First stereoselective total synthesis of an anti-fouling agent, C2-symmetric natural macrolide trichobotryside A

Article abstract of DOI:10.24820/ark.5550190.p010.795

A stereoselective total synthesis of 16-membered macrodiolide trichobotryside A has been accomplished. The key features are: regioselective epoxide opening, Reetz anti-allylation, Sharpless asymmetric epoxidation, cross metathesis and Yamaguchi protocols

Full text of DOI:10.24820/ark.5550190.p010.795

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First stereoselective total synthesis of an anti-fouling agent, C2-symmetric
natural macrolide trichobotryside A
Siva Ganesh Narala, G. Nagalatha, and A. Venkat Narsaiah*
Organic Synthesis Laboratory, Fluoro-Agro Chemicals Department,
CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India
Email: vnakkirala2001@yahoo.com; vnakkirala@csiriict.in
Received 10-24-2018
Accepted 12-16-2018
Published on line 12-27-2018
Abstract
A stereoselective total synthesis of 16-membered macrodiolide trichobotryside A has been accomplished. The
key features are: regioselective epoxide opening, Reetz anti-allylation, Sharpless asymmetric epoxidation,
cross metathesis and Yamaguchi protocols for esterification followed by macrolactonization.
Keywords: Macrodiolide, anti-fouling agent, Reetz allylation, Sharpless asymmetric epoxidation, Grubbs cross
metathesis, Yamaguchi lactonization
DOI: https://doi.org/10.24820/ark.5550190.p010.795
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Introduction
Marine organisms have been widely explored for potential bioactive lead compounds, within many different
chemical classes of compounds such as peptides, terpenoids, steroids, alkaloids, macrolides and other
polyketide lactones.1-3 The macropolylides, essentially 16-membered macrodiolides such as pyrenophorol,
pyrenophorin, and vermiculin (Figure 1) have strong antifungal and anthelmintic activity. Trichobotryside A is
C2-Symmetric 16-membered macrodiolide isolated by the Shu-Hua Qi group from deep sea sediment of the
South China Sea fungal strain Trychobotrys effuse DFFSCS021. These compounds were screened against cancer
cell lines as well as the HSV-1 virus. Trichobotryside A exhibits strong antifouling activity against larva
settlement of Bugula neritina and Balamus amphitrite with EC50 values of 7.3, 2.5 µg/mL and LC50/EC50 > 40.5,
37.4 respectively.4-6 The structure of trichobotryside A was determined by 1H and 13C NMR data along with 2D-
1
NMR experiments such as H-1H COSY, HSQC and HMBC spectra. The absolute configuration was established
by methanolysis and the modified Mosher's method and its molecular formula determined on the basis of
HRMS (ESI+) 423.1987 (M+Na+).7-9
Figure 1
The biological activity and the structural fascination of trichobotryside A attracted us to carry out its
total synthesis. As part of our regular research program in synthesis of biologically active natural and synthetic
compounds, herein we demonstrate the first stereoselective total synthesis of the 16-membered macrodiolide
trichobotryside A.
Results and Discussion
As envisaged in the retrosynthetic analysis (Scheme 1) trichobotryside A could be reached from
the monomer 18 after Wittig, Sharpless epoxidation and cross metathesis. The intermediate 8 could be
obtained after the Reetz allylation and hydroboration of commercially available propylene oxide (1) and
dithiane 2.
Scheme 1
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The synthesis commenced with regioselective ring opening of enantiomerically enriched (S)-2-
methyloxirane (1) with anion of 1,3-dithiane (2) using n-BuLi, HMPA, followed by protection of the secondary
hydroxyl group with benzyl bromide to obtain (S)-2-[2-(benzyloxy)propyl]-1,3-dithiane (4) in quantitative
yield.10 Oxidative cleavage of dithiane 4 was performed smoothly with [bis(trifluoroacetoxy)iodo]benzene and
SrCO3 to afford aldehyde 5 in 65% yield.11,12 The aldehyde was immediately subjected to chelation controlled
o
1,3-anti-allylation under Reetz conditions (TiCl4, CH2Cl2, -78 C, 1 h) using allyltrimethylsilane to furnish
1
homoallylic alcohol 6 in 76% yield, with an excellent diastereomeric ratio (dr 95:5), confirmed by H NMR
spectroscopy.13-15 The relative stereochemistry of 1,3-anti-diols (major isomer) was confirmed by chemical
shift correlations of the acetonide carbons in 13C NMR, as described by the Rychnovsky and Skalitzky protocol
[deprotection of the benzyl group with Li-metal in liquid ammonia, followed by protection of the 1,3-diol as its
acetonide with 2,2-DMP]. Examination of the 13C spectrum of the acetonide showed chemical shift values of
the acetonide methyl groups at δ 24.75 and 24.83 ppm and the ketal carbon at 100.1 ppm. These chemical
shift values correlate with a twist boat conformation of a 1,3-anti-diol.16,17 The secondary alcohol 6 was
protected as its tert-butyldimethylsilyl ether and the terminal olefin was converted to primary alcohol 8 by
hydroboration.18 Oxidation of 8 under Swern conditions afforded aldehyde 9 in very good yield19,20 and
subsequent olefination of the aldehyde with a two carbon Wittig ylide in benzene under reflux afforded olefin
1
10 in 86% yield (95:5, E/Z).21-23 The E/Z ratio was determined by H NMR analysis of the crude product.
Chemoselective reduction of ester 10 with DIBAL-H at -40 oC gave the allylic alcohol 11 in excellent yield.24,25
Scheme 2. Reagents and Conditions: (a) n-BuLi, HMPA, dry THF, -78 oC, 1 h, 92%; (b) NaH, BnBr, dry THF, 0 oC
to rt, 4 h, 87%; (c) PIFA, SrCO3, CH3CN/H2O, 9:1, 30 min, 65%; (d) TiCl4, allyltrimethylsilane, dry CH2Cl2, -78 oC, 1
h, 76%; (e) tert-butyldimethylsilyl chloride, imidazole, CH2Cl2, rt, 4 h, 94%; (f) BH3.DMS, NaOH, H2O2, dry THF,
12 h, 79%; (g) (COCl)2, DMSO, Et3N, dry CH2Cl2, -78 oC, 3 h; (h) Ph3P=CHCO2Et, benzene, reflux, 8 h, 86% (two
steps); (i) DIBAL-H, dry CH2Cl2, -40 oC, 3 h, 94%; (j) (-)-DET, 4 Å, Ti(OiPr)4, cumene hydroperoxide, dry CH2Cl2, -20 oC, 12
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h, 80%; (k) I2, PPh3, imidazole, Et2O:CH3CN (3:1), rt, 2 h, 77%; (l) Zn, NaI, EtOH, reflux, 5 h, 83%; (m) MeOCH2Cl, DIPEA, dry
CH2Cl2, DMAP, 6 h, 92%; (n) CH2=CHCO2Et, Grubbs 2nd generation catalyst, dry CH2Cl2, reflux, 12 h, 84%; (o) NaOH,
CH3OH, rt, 3 h, 92%; (p) TBAF, dry THF, reflux, 5 h, 95%.
The allylic alcohol 11 was subjected to Sharpless asymmetric epoxidation with (-)-DET, Ti(OiPr)4 and
o
cumene hydroperoxide at -20 C to give epoxy alcohol 12 in 80% yield with excellent diastereoselectivity (dr
19:1), established by 1H NMR spectroscopy.26-28 The free alcohol 12 was converted into iodide 13 in 77% yield
by using molecular iodine, triphenylphosphine and imidazole in Et2O/CH3CN (3:1) mixture. The iodo compound
13 was subjected to immediate reductive elimination using zinc in ethanol under reflux to achieve the
rearranged allylic alcohol 14 in 83% yield.29 The resulting secondary hydroxyl group in 14 was protected as its
MOM ether by treating with methoxymethylchloride and diisopropylethylamine to furnish 15 in 92% yield.
Cross metathesis of 15 with ethyl acrylate in the presence of Grubbs 2nd generation catalyst in dry CH2Cl2 led
1
to the formation of trans-olefinic ester 16 in 84% yield30-32 as confirmed by H NMR spectroscopic data. The
ester 16 on hydrolysis with 2 N NaOH in MeOH gave acid 17 in 92% yield and subsequent deprotection of the
silyl group with TBAF in THF under reflux conditions furnished monomer seco-acid 18) in 95% yield as shown in
Scheme 2.
Macrodilactonization of seco-acid 18 was attempted as displayed in Scheme 3, by using Yamaguchi,
Shiina and DMC conditions,33,34 but the required dimer product 22 was not obtained and the starting material
also could not be recovered. Whereas, Yamaguchi conditions at high dilution, yielded the dimer product 22,
but only in 5% yield and the starting material was decomposed.
Scheme 3
After the above experiments, the acid group in seco-acid 18 was converted into its methyl ester using
N-nitroso-N-methylurea salt in presence of KOH and the afforded compound 19 was allied with compound 17
under Yamaguchi conditions to furnish 20 in 85% yield.
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Scheme 4. Reagents and Conditions: (a) N-nitroso-N-methylurea, KOH, ether, 0 oC, 15 min, 96%; (b) 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, dry CH2Cl2, rt, 90 min, 85%; (c) Me3SnOH, EDC, 80 oC, 10 h; (d)
HF.pyridine, THF, rt, 6 h, 45%; (e) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, CH2Cl2, 40 oC, 29 h, 42%; (f)
TiCl4, CH2Cl2, rt, 2 h, 50%.
The methyl ester 20 was hydrolyzed in presence of trimethyltin hydroxide followed by deprotection of
tert-butyldimethylsilyl ether with HF.pyridine in THF to obtain seco-acid 21 in good yield over two steps.35-37
Thus obtained seco-acid 21 was subjected to Yamaguchi macrolactonization to afford bis-MOM, bis-benzyl
protected trichobotryside A 22 in 42% yield. Global deprotection of MOM and benzyl groups in 22 was
achieved in a single step by using excess TiCl4 in dry CH2Cl2 to obtain trichobotryside A in 50% yield, as shown
in Scheme 4.38 The optical rotation of the synthesized trichobotryside A was [α]D25 +65.7 (c = 0.12, CH3OH) and
that of the natural product is lit[α]D20 +50.09 (c = 1.58, CH3OH).7
Conclusions
The first stereoselective total synthesis of the naturally occurring, 16-membered macrodiolide, trichobotryside
A has been accomplished in 16 steps with 0.54% overall yield. The key reactions involved are regioselective
epoxide opening, Reetz anti-allylation, Sharpless asymmetric epoxidation, cross metathesis and Yamaguchi
protocols for esterification followed by macrolactonization.
Experimental Section
General. All the air and moisture sensitive reactions were carried out under an inert atmosphere (nitrogen
or argon). Oven-dried glass apparatus was used to perform all the reactions. Freshly distilled anhydrous
solvents were used for air and moisture sensitive reactions. Commercially available reagents were used as
such. Purification of compounds was carried out via column chromatography by using silica gel (60-120 mesh)
packed in glass columns. 1H NMR and 13C NMR were recorded in CDCl3 and DMSO-d6 solvents on 400 MHz and
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500 MHz spectrometer respectively, using TMS as an internal standard. IR spectra were recorded on a Perkin-
Elmer FT-IR 240-c Spectrophotometer using KBr / Thin Film optics. Optical rotation values were recorded on a
Horiba sepa 300 polarimeter using a 2 mL cell with a 10 mm path length. Mass spectra were recorded on a
Finnigan MAT 1020 mass spectrometer operating at 70 eV. High resolution mass spectra (HRMS) (ESI+) were
obtained using either a TOF or a double focusing spectrometer.
(S)-1-(1,3-Dithian-2-yl)propan-2-ol (3). To a stirred solution of 1,3-dithiane (5 g, 41.6 mmol) in dry THF (50 mL)
was added HMPA (25 mL, 145.6 mmol) and n-BuLi (26 mL, 1.6 M, hexanes, 41.6 mmol) at -78 °C under
nitrogen. The mixture was warmed to 0 °C and stirred for 2 h. Then, the reaction mixture was cooled to -78 °C,
and (S)-2-methyloxirane 1 (4.4 mL, 68.4 mmol) added and stirred for a further 1 h, then the reaction mixture
was quenched with saturated NH4Cl and warmed to rt. The solvent was removed under vacuum. The residue
was dissolved in EtOAc (150 mL), washed with water, followed by brine and dried over Na2SO4 and
concentrated under vacuum. The crude product was purified by column chromatography using silica gel (60-
120 mesh) by eluting with hexane/EtOAc (4:1) mixture to give pure compound 3 (6.85 g, 92%) as a colorless
1
oil. [α]D25 +23 (c = 1, CHCl3); IR (neat): 3396, 2899, 1453, 1420, 1276, 1182, 1029, 869, 771 cm-1; H NMR (400
MHz, CDCl3): δ 4.20 (dd, 1H, J 8.2, 6.1 Hz), 4.19 - 4.07 (m, 1H), 2.97 - 2.80 (m, 4H), 2.18 - 2.07 (m, 1H), 1.99 -
1.79 (m, 4H), 1.23 (d, 3H, J 6.3 Hz); 13C NMR (100 MHz, CDCl3): δ 64.9, 44.2, 30.2, 30.0, 25.8, 23.5; MS (ESIMS):
m/z 201 [M+Na]+.
(S)-2-[2-(Benzyloxy)propyl]-1,3-dithiane (4). To a stirred solution of NaH (2.2 g, 55 mmol, 60% mineral oil) in
dry THF (30 mL) was added compound 3 [6.5 g, 36.5 mmol, dissolved in dry THF (20 mL) at 0 oC under nitrogen.
After 45 minutes stirring was added benzyl bromide (5.2 mL, 43.8 mmol) and the reaction mixture slowly
warmed to rt. Then a catalytic amount of tetrabutyl ammonium iodide was added and the stirring maintained
for 12 hr. After completion of the reaction as indicated by TLC, solvent was removed under reduced pressure
and quenched with saturated NH4Cl and extracted with EtOAc (2x50 mL), the combined organic layers were
washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel
(60-120 mesh) column chromatography by eluting with Hexane/EtOAc (9:1) mixture to give compound 4 (8.5
g, 87%) as a colorless oil. [α]D25 -3.24 (c = 1, CHCl3). IR (neat): 3030, 2922, 2853, 1727, 1643, 1455, 1364, 772
cm-1; 1H NMR (400 MHz, CDCl3): δ 7.37 - 7.27 (m, 5H), 4.60 (d, 1H, J 11.6 Hz), 4.47 (d, 1H, J 11.3 Hz), 4.21 (dd,
1H, J 9.4 Hz), 3.85 (dt, 1H, J 8.6 Hz), 3.71 - 3.67 (m, 2H), 2.90 - 2.77 (m, 3H), 1.95 - 1.88 (m, 3H), 1.23 (d, 3H, J
6.1 Hz); 13C NMR (100 MHz, CDCl3): δ 138.7, 128.7, 128.4, 127.6, 126.8, 70.7, 43.9, 42.6, 36.8, 30.2, 29.5, 25.9,
21.8, 19.7; MS (ESIMS): m/z 269 (M+H)+, 291 (M+Na)+; HRMS (ESI) calcd for C14H21OS2 (M+H+) 269.1028; Found
269.1028.
(4S,6S)-6-(Benzyloxy)hept-1-en-4-ol (6). To a stirred suspension of dithiane compound 4 (8 g, 29.8 mmol) in
o
solvent mixture (80 mL, CH3CN:H2O, 9:1) SrCO3 (22 g, 149 mmol) was added at 0 C, followed by PIFA (12.8 g,
29.8 mmol). The stirring was continued for 30 min at rt and the completion of reaction confirmed by TLC, then
the reaction mixture was quenched by adding Na2CO3 saturated solution (30 mL) and Na2S2O3 (5 g) stirred at rt
for 30 min and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated under vacuum. The product was purified by flash column
chromatography to furnish (S)-3-(benzyloxy)butanal 5.
To a stirred solution of the above aldehyde 5 (3.5 g, 19.6 mmol) in CH2Cl2 (30 mL) TiCl4 (1 M, 21.44 mL, CH2Cl2,
21.44 mmol) was added slowly at -78 °C. After 20 min, allyltrimethylsilane (4.7 mL, 29.3 mmol) was added and
stirring continued for further 1 h, at -78 °C. After completion of the reaction (confirmed by TLC), the reaction
mixture was quenched by adding saturated NaHCO3 solution (50 mL) and stirred vigorously for 3 h at rt. The
reaction mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layer was washed with brine,
dried with Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography over
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silica gel (60-120 mesh) by eluting with hexanes:EtOAc (85:15) mixture to afford allylic alcohol 6 (3.28 g, 14.9
Lit
mmol, 76%) (dr 95:5) as a colorless liquid. [α]D25 +44 (c = 1, CHCl3). [α]D25 +45.2 (c = 3.12, CHCl3);15 IR (neat):
1
3439, 3030, 2931, 1641, 1432, 1343, 1343, 1145, 1027, 735 cm-1; H NMR (400 MHz, CDCl3): δ 7.38 - 7.27 (m,
5H), 5.88 - 5.78 (m, 1H), 5.13 - 5.06 (m, 2H), 4.63 (d, 1H, J 11.6 Hz), 4.46 (d, 1H, J 11.6 Hz), 3.98 - 3.92 (m, 1H),
3.87 - 3.83 (m, 1H), 2.7 (brs, 1H, OH), 2.24 - 2.20 (m, 2H), 1.68 - 1.64 (m, 2H), 1.26 (d, 3H, J 6.2 Hz); 13C NMR
(100 MHz, CDCl3): 138.3, 134.9, 128.3, 127.6, 127.5, 117.3, 72.5, 70.5, 67.5, 42.3, 42.2, 19.2; MS (ESIMS): m/z
243 (M+Na)+; HRMS (ESI): calcd for C14H21O2 (M+H)+ 221.1534, found 221.1536.
{[(4S,6S)-6-(Benzyloxy)hept-1-en-4-yl]oxy}(tert-butyl)dimethylsilane (7). To a stirred solution of compound 6
(2 g, 9.08 mmol) in dry CH2Cl2 (20 mL) at 0 oC, imidazole (1.23 g, 18.1 mmol) was added and stirred for 15 min,
then TBDMSCl (1.5 g, 10 mmol), dissolved in dry CH2Cl2 (5 mL), was added followed by catalytic amount of
DMAP and stirred at rt for 4 h. Completion of reaction was confirmed by TLC and water was added and
extracted with CH2Cl2 (2 x 20 mL), the combined organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography using
silica gel (60-120 mesh) by eluting with hexane/EtOAc 9:1 mixture to furnish corresponding TBDMS protected
olefin 7 (2.85 g, 94%) as colorless liquid. [α]D25 +68.8 (c = 2, CHCl3); IR (neat): 3070, 2929, 2857, 1710, 1427,
1
1336, 1219, 1108, 702 cm-1; H NMR (400 MHz, CDCl3): δ 7.37 - 7.27 (m, 5H), 5.88 - 5.79 (m, 1H), 5.06 - 5.01
(m, 2H), 4.59 (d, 1H, J 11.4 Hz), 4.41 (d, 1H, J 11.4 Hz), 4.04 - 3.98 (m, 1H), 3.70 - 3.78 (m, 1H), 2.30 - 2.18 (m,
2H), 1.74 (dt, 1H, J 14.2, 8.8 Hz), 1.50 (dt, 1H, J 12.6, 8.7 Hz), 1.22 (d, 3H, J 6.1 Hz), 0.90 (s, 9H), 0.07 (s, 3H),
0.05 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 139.1, 134.7, 128.4, 127.3, 127.2, 116.9, 72.1, 70, 68.6, 44.7, 42.6,
25.9, 20.1, 18.1, -4.1, -4.5; MS (ESIMS): m/z 335 (M+H)+; HRMS (ESI+): calcd for C20H35O2Si (M+H)+ 335.2402;
Found 335.2400.
(4S,6S)-6-(Benzyloxy)-4-[(tert-butyldimethylsilyl)oxy]heptan-1-ol (8). To a stirred solution of compound 7 (2.8
o
g, 8.4 mmol) in dry THF (25 mL) borane-dimethylsulfide (1.6 mL, 16.7 mmol) was added at 0 C. The reaction
mixture was allowed to rt and stirred for 2 h. After consumption of starting material as indicated by TLC, the
o
reaction mixture was cooled to 0 C, NaOH solution (100 mL, 3 M) was added followed by H2O2 (50 mL, 33%
w/w H2O) and the reaction mixture was stirred for 12 h at rt. Then, solvent was removed under vacuum and
extraction was performed with EtOAc (3 x 30 mL). The organic layers were washed with brine, dried over
Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography using
silica gel (60-120 mesh) by eluting with hexane:EtOAc (8:2) mixture to afford 8 (2.32 g, 79%) as colorless liquid.
[α]D25 +32.1 (c = 2, CHCl3); IR (neat): 3395, 3069, 2929, 2857, 1710, 1427, 1336, 1219, 1108, 702 cm-1; 1H NMR
(400 MHz, CDCl3): δ 7.36 - 7.27 (m, 5H), 4.59 (d, 1H, J 11.4 Hz), 4.41 (d, 1H, J 11.4 Hz), 3.95 - 4.05 (m, 1H), 3.67
- 3.72 (m, 1H), 3.64 - 3.57 (m, 2H), 1.98 (brs, 1H), 1.77 - 1.63 (m, 2H), 1.61 - 1.54 (m, 4H), 1.22 (d, 3H, J 6.1 Hz),
0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 138.9, 128.2, 127.4, 127.3, 72.1, 70.1, 68.9,
63.1, 44.4, 34.2, 27.6, 25.9, 2.1, 18.1, -4.2, -4.6; MS (ESIMS): m/z 375 (M+Na)+; HRMS (ESI+): calcd for
C20H37O3Si (M+H)+ 353.2513; Found 353.2506.
(6S,8S,E)-ethyl-8-(benzyloxy)-6-[(tert-butyldimethylsilyl)oxy]non-2-enoate (10). A solution of oxalyl chloride
o
(1.2 mL, 15.3 mmol) in dry CH2Cl2 (5 mL) and DMSO (1.9 mL, 26.8 mmol) was stirred at -78 C for 30 minutes
and then added a solution of alcohol 8 [(2.3 g, 6.5 mmol, dissolved in CH2Cl2 (2 mL)] at the same temperature
o
and stirred for further 3 h. Then, added Et3N (1.95 mL, 13.9 mmol) at 0 C and stirred for further 45 minutes.
The reaction mixture was diluted with water (5 mL) and extracted with CH2Cl2 (3x10 mL). The combined
organic layers were washed with brine, dried over Na2SO4 and concentrated to give aldehyde compound 9 in
quantitative yield as a pale yellow syrup, which was used for next reaction without purification.
The above aldehyde 9 (1.89 g, 5.4 mmol) was dissolved in dry benzene (20 mL) and added Wittig ylide (2.4 g,
6.9 mmol). The reaction mixture was refluxed for 8 h. After completion of the reaction (monitored by TLC)
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solvent was removed under reduced pressure and residue was extracted with EtOAc (2x20 mL). The organic
extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude
product was purified by column chromatography using silica gel (60-120 mesh) by eluting with hexane/EtOAc
(9:1) mixture to give ester compound 10 (1.95 g, 86%) as pale yellow liquid (95:5, E/Z). [α]D25 +43.7 (c = 1,
1
CHCl3); IR (neat): 3028, 2930, 2856, 1718, 1655, 1318, 1255, 1094, 984 cm-1.; H NMR (400 MHz, CDCl3): δ
7.35 - 7.25 (m, 5H), 6.96 (q, 1H, J 15.5, 13.8 Hz), 5.80 (dt, 1H, J 15.6, 3.7 Hz), 4.59 (d, 1H, J 11.4 Hz), 4.40 (d, 1H,
J 11.4 Hz), 4.18 (q, 2H, J 7.0 Hz), 3.93 - 3.99 (m, 1H), 3.63 - 3.71 (m, 1H), 2.28 - 2.20 (m, 2H), 1.64 - 1.74 (m, 1H),
1.51 - 1.61 (m, 3H), 1.28 (t, 3H, J 7.0 Hz), 1.22 (d, 3H, J 6.1 Hz), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 166.6, 149.2, 138.9, 128.2, 127.4, 127.3, 121.1, 72.1, 70.1, 68.5, 60.1, 44.7, 36, 27.2, 25.8,
20.1, 14.2, -4.2, -4.4; MS (ESIMS): m/z 443 (M+Na)+; HRMS (ESI): calcd for C24H41O4Si (M+H)+ 421.2759; Found
421.2768.
(6S,8S,E)-8-(Benzyloxy)-6-[(tert-butyldimethylsilyl)oxy]non-2-en-1-ol (11). To a stirred solution of compound
o
10 (1.9 g, 4.5 mmol) in dry CH2Cl2 (15 mL) was added DIBAL-H (13.6 mL, 1 M, toluene, 13.6 mmol) at -40 C,
and stirred for 3 h. After completion of reaction (monitored by TLC) the reaction mixture was quenched with
saturated Rochelle salt solution (10 mL) stirred at rt for 3 h and extracted with CH2Cl2 (2x20 mL), the
combined organic layers washed with H2O, brine, dried over Na2SO4 and concentrated under vacuum. The
crude product was purified by flash column chromatography using silica gel (60-120 mesh) by eluting with
hexane/EtOAc (8:2) mixture to afford allylic alcohol 11 (1.6 g, 94%) as colorless oil. [α]D25 +43.9 (c = 1.5, CHCl3);
1
IR (neat): 3434, 3085, 2929, 2856, 1458, 1362, 1077, 920, 696 cm-1; H NMR (400 MHz, CDCl3): δ 7.37 - 7.27
(m, 5H), 5.70 - 5.59 (m, 2H), 4.59 (d, 1H, J 11.4 Hz), 4.41 (d, 1H, J 11.4 Hz), 4.05 (d, 2H, J 5.3 Hz), 3.90 - 3.97 (m,
1H), 3.70 - 3.77 (m, 1H), 2.10 - 2.05 (m, 2H), 1.69 - 1.76 (m, 2H), 1.57 - 1.50 (m, 2H), 1.45 (brs, 1H), 1.22 (d, 3H,
J 6.2 Hz), 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 139, 133.1, 128.9, 128.5, 127.4,
127.3, 72.2, 70.1, 68.1, 63.6, 44.8, 37.2, 27.3, 25.9, 20.1, 18.1, -4.1, -4.4; MS (ESIMS): m/z 401 (M+Na)+; HRMS
(ESI+): calcd for C22H39O3Si (M+H)+ 379.2667; Found 379.2663.
{(2R,3R)-3-[(3S,5S)-5-(Benzyloxy)-3-[(tert-butyldimethylsilyl)oxy]hexyl]oxiran-2-yl}methanol (12). To
a
stirred suspension of activated molecular (300 mg, 4 A) sieves powder in dry CH2Cl2 (15 mL) was added (-)-DET
(0.75 mL, 4.4 mmol) and Ti(OiPr)4 (1.2 mL, 4.1 mmol) at rt and the resulting mixture was stirred for 30 minutes.
o
Then, the reaction mixture was cooled to -20 C and added a solution of the allylic alcohol 11 (1.5 g, 4 mmol)
o
in dry CH2Cl2 (4 mL) dropwise. The resulting mixture was stirred for further 30 minutes at -20 C. Then added
Cumene hydroperoxide (1.65 mL, 3.6 M in toluene, 6 mmol) dropwise and the resulting mixture stirred at the
o
same temperature for 12 h. The reaction mixture was allowed to warm to 0 C, quenched with water and
stirred for 2 h at rt. Then added NaOH (20 mL, 30%) solution mixed with brine and continued stirring
vigorously further 30 minutes at rt. The mixture was filtered through Celite bed and the filter cake was washed
with CH2Cl2 (2x15 mL). The combined organic layers were washed with brine and dried over Na2SO4. The
solvent was evaporated under reduced pressure to afford the crude product, which was purified by column
chromatography using silica gel (60-120 mesh) by eluting with EtOAc/hexane (3:7) mixture to afford
epoxyalcohol 12 (1.25 g, 80%) as pale yellow liquid. [α]D25 +39.5 (c = 1, CHCl3); IR (neat): 3436, 2926, 2855,
1610, 1459, 1376, 1219, 1060, 835 cm.-1.; 1H NMR (400 MHz, CDCl3): δ 7.35 - 7.27 (m, 5H), 4.59 (d, 1H, J 11.3
Hz), 4.38 (d, 1H, J 11.3 Hz), 3.92 - 4.01 (m, 1H), 3.83 (dq, 1H, J 12.4, 8.1 Hz), 3.63 - 3.72 (m, 1H), 3.53 - 3.59 (m,
1H), 2.93 - 2.86 (m, 2H) 1.74 - 1.65 (m, 3H), 1.64 - 1.48 (m, 3H), 1.22 (d, 3H, J 6.1 Hz), 0.88 (s, 9H), 0.05 (s, 3H),
0.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 138.9, 128.3, 127.5, 127.4, 72.1, 70.1, 68.5, 61.6, 58.5, 55.9, 44.8,
33.7, 26.8, 25.8, 20.1, 18.1, -4.1, -4.5; MS (ESIMS): m/z 417 (M+Na)+; HRMS (ESI): calcd for C22H39O4Si (M+H)+
395.2618; Found 395.2612.
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{[(3S,5S)-5-(Benzyloxy)-1-[(2R,3S)-3-(iodomethyl)oxiran-2-yl]hexan-3-yl]oxy}(tert-butyl)dimethylsilane (13).
To a stirred solution of epoxy alcohol 12 (1.2 g, 3 mmol) in Et2O/MeCN (3:1, 20 mL) solvent mixture was added
triphenyl phosphene (0.8 g, 3.1 mmol) followed by imidazole (270 mg, 3.97 mmol) at 0 oC and the mixture was
stirred for 10 minutes. Then added I2 (0.85 g, 3.4 mmol) at 0 °C and the mixture was stirred for 2 h at rt. Then
the reaction mixture was quenched with saturated Na2S2O3 (5 mL) and extracted with EtOAc (3x20 mL). The
organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated and residue was
purified by column chromatography on silica gel (60-120 mesh) by eluting with EtOAc/hexane (1:9) mixture to
afford iodo compound 13 (1.18 g, 77%) as a colorless liquid. [α]D25 +31.7 (c = 0.7, CHCl3); IR (neat): 3029, 2928,
1
2855, 1495, 1433, 1252, 1097, 1005, 833, 692 cm-1; H NMR (400 MHz, CDCl3): δ 7.36 - 7.27 (m, 5H), 4.59 (d,
1H, J 11.4 Hz), 4.39 (d, 1H, J 11.4 Hz), 3.91 - 3.99 (m, 1H), 3.64 - 3.73 (m, 1H), 3.21 (dd, 1H, J 14.4, 9.5 Hz), 3.02
- 2.93 (m, 2H), 2.77 (dt, 1H, J 5.2 Hz), 1.72 - 1.48 (m, 6H), 1.22 (d, 3H, J 6.1 Hz), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 138.9, 128.3, 127.5, 127.3, 72.1, 70.1, 68.5, 62.5, 58.3, 44.8, 33.6, 26.8, 20.1,
18.5, -4.1, -4.4; MS (ESIMS): m/z 527 (M+Na)+; HRMS (ESI): calcd for C22H38O3ISi (M+H)+ 505.1631; Found
505.1629.
(3R,6S,8S)-8-(Benzyloxy)-6-[(tert-butyldimethylsilyl)oxy]non-1-en-3-ol (14). To a stirred solution of iodo
compound 13 (1.15 g, 2.28 mmol) in EtOH (15 mL) was added activated Zn dust (1.5 g, 23 mmol) and catalytic
amount of sodium iodide, then the reaction mixture was stirred at reflux for 4 h. After complete conversion of
starting material (monitored by TLC), the mixture was passed through celite bed. The filtrate was concentrated
and the residue was purified by column chromatography using silica gel (60-120 mesh) by eluting with
25
EtOAc/hexane (2:8) mixture to afford allylic alcohol 14 (0.72 g, 83%) as colorless liquid. [α]D +46.9 (c = 1,
CHCl3); IR (neat): 3364, 3031, 2952, 2856, 1714, 1456, 1376, 1219, 1060 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.35
- 7.25 (m, 5H), 5.81 - 5.89 (m, 1H), 5.21 (dt, 1H, J 17.2 Hz), 5.09 (dt, 1H, J 10.3 Hz), 4.59 (d, 1H, J 11.4 Hz), 4.40
(d, 1H, J 11.4 Hz), 4.05 (q, 1H, J 11.5, 5.7 Hz), 3.95 - 4.02 (m, 1H), 3.64 - 3.71 (m, 1H), 2.26 (brs, 1H, OH), 1.71 -
1.77 (m, 1H), 1.66 - 1.51 (m, 5H), 1.21 (d, 3H, J 6.1 Hz), 0.89 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 141.1, 138.9, 127.4, 127.3, 114.4, 73.2, 72.1, 70.1, 69, 44.5, 33.8, 32.1, 25.9, 20, 18.1, -4.2, -4.6;
MS (ESIMS): m/z 379 (M+H)+, 401 (M+Na)+; HRMS (ESI+): calcd for C22H39O3Si (M+H)+ 379.2667; Found
379.2663.
(5R,8S)-8-[(S)-2-(Benzyloxy)propyl]-10,10,11,11-tetramethyl-5-vinyl-2,4,9-trioxa-10-siladodecane (15). To a
stirred solution of compound 14 (0.7 g, 1.9 mmol) in dry CH2Cl2 (5 mL) was added DIPEA (0.93 mL, 5.5 mmol)
o
at 0 C, stirred for 10 minutes, then methoxymethyl chloride (0.61 mL, 6 M in methanol, 3.7 mmol). The
o
reaction temperature slowly rised to 25 C, then added catalytic amount of DMAP and then stirred for 6 h.
After completion of reaction (monitored by TLC), water was added and extracted with CH2Cl2 (2x10 mL). The
combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The crude
product was purified by flash column chromatography using silica gel (60-120 mesh) by eluting with hexane /
25
EtOAc (9:1) mixture to afford compound 15 (0.72 g, 92%) as colorless liquid. [α]D +105 (c = 1, CHCl3); IR
(neat): 3012, 2943, 1442, 1347, 1182, 1182, 1119, 1023, 900 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.35 - 7.24 (m,
5H), 5.59 - 5.69 (m, 1H), 5.20 - 5.15 (m, 2H), 4.69 (d, 1H, J 6.7 Hz), 4.58 (d, 1H, J 11.5 Hz), 4.52 (d, 1H, J 6.7 Hz),
4.40 (d, 1H, J 11.4 Hz), 3.93 (m, 1H), 3.63 - 3.71 (m, 1H), 3.35 (s, 3H), 1.75 - 1.63 (m, 2H), 1.59 - 1.40 (m, 4H),
1.21 (d, 3H, J 6.1 Hz), 0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 139.1, 138.3, 128.3,
127.4, 127.2, 117.2, 93.6, 77.6, 72.2, 70.1, 69.8, 55.3, 33.5, 30.3, 25.9, 18.1, -4.2, -4.5; MS (ESIMS): m/z 423
(M+H)+, 445 (M+Na)+; HRMS (ESI): calcd for C25H43O4Si (M+H)+ 423.2936; Found 423.29153.
(4R,7S,9S,E)-Ethyl-9-(benzyloxy)-7-[(tert-butyldimethylsilyl)oxy]-4-(methoxymethoxy)dec-2-enoate (16). To a
stirred solution of compound 15 (0.7 g, 1.7 mmol) in dry CH2Cl2 (10 mL) was added ethyl acrylate (0.53 mL, 5
mmol), then the mixture was degassed with N2 for 20 minutes. Then added Grubbs II catalyst (42 mg, 0.05
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mmol) under argon atmosphere. Then the mixture was refluxed for 12 h. After completion of reaction
(monitored by TLC), the solvent was removed under reduced pressure and the crude product was purified by
column chromatography on silica gel (60-120 mesh) by eluting with EtOAc/hexane (1:9) mixture to afford
compound 16 (0.69 g, 84%) as colorless liquid. [α]D25 +77.5 (c = 2, CHCl3); IR (neat): 3068, 2930, 2857, 1695,
1454, 1357, 1107, 986 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.34 - 7.24 (m, 5H), 6.79 (dd, 1H, J 15.7, 6.3 Hz), 5.96
(dd, 1H, J 15.7, 1.2 Hz), 4.62 - 4.55 (m, 3H), 4.39 (d, 1H, J 11.4 Hz), 4.20 (q, 2H, J 14.3, 7.2 Hz), 4.17 - 4.13 (m,
1H), 3.90 - 3.99 (m, 1H), 3.63 - 3.70 (m, 1H), 3.35 (s, 3H), 1.72 - 1.58 (m, 4H), 1.55 -1.41 (m, 2H), 1.29 (t, 3H, J
7.2 Hz), 1.21 (d, 3H, J 6.1 Hz), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.7, 147.7,
139.0, 128.3, 127.4, 127.3, 121.9, 94.5, 75.3, 72.1, 70.1, 68.8, 60.4, 55.5, 44.9, 33.1, 29.6, 25.9, 20.1, 18.1,
14.2, -4.2, -4.5; MS (ESIMS): m/z 495 (M+H)+, 517 (M+Na)+; HRMS (ESI): calcd for C27H47O6Si (M+H)+ 495.3124;
Found 495.3136.
(4R,7S,9S,E)-9-(Benzyloxy)-7-[(tert-butyldimethylsilyl)oxy]-4-(methoxymethoxy)dec-2-enoic acid (17). To a
stirred solution of compound 16 (0.67 g, 1.4 mmol) in methanol (5 mL) was added NaOH solution (1.36 mL, 3
o
N, 4.1 mmol) at 0 C. Then the reaction mixture slowly warmed to rt and stirred for 3 h. After completion of
reaction (monitored by TLC), the solvent was removed under vacuum and extracted was with EtOAc (2x20
mL). The combined organic layers were separated, washed with brine, dried over Na2SO4, concentrated under
vacuum. The crude product was purified by column chromatography on silica gel (60-120 mesh) by eluting
with EtOAc/hexane (3:7) mixture to afford compound 17 (0.58 g, 92%) as colorless liquid. [α]D25 +111.2 (c = 0.4,
1
CHCl3); IR (neat): 2923, 2853, 1739, 1461, 1252, 1061, 835 cm-1; H NMR (400 MHz, CDCl3): δ 7.34 - 7.24 (m,
5H), 6.91 (dd, 1H, J 15.6, 5.9 Hz), 5.98 (dd, 1H, J 15.7, 1.3 Hz), 4.62 - 4.57 (m, 2H), 4.40 (d, 1H, J 11.4 Hz), 4.15 -
4.23 (m, 1H), 3.91 - 3.99 (m, 1H), 3.63 - 3.73 (m, 1H), 3.35 (s, 3H), 1.72 - 1.58 (m, 4H), 1.56 - 1.39 (m, 2H), 1.21
(d, 3H, J 6.1 Hz), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.2, 150.6, 138.9, 129.2,
127.4, 127.3, 120.7, 94.6, 75.3, 72.1, 68.8, 55.6, 44.8, 33.1, 29.5, 25.8, 20.1, 18.1, -4.2, -4.5; MS (ESIMS): m/z
467 (M+H)+; HRMS (ESI): calcd for C25H43O6Si (M+H)+ 467.2823; Found 467.2823.
(4R,7S,9S,E)-9-(Benzyloxy)-7-hydroxy-4-(methoxymethoxy)dec-2-enoic acid (18). To a stirred solution of
o
compound 17 (0.57 g, 1.2 mmol) in dry THF (5 mL) was added TBAF (1.9 mL, 1 M in THF, 1.8 mmol) at 0 C.
Then the reaction mixture was refluxed for 5 h. After completion of the reaction (monitored by TLC), then the
reaction mixture was quenched with saturated NH4Cl and solvent was removed under reduced pressure. The
residue was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine dried over
Na2SO4, concentrated under vacuum. The crude product was purified by column chromatography using silica
gel (60-120 mesh) by eluting with EtOAc/hexane (8:2) mixture to afford 18 (0.41 g, 95%) as pale yellow liquid.
[α]D25 +72.6 (c = 1, CHCl3).; IR (neat): 3435, 3365, 2926, 1702, 1658, 1452, 1376, 1271, 1149, 1030, 772 cm-1.;
1H NMR (400 MHz, CDCl3): δ 7.36 - 7.27 (m, 5H), 6.92 (dd, 1H, J 15.7 Hz), 5.99 (d, 1H, J 15.7 Hz), 4.64 - 4.59 (m,
2H), 4.44 (d, 1H, J 11.5 Hz), 4.22 - 4.27 (m, 1H), 3.94 - 3.84 (m, 2H), 3.37 (s, 3H), 1.84 - 1.77 (m, 1H), 1.73 - 1.60
(m, 2H), 1.58 - 1.48 (m, 2H), 1.26 (d, 3H, J 6.2 Hz).; 13C NMR (100 MHz, CDCl3): δ 169.6, 150.2, 138.3, 128.5,
127.7, 120.9, 94.9, 75.3, 72.6, 70.5, 68.3, 57.7, 42.7, 32.9, 31.1, 19.1; MS (ESIMS): m/z 375 (M+Na)+; HRMS
(ESI): calcd for C19H29O6 (M+H)+ 353.1963; Found 353.1958.
(4R,7S,9S,E)-Methyl-9-(benzyloxy)-7-hydroxy-4-(methoxymethoxy)dec-2-enoate (19). To a stirred solution of
N-Nitroso-N-Methylurea salt (53 mg, 0.06 mmol) in dry ether was added KOH solution (0.2 mL, 2 N, 0.05
o
mmol) at 0 C and stirred for 10 minutes, the pale yellow color results the formation of diazomethane. The
ether layer was separated, passed through Na2SO4, at cooling condition immediately poured into seco-acid 18
(20 mg, 56.8 μmol), which was dissolved in dry ether (2 mL) and stirred for 10 minutes. After completion of
the reaction (monitored by TLC), organic layers were separated, washed with brine, dried over Na2SO4 and
concentrated under vacuum. The crude product was purified by column chromatography using silica gel (60-
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25
120 mesh) by eluting with hexane/EtOAc (6:4) mixture to afford 19 (20 mg, 96%) as colorless liquid. [α]D
+77.4 (c = 0.5, CHCl3).; IR (neat): 3340, 2956, 2858, 1723, 1460, 1256,1170, 1043, 833.9 cm.-1; H NMR (400
1
MHz, CDCl3): δ 7.37 - 7.27 (m, 5H), 6.82 (dd, 1H, J 15.7, 6.3 Hz), 5.98 (dd, 1H, J 15.7, 1.35 Hz), 5.45 (q, 1H, J 11.1
Hz), 4.65 - 4.58 (m, 2H), 4.44 (d, 1H, J 11.6 Hz), 4.22 (q, 1H, J 11.8, 5.5 Hz), 3.94 - 3.85 (m, 2H), 3.74 (s, 3H), 3.37
(s, 3H), 1.86 - 1.75 (m, 1H), 1.68 - 1.47 (m, 5H), 1.42 (d, 3H, J 5.5 Hz).; 13C NMR (100 MHz, CDCl3): δ 166.6, 148,
138.2, 128.4, 127.7, 121.4, 102.9, 94.6, 75.2, 72.6, 70.5, 68.2, 55.7, 51.6, 42.6, 32.9, 31.1, 29.6, 19.; MS
(ESIMS): m/z 367 (M+H)+; HRMS (ESI+): calcd for C20H31O6 (M+H)+ 367.2120; Found 367.2115.
(4R,7S,9S,E)-(2S,4S,7R,E)-2-(Benzyloxy)-10-methoxy-7-(methoxymethoxy)-10-oxodec-8-en-4-yl-9-(benzyloxy)
-7-[(tert-butyldimethylsilyl)oxy]-4-(methoxymethoxy)dec-2-enoate (20). To a stirred solution of compound
17 (50 mg, 142 μmol) in dry CH2Cl2 (5 mL) was added compound 19 (19.6 mg, 54 μmol) and the mixture was
concentrated under reduced pressure and dried at high vacuum. The resulting thick paste was dissolved in
toluene (0.6 mL) and under stirring was added Et3N (43 μmL, 426 μmol) at rt. The resulting mixture was stirred
for 5 minutes and added DMAP (68 mg, 568 μmol) followed by TCBC (44.4 μmL 284 μmol) and continued
stirring for 30 minutes then the solution becomes sticky. At this moment was added toluene (1 mL) and
shaken manually then stirred for 1 h. After completion of reaction (monitored by TLC) the reaction mixture
concentrated under vacuum. The crude product was purified by column chromatography using silica gel (60-
120 mesh) by eluting with hexane/EtOAc (8:2) mixture to afford compound 20 (57.5 mg, 85%) as sticky
material. [α]D25 +180.3 (c = 0.3, CHCl3).; IR (neat): 2927, 2855, 1723, 1605, 1453, 1376, 1219, 1029, 772 cm-1.;
1H NMR (400 MHz, CDCl3): δ 7.34 - 7.25 (m, 10H), 6.77 (ddd, 1H, J 15.7, 10.1, 6.1 Hz), 5.95 (ddd, 2H, J 15.7, 9.1,
7.8 Hz), 5.22 - 5.28 (m, 1H), 4.62 - 4.50 (m, 6H), 4.37 (dd, 2H, J 15.4, 11.4 Hz), 4.11 - 4.18 (m, 1H), 3.99 - 3.93
(m, 1H), 3.73 (s, 3H), 3.71 - 3.64 (m, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 1.75 - 1.59 (m, 8H), 1.54 - 1.43 (m, 2H), 1.20
(t, 6H, J 5.8 Hz), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.5, 165.7, 147.8, 147.6,
139, 138.5, 128.3, 128.2, 127.9, 127.5, 127.4, 121.9, 121.7, 94.6, 75.4, 74.9, 72.1, 71.5, 71.2, 70.1, 68.8, 55.6,
51.6, 44.8, 42.2, 33.2, 30.5, 29.6, 25.9, 20.1, 19.8, 18, -4.1, -4.5; MS (ESIMS): m/z 838 (M+Na)+; HRMS (ESI+):
calcd for C45H70O11SiNa (M+Na)+ 837.4594; Found 837.4579.
(4R,7S,9S,E)-9-(Benzyloxy)-7-{[(4R,7S,9S,E)-9-(benzyloxy)-7-hydroxy-4-(methoxymethoxy)dec-2-enoyl]oxy}-4
-(methoxymethoxy)dec-2-enoic acid (21). To a stirred solution of compound 20 (55 mg, 67.48 μmol) in
ethylene dichloride (2.5 mL) was added trimethyltin hydroxide (122 mg, 674.70 μmol) at rt and the reaction
mixture was refluxed for 10 h. After completion of reaction (monitored by TLC), solvent was removed under
reduced pressure and the resulting residue was dissolved in water and extracted with EtOAc (3x5 mL) and the
combined organic layers washed with solution of KHSO4 (0.01 N, 3x5 mL), brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude compound was used for further reaction without
purification.
The above acid compound was dissolved in dry THF (2 mL) and added HF.pyridine (0.01 mL, 337.4
o
μmol, 70% HF.30% pyridine) at 0 C. Then slowly warmed to rt and stirred for 6 h. After completion of the
o
reaction (monitored by TLC), the mixture was cooled to 0 C and quenched with saturated NaHCO3 (5 mL),
followed by 0.05 N HCl (5 mL). The reaction mixture was extracted with EtOAc (2x10 mL), the combined
organic layers were washed with brine and dried over Na2SO4 concentrated under vacuum. The crude product
was purified by column chromatography using silica gel (60-120 mesh) by eluting with EtOAc/ MeOH (9:1)
25
mixture to afford, compound 21 in 23 mg (45% over two steps) as sticky material. [α]D +226.1 (c = 0.2,
CHCl3).; IR (neat): 3424, 3031, 2981, 2926, 2854, 1716, 1639, 1494, 1452, 1028, 1148, 1070, 741 cm-1; 1H NMR
(400 MHz, CDCl3): δ 7.38 - 7.24 (m, 10H), 6.89 (ddd, 1H, J 15.7, 6.1 Hz), 6.80 (ddd, 1H, J 18.5, 9.1 Hz), 5.91 -
6.02 (m, 2H), 5.22 - 5.28 (m, 1H), 4.67 - 4.56 (m, 4H), 4.52 (d, 1H, J 11.1 Hz), 4.44 (d, 1H, J 11.6 Hz), 4.36 (d, 2H,
J 11.1 Hz), 4.27 - 4.16 (m, 2H), 3.96 - 3.84 (m, 2H), 3.58 - 3.51 (m, 1H), 3.37 (s, 3H), 3.34 (s, 3H), 2.85 (brs, 1H,
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OH), 2.42 - 2.30 (m, 1H), 2.06 - 1.98 (m, 1H), 1.85 - 1.58 (m, 8H), 1.56 - 1.45 (m, 2H), 1.26 (d, 3H, J 6.1 Hz), 1.20
(d, 3H J 6.1 Hz).; 13C NMR (100 MHz, CDCl3): δ 169.9, 165.7, 150, 149.4, 147.8, 138.5, 138.2, 128.4, 128.3,
127.9, 127.7, 127.4, 121.9, 121.3, 121, 94.7, 75.3, 74.8, 72.6, 71.5, 71.2, 70.8, 70.5, 68.3, 68.2, 55.6, 49.4, 42.6,
42, 32.9, 32.8, 31.1, 31, 30.6, 30.2, 29.6, 19.8, 19, 17.6; MS (ESIMS): m/z 686 (M-H)+; HRMS (ESI+): calcd for
C38H56O11 (M+H)+ 688.3797; Found 688.3817.
(3E,5R,8S,11E,13R,16S)-8,16-Bis[(S)-2-(benzyloxy)propyl]-5,13-bis(methoxymethoxy)-1,9-dioxacyclohexa
deca-3,11-diene-2,10-dione (22). To a stirred solution of the seco-acid 21 (15 mg, 21.86 μ mol) in toluene (8.1
mL) was added TCBC (53.33 μ mL, 218.6 μ mol) and Et3N (33.45 μL, 240.46 μ mol) at rt. The resulting reaction
mixture was stirred for 1 hr and diluted by the addition of toluene (8.1 mL). Then, the reaction mixture was
added to a solution of DMAP (11 mg, 87.4 μ mol, in toluene 20.2 mL) at 40 °C, over 5 h, via syringe pump.
After the addition was completed, stirring was continued for 24 h. Then the solvent was removed under
reduced pressure and the residue was loaded on silica gel (60-120 mesh) by eluted with hexane/EtOAc (7:3)
25
mixture to give compound 22 (6.15 mg, 42%) as a white sticky material. [α]D +108.2 (c = 0.5, CHCl3).; IR
1
(neat): 2924, 2853, 1725, 1550, 1516, 1463, 1415, 1378, 1261, 1219, 772 cm-1; H NMR (400 MHz, CDCl3): δ
7.41 - 7.29 (m, 10H), 6.76 (dd, 2H, J 15.8, 5.6 Hz), 5.89 (dd, 2H, J 15.8, 1.2 Hz), 5.39 (sextet, 2H, J 11.9, 7.6 Hz),
4.63 - 4.56 (m, 4H), 4.53 (d, 2H, J 11.1 Hz), 4.44 - 4.40 (m, 2H), 4.39 (d, 1H, J 11.1 Hz), 3.55 - 3.48 (m, 2H), 3.35
(s, 6H), 2.05 - 1.87 (m, 2H), 1.79 - 1.59 (m, 10H), 1.20 (d, 6H, J 6.1 Hz); 13C NMR (100 MHz, CDCl3): δ 164.9,
147.6, 138.4, 128.3, 128, 127.5, 122.7 94.3, 73.7, 71.5, 70.9, 70.2, 39.7, 29.6, 27.9, 26.8, 19.8; MS (ESIMS): m/z
692 (M+Na+); HRMS (ESI+): calcd for C38H52O10Na (M+Na)+ 691.3460; Found 691.3465.
(3E,5R,8S,11E,13R,16S)-5,13-Dihydroxy-8,16-bis[(S)-2-hydroxypropyl]-1,9-dioxacyclohexadeca-3,11-diene-2,
10-dione (trichobotryside A). To a stirred solution of compound 22 (4 mg, 6 μmol) in dry CH2Cl2 (1 mL) was
added TiCl4 (0.1 mL, dissolved in dry CH2Cl2 10 mL) dropwise at 0 oC. The reaction mixture was slowly warmed
to rt and stirred for 2 h. After completion of the reaction (monitored by TLC), the mixture was quenched by
adding saturated NaHCO3 (5 mL) and extracted with chloroform (2x5 mL), the combined organic layers was
washed with brine, dried over Na2SO4 and concentrated under vacuum. The sticky foam material was purified
by column chromatography on silica gel (100-200 mesh) by eluting with CHCl3/CH3OH (8:2) mixture to give
25
20
target molecule trichobotryside A (1.2 mg, 50%). [α]D +65.7 (c = 0.12, CH3OH), lit[α]D +50.1 (c = 1.58,
CH3OH); IR (neat): 3436, 3395, 3081, 2930, 1644, 1467, 1253, 1082, 773 cm-1; 1H NMR (500 MHz, DMSO-d6): δ
6.76 (dd, 2H, J 15.7 Hz), 5.81 (dd, 2H, J 15.7 Hz), 5.41 (brs, OH), 5.34 - 5.30 (m, 1H), 5.05 (d, 2H, J 4.2 Hz), 4.47 -
13
4.42 (m, 2H), 3.54 - 3.49 (m, 2H), 1.99 - 1.94 (m, 8H), 1.52 - 1.42 (m, 4H), 1.05 (d, 6H, J 6.1 Hz); C NMR (125
MHz, DMSO-d6): δ 164.9, 150.9, 120.2, 70.7, 69.8, 62, 40.6, 29.1, 25.9, 22.2; MS (ESIMS): m/z 423 (M+Na+);
HRMS (ESI): calcd for C20H32O8Na (M+Na)+ 423.1986; Found 423.2009.
Acknowledgements
Authors SGN and GNL are thankful to UGC-New Delhi and CSIR-New Delhi respectively for providing
fellowships and Minister of Science and Technology for providing financial support under DST-SERB-GAP-0563
and Director CSIR-IICT for providing facilities.
Supplementary Material
Copies of 1H NMR, 13C NMR spectra associated with this paper can be found in the online version.
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