiv) gave 8 (29.3 mg, 76%) as colorless oil. [α]D ‒21.8
(4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(prop-2-yn-1-
yl)dihydrofuran-2(3H)-one (3). To a solution of alcohol 10
(100 mg, 0.384 mmol) in dry CH2Cl2 (10 mL) was added PCC
(124 mg, 0.576 mmol, 1.5 equiv) and NaOAc (63 mg, 0.768
mmol, 2.0 equiv) at 0 C. The reaction mixture was stirred
at 0 C for 3 h and then filtered through a pad of Celite and
silica gel and the pad washed with CH2Cl2. The filtrate was
concentrated to give the aldehyde (90 mg) which was used
for next step without purification.
To a solution of diethyl (diazomethyl)phosphonate Z
(136.8 mg, 0.768 mmol, 2.0 equiv) in THF (3 mL), cooled to
−78 C under N2 was added t-BuOK (86.2 mg, 0.768 mmol,
2.0 equiv). The reaction mixture was stirred for 15 min and
then a solution of above aldehyde (90 mg) in THF (2 mL)
was added dropwise at −78 C. The mixture was stirred at
−78 C for 2 h and then quenched with sat. aq. NH4Cl solu-
tion. The solution was extracted with EtOAc (3  10 mL).
The combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The residue was purified by
(c 1.0, CHCl3); IR (CHCl3): νmax = 2959, 2932, 2856, 1780,
1462, 1428, 1363, 1203, 1159, 1112, 1078, 1028, 936, 897,
822, 741, 702, 612, 506 cm-1;1H NMR (500 MHz, CDCl3): δ =
7.63–7.60 (m, 4H), 7.48–7.24 (m, 11H), 4.58–4.51 (m, 2H),
4.50–4.45 (m, 2H), 3.65 (dd, J = 7.4, 4.6 Hz, 2H), 2.40 (dd, J =
17.5, 5.1 Hz, 1H), 2.37 (dd, J = 17.5, 2.0 Hz, 1H), 2.22−2.15
(m, 1H), 2.07–2.01 (m, 1H), 1.07 (s, 9H); 13C{1H} NMR (125
MHz, CHCl3): δ = 175.2, 138.1, 135.8, 135.7, 133.0, 132.4,
130.2, 128.4, 128.0, 127.95, 127.8, 127.7, 81.8, 73.3, 70.9,
66.5, 39.1, 29.8, 26.9, 19.3 ppm; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C29H34O4SiNa 497.2119; Found 497.2116.
HPLC: CHIRALCEL AD-H column, hexane/i-PrOH = 95:5,
flow rate = 1.0 mL/min, tR = 7.55 min (major) and 9.45 min
(minor), 99% ee.
(4S,5S)–5-(2-Benzyloxyethyl)-4-(tert-butyldimethylsi-
lyloxy)dihydrofuran-2(3H)-one (4). To a stirred solution of
alcohol 8 (750 mg, 3.174 mmol) in CH2Cl2 (15 mL) at 0 C
was added imadazole (432 mg, 6.35 mmol, 2.0 equiv) and
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.
silica gel column chromatography using petroleum
mL) cooled at 0 C was added K2OsO4 2H2O (3.3 mg, 0.00893
mmol, 0.6 mol%) followed by methane sulfonamide (137.7
mg, 1.448 mmol, 1.0 equiv). After stirring for 5 min at 0 C,
the olefin 12 (0.2 g, 1.448 mmol) was added in one portion.
The reaction mixture was stirred at 0 C for 24 h and then
quenched with solid Na2SO3 (1.0 g) with stirring continued
for an additional 45 min. The solution was extracted with
EtOAc (2  30 mL). The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated. The
residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (3:2) as eluent to give methyl
(2R,3S)-2,3-dihydroxyhept-6-ynoate 15 (23.4 mg, 9.4%) as
colorless oil. Further elution provided the lactone 13 (152.2
1
2
3
4
5
6
7
8
ether/EtOAc (4:1) as eluent to give the alkyne 3 (52.8 mg,
25
54%) as yellow solid, M.p. 55−58 C, [α]D +4.1 (c 1.0,
CHCl3); IR (CHCl3): νmax= 3302, 2930, 2253, 1781, 1620,
1
1416, 1350, 1193, 1159, 1031, 987, 911, 736, 649 cm-1; H
NMR (500 MHz, CDCl3): δ = 4.55 (dt, J = 8.6, 4.8 Hz, 1H),
4.50−4.46 (m, 1H), 2.75−2.68 (m, 3H), 2.47 (dd, J = 17.3, 1.0
Hz, 1H), 2.0 (t, J = 2.6 Hz, 1H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10
(s, 3H) ppm; 13C{1H} NMR (125 MHz, CHCl3): δ = 174.7, 82.4,
78.9, 70.7, 68.6, 39.6, 25.6, 18.6, 17.9, –4.7 −5.2 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C13H22O3Si Na 277.1230;
Found 277.1231.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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5-Bromopenta-2,4-diyn-1-ol (2). The titled compound 2
was prepared from propargyl alcohol 11 in a two-step se-
quence following our earlier report.11 1H NMR (400 MHz,
CDCl3): δ = 4.32 (s, 2H), 1.86 (br s, 1H, OH) ppm; 13C {1H}
NMR (100 MHz, CDCl3): δ = 73.1, 70.7, 64.7, 51.3, 41.8 ppm.
mg, 75%) as colorless oil.
25
Data for 15: [α]D ‒8.8 (c 1.0, CHCl3); IR (CHCl3): νmax
=
3488, 3308, 3016, 2955, 2935, 2861, 2332, 2115, 1741,
1439, 1395, 1283, 1246, 1120, 1061, 988, 926, 810, 671,
638 cm-1; 1H NMR (400 MHz, CDCl3): 4.12 (d, J = 2.0 Hz, 1H),
4.10‒4.06 (m, 1H), 3.84 (s, 3H), 2.37 (td, J = 7.4, 2.6 Hz, 2H),
1.99 (t, J = 2.6 Hz, 1H), 1.92–1.71 (m, 2H); 13C{1H} NMR(100
MHz, CHCl3): δ =173.7, 83.4, 73.2, 71.1, 69.1, 52.9, 32.2, 14.9
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C8H12O4Na
(4S,5S)-4,8-Dihydroxy-3,4-dihydrovernoniyne (1b). The ti-
tled compound was prepared from 3 and 2 following our
earlier report11 in overall 69% yield over two steps as a pale
25
yellow solid, M.p. 107−108 °C; [α]D ‒14.8 (c 0.78, EtOH),
195.0628; Found 195.0623
lit.11 M.p. 106−109 °C; [α]D25 ‒17.6 (c 0.83, EtOH), lit.10 M.p.
25
Data for 13: [α]D –10.5 (c 1.0, CHCl3); IR (CHCl3): νmax
=
25
108−110 °C; [α]D ‒61.5 (c 0.94, EtOH). Spectral data is
3433, 3303, 2929, 2253, 2123, 1783, 1626, 1416, 1350,
1293, 1200, 1158, 1097, 1074, 1031, 987, 958, 911, 816,
736, 649, 557 cm-1; 1H NMR (500 MHz, CDCl3): δ = 4.65 (t, J
= 4.3 Hz, 1H), 4.53 (dt, J = 6.0, 3.8 Hz, 1H), 2.83−2.76 (m, 2H),
2.75−2.71 (m, 1H), 2.64 (s, 1H), 2.60 (d, J = 17.8 Hz, 1H), 2.08
(t, J = 2.6 Hz, 1H) ppm; 13C{1H} NMR (125 MHz, CHCl3): δ =
175.3, 81.7, 78.4, 71.3, 68.0, 38.6, 18.6 ppm; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C7H8O3Na 163.0366; Found
163.0361. The enantiomeric excess of 13 was determined
by converting it into its OTBDPS ether 13 using TBDPS-Cl
and by following a similar procedure as described for com-
pound 4. Reaction of 13 (20 mg, 0.142 mmol) using TBDPS-
same as reported earlier.11
Methyl (E)-hept-3-en-6-ynoate (12). To a solution of DMSO
(1.3 mL, 17.83 mmol, 3.0 equiv) in CH2Cl2 (40 mL) at −78 C
under argon was added oxalyl chloride (0.76 mL, 8.91
mmol, 1.5 equiv) dropwise. The resulting solution was
stirred at −78 °C for 20 min and then a solution of alcohol
14 (0.5 g, 5.94 mmol) in CH2Cl2 (5 mL) was added slowly,
and the reaction mixture was stirred at −78 °C for 1 h. Et3N
(3.7 mL, 26.8 mmol) was then added, and the reaction mix-
ture was maintained at −78 °C for 10 min before being
warmed to room temperature and stirred for 30 min. The
reaction was then quenched with water (100 mL), and the
phases were separated. The organic layer was washed se-
quentially with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL),
brine (20 mL), and then dried (Na2SO4) and concentrated to
give the crude aldehyde (0.5 g), which was used for next
step without purification. To the aldehyde (0.5 g) was added
mono methyl malonate 7 (0.701 g, 5.94 mmol, 1.0 equiv)
followed by Et3N (0.83 mL, 5.94 mmol, 1.0 equiv). The reac-
tion mixture was refluxed for 18 h. It was then cooled and
concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1) as elu-
ent to give ester 12 (0.55 g, 67%, ,- v/s ,-unsaturated =
6.8:1) as colorless oil. IR (CHCl3): νmax= 3308, 3018, 2955,
2926, 2897, 2849, 2401, 2121, 1735, 1661, 1523, 1437,
1422, 1391, 1361, 1220, 1168, 1078, 1043, 971, 929, 878,
849, 760, 667, 644, 525 cm-1. 1H NMR (400 MHz, CDCl3): δ =
5.87−5.80 (m, 1H), 5.59−5.52 (m, 1H), 3.68 (s, 3H), 3.07 (dd,
J = 7.1, 1.4 Hz, 2H), 2.96−2.94 (m, 2H), 2.10 (t, J = 2.4 Hz, 1H)
ppm; 13C{1H} NMR (100 MHz, CHCl3): δ = 172.0, 127.7,
123.9, 81.1, 70.4, 50.8, 37.4, 21.6 ppm. Since it is a mixture,
HRMS is not recorded.
Cl (58.9 mg, 0.214 mmol, 1.5 equiv) gave 13 (40 mg, 74%)
25
as colorless oil. [α]D –5.2 (c 1.0, CHCl3); IR (CHCl3): νmax
=
3292, 3073, 2958, 2857, 2253, 2123, 1788, 1643, 1472,
1427, 1345, 1297, 1200, 1151, 1112, 1079, 1038, 978, 934,
1
886, 822, 742, 703, 613, 506 cm-1; H NMR (500 MHz,
CDCl3): δ = 7.69–7.60 (m, 4H), 7.51–7.35 (m, 6H), 4.60 (dd, J
= 6.8, 4.9 Hz, 1H), 4.44 (dd, J = 10.8, 6.5 Hz, 1H), 2.82 (dt, J =
5.3, 2.6 Hz, 2H), 2.42 (dd, J = 17.6, 4.2 Hz, 1H), 2.35 (dd, J =
17.2, 5.5 Hz, 1H), 2.05 (t, J = 2.5 Hz, 1H), 1.09 (s, 9H); 13C{1H}
NMR(125 MHz, CHCl3): δ = 174.4, 135.8, 135.7, 132.9, 132.0,
130.3, 130.2, 128.0, 127.9, 82.0, 79.1, 71.0, 69.8, 38.5, 26.8,
19.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C23H26O3SiNa 401.1543; Found 401.1540. HPLC 13:
CHIRALCEL AD-H column, hexane/i-PrOH = 98:2, flow rate
= 0.8 mL/min, tR = 13.21 min (major) and 15.24 min (mi-
nor), 93% ee.
(4R,5R)-4-Hydroxy-5-(prop-2-yn-1-yl)dihydrofuran-2(3H)-
one (ent-13)16 and Methyl (2S,3R)-2,3-dihydroxyhept-6-yno-
ate (ent-15). The titled compounds were obtained from 12
(0.150 g, 1.09 mmol) using (DHQD)2-PHAL ligand and
following a similar procedure as described for 13, to give
methyl (2S,3R)-2,3-dihydroxyhept-6-ynoate ent-15 (18 mg,
9.6%) and the alkyne lactone ent-13 (116 mg, 76%) as col-
orless oils, respectively.
(4S,5S)-4-Hydroxy-5-(prop-2-yn-1-yl)dihydrofuran-2(3H)-
one (13)16 and Methyl (2R,3S)-2,3-dihydroxyhept-6-ynoate
(15). To a mixture of K3Fe(CN)6 (1.43 g, 4.34 mmol, 3.0
equiv), K2CO3 (600 mg, 4.34 mmol, 3.0 equiv), (DHQ)2-PHAL
(11.2 mg, 0.0144 mmol, 1.0 mol%) in t-BuOH-H2O (1:1, 20
25
Data for ent-15: [α]D +9.3 (c 1.0, CHCl3). Other spectral
data is same as 15.
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Data for ent-13: [α]D +12.4 (c 1.0, CHCl3). Other spectral
data is same as 13. The enantiomeric excess of ent-13 was
determined by converting it into its OTBDPS ether ent-13
using TBDPS-Cl and by following a similar procedure as de-
scribed for compound 4. Reaction of ent-13 (25 mg, 0.178
mmol) using TBDPS-Cl (73.5 mg, 0.267 mmol, 1.5 equiv)
1
2
3
4
5
6
7
8
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank SERB New Delhi, Grant No. EMR/2017/000499 for
financial support. G.V.R. thanks CSIR New Delhi for senior re-
search fellowship.
25
gave ent-13 (49.5 mg, 75%) as colorless oil. [α]D +5.8 (c
1.0, CHCl3). Other spectral data is same as 13. HPLC ent-13:
CHIRALCEL AD-H column, hexane/i-PrOH = 98:2, flow rate
= 0.8 mL/min, tR = 12.99 min (minor) and 15.14 min (ma-
jor), 94% ee.
REFERENCES
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bility Liposomes from Macrocyclic Diyne Phospholipids.
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2. (a) Ross, C.; Scherlach, K.; Kloss, F.; Hertweck, C. The Mo-
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W. Polyacetylenes of Marine Origin: Chemistry and Bio-
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Waksmundzka-Hajnos, M.; Sherma, J.; Kowalska, T.,
Eds.; CRC Press: Boca Raton, FL, 2008.
4. (a) Glaser, C. Beiträge zur Kenntniss des Acetenylben-
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C. Untersuchungen über einige Derivate der Zim-
mtsäure. Ann. Chem. Pharm. 1870, 154, 137–171. (c)
Hay, A. S. Oxidative Coupling of Acetylenes. J. Org. Chem.
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of Acetylenes II. J. Org. Chem. 1962, 27, 3320–3321. (e)
Siemsen, P.; Livingston, R. C.; Diederich, F. Acetylenic
Coupling: A Powerful Tool in Molecular Construction.
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11
12
13
14
15
16
17
18
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20
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22
23
24
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26
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32
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49
50
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58
59
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(4S,5S)-4,8-Dihydroxy-3,4-dihydrovernoniyne (1b). To the
flask containing CuCl (3.5 mg, 0.0356 mmol, 10 mol%) was
added a 30% aq. solution of n-BuNH2 (1.2 mL) at room tem-
perature under nitrogen to form a blue color solution. A few
crystals of hydroxylamine hydrochloride were added to dis-
charge the blue color. To this solution, was added alkyne 13
(50 mg, 0.356 mmol) in CH2Cl2 (1 mL) at 0 C to result in the
formation of a yellow acetylide suspension that was imme-
diately cooled with an ice-water mixture. To this reaction
mixture, bromodiyne 2 (85 mg, 0.534 mmol, 1.5 equiv) was
added at once. More crystals of hydroxylamine hydrochlo-
ride were added throughout the reaction as necessary to
prevent the solution from turning blue or green. The reac-
tion mixture was stirred at 0 C for 1.5 h and then extracted
with CH2Cl2 (4 × 20 mL). The combined organic layers were
dried (Na2SO4) and concentrated. The crude product was
purified by silica gel column chromatography using petro-
leum ether/EtOAc (1:1) as eluent to afford 1b (63.7 mg,
25
82%) as a pale yellow solid, M.p. 107−109 °C; [α]D ‒14.6
25
(c 0.73, EtOH), lit.11 M.p. 106−109 °C; [α]D ‒17.6 (c 0.83,
EtOH); lit.10 M.p. 108−110 °C; [α]D25 ‒61.5 (c 0.94, EtOH); IR
(CHCl3): νmax= 3416, 3024, 2928, 2858, 2220, 1774, 1453,
1
1407, 1350, 1152, 1104, 1021, 924, 901, 809, 667 cm-1; H
NMR (500 MHz, Acetone‒d6): δ = 4.85 (d, J = 4.4 Hz, 1H),
4.64 (ddd, J = 7.6, 6.0, 3.8 Hz, 1H), 4.61‒4.59 (m, 1H), 4.54
(t, J = 6.1 Hz, 1H), 4.31 (d, J = 6.0 Hz, 2H), 2.93 (dd, J = 17.4,
5.3 Hz, 1H), 2.89−2.81 (m, 2H), 2.42 (dd, J = 17.4, 1.1 Hz, 1H)
ppm; 13C{1H} NMR (125 MHz, Acetone‒d6): δ = 175.5, 82.2,
78.9, 78.0, 69.2, 68.6, 66.8, 63.5, 60.5, 51.0, 39.8, 20.4 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H11O4 219.0652;
Found 219.0659.
(4R,5R)-4,8-Dihydroxy-3,4-dihydrovernoniyne
(ent-1b).
The titled compound was prepared from ent-13 (40 mg,
0.285 mmol) by a similar procedure as described for 1b, to
give ent-1b (50.4 mg, 81%) as pale yellow solid, M.p.
105−107 °C, [α]D25 +15.1 (c 0.75, EtOH). Other spectral data
is same as its enantiomer 1b.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: rfernand@chem.iitb.ac.in
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Synthesis of Acetylenes: Catalytic Substitutions of Acet-
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Bromopyridines. Tetrahedron Lett. 1975, 16,
ORCID
Rodney A. Fernandes: 0000-0001-8888-0927
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The Journal of Organic Chemistry
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