'Chiron' approach to the total synthesis of macrolide (+)-Aspicilin

Article abstract of DOI:10.1039/c3ra45530k

An efficient total synthesis of 18 membered macrolactone, (+)-Aspicilin (lichen macrolide) has been achieved in 12 linear steps with 10.2% overall yield from carbohydrate based building block d-glucal. Highlights of the strategy include preparation of 2-deoxysugar from protected glycal 14, two-carbon Wittig olefination of the Swern oxidised intermediate 7, union of 'carbohydrate based' fragment 5 and a long chain (C-11) chiral alcohol 6 by Yamaguchi esterification and finally ring closing metathesis of the resulting compound 4.

Full text of DOI:10.1039/c3ra45530k

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‘Chiron’ approach to the total synthesis of
macrolide (+)-Aspicilin†
Cite this: RSC Adv., 2014, 4, 4253
*
Puli Saidhareddy, Sama Ajay and Arun K. Shaw
An efficient total synthesis of 18 membered macrolactone, (+)-Aspicilin (lichen macrolide) has been
achieved in 12 linear steps with 10.2% overall yield from carbohydrate based building block D-glucal.
Highlights of the strategy include preparation of 2-deoxysugar from protected glycal 14, two-carbon
Wittig olefination of the Swern oxidised intermediate 7, union of ‘carbohydrate based’ fragment 5 and a
long chain (C-11) chiral alcohol 6 by Yamaguchi esterification and finally ring closing metathesis of the
resulting compound 4.
Received 2nd October 2013
Accepted 1st November 2013
DOI: 10.1039/c3ra45530k
www.rsc.org/advances
predominantly from carbohydrates,6 stimulated us to explore a
convenient approach to the synthesis of (+)-Aspicilin 1 from
Introduction
D-glucal 2.
The retrosynthetic strategy for (+)-Aspicilin (1) is delineated
(+)-Aspicilin 1, an eighteen membered macrocyclic lactone, was
rst isolated in 1900 by Hesse1 from the lichen of Lecanoraceae
family and the basic structure was elucidated in 1973 by Huneck
et al.2 The relative and absolute congurations (4R,5S,6R,17S)
associated with (+)-Aspicilin 1 were nally established in 1985
by using various spectroscopic methods, single crystal X-ray
analysis and synthetic studies.3 Zwanenburg et al. reported the
rst total synthesis of Aspicilin by using photolactonisation of
the diastereomeric o-quinol acetates as the key step.4 Although a
signicant biological importance of the title molecule 1 has not
yet been discovered,5b the architecture of this molecule (three
contiguous stereocenters (4R,5S,6R) and a macrolactone ring)
attracts the attention of many synthetic chemists (Fig. 1).
Among the different synthetic approaches reported for this
molecule till date,5 to the best of our knowledge, only two of
them utilized carbohydrates as chiral starting materials.5d,s Our
ongoing interest towards the synthesis of various natural
products and their analogues from chiral building blocks
in Scheme 1. We envisaged that 1 could be obtained from
protected macrolactone 3, a synthetic precursor of Aspicilin, by
hydrogenation of the isolated double bond and cleavage of the
protecting groups. The intermediate 3 could in turn be prepared
by esterication of functionalized olenic acid 5 with an
appropriate long chain chiral alcohol 6 followed by ring closing
metathesis (RCM). The acid 5, which contains three required
stereocenters of the natural product and a,b-unsaturated
carbonyl functionality, could be prepared from the intermediate
9 by the sequence of reactions like Wittig olenation and Swern
Fig. 1 Structure of (+)-Aspicilin 1.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute
(CSIR-CDRI), Sector 10, Jankipuram Extension, Sitapur road, Lucknow-226031,
India. E-mail: akshaw55@yahoo.com; Tel: +91-9415403775
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c3ra45530k
Scheme 1 Retrosynthetic analysis of (+)-Aspicilin.
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oxidation. While the hemiacetal 9 could be synthesized from respectively. Thus, the aldehyde 7, without its column puri-
protected glycal 14 by using LiBr/ion exchange resin, the frag- cation, was treated with methyl (triphenylphosphoranylidene)
ment 6 could be synthesized from 1,5-dibromopentane.
acetate to obtain a,b-unsaturated methyl ester 17 in 85% yield
over two steps followed by saponication with LiOH to furnish
the fragment 5 in 86% yield.
Results and discussion
The preparation of C-11 fragment 6, which contains terminal
alkene for the RCM and C2–OH with (S)-conguration for
esterication, was started from commercially available 1,5-
dibromopentane 12 (Scheme 3).5c The C–C coupling of 12 with
in situ-generated allylmagnesium bromide in the presence of
freshly prepared catalyst Li2CuCl4 (prepared from 2 equiv. of
LiCl and 1 equiv. of CuCl2 in conc. of 0.10 mol per lit. in THF)10
at 0 ꢀC gave the 8-bromo-1-octene 10 in 35% yield.11 It was then
converted to the corresponding Grignard reagent followed by its
in situ reaction with (S)-propylene oxide in the presence of a
catalytic amount of CuCN, thereby delivering the desired
(S)-undec-10-en-2-ol 6 in 89% yield.
As shown in the retrosynthesis (Scheme 1), our approach to the
total synthesis of the title molecule 1 was initiated by regiose-
lective protection of the primary alcoholic group of D-glucal 2
with t-butyldiphenylsilylchloride (TBDPSCl) in the presence of
imidazole to obtain the compound 13 in 92% yield.7 Methox-
ymethyl ether (MOM) protection of remaining two hydroxyl
groups of 13 with chloromethyl methyl ether (MOMCl) in the
presence of N,N-diisopropylethylamine (DIPEA) as a base and a
catalytic amount of N,N-dimethylaminopyridine (DMAP) fur-
nished the MOM protected glucal 14 in 82% yield. The prepa-
ration of 2-deoxyglucopyranoside 9 in 89% yield was achieved
from the protected glucal 14 by its hydration in the presence of
LiBr catalyzed by amberlite IR-120 (plus) ion exchange resin.8,9
Its Wittig olenation with methyltriphenylphosphonium
bromide in the presence of t-BuOK, used as base, furnished the
compound 15 in 60% yield. However, its yield was increased to
79% when n-BuLi was used.6f To simplify the deprotection in
the last step as depicted in the retrosynthesis (Scheme 1), the
alcohol 15 was also protected as its MOM ether to obtain the
terminal olen 8 in 76% yield (Scheme 2). Its TBDPS depro-
tection with tetrabutylammonium uoride (TBAF) in THF
afforded primary alcohol 16 in 88% yield. The key intermediate
acid 5, required for the Yamaguchi esterication was prepared
in three steps from 16. In the rst step, the alcohol 16 was
converted into aldehyde 7 by Swern oxidation. The Wittig
olenation of the aldehyde and the saponication of the
resulting methyl ester were performed in the subsequent steps
With these two fragments in hand, we now aimed to
synthesize the target molecule (+)-Aspicilin 1. The unication of
fragments 5 and 6 was achieved under Yamaguchi esterication
conditions.12 Accordingly, compound 5 was rst treated with
2,4,6-trichlorobenzoyl chloride and Et3N to form
a tri-
chlorobenzoyl ester of 5, then it was reuxed with the alcohol 6
in the presence of DMAP to obtain a RCM precursor 4 in 85%
yield. Initial attempts for ring closing metathesis of compound
4 with Grubbs second generation catalyst at reux in DCM were
futile and an undesired tri-O-MOM protected cyclohexene 19, a
product of the RCM across the double bond of the a,b-unsatu-
rated ester, was formed exclusively (Scheme 4). However, the
participation of two terminal double bonds of 4 in the ring
closure was successfully achieved by Grubbs rst generation
catalyst at reux in DCM. Here a mixture of cis–trans (3 : 1)
isomers of the desired macrocyclic ring 3 and cyclohexene 19
was obtained in 1 : 1 ratio. Gratifyingly, the ratio of 3 to 19 was
increased to 2 : 1 when the reaction was performed at below
ꢀ
room temperature (15–25 C) (Table 1).
Further, the regioselective reduction of the isolated double
bond with Rosenmund reducing reagent (H2/Pd–BaSO4) yielded
the MOM protected Aspicilin 18 in 98% yield.5d Its MOM
deprotection with 1,2-ethanedithiol and boron triuoride
etherate under ice-cold conditions afforded the target molecule
1 in 76% yield. The melting point, specic rotation (mp 150–
20
26
153 C, [a]D +33.5 (c 0.10 in CHCl3) (lit.5k mp: 152–155 C [a]D
+37.5 (c 0.55 in CHCl3))) and NMR data (1H, 13C, HSQC, NOESY
spectra) of 1 were in excellent agreement with the reported one.
ꢀ
ꢀ
Scheme 2 Synthesis of fragment 5. Reagents and conditions: (a)
TBDPSCl, imidazole, DMF, ꢁ18 ꢀC, 24 h, 92%; (b) MOMCl, DIPEA, DMAP,
dry DCM, 0 ꢀC to RT, 14 h, 82%; (c) LiBr, amberlite IR-120 (plus) ion
exchange resin, CH3CN–H2O, 90 min, 89%; (d) (Ph)3PCH3Br, n-BuLi,
dry THF, ꢁ78 ꢀC to RT, 2 h, 79%; (e) MOMCl, DIPEA, DMAP, dry DCM, Scheme 3 Synthesis of fragment 6. Reagents and conditions: (a)
0 ꢀC to RT, 24 h, 76%; (f) TBAF, THF, 0 ꢀC to RT, 3 h, 88%; (g) (i) (COCl)2, AllylMgBr, LiCl, CuCl2, dry ether, ꢁ10 ꢀC, 5 h, 35%; (b) (i) Mg, dry THF,
DMSO, Et3N, dry DCM, ꢁ78 ꢀC, 1 h; (ii) (Ph)3PCHCO2Me, dry DCM, 1,2-dibromoethane, 5 h, reflux. (ii) (S)-propylene oxide, CuCN, dry THF,
reflux, 3 h, 85% (over two steps); (h) LiOH, H2O, CH3CN, RT, 12 h, 86%. ꢁ15 ꢀC, 4 h, 89%.
4254 | RSC Adv., 2014, 4, 4253–4259
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recorded in CDCl3 at 25 ꢀC. Chemical shi values are given on d
scale with reference to TMS at 0.00 ppm for proton and carbon.
The reference CDCl3 appeared at 77.40 ppm for 13C NMR. NMR
spectra were recorded on Bruker Avance 300 MHz spectrometer
at 300 MHz (1H) and 75 MHz (13C), 400 MHz spectrometer at 400
MHz (1H) and 100 MHz (13C). Optical rotations were determined
ꢀ
on an Autopol III polarimeter using a 1 dm cell at 17–32 C in
chloroform; concentrations mentioned are in g/100 ml. For IR
spectra were recorded on Perkin-Elmer 881 and FTIR-8210 PC
Shimadzu spectrophotometers. Mass spectra were recorded on
a JEOL JMS-600H high resolution spectrometer using EI mode
at 70 eV. ESI-HRMS were recorded on a JEOL-AccuTOF, JMS-
T100LC spectrometer.
(2R,3S,4R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-3,4-dihy-
dro-2h-pyran-3,4-diol 13. To a two necked 50 ml round bottom
ask, equipped with a magnetic stir bar, rubber septum and
nitrogen inlet, were added imidazole (326 mg, 4.788 mmol) and
a solution of D-glucal 2 (350 mg, 2.39 mmol) in DMF (10 ml). The
reaction mixture was cooled to ꢁ18 ꢀC and then TBDPSCl (0.62
ml, 2.39 mmol) was added drop wise to it. The stirring of the
resulting reaction mixture was continued for 24 h at the same
temperature. Aer completion of the reaction, the reaction
mixture was quenched with H2O and the organic layer was
extracted with ether (4 ꢂ 5 ml). The combined organic layers
were dried over Na2SO4 and the solvent was removed under
reduced pressure, followed by silica gel column chromatog-
raphy of the resulting residue with EtOAc–hexane (25/75 v/v) as
an eluent to obtain 13 in 92% yield (847 mg, 2.20 mmol) as a
colorless oil; [a]2D3 +46.5 (c 0.3 in CHCl3); Rf: 0.57 (1 : 1 EtOAc–
hexane); IR (Neat): nmax 3426, 3019, 2930, 1645, 1472, 1428,
1216, 757, 669 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 7.67–7.70 (m,
4H), 7.36–7.46 (m, 6H), 6.31 (dd, Ja ¼ 1.56 Hz, Jb ¼ 6.02 Hz, 1H),
4.71 (dd, Ja ¼ 2.07 Hz, Jb ¼ 6.03 Hz, 1H), 4.27 (d, J ¼ 6.75 Hz,
1H), 3.77–3.99 (m, 4H), 3.12 (br s, 1H), 2.61 (br s, 1H), 1.07
(s, 9H); 13C NMR (75 MHz, CDCl3) d 144.70, 136.04, 135.94,
133.33, 133.13, 130.32, 130.29, 128.24, 128.18, 102.76, 77.45,
72.09, 70.04, 64.23, 27.21, 19.65; ESI-HRMS: m/z [M + Na]+ calcd
for C22H28NaO4Si+ 407.1655, measured 407.1650.
Scheme 4 Synthesis of target molecule (+)-Aspicilin. Reagents and
conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, RT, 1 h then
6, DMAP, toluene, reflux, 3 h, 85% (b) Grubbs 2nd gen., DCM, reflux, 5 h,
78% (c) Grubbs 1st gen., DCM, 15 ꢀC, 16 h, 62% for 3 (d) H2/Pd–BaSO4,
EtOAc, RT, 1 h, 98% (e) HS(CH)2SH, BF3$Et2O, DCM, 0 ꢀC, 3 h, 76%.
Table 1 Conditions for the RCM
S. no
Catalyst
Conditions
Product
Isolated yield (%)
1
2
2nd generation
Reux
19
19
3 and 19
3 and 19
78
70
45 : 42
62 : 30
15–25 ꢀC
Reux
1
st generation
15–25 ꢀC
Conclusion
In summary, we have demonstrated a new and efficient chiral
substrate approach to the total synthesis of (+)-Aspicilin 1
starting from commercially available D-glucal in 12 linear steps
and an overall yield of 10.2%. The stereocenters of the starting
material 2 at C3, C4 and C5 (R, S and R respectively) were
conserved in the nal target molecule at C4, C5 and C6 (R, S and
R respectively), thus showing the selection of D-glucal as the
starting chiral pool material was well conceived. Compared to
earlier reports on its synthesis starting from carbohydrates, our
approach involves fewer reaction steps.5d,s Hydration of the
protected glycal, Swern oxidation, Wittig olenation, Yama-
guchi esterication and ring closing metathesis are employed
as efficient steps for the total synthesis of this target macrolide.
(((2R,3S,4R)-3,4-Bis(methoxymethoxy)-3,4-dihydro-2H-pyran-
2-yl)methoxy)(tert-butyl)diphenylsilane 14. To the stirred solu-
tion of compound 13 (429 mg, 1.11 mmol) dissolved in dry DCM
(15 ml) in a 50 ml two necked round bottom ask, equipped with
a magnetic stir bar, rubber septum and N2 inlet, was added the
ꢀ
DIPEA (1.16 ml, 6.69 mmol) at 0 C. The MOMCl (0.4 ml, 4.46
mmol) was added drop wise to it followed by the catalytic
amount of DMAP. Stirring was continued for 14 h at room
temperature. Aer completion of the reaction shown by the TLC,
the reaction mixture was quenched with cold water. The two
Experimental section
General
The organic solvents were made anhydrous by standard layers were separated and the aqueous layer was extracted with
methods before their use. Silica gel (60F-254) 2.5 ꢂ 5 cm TLC DCM (3 ꢂ 5 ml). The combined organic layers were washed with
plates coated with a 0.25 mm thickness were used to monitor water and brine solution sequentially and dried over the Na2SO4.
the progress of the reaction. Visualization of the spots was done The solvent was removed under reduced pressure and the
by spraying the plate with CeSO4 (1% in 2 N H2SO4) and resulting residue was subjected to silica gel column chroma-
subsequent charring over a hot plate. Silica gel (60–120 mesh) tography with EtOAc–hexane (6/94 v/v) as an eluent, to obtain
and silica gel (230–400 mesh) were used for column chroma- the pure compound 14 in 82% yield (432 mg, 0.88 mmol) as a
tography. All the intermediates were characterized by NMR, IR pale yellow oil; [a]2D2 +56.2 (c 0.1 in CHCl3); Rf: 0.43 (1 : 5.6,
ESI-HRMS and optical rotation. NMR experiments were EtOAc–hexane); IR (Neat): nmax 3015, 2930, 2855, 1645, 1472,
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1216, 757, 665 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 7.68–7.71 3.38 (s, 3H), 3.26 (s, 3H), 3.19–3.21 (br m, 1H), 2.36–2.49 (m, 2H),
(m, 4H), 7.36–7.39 (m, 6H), 6.35 (d, J ¼ 6.18 Hz, 1H), 4.82 (dd, Ja 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3) d 136.00, 135.97, 134.90,
¼ 3.39 Hz, Jb ¼ 6.24 Hz, 1H), 4.72–4.79 (m, 2H), 4.67–4.70 (m, 133.62, 133.59, 130.12, 128.08, 118.00, 98.64, 97.25, 80.38, 77.61,
2H), 4.11–4.12 (m,1H), 4.00–4.07 (m, 2H), 3.92–3.94 (m, 2H), 71.54, 65.29, 56.40, 56.30, 35.95, 27.25, 19.62; ESI-HRMS: m/z [M
3.34 (s, 3H), 3.33 (s, 3H), 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3) d + Na]+ calcd for C27H40NaO6Si+ 511.2492, measured 511.2486.
144.83, 136.12, 136.01, 133.94, 133.81, 130.01, 129.98, 128.0,
8-Bromo-1-octene 10. To a 100 ml oven and ame dried two
127.95, 100.11, 97.02, 95.87, 78.08, 72.58, 72.31, 62.41, 56.26, necked round bottom ask tted with water condenser on one
55.85, 27.19, 19.66; ESI-HRMS: m/z [M + Na]+ calcd for side while the other side with rubber septum, were added dry
C27H40NaO6Si+ 495.2179, measured 495.2155.
ether (20 ml), magnesium turnings (3 g, 0.130 mol) and a
(4R,5S,6R)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-4,5-bis- catalytic amount of I2. Aer stirring the solution for ve
(methoxymethoxy)tetrahydro-2H-pyran-2-ol 9. To the stirred minutes, the allylbromide (7.5 ml, 0.087 mmol) was added drop
solution of the protected glycal 14 (250 mg, 0.53 mmol) and wise to the above reaction mixture under cold water supply in
lithium bromide (138 mg, 1.59 mmol) in acetonitrile (10 ml) were the presence of N2 atmosphere. During addition the color of I2
added amberlite IR-120 (plus) ion exchange resin (130 mg) and slowly disappeared. Aer completion of the addition, stirring
water (2 ml) and the reaction mixture stirring was continued for was continued for 3 h.
90 min at room temperature. The solution was ltered, neutral-
To a solution of LiCl (553 mg, 0.013 mmol) and CuCl2 (877
ized with triethylamine and evaporated to dryness. The residue mg, 0.006 mmol) in dry THF (20 ml) in a two necked round
was dissolved in dichloromethane and washed with water, ice-cold bottom ask equipped with magnetic stir bar, N2 inlet and
1 M hydrochloric acid solution, and sodium bicarbonate solution. rubber septum, was added 1,5-dibromopentane (10 g, 0.043
Evaporation of the solvent le a oily syrup, which was puried by a mol). To this solution, the above freshly prepared allylmagne-
silica gel column chromatography with EtOAc–hexane (12/88 v/v) sium bromide was added drop wise for 30 min at ꢁ10 ꢀC. A
as an eluent to obtain the pure compound in 89% yield (230 mg, color change from green to colorless and then to black was
0.469 mmol); [a]2D3 +96.9 (c 0.4 in CHCl3); Rf: 0.48 (1 : 1, EtOAc– noticed during the addition of the Grignard reagent. The reac-
hexane); IR (Neat): nmax 3425, 3019, 2931, 1638, 1428, 1217, 1109, tion mixture was allowed to stir at the same temperature for 5 h.
1
762, 669 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.70–7.72 (m, 4H), Aerward, it was quenched with 1 N HCl (20 ml) and the
7.37–7.39 (m, 6H), 5.28–5.32 (m, 1H), 4.71–4.80 (m, 4H), 3.89–4.07 resulting solution was extracted with EtOAc (3 ꢂ 10 ml). The
(m, 3H), 3.61–3.64 (m, 2H), 3.50–3.58 (m, 3H), 3.43–3.48 (m, 2H), organic layer was dried over Na2SO4 and evaporated under
3.36 (s, 3H), 3.19–3.22 (m, 3H), 2.93 (br s, 1H), 2.21–2.34 (m, 1H), reduced pressure. The residue was puried by silica gel column
1.48–1.70 (m, 1H), 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3) d 136.30, chromatography using pure hexane as an eluent to give
136.23, 136.04, 136.02, 134.30, 134.26, 133.94, 133.87, 129.94, compound 10 (8-bromo-1-octene) in 35% yield (2.9 g, 0.02 mol)
129.90, 127.95, 127.85, 98.36, 96.64, 96.37, 94.11, 92.07, 77.55, as a colorless oil; Rf: 0.80 (pure hexane); IR (Neat): nmax 3020,
76.67, 76.48, 75.94, 75.40, 72.55, 63.98, 63.93, 56.47, 56.44, 55.81, 2975, 2927, 2855, 1634, 849, 757 cmꢁ1 1H NMR (300 MHz,
;
55.77, 39.13, 36.81, 27.25, 19.71, 19.67; ESI-HRMS: m/z [M + H]+ CDCl3) d 5.74–5.87 (m, 1H), 4.93–5.03 (m, 2H), 3.41 (t, J ¼ 6.72
calcd for C26H39O7Si+ 491.2465, measured 491.2460.
Hz, 2H), 2.02–2.07 (m, 2H), 1.81–1.88 (m, 2H), 1.33–1.49 (m,
(5R,6R,7R)-5-Allyl-6-(methoxymethoxy)-11,11-dimethyl-10,10- 6H); 13C NMR (75 MHz, CDCl3) d 139.27, 114.78, 34.38, 34.02,
diphenyl-2,4,9-trioxa-10-siladodecan-7-ol
15.
Methyl- 33.14, 29.05, 28.59, 28.39; ESI-HRMS: m/z [M ꢁ H]ꢁ calcd for
triphenylphosphonium bromide (1.83 g, 5.13 mmol) was placed C8H14Brꢁ 191.0435, measured 191.0428.
in a oven dried ask containing dry THF (10 ml) and the mixture
(S)-Undec-10-en-2-ol 6. A portion of 8-bromo-1-octene
ꢀ
was cooled to ꢁ78 C. n-BuLi (2.29 ml, 3.37 mmol) was added (approx. 50 mg) dissolved in dry THF (10 ml) and magnesium
drop wise to the reaction mixture under N2 atmosphere and the turnings (178 mg, 7.33 mmol) were placed in a 50 ml two necked
resulting mixture was stirred for 1 h at ꢁ30 ꢀC. The compound 9 round bottom ask, equipped with a magnetic stir bar, a N2
(360 mg, 0.73 mmol) dissolved in dry THF (8 ml) was added to inlet and a rubber septum. Two drops of dibromoethane were
ꢀ
the above Wittig salt drop wise at ꢁ30 C and the stirring was added to it and the reaction mixture was reuxed under
continued at the same temperature for 30 min. Aerward the vigorous stirring followed by the drop wise addition of the
temperature of the reaction bath was raised to room tempera- remaining solution of 8-bromo-1-octene (700 mg, 3.66 mmol) in
ture (25 ꢀC). Aer completion of the reaction (2 h), the reaction THF (5 ml) to it. The resulting reaction mixture was continued
mixture was quenched with NH4Cl and washed with brine to reux for another 4 h and aerward the solution was cooled
solution. The combined organic layers were dried over Na2SO4 to room temperature.
and concentrated under reduced pressure. The silica gel column
To another 50 ml two necked round bottom ask equipped
chromatography of the crude residue mixture using EtOAc– with a magnetic stir bar, a N2 inlet and a rubber septum, were
hexane (12.5/87.5 v/v) as an eluent, yielded the pure compound added (S)-propyleneoxide (0.26 ml, 3.66 mmol) and CuCN (16.4
15 in 79% yield (283 mg, 0.58 mmol); [a]2D6 ꢁ6.3 (c 0.1 in CHCl3); mg, 0.183 mmol) in dry THF (15 ml) and the reaction mixture
ꢀ
(c 0.56, CHCl3); Rf: 0.50 (1 : 4, EtOAc–hexane); IR (Neat): nmax was cooled to ꢁ15 C. To the above stirred solution the freshly
3427, 3015, 2930, 1641, 1427, 1217, 1106, 919, 764 cmꢁ1; 1H NMR prepared Grignard reagent as mentioned above was added drop
(300 MHz, CDCl3) d 7.67–7.70 (m, 4H), 7.36–7.42 (m, 6H), 5.77– wise by using a long needle. Aer completion of the addition,
5.91 (m, 1H), 5.08–5.16 (m, 2H), 4.69–4.70 (m, 3H), 4.59–4.61 the stirring was continued at ꢁ15 ꢀC for 4 h and an additional 2
(m, 1H), 3.95–4.00 (m, 1H), 3.85–3.88 (m, 2H), 3.69–3.79 (m, 2H), h at room temperature. Aer completion of the reaction, a
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saturated solution of NH4Cl was added and stirring was 134.61, 118.14, 98.76, 97.22, 97.15, 80.50, 79.19, 77.53, 62.44,
continued until a blue aqueous layer was obtained. The two 56.69, 56.28, 56.12, 36.30; ESI-HRMS: m/z [M + Na]+ calcd for
layers were separated and the aqueous layer was extracted with
C
13H26NaO7+ 317.1576, measured 317.1569.
ether (3 ꢂ 10 ml). The organic layers were combined, dried over
(4R,5S,6R,E)-Methyl4,5,6-Tris(methoxymethoxy)nona-2,8-dien-
Na2SO4 and evaporated in vacuo. The crude residue was puried oate 17. A solution of oxalylchloride (0.13 ml, 0.528 mmol) dis-
by silica gel column chromatography using EtOAc–hexane solved in dry DCM (5 ml) in a 50 ml double necked round bottom
(12/88 v/v) as an eluent to furnish the pure compound 6 in 89% ask equipped with a magnetic stir bar, nitrogen inlet and a
yield (555 mg, 3.26 mmol); [a]2D1 +12.4 (c 0.3 in CHCl3); Rf: 0.55 rubber septum was cooled at ꢁ78 ꢀC. To this solution, DMSO
(1 : 5 EtOAc–hexane); IR (Neat): nmax 3433, 3019, 2974, 2928, (0.22 ml, 3.057 mmol) was added drop wise and the stirring was
1
2856, 1639, 757 cmꢁ1; H NMR (300 MHz, CDCl3) d 5.76–5.86 continued for 5 min. Then alcohol 16 (300 mg, 1.019 mmol) was
(m, 1H), 4.91–5.01 (m, 2H), 3.78–3.79 (m, 1H), 2.01–2.05 (m, added drop wise and the stirring was further continued for 30 min
2H), 1.62 (br s, 1H), 1.26–1.41 (m, 12H), 1.18 (d, J ¼ 6.0 Hz, 3H); at the same temperature. To the stirred solution of the above
13C NMR (75 MHz, CDCl3) d 139.49, 114.47, 68.44, 39.70, 34.12, reaction mixture Et3N (0.71 ml, 5.096 mmol) was then added drop
29.94, 29.79, 29.41, 29.25, 26.09, 23.79; ESI-HRMS: m/z [M + H]+ wise and stirring was continued till the completion of the reac-
calcd for C11H23O+ 171.1749, measured 171.1744.
tion. The reaction mixture was quenched with saturated NH4Cl
(5R,6S,7R)-5-allyl-6,7-Bis(methoxymethoxy)-11,11-dimethyl- and extracted with DCM (3 ꢂ 5 ml). The combined organic layers
10,10-diphenyl-2,4,9-trioxa-10-siladodecane 8. To stirred were dried over Na2SO4 and the solvent was removed under
a
solution of compound 15 (200 mg, 0.409 mmol) in dry DCM reduced pressure. The crude compound was used for the next step
(5 ml) in a 100 ml two necked round bottom ask was added without further purication.
DIPEA (0.28 ml, 1.637 mmol). The reaction mixture was cooled
To a stirred solution of the crude product of the previous step
ꢀ
to ꢁ10 C. To this mixture MOMCl (0.06 ml, 0.818 mmol) was (300 mg, 1.027 mmol) in dry DCM (5 ml) was added (methox-
added drop wise followed by a catalytic amount of DMAP and ycarbonylmethyl)triphenylphosphonium bromide (515 mg,
then the stirring was continued for 24 h at room temperature. 1.541 mmol) and the reaction mixture was reuxed for 3 h. Aer
Aer completion of the reaction (TLC control), the reaction completion of the reaction, the solvent was evaporated under
mixture was quenched with cold water. The two layers were reduced pressure and the resulting residue was puried by
separated and the aqueous layer was extracted with DCM (3 ꢂ 7 silica gel column chromatography using EtOAc–hexane (12/88 v/
ml). The combined organic layers were dried over Na2SO4 and v) as an eluent, affording the compound 17 in 85% yield (302
concentrated under reduced pressure. The crude residue was mg, 0.87 mmol) (over two steps); [a]2D2 ꢁ42.0 (c 0.3 in CHCl3); Rf:
puried by column chromatography using EtOAc–hexane (8/92, 0.54 (1 : 5, EtOAc–hexane); IR (Neat): nmax 3019, 2928, 2854,
v/v) as an eluent to furnish the pure compound 8 in 76% yield 1721, 1643, 1215, 758, 669 cmꢁ1; H NMR (400 MHz, CDCl3) d
1
(166 mg, 0.31 mmol); [a]2D3 ꢁ8.1 (c 0.3 in CHCl3); Rf: 0.38 (1 : 5, 6.97 (dd, Ja ¼ 9.12 Hz, Jb ¼ 15.8 Hz, 1H), 6.08 (d, J ¼ 15.7 Hz,
EtOAc–hexane); IR (Neat): nmax 3072, 3013, 2934, 2052, 1640, 1H), 5.80–5.90 (m, 1H), 5.10–5.17 (m, 2H), 4.62–4.75 (m, 6H),
1465, 1216, 760, 669; 1H NMR (400 MHz, CDCl3) d 7.67–7.69 4.40–4.42 (m, 1H), 3.75–3.78 (m, 5H), 3.37–3.40 (m, 9H), 2.45–
(m, 4H), 7.36–7.42 (m, 6H), 5.79–5.89 (m, 1H), 5.08–5.14 (m, 2.51 (m, 1H), 2.32–2.39 (m, 1H); 13C NMR (75 MHz, CDCl3) d
2H), 4.63–4.77 (m, 6H), 3.77–3.89 (m, 5H), 3.32–3.36 (m, 9H), 166.69, 145.33, 134.57, 123.74, 118.18, 98.07, 97.40, 95.17,
2.39–2.46 (m, 1H), 2.26–2.33 (m, 1H), 1.05 (s, 9H); 13C NMR 80.42, 77.72, 75.84, 56.49, 56.26, 51.99, 36.42; ESI-HRMS: m/z
(100 MHz, CDCl3) d 136.06, 136.03, 134.74, 133.70, 130.09, [M + Na]+ calcd for C16H28NaO8+ 371.1682, measured 371.1692.
130.04, 128.05, 118.0, 98.05, 97.31, 96.82, 79.30, 78.36, 77.72,
(4R,5S,6R,E)-4,5,6-Tris(methoxymethoxy)nona-2,8-dienoic
64.25, 56.30, 56.14, 56.02, 36.60, 27.22, 19.52; ESI-HRMS: m/z [M acid 5. To a stirred solution of compound 17 (200 mg, 0.574
+ Na]+ calcd for C29H44NaO7Si+ 555.2754, measured 555.2750.
mmol) dissolved in acetonitrile (5 ml) were added LiOH (68.76
(2R,3S,4R)-2,3,4-Tris(methoxymethoxy)hept-6-en-1-ol
16. mg, 7.705 mmol) and a small amount of water (3 ml) at room
TBAF (0.84 ml, 1.0 M solution in THF, 0.844 mmol) was added temperature and stirring was continued at the same tempera-
drop wise to a stirred solution of compound 8 (300 mg, 0.375 ture overnight. Aer completion of the reaction, the reaction
mmol) in THF (10 ml) at 0 ꢀC and the stirring was continued for mixture was acidied with saturated NH4Cl and extracted with
3 h. Aer completion of the reaction, the reaction mixture was ether (5 ꢂ 5 ml). The combined organic layers were dried over
quenched with water and the organic layer was separated. The Na2SO4, ltered and concentrated. The crude residue was puri-
aqueous layer was extracted with EtOAc (3 ꢂ 5 ml) and the ed by column chromatography using EtOAc–hexane (35/65 v/v)
combined organic layers were dried over Na2SO4. The solvent as an eluent, furnishing compound 5 in 86% yield (165 mg, 0.49
was removed under reduced pressure and the crude reaction mmol); [a]2D3 +3.5 (c 0.1 in CHCl3); Rf: 0.43 (1:1, EtOAc–hexane);
mixture was puried by silica gel column chromatography by IR (Neat): nmax 3440, 3010, 2925, 2845, 1705, 1645, 1205, 758, 669
1
using EtOAc–hexane (20/80 v/v) as an eluent, to furnish the cmꢁ1; H NMR (400 MHz, CDCl3) d 7.08 (dd, Ja ¼ 6.44 Hz, Jb ¼
compound 16 in 88% yield (146 mg, 0.49 mmol); [a]2D4 +47.1 15.72 Hz, 1H), 6.09 (d, J ¼ 15.72 Hz, 1H), 5.79–5.90 (m, 1H), 5.10–
(c 0.4 in CHCl3); Rf: 0.34 (1 : 2.8, EtOAc–hexane); IR (Neat): nmax 5.17 (m, 2H), 4.62–4.76 (m, 6H), 4.44–4.46 (m, 2H), 3.77–3.79 (m,
3682, 3449, 3018, 2937, 1520, 1216, 760, 671; 1H NMR (400 MHz, 2H), 3.38–3.41 (m, 9H), 2.35–2.52 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 5.78–5.87 (m, 1H), 5.10–5.17 (m, 2H), 4.70–4.81 CDCl3) d 171.02, 147.76, 134.51, 123.28, 118.24, 98.03, 97.32,
(m, 6H), 3.72–3.89 (m, 5H), 3.40–3.45 (m, 9H), 3.22–3.25 (m, 95.34, 80.44, 77.70, 75.92, 56.50, 56.27, 36.37; ESI-HRMS: m/z [M
1H), 2.46 (t, J ¼ 6.72 Hz, 2H); 13C NMR (75 MHz, CDCl3) d + Na]+ calcd for C15H26NaO8+ 357.1525, measured 357.1520.
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3.36–3.41 (m, 9H), 1.54–1.57 (m, 6H), 1.24–1.25 (m, 17H); 13C
NMR (75 MHz, CDCl3) d 165.90, 143.67, 125.64, 97.98, 97.74,
94.26, 81.48, 78.25, 75.24, 71.24, 56.35, 56.28, 55.91, 35.75,
31.60, 30.09, 28.60, 28.51, 27.84, 27.41, 27.09, 26.71, 25.84,
(4R,5S,6R,E)-((S)-undec-10-en-2-yl) 4,5,6-tris(methoxymethoxy)-
nona-2,8-dienoate 4. To a stirred solution of compound 5 (230 mg,
0.660 mmol) in THF (7 ml) were added Et3N (0.110 ml, 0.792
mmol) and 2,4,6-trichlorobenzoyl chloride (0.12 ml, 0.729 mmol)
and the stirring was continued for 1 h at room temperature. The
reaction mixture was then added to a solution of alcohol 6
(135 mg, 0.792 mmol) and DMAP (403 mg, 3.30 mmol) in toluene
(5 ml) and heated at reux for 3 h. The reaction mixture was then
cooled to room temperature and quenched with saturated
NaHCO3 solution. The two layers were separated and the aqueous
layer was extracted with EtOAc (3 ꢂ 5 ml). The combined organic
layers were dried over Na2SO4, concentrated under reduced pres-
sure and puried by silica gel column chromatography using
EtOAc–hexane (8/92 v/v) as an eluent to afford compound 4 in 85%
yield (284 mg, 0.58 mmol); [a]2D7 ꢁ22.1 (c 0.03 in CHCl3); Rf: 0.50
(1 : 5, EtOAc–hexane); IR (Neat): nmax ¼ 3017, 2930, 2856, 1712,
1646, 1279, 1151, 759, 668 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 6.92
(dd, Ja ¼ 6.8 Hz, Jb ¼ 15.76 Hz, 1H), 6.04 (d, J ¼ 15.76 Hz, 1H),
5.75–5.90 (m, 2H), 5.09–5.16 (m, 2H), 4.91–5.01 (m, 3H), 4.63–4.76
(m, 6H), 4.39–4.42 (m, 1H), 3.76–3.79 (m, 2H), 3.37–3.40 (m, 9H),
2.33–2.51 (m, 2H), 2.01–2.06 (m, 2H), 1.48–1.62 (m, 2H), 1.23–1.38
(m, 13H); 13C NMR (100 MHz, CDCl3) d 165.93, 144.67, 139.50,
134.64, 124.75, 118.15, 114.51, 98.11, 97.45, 95.21, 80.45, 75.93,
71.64, 56.53, 56.27, 36.47, 36.32, 34.12, 29.75, 29.73, 29.39, 29.25,
23.96, 20.83; ESI-HRMS: m/z [M + Na]+ calcd for C26H46NaO8
+
483.2934, measured 483.2930.
Aspicilin 1. To the stirred solution of MOM ether 18 (31 mg,
0.067 mmol) and 1,2-ethanedithiol (0.045 ml, 0.61 mmol) in
DCM (1 ml) was added BF3$OEt2 (0.051 ml, 0.41 mmol) at ice
cold condition and the resulting reaction mixture was shied to
room temperature and stirred for 3 h. Aer consumption of the
starting material, saturated NaHCO3 and EtOAc (5 ml) were
added to the reaction mixture and it was allowed to stir for 10
min. The layers were separated and the aqueous layer was
extracted with EtOAc. The combined extracts were dried over
Na2SO4 and concentrated in vacuo to obtain the crude residue
which was puried by chromatography on silica gel using
EtOAc–hexane (35/65 v/v) as an eluent to afford (+)-Aspicilin 1,
as a colorless solid in 76% yield (17 mg, 0.05 mmol); [a]2D4 +33.5
(c 0.1 in CHCl3); mp: 150–153 ꢀC; Rf: 0.50 (1 : 1, EtOAc–hexane);
IR (KBr): nmax ¼ 3450, 3281, 2930, 2908, 1720, 1650, 1455, 1350,
1245, 1156, 1075 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 6.91 (dd, Ja
¼ 5.0 Hz, Jb ¼ 15.8 Hz, 1H), 6.12 (d, J ¼ 18.2 Hz, 1H), 5.03–5.09
(m, 1H), 4.58 (br m, 1H), 3.77 (m, 1H), 3.58 (m, 1H), 1.55–1.56
(m, 5H), 1.24–1.26 (m, 18H); 13C NMR (100 MHz, CDCl3) d
165.97, 145.06, 123.44, 75.14, 73.73, 71.57, 70.29, 36.08, 32.44,
30.08, 28.70, 28.16, 27.95, 27.62, 27.50, 26.78, 24.67, 23.97,
+
25.73, 20.33; ESI-HRMS: m/z [M + Na]+ calcd for C26H46NaO8
509.3090, measured 509.3087.
(3E,5R,6S,7R,9E,18S)-5,6,7-Tris(methoxymethoxy)-18-meth-
yloxacyclooctadeca-3,9-dien-2-one 3. A solution of 1st genera-
tion Grubbs catalyst (17 mg, 0.020 mmol) in dry DCM (150 ml)
was added drop wise to a stirred solution of compound 4 (100
mg, 0.205 mmol) in dry DCM, which was maintained at 15–25 ꢀC
under an atmosphere of N2. The reaction mixture was allowed to
stir for 14 h at the same temperature until the TLC analysis
indicated that no starting material was le. The reaction mixture
was concentrated under reduced pressure to afford the crude
product as a dark oil which was subjected to column chroma-
tography to furnish the mixture of diastereomers of compound 3
in 62% yield (58 mg, 0.13 mmol) (E/Z 1 : 3 ratio determined by 1H
NMR).
+
20.84; ESI-HRMS: m/z [M + H]+ calcd for C18H33O5 329.2328,
measured 329.2322.
Acknowledgements
Dedicated to Mr. Bholanath Banerjee on the occasion of his
75th birthday. We are thankful to Mr A. K. Pandey for technical
assistance and SAIF, CDRI, for providing spectral data. P.S.
thanks the CSIR, New Delhi for awarding a Junior Research
Fellowship and S.A. thanks the CSIR, New Delhi for awarding a
Senior Research Fellowship. The nancial grant from DST
(project SR/SI/OC-17/2010) is also acknowledged. CDRI
Communication No. 8560.
(5R,6S,7R,18S,E)-5,6,7-Tris(methoxymethoxy)-18-methylox-
acyclooctadec-3-en-2-one 18. To the stirred solution of
compound 3 (50 mg, 0.109 mmol) dissolved in ethyl acetate
(5 ml) was added 5% Pd on BaSO4 (15 mg) and the resulting
solution was stirred under hydrogen atmosphere at room
temperature for 1 h. The reaction mixture was ltered through a
short pad of celite bed and this bed was washed with ethyl
acetate (4 ml) for 2–3 times. The combined ltrates were
concentrated in vacuo to afford a clear oil which was subjected
to column chromatography (EtOAc–hexane, 8/92 v/v) to afford
the pure compound 18 in 98% yield (49.2 mg, 0.11 mmol); [a]D22
ꢁ19.1 (c 0.03 in CHCl3); Rf: 0.43 (1 : 5, EtOAc–hexane); IR (Neat):
nmax 3015, 2930, 2856, 1722, 1656, 1462, 1253, 1122, 1063, 755,
665 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 6.96 (dd, Ja ¼ 8.32 Hz, Jb
¼ 15.8 Hz, 1H), 6.02 (d, J ¼ 15.8 Hz, 1H), 5.02–5.10 (m, 1H),
4.74–4.85 (m, 3H), 4.59–4.65 (m, 3H), 4.44 (d, J ¼ 8.36 Hz, 1H),
3.88–3.90 (dd, Ja ¼ 1.28 Hz, Jb ¼ 6.52 Hz, 1H), 3.52–3.58 (m, 1H),
Notes and references
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This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 4253–4259 | 4259