Stereoselective total synthesis of (+)-hyptolide

Article abstract of DOI:10.1039/c3ra45042b

Stereoselective synthesis of the naturally occurring 6-membered lactone hyptolide 1 is described. The main feature of the synthesis is the utility of the hitherto unexplored alkyne fragment derived from commercially available 3-butyn-1-ol (homopropargylic alcohol).

Full text of DOI:10.1039/c3ra45042b

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Stereoselective total synthesis of (+)-hyptolide†
*
Gowravaram Sabitha, A. Raju, C. Nagendra Reddy and J. S. Yadav
Cite this: RSC Adv., 2014, 4, 1496
Stereoselective synthesis of the naturally occurring 6-membered lactone hyptolide 1 is described. The main
feature of the synthesis is the utility of the hitherto unexplored alkyne fragment derived from commercially
available 3-butyn-1-ol (homopropargylic alcohol).
Received 12th September 2013
Accepted 4th November 2013
DOI: 10.1039/c3ra45042b
www.rsc.org/advances
the synthesis of hyptolide. In the present communication, we
disclose the stereoselective total synthesis of (+)-hyptolide from
commercially available 3-butyn-1-ol.
Retrosynthetic analysis (Scheme 1) reveals that compound
1 could be synthesized from homoallylic alcohol 6 by acryl-
oylation followed by a RCM reaction and semihydrogenation
of the triple bond. The compound 6 in turn can be synthe-
sized from 7 and 8 by a coupling reaction. Whereas, the
aldehyde 7 and alkyne 8 intermediates could be derived from
3-butyn-1-ol.
Introduction
In 1920, Gorter1 reported the isolation of a crystalline lactone,
(+)-hyptolide 1, from leaves of Hyptis pectinata, a plant that is
used in folk medicine. Various biological effects were found
with its extracts, such as: analgesic, anti-inammatory, and
anti-microbial. The structure proposed was proved wrong when
hyptolide was subjected to reinvestigation by Birch and Butler2
in 1964. Later, the absolute conguration was established by
Anders Kjaer et al.3 by detailed H and 13C NMR spectroscopic
1
studies and on the basis of single-crystal X-ray diffraction
data
as
6R-(1Z,3S,5R,6S)-5,6-dihydro-6-[3,5,6-tris(acetoxy)-
Results and discussion
1-heptenyl]-2H-pyran-2-one. Hyptolide (1) is structurally similar
to other members of the polyhydroxy d-pyranone natural
product family such as spicigerolide (2),4 synrotolide (3),5
synargentolide A (4),6 anamarine (5)7 (Fig. 1). Earlier, two
syntheses8 were reported for the synthesis of (+)-hyptolide.
While our manuscript was under preparation, a silicon tethered
RCM route for hyptolide was published by Kumar and his co-
workers.9 As part of our continuing interest in the synthesis of
natural products having d-lactone rings,10 we were interested in
Our synthetic endeavor began with the benzyl protected
2,3-epoxy alcohol 9 (Scheme 2) prepared from 3-butyn-1-ol
similarly as reported for the preparation of PMB(para-
methoxybenzyl) protected 2,3-epoxy alcohol.11 We then turned
our attention to the key step for the introduction of benzoate
via nucleophilic epoxide ring opening with benzoic acid,
which culminates in the creation of a C50 chiral center of the
molecule. Thus, regio- and stereoselective ring opening
of ((2S,3S)-3-(2-(benzyloxy)ethyl)oxiran-2-yl)methanol 9 was
Fig. 1 Hyptolide type pyranone polyacetates.
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology
(IICT), Hyderabad 500 007, India. E-mail: gowravaramsr@yahoo.com; sabitha@iict.
res.in; Fax: +91-40-27160512
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all compounds. See DOI: 10.1039/c3ra45042b
Scheme 1 Retrosynthesis.
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Scheme 3 Synthesis of chiral propargylic alcohol 8.
Dess–Martin Periodinane (DMP) gave ynone 19 in 82%
yield (Scheme 4).
Initially, our efforts towards the reduction of 19 to the
corresponding hydroxy compound 21 were not fruitful under
ꢁ
CBS conditions. Use of 1 M solution of BH3$DMS at ꢀ40 C
gave low yields of the reduced product. Whereas, using conc.
BH3$DMS solution either in dry toluene or THF furnished the
alcohol (21) as a diastereomeric mixture in 6 : 4 ratio
Scheme 2 Synthesis of aldehyde 7.
achieved at C-3 with benzoic acid and Ti(OiPr)4 within 1 h in however, the ketone functionality was reduced with Noyori’s
CH2Cl2,12 affording a 75% yield of the benzoate diol 10. The catalyst
Ru[(1S,2S)-p-TsNCH(Ph)CH(Ph)NH](h6-p-cymene)
diol 10 was converted into epoxide 11 in 90% yield by following (20)15 in HCOOH affording 21 in 90% yield and 95% de.16
the Forsyth protocol.13 Lithium aluminium hydride reduction Then, we tried to minimize the use of protecting groups by
of epoxide 11 delivered terminal methyl compound 12. The maintaining the oxygenated functional groups as acetates.
diol 12 having anti-conguration was protected as an aceto- Thus, hydrolytic cleavage of acetonide protecting group in 21
nide 13 followed by removal of benzyl group resulted in leading to a triol, which was acetylated in situ with acetic
primary alcohol 14. Swern oxidation of 14 led to the formation anhydride in the presence of NEt3 and DMAP to form the tri-
of aldehyde 7.
acetate 22 in 90% yield for the two steps. The alcohol 22 was
The synthesis of hitherto unexplored alkyne fragment 8 transformed into its acrylic ester 23 in 80% yield by treating
began by converting commercially available 3-butyn-1-ol with acryloyl chloride, catalytic amounts of DMAP and tri-
(homopropargylic alcohol) to the known PMB protected chiral ethylamine in CH2Cl2. Ring closing metathesis17 reaction of
propargylic alcohol 15 following
a reported procedure 23 in reuxing DCM for 24 h using 10 mol% rst generation
(Scheme 3).10g,14a–c The free secondary hydroxyl group of the Grubbs’ catalyst, bis(tricyclohexylphosphine)benzylidene
latter was protected as silyl ether 16 and DDQ-mediated ruthenium(IV) dichloride produced the lactone 24 in
oxidative cleavage of the PMB (para-methoxybenzyl) ether 80% yield.
produced primary alcohol 17. Swern oxidation of alcohol
afforded aldehyde followed by one-carbon Wittig olenation using Lindlar’s catalyst in EtOAc would provide hyptolide.
(n-BuLi, CH3PPh3+Iꢀ, dry THF) to furnish key intermediate 8.
However, this reaction was base as well as time sensitive, maybe
We envisioned that partial hydrogenation of the triple bond
At this point, we were set to couple the appropriate it is attributed for the presence of three OAc groups. Hydroge-
fragments to generate the carbon frame work of hyptolide. nation using Pd/BaSO4 for 10 min resulted in fully saturated
Formation of the chiral propargyl alcohol 21 was envisioned by compound by reduction of triple bond and lactone double
lithiated alkyne 8 coupling to the aldehyde 7 followed by bond. Use of Pd/CaCO3 in 10 min also resulted in partial
adopting an oxidation/selective reduction protocol. Alkyne 8 hydrogenation of the triple bond to the Z-olen of along with
on reaction with n-BuLi followed by coupling of the generated reduction of the lactone double bond. However, reducing the
lithium acetylide with aldehyde 7 afforded a mixture of time to 3 min in the presence of Pd/CaCO3 provided the target
propargylic alcohols 18 (65%), which on oxidation with lactone, (+)-hyptolide (1) by achieving the partial hydrogenation
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Experimental section
All the solvents and reagents were puried by standard tech-
niques, reactions were performed in oven-dried round bottom
asks; crude products were puried by column chromatography
on silica gel (60–120 mesh). Thin layer chromatography plates
were visualized by exposure to ultraviolet light and/or by expo-
sure to an methanolic acidic solution of p-anisaldehyde on a hot
plate (ꢂ250 ꢁC). Organic solutions were concentrated on rotary
evaporator at 40–45 ꢁC. IR spectra were recorded on Perkin–
1
Elmer 683, Thermo Nicolet Nexus 670 spectrometer. H NMR
and 13C NMR spectra were recorded in CDCl3 solvent on a
Varian Gemini 200, Bruker AV-300 and Varian Innova 500 NMR
spectrometer. Chemical shis were reported in parts per
million (ppm) with respect to internal TMS. Coupling constants
(J) are quoted in Hertz (Hz). s, br s, d, dd, ddd, dt, t, q, qt and m
refer to singlet, broad singlet, doublet, doublet of doublet,
doublet of doublet of doublet, triplet, quartet, quintet and
multiplet, respectively. The optical rotations were measured on
a Perkin Elmer-343 polarimeter. The diastereomeric excess of
the products were measured by HPLC using Shimadzu LC-20AT
series with XDB C18, 150 ꢃ 4.6, 5U column. Mass spectra were
recorded on Micromass VG-7070H mass spectrometer for ESI
and EI are given in mass-to-charge (m/z). High-resolution mass
spectra (HRMS) [ESI] were obtained using either a TOF or a
double focusing spectrometer.
(2S,3R)-5-(Benzyloxy)-1,2-dihydroxypentan-3-yl benzoate (10)
To a stirred solution of epoxy alcohol 9 (7 g, 33.65 mmol) in dry
CH2Cl2 (35 mL) containing benzoic acid nuleophile (4.51 g,
37.09 mmol), Ti(O-i-Pr)4 (15.0 mL, 50.52 mmol) was added at
room temperature. The mixture was stirred for 1 h at the same
temperature. Aer completion of the reaction, as determined by
TLC, the reaction mixture was cooled to 0 ꢁC and quenched with
dropwise addition of saturated aqueous NaHCO3 (20 mL). The
resulting milky solution was stirred vigorously for 10 h and then
ltered through a pad of Celite (CH2Cl2 rinse) and extracted
with ethyl acetate (4 ꢃ 50 mL). The combined organic extracts
were dried over Na2SO4 and concentrated under reduced pres-
sure and the crude product was puried by silica gel column
chromatography (4 : 6, EtOAc–hexane) to afford 10 (8.32 g,
Scheme 4 Synthesis of hyptolide 1.
25
25.24 mmol, 75%) as a viscous liquid. [a]D ¼ +7.4 (c 1.1,
CHCl3); IR (KBr): 3420, 2867, 1715, 1275, 1112, 1070, 713 cmꢀ1
;
of the triple bond to the Z-olen in 90% yield. The synthetic
(+)-hyptolide (1) spectroscopic data was identical to that of the
natural product.
Overall yields 7.14%, 15.34% and 20.27% reported respec-
tively by Marco & Carda et al.,8a Chakraborty et al.8c and Kumar
et al.9 for previous synthetic routes.
1H NMR (500 MHz, CDCl3):d 8.01–7.98 (m, 2H), 7.60–7.56 (m,
1H), 7.46–7.41 (m, 2H), 7.37–7.22 (m, 5H), 5.24–5.20 (m, 1H),
4.51 (ABq, J ¼ 17.5, 11.7 Hz, 2H), 3.85–3.80 (m, 1H), 3.74–
3.63 (m, 2H), 3.62–3.56 (m, 2H), 2.64 (br s, 1H), 2.27–2.19 (m,
1H), 2.17–2.08 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 166.4,
137.5, 133.2, 129.6, 128.3, 127.7, 73.2, 72.6, 7 2.2, 66.0, 62.8,
30.9; HRMS (ESI) for C19H22O5Na [M + Na]+ found 353.13594,
calcd 353.13531.
Conclusion
We have successfully completed the total synthesis of
(+)-hyptolide from 3-butyn-1-ol with an overall yield of
(R)-3-(Benzyloxy)-1-((S)-oxiran-2-yl)propyl benzoate (11)
7.08% relying on regioselective epoxide opening, sharpless To a stirred solution of 60% sodium hydride dispersion in
asymmetric epoxidation, aldehyde alkyne coupling and ring- mineral oil (1.45 g, 60.41 mmol) in THF (17 mL) was added the
closing metathesis reactions as key steps.
diol 10 (8.0 g, 24.24 mmol) followed by tosyl-imidazole (10.76 g,
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ꢁ
48.46 mmol), and the mixture was stirred for 1 h at 0 C. Aer
completion of reaction, water was added and extracted with
EtOAc (3 ꢃ 50 mL). The combined organic fraction was dried
over anhydrous Na2SO4, and solvent was removed under
reduced pressure. The residue was puried on silica gel column
chromatography (3 : 7 EtOAc–hexane) to afford the epoxide 11
2-((4R,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-Yl)ethanol (14)
To a stirred solution of naphthalene (13.82 g, 107.96 mmol) in
THF (30 mL) were added lithium granules (0.88 g, 125.71 mmol)
at room temperature, and the solution was allowed to stir at
room temperature for 45 min to generate Li naphthalenide. To
the resulting dark green solution was added benzyl ether 13
(4.5 g, 18.0 mmol) at ꢀ10 ꢁC, and the mixture was allowed to stir
at the same temperature for 1 h, quenched with aqueous NH4Cl,
extracted into EtOAc (3 ꢃ 50 mL), dried over Na2SO4, concen-
trated, and puried on silica gel (3 : 7 EtOAc–hexane) to give
alcohol 14 (2.3 g, 14.37 mmol, 81%) as a colorless liquid.
25
(6.8 g, 21.8 mmol, 90%) as colorless oil. [a]D ¼ +14.8 (c 1.0,
CHCl3); IR (KBr): 1721, 1269, 1107, 711 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d 8.03–7.99 (m, 2H); 7.59–7.54 (m, 1H); 7.46–
7.41 (m, 2H); 7.34–7.20 (m, 5H); 5.21 (td, J ¼ 8.0, 4.8 Hz, 1H),
4.48 (ABq, DdAB ¼ 0.02, JAB ¼ 11.9 Hz, 2H), 3.67–3.58 (m, 2H);
3.18–3.15 (m, 1H); 2.83 (dd, J ¼ 5.0 Hz, 1H); 2.79 (dd, J ¼ 5.0 Hz,
1H); 2.18–2.07 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 165.5,
137.9, 132.9, 129.5, 128.2, 128.1, 127.5, 127.4, 72.9, 70.8, 65.7,
52.3, 45.4, 31.2; HRMS (ESI) for C19H20O4Na [M + Na]+ found
335.12538, calcd 335.12476.
25
[a]D ¼ +25.5 (c 0.6, CHCl3); IR (KBr): 3423, 2984, 1376, 1246,
1
1218, 1085, 1058, 1005, 853 cmꢀ1; H NMR (300 MHz, CDCl3):
d 4.35–4.21 (m, 2H), 3.87–3.79 (m, 2H), 2.49 (br s, 1H), 1.85–1.71
(m, 1H), 1.65–1.54 (m, 1H), 1.47 (s, 3H), 1.19 (d, J ¼ 6.0 HZ, 3H);
13C NMR (CDCl3, 75 MHz): d 107.6, 76.5, 73.5, 60.5, 32.0, 28.2,
25.6, 15.2; HRMS (ESI) for C8H16O3Na [M + Na]+ found 183.0995,
calcd 183.0992.
(2S,3R)-5-(Benzyloxy)pentane-2,3-diol (12)
To a stirred suspension of LiAlH4 (2.41 g, 63.42 mmol) in
anhydrous THF (15 mL) at 0 ꢁC was added dropwise a solution
of terminal epoxide 11 (6.6 g, 21.15 mmol) in anhydrous THF
(30 mL). The reaction mixture was allowed to warm to 25 ꢁC and
2-((4R,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)acetaldehyde (7)
To a stirred solution of oxalyl chloride (2.33 mL, 27.55 mmol)
in dry CH2Cl2 (15 mL) at ꢀ78 ꢁC, dry DMSO (3.9 mL,
55.0 mmol) was added dropwise. Aer 30 min, alcohol 14
(2.2 g, 13.75 mmol) in CH2Cl2 (20 mL) was added over 10 min
giving a copious white precipitate. Aer stirring for 2 h at
ꢁ
stirred for 3 h. Reaction mixture was then cooled to 0 C and
quenched with dropwise addition of saturated aqueous Na2SO4
(20 mL). The precipitate formed was ltered and washed with
ethyl acetate. The combined organic extracts were dried over
Na2SO4 and concentrated under reduced pressure and the crude
product was puried by silica gel column chromatography
(4 : 6, EtOAc–hexane) to afford 12 (4.12 g, 19.62 mmol, 93%) as a
ꢁ
ꢀ78 C, Et3N (10.97 mL, 82.42 mmol) was added slowly and
stirred for 30 min allowing the reaction mixture to warm to rt.
The reaction mixture was then diluted with water (20 mL) and
expected with CH2Cl2 (3 ꢃ 50 mL). The combined organic
layer was washed with water (15 mL), brine (10 mL), dried over
Na2SO4, and concentrated in vacuo to afford the aldehyde 7,
which was directly used for further reaction without
purication.
25
viscous liquid. [a]D ¼ ꢀ8.2 (c 0.8, CHCl3); IR (KBr): 3417, 2867,
1
1367, 1075, 741, 698 cmꢀ1; H NMR (500 MHz, CDCl3): d 7.39–
7.28 (m, 5H), 4.54 (s, 2H), 3.83–3.73 (m, 2H), 3.72–3.66 (m, 2H),
3.29 (br s, 1H), 1.90–1.80 (m, 1H), 1.77–1.70 (m, 1H), 1.16 (d, J ¼
6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 137.6, 128.4, 127.7,
127.6, 74.5, 73.2, 69.9, 68.8, 30.5, 17.4; HRMS (ESI) for
C
12H18O3Na [M + Na]+ found 233.11482, calcd 233.11458.
(R)-tert-Butyl(5-(4-methoxybenzyloxy)pent-1-yn-3-yloxy)
diphenylsilane (16)
(4R,5S)-4-(2-(Benzyloxy)ethyl)-2,2,5-trimethyl-1,3-dioxolane
(13)
Imidazole (3.7 g, 54.41 mmol), and TBDPSCl (7.5 ml,
27.27 mmol) were added to a stirred solution of compound 15
2,2-Dimethoxypropane (3.96 mL, 38.07 mmol) and catalytic (6.0 g, 27.2 mmol) in CH2Cl2 (35 mL) at 0 ꢁC. Stirring was
PTSA (0.4 g, 2.32 mmol) were added successively to a solution of continued for 10 h and then the mixture was diluted with
diol 12 (4 g, 19.04 mmol) in a mixture of CH2Cl2 : Me2CO (1 : 1) CH2Cl2 (20 mL). Evaporation of the solvent under reduced
(40 mL). The solution was stirred for 10 h at room temperature pressure followed by column chromatography (1 : 9, EtOAc–
and then quenched with solid NaHCO3. The crude compound hexane) afforded the silyl ether 16 (11.87 g, 25.91 mmol, 95%) as
25
was concentrated in vacuo and puried by column chromatog- a colorless liquid. [a]D ¼ +11.8 (c 0.7, CHCl3); IR (KBr): 2931,
1
raphy (1 : 9, EtOAc–hexane) to afford the acetonide product 13 2857, 1512, 1246, 1108, 702 cmꢀ1; H NMR (500 MHz, CDCl3):
25
(4.52 g, 18.08 mmol, 90%) as a colorless liquid. [a]D ¼ +30.5 d 7.75–7.65 (m, 4H), 7.44–7.33 (m, 6H), 7.15 (d, J ¼ 8.6 HZ, 2H),
(c 1.0, CHCl3); IR (KBr): 2983, 1374, 1217, 1089, 771, 739 cmꢀ1
;
6.84 (d, J ¼ 8.6 HZ, 2H), 4.5679 (td, J ¼ 6.4, 1.9 Hz, 1H), 4.30 (s,
1H NMR (500 MHz, CDCl3): d 7.35–7.25 (m, 5H), 4.52 (ABq, J ¼ 2H), 3.80 (s, 3H), 3.63–3.55 (m, 2H), 2.28 (d, J ¼ 2.1 HZ, 1H),
16.1, 11.9 Hz, 2H), 4.29–4.19 (m, 2H), 3.67–3.58 (m, 2H), 1.82– 2.07–1.94 (m, 2H), 1.07 (s, 9H); 13C NMR (CDCl3, 125 MHz):
1.72 (m, 2H), 1.44 (s, 3H), 1.33 (s, 3H), 1.15 (d, J ¼ 6.4 Hz, 3H); d 159.0, 136.0, 135.8, 134.7, 129.7, 129.6, 129.5, 129.1, 127.6,
13C NMR (CDCl3, 125 MHz): d 138.2, 128.0, 127.3, 127.2, 74.7, 127.5, 127.3, 113.6, 84.5, 72.9, 72.4, 65.9, 61.0, 55.2, 38.4, 26.8,
73.3, 72.8, 67.1, 30.1, 28.3, 25.6, 15.3; HRMS (ESI) for 19.2; HRMS (ESI) for C29H34O3NaSi [M + Na]+ found 481.21694,
C
15H22O3Na [M + Na]+ found 273.14612, calcd 273.14540.
calcd 481.21619.
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(R)-3-(tert-Butyldiphenylsilyloxy)pent-4-yn-1-ol (17)
(R)-5-(tert-Butyldiphenylsilyloxy)-1-((4R,5S)-2,2,5-trimethyl-
1,3-dioxolan-4-yl)oct-7-en-3-yn-2-one (19)
Compound 16 (11.89 g, 25.76 mmol) was taken in 30 mL of
CH2Cl2 : pH 7 buffer (9 : 1), DDQ (6.43 g, 28.32 mmol) was To a stirred solution of alkyne 8 (2 g, 5.98 mmol) in dry THF
added to it, and the solution was stirred for 2 h at room (20 mL) was slowly added n-BuLi (2.0 M, 4.5 mL, 8.98 mmol,
ꢁ
temperature. The reaction mixture was ltered off and the solution in hexanes) at ꢀ20 C under N2. The reaction mixture
ltrate was washed with 5% NaHCO3 solution (30 mL) and brine was stirred for 30 min at ꢀ78 ꢁC, and a solution of compound 7
(30 mL), dried over anhydrous Na2SO4. The solvent was removed (1.13 g, 7.15 mmol) in dry THF (15 mL) was added dropwise with
under reduced pressure and puried by silica gel column stirring. The mixture was kept at ꢀ40 ꢁC for 2 h and then
chromatography (2 : 8, EtOAc–hexane) to afford 17 as a light allowed to warm to rt for 2 h. The reaction was quenched with
25
yellow colored liquid (7.04 g, 20.82 mmol, 81%). [a]D ¼ +33.8 saturated aqueous NH4Cl solution, and extracted with EtOAc,
(c 0.6, CHCl3); IR (KBr): 3301, 2957, 2933, 2859, 1108, 1050, dried over anhydrous Na2SO4, and concentrated under reduced
703 cmꢀ1; 1H NMR (500 MHz, CDCl3): d 7.75 (dt, J ¼ 6.7, 1.3 Hz, pressure. The crude product was puried by silica gel column
2H), 7.70 (dt, J ¼ 6.5, 1.3 Hz, 2H), 7.44 (dt, J ¼ 7.4, 2.4 Hz, 2H), chromatography (hexane–EtOAc ¼ 75 : 25) to afforded alcohol
7.41–7.37 (m, 4H), 4.59 (td, J ¼ 5.3, 2.1 Hz, 1H), 3.96–3.88 (m, 18 as a 1 : 1 mixture of diastereomers (determined by chiral
1H), 3.81–3.74 (m, 1H), 2.36 (d, J ¼ 2.1 Hz, 1H), 2.02–1.96 (m, HPLC analysis) in approximately 65% yield.
1H), 1.89–1.82 (m, 1H), 1.09 (s, 9H); 13C NMR (CDCl3, 125 MHz):
To the above obtained alcohol 18 (1.8 g, 3.65 mmol) in 20 mL
d 135.9, 135.6, 129.8, 129.7, 127.6, 127.3, 83.9, 73.6, 62.0, 59.1, of dry CH2Cl2, Dess–Martin periodinate (2.32 g, 5.46 mmol) and
39.9, 26.7, 19.1; HRMS (ESI) for C21H26O2NaSi [M + Na]+ found NaHCO3 (0.92 g, 10.95 mmol) were added at 0 ꢁC and stirred for
361,15943 calcd 361.15887.
2 h. Aer completion of the reaction, the reaction was quenched
with aqueous sodium thiosulfate solution (6 mL) and saturated
aqueous sodium bicarbonate solution (10 mL). The reaction
mixture was extracted with CH2Cl2 (2 ꢃ 20 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
puried by column chromatography (3 : 7, EtOAc–hexane) to
afford 19 (1.46 g, 2.97 mmol, 82%) as a yellow liquid.
(R)-tert-Butyl(hex-5-en-1-yn-3-yloxy)diphenylsilane (8)
To a stirred solution of oxalyl chloride (3.5 mL, 41.41 mmol) in
dry CH2Cl2 (30 mL) at ꢀ78 ꢁC, dry DMSO (5.88 mL, 82.81 mmol)
was added drop wise. Aer 30 min, alcohol 17 (7.0 g,
20.71 mmol) in CH2Cl2 (25 mL) was added over 10 min giving a
copious white precipitate. Aer stirring for 2 h at ꢀ78 ꢁC, Et3N
(16.53 mL, 124.22 mmol) was added slowly and stirred for 30
min allowing the reaction mixture warm to rt. The reaction
mixture was then diluted with water (20 mL) and CH2Cl2 (3 ꢃ
60 mL). The combined organic layer was washed with water
(30 mL), brine (20 mL), dried over Na2SO4, and concentrated in
vacuo to afford the aldehyde, which was directly used as such for
further reaction.
25
[a]D ¼ +50.1 (c 0.5, CHCl3); IR (KBr): 2983, 2924, 2860, 1679,
1109, 1083, 704 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.76–
;
7.65 (m, 4H), 7.46–7.35 (m, 6H), 5.91–5.74 (m, 1H), 5.16–
5.05 (m, 2H), 4.56–4.44 (m, 2H), 4.29 (t, J ¼ 6.0 Hz, 1H),
2.66–2.35 (m, 4H), 1.41 (s, 3H), 1.32 (s, 3H), 1.12–1.03 (m, 12H);
13C NMR (CDCl3, 125 MHz): d 184.2, 135.8, 135.7, 134.4, 130.0,
129.8, 129.5, 118.6, 107.7, 92.8, 83.7, 73.4, 73.0, 63.3, 46.1, 41.9,
28.2, 26.7, 25.6, 19.2, 15.2; HRMS (ESI) for C30H38O4NaSi
[M + Na]+ found 513.24316, calcd 513.24268.
To a stirred suspension of methyltriphenylphosphonium
iodide (13.37 g, 33.09 mmol) in dry THF (35 mL) at ꢀ78 ꢁC,
n-BuLi in hexane (2.0 M, 12.41 mL, 24.82 mmol) was added drop
(2S,5R)-5-(tert-Butyldiphenylsilyloxy)-1-((4R,5S)-2,2,5-
trimethyl-1,3-dioxolan-4-yl)oct-7-en-3-yn-2-ol (21)
wise under an N2 atmosphere and allowed to return to room To a mixture of propargyl ketone 19 (1.0 g, 2.04 mmol) in formic
temperature. Aer 45 min, the reaction mixture was again acid (0.77 mL, 20.21 mmol) and triethylamine (1.13 mL,
cooled toꢀ78 ꢁC and the aldehyde compound (5.56 g, 8.15 mmol) were added at room temperature an aliquant
16.54 mmol) dissolved in dry THF (20 mL) was added dropwise amount of the stock solution of the RuCl[N-(tosyl)-(1,2-diphe-
and stirred for another 45 min. The reaction mixtuꢁre was nylethylenediamine)(p-cymene)] complex 0.0337 M in CH2Cl2
quenched with saturated NH4Cl solution (15 mL) at 0 C and (1.51 mL, 0.051 mmol), prepared according to ref. 15. The
extracted with diethyl ether (2 ꢃ 40 mL). The combined organic reaction mixture was stirred at room temperature for overnight.
extracts were washed with brine (2 ꢃ 20 mL), dried over anhy- The reaction was quenched with saturated aqueous NaHCO3
drous Na2SO4, and concentrated in vacuo. The residue was solution, and extracted with CH2Cl2, dried over anhydrous
puried by column chromatography (1 : 9, EtOAc–hexane) to Na2SO4, and concentrated under reduced pressure. The crude
afford pure compound 8 (3.31 g, 9.91 mmol, 60% over two steps) product was puried by silica gel column chromatography
25
as a pale yellow liquid. [a]D ¼ +16.2 (c 1.0, CHCl3); IR (KBr): (3 : 7, EtOAc–hexane) to afford chiral propargyl alcohol 21 (0.9 g,
1
25
2933, 2858, 1109, 1082, 702 cmꢀ1; H NMR (300 MHz, CDCl3): 1.82 mmol, 90%) as a light yellow colored liquid. [a]D ¼ +54.6
d 7.77–7.66 (m, 4H), 7.48–7.32 (m, 6H), 5.91–5.76 (m, 1H), 5.10– (c 0.9, CHCl3); IR (KBr): 3448, 2933, 2892, 1109, 1081, 705 cmꢀ1
;
5.00 (m, 2H), 4.37 (td, J ¼ 5.2, 2.2 Hz, 1H), 2.50–2.35 (m, 2H), 1H NMR (500 MHz, CDCl3): d 7.77–7.73 (m, 2H), 7.72–7.68 (m,
2.34 (d, J ¼ 1.5, Hz, 1H), 1.08 (s, 9H); 13C NMR (CDCl3, 2H), 7.45–7.34 (m, 6H), 5.91–5.81 (m, 1H), 5.11–5.04 (m, 2H),
125 MHz): d 135.9, 135.8, 133.2, 129.7, 129.6, 127.5, 127.4, 117.9, 4.47 (td, J ¼ 6.1, 1.3 Hz, 1H), 4.42–4.37 (m, 1H), 4.25–4.18 (m,
84.4, 73.0, 63.3, 42.7, 26.8, 19.2; anal. calcd for C22H26OSi: C, 1H), 4.10–4.04 (m, 1H), 2.52–2.38 (m, 2H), 1.83–1.67 (m, 2H),
78.99; H, 7.83%; found: C, 78.60; H, 7.77%.
1.43 (s, 3H), 1.31 (s, 3H), 1.12 (d, J ¼ 6.4 Hz, 3H), 1.06 (s, 9H); 13
C
1500 | RSC Adv., 2014, 4, 1496–1502
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NMR (CDCl3, 125 MHz): d 135.9, 135.7, 133.5, 129.7, 129.5,
127.5, 127.2, 117.7, 107.8, 85.4, 73.4, 76.1, 73.4, 63.5, 61.1, 42.7,
37.6, 28.3, 26.7, 25.6, 19.2, 15.2; HRMS (ESI) for C30H40O4NaSi
[M + Na]+ found 515.25881, calcd 515.25707.
(2S,3R,5S,8R)-8-(Acryloyloxy)undec-10-en-6-yne-2,3,5-triyl
triacetate (23)
Acryloyl chloride (0.058 mL, 0.74 mmol) was added drop wise
under N2 to a solution of alcohol 6 (0.17 g, 0.5 mmol), Et3N
(0.13 mL, 1.0 mmol), and DMAP (5 mg, 0.041 mmol) in anhyd
CH2Cl2 (10 mL). The mixture was stirred at room temperature
for 1 h until the reaction was complete (TLC). The mixture was
then poured into brine and extracted with CH2Cl2 (2 ꢃ 10 mL).
The organic phases were washed with 1 M aq. HCl (5 mL) and
brine (8 mL), dried over Na2SO4, and evaporated under reduced
pressure. The crude product was puried by column chroma-
tography (2 : 8, EtOAc–hexane) to give 23 (0.15 g, 0.38 mmol,
(2S,3R,5S,8R)-8-(tert-Butyldiphenylsilyloxy) undec-10-en-6-
yne-2,3,5-triyl triacetate (22)
To a stirred solution of compound 21 (0.8 g, 1.62 mmol) in a
MeOH (20 mL) and was added PTSA (0.2 g, 1.16 mmol) under
N2, then the mixture was stirred at room temperature for 8 h.
The mixture was quenched with solid NaHCO3 (0.2 g) and
ltered, the solvent was removed under reduced pressure and
the crude triol was directly used for the next step without further
purication.
25
80%) as a light yellow liquid. [a]D ¼ +10.8 (c 0.7, CHCl3); IR
1
(KBr): 2984, 2930, 1733, 1228, 1181, 1083, 1024 cmꢀ1; H NMR
(300 MHz, CDCl3): d 6.47 (dd, J ¼ 30.6, 17.2 Hz, 1H), 6.18–
6.08 (m, 1H), 5.90–5.75 (m, 2H), 5.53–5.43 (m, 2H), 5.19–
5.06 (m, 4H), 2.56 (t, J ¼ 6.5 Hz, 2H), 2.19–2.09 (m, 1H), 2.08
(s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03–1.96 (m, 1H), 1.20 (d, J ¼
6.5 Hz, 3H); 13C NMR (CDCl3,75 MHz): d 170.2, 170.1, 169.5,
164.8, 131.6, 127.8, 118.9, 83.3, 81.9, 71.3, 70.1, 63.0, 61.1, 38.8,
33.9, 21.0, 20.9, 15.2; HRMS (ESI) for C20H26O8Na [M + Na]+
found 417.15199 calcd 417.15074.
Anhydrous Et3N (0.92 mL, 6.63 mmol), Ac2O (0.33 mL,
3.23 mmol), and DMAP (10 mg, 0.082 mmol) were added to a
solution of triol (0.5 g, 1.10 mmol) in anhydrous CH2Cl2 (15 mL)
under nitrogen atmosphere at room temperature. The mixture
was stirred at room temperature for 45 min. The solvent was
removed under reduced pressure, and the mixture was puried
by silica gel column chromatography (2 : 8, EtOAc–hexane) to
afford 22 (0.57 g, 0.98 mmol, 90% over two steps) as a light
25
yellow colored liquid.[a]D ¼ +16.0 (c 0.9, CHCl3); IR (KBr):
1745, 1370, 1228, 1109, 1079, 1023, 702 cm; 1H NMR (500 MHz,
CDCl3): d 7.72 (dd, J ¼ 7.9 Hz, 2H), 7.67 (dd, J ¼ 7.9 Hz, 2H),
7.44–7.35 (m, 6H), 5.86–5.76 (m, 1H), 5.31 (td, J ¼ 5.9, 1.3 Hz,
1H), 5.09–5.02 (m, 4H), 4.39 (td, J ¼ 6.5, 1.2 Hz, 1H), 2.47–
2.35 (m, 2H), 2.03 (s, 3H), 2.02 (s, 3H), 2.0 (s, 3H), 1.28–1.24 (m,
2H), 1.17 (d, J ¼ 6.4 Hz, 3H), 1.06 (s, 9H); 13C NMR (CDCl3,
75 MHz): d 170.1, 169.9, 169.4, 135.9, 135.7, 133.2, 129.7, 129.5,
127.5, 127.3, 117.9, 87.0, 81.1, 71.4, 70.0, 63.3, 61.2, 42.5, 33.9,
26.7, 21.0, 20.8, 19.2, 15.2; HRMS (ESI) for C33H42O7NaSi
[M + Na]+ found 601.25920, calcd 601.25842.
(2S,3R,5S)-7-((R)-6-oxo-3,6-Dihydro-2H-pyran-2-yl)hept-6-yne-
2,3,5-triyl triacetate (24)
Grubbs’ rst-generation catalyst (0.033 g, 0.0415 mmol) was
added to a solution of 23 (0.1 g, 0.25 mmol) in anhyd. CH2Cl2
(25 mL) at 0 ꢁC, and the mixture was allowed to warm to room
temperature over 24 h. Aer completion of the reaction (TLC),
the solvent was removed under reduced pressure and the
residue was puried by column chromatography (5 : 5, EtOAc–
hexane) to give 24 (0.073 g, 0.19 mmol, 80%) as a colorless
25
liquid. [a]D ¼ ꢀ4.0 (c 0.3, CHCl3); IR (KBr): 2924, 2853, 1739,
1374, 1231, 1049, 1025 cmꢀ1; 1H NMR (500 MHz, CDCl3): d 6.90
(dt, J ¼ 9.7, 4.2 Hz, 1H), 6.08 (dt, J ¼ 9.9, 1.8 Hz, 1H), 5.40 (dddd,
J ¼ 14.8, 9.1, 5.4, 1.3 Hz, 1H), 5.21 (td, J ¼ 7.0, 1.2 Hz, 1H), 5.17
(dt, J ¼ 10.2, 3.0 Hz, 1H), 5.08–5.03 (m, 1H), 2.70–2.65 (m, 2H),
2.17–2.10 (m, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.03–
1.96 (m, 1H), 1.2 (d, J ¼ 6.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 170.2, 169.5, 162.2, 144.1, 121.3, 82.7, 82.4, 71.1, 70.2, 66.7,
60.9, 33.8, 30.9, 21.0, 20.9, 20.8, 15.1; HRMS (ESI) for
(2S,3R,5S,8R)-8-Hydroxyundec-10-en-6-yne-2,3,5-triyl
triacetate (6)
A 1 M solution of TBAF in THF (1.73 mL, 1.73 mmol) was added
to a solution of compound 22 (0.5 g, 0.86 mmol) in dry THF
(15 mL) at 0 ꢁC. The mixture was stirred at room temperature for
3 h. Aer completion of the reaction, the mixture was diluted
with EtOAc (15 mL). The combined organic layers were washed
with sat. NaCl, and the mixture was extracted with ethyl acetate
(3 ꢃ 10 mL). The organic extracts were washed with brine and
dried over Na2SO4. The solvent was removed under reduced
pressure, and the mixture was puried by silica gel column
C
18H22O8Na [M + Na]+ found 398.12069 calcd 389.12062.
6R-(1Z,3S,5R,6S)-5,6-Dihydro-6-[3,5,6-tris(acetoxy)-1-
heptenyl]-2H-pyran-2-one (hyptolide) (1)
chromatography (3 : 7, EtOAc–hexane) to afford 6 (0.2 g, To solution of compound 24 (0.04 g, 0.10 mmol) in EtOAc
25
0.58 mmol, 70%) as a colorless liquid. [a]D ¼ ꢀ21.5 (c 0.7, (10 mL), one drop of quinoline and Lindlar’s catalyst (Pd/
1
CHCl3); IR (KBr): 3465, 1741, 1372, 1230, 1024 cmꢀ1; H NMR CaCO3) were added and stirred at room temperature under H2
(300 MHz, CDCl3): d 5.94–5.78 (m, 1H), 5.45 (dq, J ¼ 5.4, 1.5 Hz, atm for 3 min. Aer completion of the reaction, the reaction
1H), 5.31–5.03 (m, 4H), 4.43 (t, J ¼ 5.4 Hz, 1H), 2.62 (brs, 1H), mixture was ltered and the solvent was removed under
2.50–2.42 (m, 2H), 2.19–2.10 (m, 1H), 2.09 (s, 3H), 2.08 (s, 3H), reduced pressure. The crude product was puried on silica gel
2.04 (s, 3H), 2.02–1.92 (m, 1H), 1.22 (d, J ¼ 6.6 Hz, 3H); 13C NMR column chromatography (ethyl acetate–hexane, 5 : 5) to give
(CDCl3, 75 MHz): d 170.4, 170.1, 169.5, 132.7, 118.8, 87.4, 80.8, hyptolide 1 (32 mg, 0.087 mmol, 80%) as a solid, mp 83–87 ꢁC,
25
71.2, 70.4, 61.3, 61.2, 41.7, 34.1, 21.0, 20.9, 20.8, 14.7; HRMS (ESI) (ref. 3 m.p. 87–88 ꢁC); [a]D ¼ +12.5 (c 0.7, CHCl3); {ref. 3
for C17H24O7Na [M + Na]+ found 363.14142 calcd 363.14077.
[a]D ¼ +11.2 (c ¼ 0.6, CHCl3)}. IR (KBr): 1738, 1373, 1238,
25
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1045 cmꢀ1 1H NMR (500 MHz, CDCl3): d 6.91–6.86 (m, 1H),
6.07–6.03 (m, 1H), 5.81–5.76 (m, 1H), 5.57–5.50 (m, 2H), 5.32–
5.25 (m, 1H), 5.02–4.96 (m, 1H), 4.92 (dt, J ¼ 9.4, 3.2 Hz, 1H),
2.48–2.38 (m, 2H), 2.10–2.06 (m, 4H), 2.05 (s, 3H), 2.03 (s, 3H),
1.87–1.80 (m, 1H), 1.20 (d, J ¼ 6.5 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 170.5, 170.2, 165.0, 163.3, 144.5, 131.2, 130.7, 121.5,
73.8, 70.9, 70.4, 66.5, 34.8, 30.9, 21.2, 21.1, 21.0, 14.7; HRMS
(ESI) for C18H24O8Na [M + Na]+ found 391.13634 calcd 391.13530.
Paper
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Acknowledgements
AR and CNR thank UGC, New Delhi for the award of fellow-
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´
16 The diastereomeric excess of the product was determined
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1502 | RSC Adv., 2014, 4, 1496–1502
This journal is © The Royal Society of Chemistry 2014