Total synthesis of macrosphelide M from diacetone glucose

Article abstract of DOI:10.1002/ejoc.201101603

The total synthesis of macrosphelide M is described. The key steps include the preparation of the acid and alcohol fragments from diacetone glucose and (S)-malic acid, respectively, followed by Yamaguchi esterification and macrocyclization of the tris-olefin by ring-closing metathesis. Finally, one-pot deprotection of the PMB and TBS groups with TiCl₄ results in the target. The C-3/C-4 stereocenters of diacetone glucose are used for the introduction of four stereocenters, whereas the fifth stereocenter is realized from (S)-malic acid. The total synthesis of macrosphelide M was achieved from diacetone glucose and (S)-malic acid. The key steps include Yamaguchi esterification and macrocyclization of the tris-olefin by the second-generation Grubbs catalyst.

Full text of DOI:10.1002/ejoc.201101603

FULL PAPER
DOI: 10.1002/ejoc.201101603
Total Synthesis of Macrosphelide M from Diacetone Glucose
Gangavaram V. M. Sharma*[a] and Post Sai Reddy[a]
Dedicated to Dr. Christian Bruneau on the occasion of his 60th birthday[‡]
Keywords: Carbohydrates / Esterification / Metathesis / Macrocycles
The total synthesis of macrosphelide M is described. The key
steps include the preparation of the acid and alcohol frag-
one-pot deprotection of the PMB and TBS groups with TiCl4
results in the target. The C-3/C-4 stereocenters of diacetone
ments from diacetone glucose and (S)-malic acid, respec- glucose are used for the introduction of four stereocenters,
tively, followed by Yamaguchi esterification and macrocycli-
zation of the tris-olefin by ring-closing metathesis. Finally,
whereas the fifth stereocenter is realized from (S)-malic acid.
Introduction
Results and Discussion
Macrosphelides A–L[1] are a 16-membered macrotriolide
class of antibiotics having a trilactone backbone in their
structures, whereas macrosphelide M[2] (1) is a 15-mem-
bered macrotriolide that is a positional isomer of macro-
sphelide E[3] (2, Scheme 1). compound 1 was isolated[2] from
a strain of Periconia byssoides, originally isolated from
Aplysia kurodai. The absolute stereochemistry of 1 was re-
ported by Yamada et al.[2] on the basis of its spectroscopic
analysis and some chemical transformations. Tris-lactone 1
has five stereocenters, whose absolute configuration was de-
fined as (3R,8R,9S,14R,15S) and whose skeleton contained
two trans double bonds. It was found to inhibit the ad-
hesion of human leukemia HL-60 cells to human umbilical
vein endothelial cells (HUVEC). Herein, we report a carbo-
hydrate-based[3b,4] total synthesis of macrosphelide M (1)
from diacetone glucose (9) by using ring-closing metathesis
(RCM) to construct the macrocycle.[3d,5]
Retrosynthetic analysis of 1 is shown in Scheme 2. The
formation of 1 was envisaged to occur through macrocycli-
zation of 3, which could be obtained by Yamaguchi esterifi-
cation of fragments 4 and 5. Both fragments 4 and 5 could
be obtained from common intermediate 7, realized from
diacetone glucose (9), whereas acid 8 could be made from
(S)-malic acid.
Accordingly, known PMB-ether 10[6] (Scheme 3), pre-
pared from 9, upon selective hydrolysis with 60% aq.
CH3COOH gave diol 11[6] (88%), which upon treatment
[7a]
with Ph3P, imidazole, and I2
was converted into olefin
12[7b] in 65% yield. Hydrolysis of olefin 12 with 60% aq.
CH3COOH and a catalytic amount of concentrated HCl
afforded diol 13[7b] (68%). Oxidative cleavage of diol 13
with NaIO4 in acetone/water and subsequent reduction of
unstable aldehyde 14 with LiAlH4 gave 15 in 81% yield by
concomitant reduction of the formyl group and formate es-
ter. Diol 15 was treated with pTsCl and Et3N in CH2Cl2 to
give the primary tosylate, which upon subsequent reduction
with LiAlH4 furnished alcohol 7 in 89% yield. Alcohol 7 is
a common fragment for 4 and 5.
The synthesis of fragment 5 (Scheme 4) was initiated
from commercially available diol 17, which was prepared
from known ester 16[8a] in two steps. Accordingly, selective
tosylation (pTsCl, Et3N, CH2Cl2) of 16 and subsequent re-
duction of the resulting tosylate with LiAlH4 afforded 1,3-
diol 17[8b,8c] in 82% yield. Reaction of 17 with benzoyl
chloride and Et3N gave benzoate 18 (85%), which upon sil-
ylation with TBSCl and imidazole furnished 19 in 96%
yield. Base hydrolysis of ester 19 with K2CO3 and MeOH
gave 20 (89%), which upon oxidation with TEMPO and
BAIB[9] afforded carboxylic acid 8 in 79% yield. Yamaguchi
esterification[10] of alcohol 7 with acid 8, through the mixed
Scheme 1. Structures of macrosphelides M and E.
[a] Organic and Biomolecular Chemistry Division,
CSIR-Indian Institute of Chemical Technology,
Hyderabad-500607, India
Fax: +91-40-27160387
E-mail: esmvee@iict.res.in
[‡] Dr. Christian Bruneau, CNRS-Université de Rennes 1, Rennes,
France.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101603.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Total Synthesis of Macrosphelide M from Diacetone Glucose
Scheme 4. Synthesis of segment 5.
were separated by column chromatography]. Deprotection
of PMB-ether in 6 with DDQ in CH2Cl2/H2O gave alcohol
25 (88%), which upon treatment with acryloyl chloride,
DIPEA, and DMAP in CH2Cl2 afforded 26 in 94% yield.
Selective removal of the p-toluenesulfonylethyl ester group
Scheme 2. Retrosynthesis of macrosphelide M.
anhydride prepared upon reaction of 8 with 2,4,6-tri- in 26 was effected with DBN[12] in benzene at room tem-
chlorobenzoyl chloride (Et3N, THF) in the presence of perature to furnish carboxylic acid 4 in 64% yield {[α]D27
DMAP in toluene, afforded ester 21 in 76% yield. Finally, –33.1 (c = 0.20, CHCl3)}.
=
desilylation of 21 with TBAF in THF afforded alcohol frag-
Yamaguchi esterification[10] of alcohol 5 with carboxylic
ment 5 in 90% yield {[α]2D7 = –90.7 (c = 0.15, CHCl3)}.
acid 4 (Scheme 6) by using 2,4,6-trichlorobenzoyl chloride
For the synthesis of fragment 4 (Scheme 5), allylic and Et3N in THF in the presence of DMAP in toluene
alcohol 7 was treated with TBSCl and imidazole in CH2Cl2 afforded ester 3 in 62% yield {[α]2D7 = +11.9 (c = 0.15,
to afford 22 in 98% yield. Dihydroxylation[11] of olefin 22 CHCl3)}. Macrocyclization by RCM of 3 with Grubbs sec-
with OsO4 and NMO in acetone/water gave diol 23 (92%), ond generation catalyst[5,13] (5 mol-%) gave 27 in 74% yield
which upon oxidative cleavage with NaIO4 in acetone/water {based on 20% recovery of the starting material, [α]D27
=
and subsequent olefination of aldehyde 24 with (p-toluene- +1.0 (c = 0.10, CHCl3)}. Finally, treatment of 27 with TiCl4
sulfonylethoxycarbonylmethylene)triphenylphosphorane[12] in CH2Cl2 afforded 1 in 67% yield {[α]D22 = +8.9 (c = 0.15,
gave ester 6 in 70% yield [cis (6a)/trans (6) = 1:4, isomers EtOH); ref.[2] [α]D22 = +5.5 (c = 0.30, EtOH)}.
Scheme 3. Synthesis of segment 7.
Eur. J. Org. Chem. 2012, 2414–2421
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G. V. M. Sharma, P. S. Reddy
FULL PAPER
Scheme 5. Synthesis of 4.
cept for compound 1 ([D6]acetone) with respect to internal TMS
(tetramethylsilane) reference. FTIR spectra were measured with a
Thermo Nicolet Nexus 670 spectrometer. Optical rotations were
measured with a JASCO DIP 300 digital polarimeter. Mass spectra
were recorded with a Fannigan Mat 1210 double-focusing mass
spectrometer operating with a direct inlet system.
(R)-1-[(3aR,5R,6R,6aR)-6-(4-Methoxybenzyloxy)-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol (11): A solution of
10 (14.25 g, 37.50 mmol) in 60 % aq. CH3COOH (71 mL) was
stirred at room temperature for 10 h. The reaction mixture was
neutralized with solid NaHCO3 (143 g), and the crude residue was
extracted with EtOAc (3ϫ200 mL) and dried (Na2SO4). The sol-
vent was evaporated under reduced pressure, and the residue was
purified by column chromatography [60–120 mesh silica gel, 50%
EtOAc in petroleum ether (PE)] to afford diol 11 (8.67 g, 88%) as
a colorless syrup. [α]2D2 = +99.2 (c = 0.30, CHCl3). 1H NMR
(300 MHz, CDCl3, 295 K): δ = 7.25 (d, J = 8.3 Hz, 2 H, Ar-H),
6.84 (d, J = 8.3 Hz, 2 H, Ar-H), 5.71 (d, J = 3.8 Hz, 1 H, C1 H),
4.71 (d, J = 11.0 Hz, 1 H, OCHPMP), 4.55 (m, 1 H, C2 H), 4.43
(d, J = 11.0 Hz, 1 H, OCHЈPMP), 4.01 (dd, J = 3.4, 8.7 Hz, 1 H,
OCH), 3.94–3.86 (m, 1 H, OCH), 3.83 (dd, J = 4.5, 9.1 Hz, 1 H,
OCH), 3.80 (s, 3 H, OCH3), 3.68–3.53 (m, 2 H, OCH, CHOPMB),
2.71–2.25 (m, 2 H, 2 OH), 1.57 (s, 3 H, CH3), 1.35 (s, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = 159.7, 130.0 (2 C),
128.6, 114.0 (2 C), 113.1, 104.1, 79.1, 77.2, 76.3, 71.8, 70.7, 63.0,
Scheme 6. Synthesis of 1.
Conclusions
55.2, 26.7, 26.5 ppm. IR (neat): ν = 3434, 2935, 1613, 1514, 1377,
˜
In summary, the synthesis of macrosphelide M was 1248, 1170, 1126, 1025, 876, 824, 758 cm–1. HRMS (ESI): calcd.
for C17H24O7 [M + Na]+ 363.1419; found 363.1413.
achieved from 9 and (S)-malic acid, wherein four stereocen-
ters (8R,9S,14R,15S) were obtained from 4 and the (3R)
stereocenter was obtained from (S)-malic acid. The 1H
NMR and 13C NMR[14] spectral data of synthetic 1
matches the data reported for the natural product well,[2]
though deviation is observed in the optical rotation value.
(3aR,5R,6R,6aR)-6-(4-Methoxybenzyloxy)-2,2-dimethyl-5-vinyltetra-
hydrofuro[2,3-d][1,3]dioxole (12): To a mixture of 11 (8.67 g,
25.49 mmol), Ph3P (26.72 g, 102.0 mmol), and imidazole (6.94 g,
102.0 mmol) in CH2Cl2 was added I2 (19.28 g, 76.50 mmol) at 0 °C,
and the mixture was stirred at room temperature for 4 h. A satu-
rated aqueous solution of NaOH was added to the reaction mix-
ture, which was then extracted with CHCl3 (100 mL). The organic
layers were washed with sat. aq. sodium thiosulphate (40 mL) and
brine (40 mL) and then dried (Na2SO4). The solvent was evapo-
rated under reduced pressure, and the residue was purified by col-
umn chromatography (60–120 mesh silica gel, 5% EtOAc in PE) to
give olefin 12 (5.07 g, 65%) as a colorless syrup. [α]2D2 = +52.0 (c =
Experimental Section
General Methods: Reactions were carried out as described in the
procedures; organic layers were dried with Na2SO4, and the crude
products were purified by column chromatography using 60–
120 mesh silica gel. 1H NMR spectra were recorded at 300, 400,
and 500 MHz, whereas 13C NMR spectra were recorded at 50 and
75 MHz. NMR spectra (1H and 13C) were recorded in CDCl3 ex-
1
0.60, CHCl3). H NMR (300 MHz, CDCl3, 295 K): δ = 7.22 (d, J
= 8.7 Hz, 2 H, Ar-H), 6.84 (d, J = 8.7 Hz, 2 H, Ar-H), 5.77 (ddd,
J = 6.4, 10.6, 17.0 Hz, 1 H, CH=CH2), 5.67 (d, J = 3.8 Hz, 1 H,
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2414–2421

Total Synthesis of Macrosphelide M from Diacetone Glucose
C1 H), 5.37 (d, J = 17.0 Hz, 1 H, =CH2), 5.20 (d, J = 10.6 Hz, 1 without any further purification. To a stirred suspension of LiAlH4
H, =CH2), 4.54–4.46 (m, 2 H, OCH2PMP), 4.42–4.35 (m, 1 H,
(0.32 g, 8.40 mmol) in THF (7.5 mL) was dropwise added a solu-
tion of tosylate in THF (9 mL) at 0 °C under a nitrogen atmo-
OCH-allyl), 3.79 (s, 3 H, OCH3), 3.39 (dd, J = 4.3, 9.1 Hz, 1 H,
OCH2), 1.59 (s, 3 H, CH3), 1.34 (s, 3 H, CH3) ppm. 13C NMR sphere, and the mixture was stirred at room temperature for 6 h.
(75 MHz, CDCl3, 295 K): δ = 159.4, 134.8, 129.5 (3 C), 118.5, 113.7
The reaction mixture was worked up as described for 15, and the
(2 C), 112.7, 103.6, 81.3, 78.9, 77.5, 71.8, 55.2, 26.6, 26.4 ppm. IR crude residue was purified by column chromatography (60–
(neat): ν = 2987, 2934, 1613, 1513, 1375, 1248, 1026, 823, 768 cm–1.
120 mesh silica gel, 12% EtOAc in PE) to afford 7 (1.87 g, 89%)
as a colorless oil. [α]2D7 = +58.4 (c = 0.35, CHCl3). 1H NMR
(300 MHz, CDCl3, 295 K): δ = 7.22 (d, J = 8.7 Hz, 2 H, Ar-H),
6.84 (d, J = 8.7 Hz, 2 H, Ar-H), 5.79 (ddd, J = 5.7, 10.2, 17.4 Hz,
1 H, CH=CH2), 5.25 (dd, J = 1.5, 17.4 Hz, 1 H, =CH2), 5.16 (dd,
J = 1.5, 10.2 Hz, 1 H, =CH2), 4.56 (d, J = 11.3 Hz, 1 H,
OCHPMP), 4.41 (d, J = 11.7 Hz, 1 H, OCHЈPMP), 4.17 (m, 1 H,
OCH-allyl), 3.79 (s, 3 H, OCH3), 3.57–3.49 (m, 1 H, CHOPMB),
1.09 (d, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
295 K): δ = 159.1, 136.5, 130.3, 129.2 (2 C), 116.3, 113.7 (2 C),
˜
HRMS (ESI): calcd. for C17H22O5 [M + Na]+ 329.1364; found
329.1375.
(3R,4R)-4-(4-Methoxybenzyloxy)-5-oxopent-1-en-3-yl Formate (14):
To a solution of 12 (5.07 g, 16.58 mmol) in 60% aq. CH3COOH
(25 mL) was added a catalytic amount of conc. HCl at room tem-
perature, and the mixture was stirred for 12 h. The reaction mixture
was neutralized with solid NaHCO3 (50 g), and the crude residue
was extracted with EtOAc (3ϫ50 mL) and dried (Na2SO4). The
solvent was evaporated under reduced pressure, and the residue was
purified by column chromatography (60–120 mesh silica gel, 45%
EtOAc in PE) to furnish 13 (3.0 g, 68%) as a colorless syrup. To a
solution of diol 13 (3.0 g, 11.28 mmol) in acetone/water (5:1,
15 mL) at 0 °C was added NaIO4 (2.90 g, 13.53 mmol), and the
mixture was stirred at room temperature for 45 min. The solvent
was evaporated under reduced pressure, and the residue was ex-
tracted with CHCl3 (30 mL), dried (Na2SO4), and concentrated to
give aldehyde 14, which was directly used in the next step without
77.0, 74.4, 70.4, 55.2, 13.9 ppm. IR (neat): ν = 3445, 2874, 2102,
˜
1612, 1513, 1456, 1379, 1301, 1247, 1173, 1085, 1034, 990, 927,
822 cm–1. HRMS (ESI): calcd. for C13H18O3 [M + Na]+ 245.1153;
found 245.1158.
(R)-Butane-1,3-diol (17): To
a stirred solution of 16 (1.0 g,
6.76 mmol) in CH2Cl2 (20 mL) was added Et3N (2.82 mL,
20.27 mmol) at 0 °C followed by pTsCl (1.29 g, 6.76 mmol) after
15 min, and the mixture was stirred at room temperature for 10 h.
The reaction mixture was treated with water (20 mL) and extracted
with CH2Cl2 (40 mL). The combined extracts were washed with
brine (20 mL) and dried (Na2SO4). The solvent was evaporated un-
der reduced pressure and the tosylate was directly used in the next
step without any further purification. To a stirred suspension of
LiAlH4 (0.51 g, 13.51 mmol) in THF (10 mL) at 0 °C was dropwise
added a solution of tosylate in THF (10 mL) under a nitrogen at-
mosphere, and the mixture was stirred at room temperature for 8 h.
The reaction mixture was worked up as described for 15, and the
residue was purified by column chromatography (60–120 mesh sil-
ica gel, 50% EtOAc in PE) to give 17 (0.50 g, 82%) as a colorless
oil. [α]2D2 = –28.8 (c = 0.50, EtOH). 1H NMR (300 MHz, CDCl3,
295 K): δ = 4.11–4.0 (m, 1 H, OCH), 3.91–3.75 (m, 2 H, OCH2),
2.58–2.41 (br. s, 2 H, 2 OH), 1.70–1.64 (m, 2 H, CH2), 1.24 (d, J
= 6.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ
1
any further purification. H NMR (300 MHz, CDCl3, 295 K): δ =
9.52 (d, J = 1.5 Hz, 1 H, CHO), 8.02 (s, 1 H, OCHO), 7.21 (d, J
= 8.3 Hz, 2 H, Ar-H), 6.82 (d, J = 8.3 Hz, 2 H, Ar-H), 5.86 (ddd,
J = 6.8, 10.6, 17.4 Hz, 1 H, CH=CH2), 5.70–5.67 (m, 1 H, OCH-
allyl), 5.33 (d, J = 17.4 Hz, 1 H, =CH2), 5.30 (d, J = 10.6 Hz, 1 H,
=CH2), 4.64 (d, J = 12.1 Hz, 1 H, OCHPMP), 4.56 (d, J = 12.1 Hz,
1 H, OCHЈPMP), 3.88–3.83 (m, 1 H, CHOPMB), 3.79 (s, 3 H,
OCH3) ppm.
(2S,3R)-2-(4-Methoxybenzyloxy)pent-4-ene-1,3-diol (15): To
a
stirred suspension of LiAlH4 (0.43 g, 11.28 mmol) in THF (7 mL)
at 0 °C was dropwise added a solution of aldehyde 14 (2.98 g,
11.28 mmol) in THF (8 mL) under nitrogen atmosphere, and the
mixture was stirred at room temperature for 1 h. The reaction mix-
ture was cooled to 0 °C, treated with saturated aq. Na2SO4 solution
(10 mL), and filtered. The mixture was washed with EtOAc
(50 mL), and the filtrate was dried (Na2SO4). The solvent was evap-
orated under reduced pressure, and the residue was purified by col-
umn chromatography (60–120 mesh silica gel, 35% EtOAc in PE)
to furnish 15 (2.18 g, 81%) as a colorless oil. [α]2D7 = +8.3 (c = 0.25,
CHCl3). 1H NMR (300 MHz, CDCl3, 295 K): δ = 7.21 (d, J =
8.5 Hz, 2 H, Ar-H), 6.83 (d, J = 8.5 Hz, 2 H, Ar-H), 5.87 (ddd, J
= 5.3, 10.6, 17.2 Hz, 1 H, CH=CH2), 5.35 (d, J = 17.2 Hz, 1 H,
=CH2), 5.22 (d, J = 10.6 Hz, 1 H, =CH2), 4.64–4.52 (m, 2 H,
OCH2PMP), 4.33 (m, 1 H, OCH-allyl), 3.79 (s, 3 H, OCH3), 3.71
(d, J = 4.3 Hz, 2 H, OCH2), 3.40 (q, J = 4.5 Hz, 1 H, CHOPMB)
ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = 159.1, 137.0, 129.8,
129.4 (2 C), 116.0, 113.7 (2 C), 80.8, 72.5, 71.6, 61.1, 55.1 ppm. IR
= 67.2, 60.7, 40.0, 23.4 ppm. IR (neat): ν = 3358, 2934, 1419, 1376,
˜
1054 cm–1. MF: C4H10O2. MS (EI): m/z (%) = 91 (38) [M + 1]+,
90 (4) [M]+, 72 (21), 57 (47), 43 (100), 41 (77).
(R)-3-Hydroxybutyl Benzoate (18): To a solution of 17 (0.50 g,
5.56 mmol) in CH2Cl2 (10 mL) was added Et3N (2.32 mL,
16.67 mmol) followed by BzCl (0.65 mL, 5.56 mmol) at 0 °C, and
the mixture was stirred at room temperature for 10 h. The reaction
mixture was treated with water (15 mL) and extracted with CH2Cl2
(20 mL). The organic layer was washed with brine (10 mL) and
dried (Na2SO4). The solvent was evaporated under reduced pres-
sure, and residue was purified by column chromatography (60–
120 mesh silica gel, 15% EtOAc in PE) to furnish 18 (0.91 g, 85%)
as a colorless oil. [α]2D2 = –24.8 (c = 0.30, CHCl3). 1H NMR
(300 MHz, CDCl3, 295 K): δ = 8.02 (d, J = 7.2 Hz, 2 H, Ar-H),
7.53 (dd, J = 7.2, 7.6 Hz, 1 H, Ar-H), 7.41 (dd, J = 7.9, 7.2 Hz, 2
H, Ar-H), 4.64–4.55 (m, 1 H, CHOBz), 4.39–4.31 (m, 1 H,
CHOBz), 3.98–3.88 (m, 1 H, OCH), 2.44–2.32 (br. s, 1 H, OH),
1.97–1.72 (m, 2 H, CH2), 1.24 (d, J = 6.0 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3, 295 K): δ = 166.9, 132.9, 130.0, 129.5 (2
(neat): ν = 3396, 2880, 1612, 1513, 1459, 1301, 1247, 1176, 1096,
˜
1035, 929, 822 cm–1. HRMS (ESI): calcd. for C13H18O4 [M +
Na]+ 261.1102; found 261.1113.
(3R,4S)-4-(4-Methoxybenzyloxy)pent-1-en-3-ol (7): To
a stirred
solution of 15 (2.0 g, 8.40 mmol) in CH2Cl2 (30 mL) was sequen-
tially added Et3N (3.51 mL, 25.21 mmol) and pTsCl (1.60 g,
8.40 mmol) at 0 °C, and the mixture was stirred at room tempera-
ture for 12 h. The reaction mixture was treated with water (20 mL)
and extracted with CH2Cl2 (40 mL). The organic layer was washed
with brine (20 mL), dried (Na2SO4), and evaporated under reduced
pressure, and the crude tosylate was directly used in the next step
C), 128.3 (2 C), 64.6, 62.1, 38.0, 23.4 ppm. IR (neat): ν = 3428,
˜
3067, 2969, 2926, 1721, 1597, 1453, 1279, 1113, 1026 cm–1. HRMS
(ESI): calcd. for C11H14O3 [M + Na]+ 217.0840; found 217.0849.
(R)-3-(tert-Butyldimethylsilyloxy)butyl Benzoate (19): To a solution
of 18 (0.91 g, 4.69 mmol) in CH2Cl2 (9.1 mL) was added imidazole
Eur. J. Org. Chem. 2012, 2414–2421
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G. V. M. Sharma, P. S. Reddy
FULL PAPER
(0.64 g, 9.38 mmol) at 0 °C followed by TBSCl (0.85 g, 5.63 mmol)
after 15 min, and the mixture was stirred at room temperature for
8 h. The reaction mixture was treated with water (10 mL) and ex-
tracted with CH2Cl2 (20 mL). The organic layer was washed with
brine (10 mL) and dried (Na2SO4). The solvent was evaporated un-
der reduced pressure, and the residue was purified by column
chromatography (60–120 mesh silica gel, 5% EtOAc in PE) to af-
ford 19 (1.38 g, 96%) as a colorless oil. [α]2D2 = –35.8 (c = 0.40,
CHCl3). 1H NMR (300 MHz, CDCl3, 295 K): δ = 7.99 (d, J =
7.2 Hz, 2 H, Ar-H), 7.52 (dd, J = 7.2, 7.6 Hz, 2 H, Ar-H), 7.41 (t,
J = 7.6 Hz, 2 H, Ar-H), 4.46–4.29 (m, 2 H, CH2OBz), 4.08–3.98
(m, 1 H, OCH), 1.96–1.76 (m, 2 H, CH2), 1.22 (d, J = 6.0 Hz, 3
temperature for 5 h. The reaction mixture was filtered through Ce-
lite, the filtrate was evaporated, and the residue was purified by
column chromatography (60–120 mesh silica gel, 7% EtOAc in PE)
to afford 21 (0.29 g, 76%) as a colorless syrup. [α]2D7 = –23.7 (c =
1
0.30, CHCl3). H NMR (300 MHz, CDCl3, 295 K): δ = 7.18 (d, J
= 8.7 Hz, 2 H, Ar-H), 6.82 (d, J = 8.7 Hz, 2 H, Ar-H), 5.83 (ddd,
J = 6.8, 10.6, 17.0 Hz, 1 H, CH=CH2), 5.36–5.22 (m, 3 H, =CH2,
CHOCO), 4.49 (d, J = 11.3 Hz, 1 H, OCHPMP), 4.46 (d, J =
11.3 Hz, 1 H, OCHЈPMP), 4.32–4.20 (m, 1 H, CHOTBS), 3.78 (s,
3 H, OCH3), 3.62–3.54 (m, 1 H, CHOPMB), 2.53 (dd, J = 6.4,
14.7 Hz, 1 H, CH), 2.38 (dd, J = 6.0, 14.7 Hz, 1 H, CHЈ), 1.18 (d,
J = 6.0 Hz, 3 H, CH3), 1.14 (d, J = 6.4 Hz, 3 H, CH3), 0.86 [s, 9
H, CH3), 0.89 [s, 9 H, C(CH3)3], 0.05 (s, 3 H, CH3), 0.04 (s, 3 H, H, C(CH3)3], 0.06 (s, 3 H, CH3), 0.04 (s, 3 H, CH3) ppm. 13C NMR
CH3) ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = 166.5, 132.8,
(50 MHz, CDCl3, 295 K): δ = 170.4, 159.0, 132.9, 130.3, 129.1 (2
130.4, 129.5 (2 C), 128.3 (2 C), 65.3, 62.1, 38.4, 25.8 (3 C), 24.1,
C), 118.4, 113.7 (2 C), 76.4, 75.5, 70.9, 65.6, 55.2, 45.0, 25.8 (3 C),
18.0, –4.4, –5.0 ppm. IR (neat): ν = 2957, 2930, 2855, 1725, 1601, 23.8, 18.0, 15.9, –4.6, –4.9 ppm. IR (neat): ν = 2938, 2859, 1739,
˜
˜
1454, 1379, 1277, 1109, 1015, 835 cm–1. HRMS (ESI): calcd. for
C17H28O3Si [M + Na]+ 331.1705; found 331.1695.
1613, 1513, 1461, 1376, 1251, 1177, 1093, 997, 829 cm–1. HRMS
(ESI): calcd. for C23H38O5Si [M + Na]+ 445.2386; found 445.2407.
(R)-3-(tert-Butyldimethylsilyloxy)butan-1-ol (20): To a solution of
(R)-[(3R,4S)-4-(4-Methoxybenzyloxy)pent-1-en-3-yl] 3-Hydroxybut-
19 (1.38 g, 4.48 mmol) in methanol (5.5 mL) was added K2CO3 anoate (5): To a solution of 21 (0.29 g, 0.67 mmol) in THF (1 mL)
(1.85 g, 13.44 mmol), and the mixture was stirred at room tempera- was added TBAF (1.0 m in THF, 0.81 mL) at 0 °C, and the mixture
ture for 2 h. Methanol was evaporated, water (20 mL) was added, was stirred at room temperature for 2 h. The reaction mixture was
and the mixture was extracted with EtOAc (2ϫ20 mL). The or-
ganic layer was washed with brine (10 mL) and dried (Na2SO4).
The solvent was evaporated under reduced pressure, and the resi-
due was purified by column chromatography (60–120 mesh silica
gel, 15% EtOAc in PE) to give 20 (0.81 g, 89%) as a colorless oil.
[α]2D2 = –27.7 (c = 0.40, CHCl3). 1H NMR (300 MHz, CDCl3,
295 K): δ = 4.14–4.02 (m, 1 H, CHOTBS), 3.86–3.61 (m, 2 H,
OCH2), 2.28 (br. s, 1 H, OH), 1.80–1.50 (m, 2 H, CH2), 1.19 (d, J
concentrated, and the residue was purified by column chromatog-
raphy (60–120 mesh silica gel, 15% EtOAc in PE) to give 5 (0.19 g,
90%) as a yellow syrup. [α]2D7 = –90.7 (c = 0.15, CHCl3). 1H NMR
(300 MHz, CDCl3, 295 K): δ = 7.22 (d, J = 8.3 Hz, 2 H, Ar-H),
6.84 (d, J = 8.3 Hz, 2 H, Ar-H), 5.81 (ddd, J = 6.4, 10.3, 16.7 Hz,
1 H, CH=CH2), 5.45 (m, 1 H, OCHO), 5.29 (d, J = 16.7 Hz, 1 H,
=CH2), 5.25 (d, J = 10.3 Hz, 1 H, =CH2), 4.51 (d, J = 11.8 Hz, 1
H, OCHPMP), 4.45 (d, J = 11.8 Hz, 1 H, OCHЈPMP), 4.17–4.11
= 6.4 Hz, 3 H, CH3), 0.89 [s, 9 H, C(CH3)3], 0.09 (s, 3 H, CH3), (m, 1 H, OCH), 3.79 (s, 3 H, OCH3), 3.61–3.59 (m, 1 H,
0.08 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = CHOPMB), 2.94 (br. s, 1 H, OH), 2.50–2.39 (m, 2 H, CH2), 1.21
68.3, 60.4, 40.4, 25.8 (3 C), 23.4, 17.9, –4.4, –5.0 ppm. IR (neat): ν
(d, J = 5.9 Hz, 3 H, CH3), 1.14 (d, J = 6.4 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3, 295 K): δ = 172.0, 159.1, 132.6, 130.1,
129.3 (2 C), 118.4, 113.7 (2 C), 76.1, 75.2, 70.7, 64.5, 55.2, 43.3,
˜
= 3401, 2917, 2849, 1723, 1588, 1429, 1109, 1019 cm–1. HRMS
(ESI): calcd. for C10H24O2Si [M + Na]+ 227.1443; found 227.1449.
22.4, 15.2 ppm. IR (neat): ν = 3446, 2974, 2932, 1733, 1613, 1514,
˜
(R)-3-(tert-Butyldimethylsilyloxy)butanoic Acid (8): To a solution of
20 (0.81 g, 3.97 mmol) in CH2Cl2/H2O (1:1, 8.1 mL) was added
TEMPO (0.19 g, 1.19 mmol) and BAIB (3.84 g, 11.91 mmol) at
0 °C, and the mixture was stirred at room temperature for 1.25 h.
The reaction mixture was diluted with CHCl3 (2ϫ15 mL), washed
with sat. aq. sodium thiosulphate (15 mL) and brine (10 mL), and
dried (Na2SO4). The solvent was evaporated under reduced pres-
sure, and the residue was purified by flash column chromatography
(60–120 mesh silica gel, 10% EtOAc in PE) to furnish 8 (0.69 g,
1249, 1175, 1092, 1035, 988, 939, 823 cm–1. HRMS (ESI): calcd.
for C17H24O5 [M + Na]+ 331.1521; found 331.1534.
tert-Butyl[(3R,4S)-4-(4-methoxybenzyloxy)pent-1-en-3-yloxy]dimeth-
ylsilane (22): To a solution of 7 (1.0 g, 4.50 mmol) in CH2Cl2
(10 mL) was added imidazole (0.61 g, 9.01 mmol) at 0 °C. After
15 min TBSCl (0.81 g, 5.41 mmol) was added portionwise at 0 °C,
and the mixture was stirred at room temperature for 3 h. The reac-
tion mixture was worked up as described for 19, and the residue
was purified by column chromatography (60–120 mesh silica gel,
H, 3% EtOAc in PE) to afford 22 (1.48 g, 98%) as a colorless oil. [α]
1
79%) as a light yellow syrup. [α]2D2 = –10.8 (c = 0.25, CHCl3). H
NMR (300 MHz, CDCl3, 295 K):
CHOTBS), 2.56–2.36 (m, 2 H, CH2), 1.23 (d, J = 6.1 Hz, 3 H,
CH3), 0.86 [s, 9 H, C(CH3)3], 0.06 (s, 3 H, CH3), 0.05 (s, 3 H, CH3) δ = 7.18 (d, J = 8.3 Hz, 2 H, Ar-H), 6.79 (d, J = 8.3 Hz, 2 H, Ar-
δ
=
4.33–4.23 (m,
1
27
1
= +0.8 (c = 0.25, CHCl3). H NMR (500 MHz, CDCl3, 295 K):
D
ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = 176.9, 65.7, 44.4,
H), 5.84 (ddd, J = 5.9, 10.2, 17.1 Hz, 1 H, CH=CH2), 5.22 (d, J =
17.1 Hz, 1 H, =CH2), 5.12 (d, J = 10.2 Hz, 1 H, =CH2), 4.46 (s, 2
H, OCH2PMP), 4.08 (m, 1 H, CHOTBS), 3.78 (s, 3 H, OCH3),
3.42–3.36 (m, 1 H, CHOPMB), 1.09 (d, J = 5.9 Hz, 3 H, CH3),
0.90 [s, 9 H, C(CH3)3], 0.05 (s, 3 H, CH3), 0.02 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3, 295 K): δ = 158.9, 138.8, 131.0, 129.1
(2 C), 115.3, 113.6 (2 C), 78.3, 76.7, 70.9, 55.1, 25.9 (3 C), 18.2,
25.7 (3 C), 23.7, 17.9, –4.6, –5.1 ppm. IR (neat): ν = 3380, 2930,
˜
2859, 1713, 1640, 1414, 1132, 1090, 1015, 835 cm–1. HRMS (ESI):
calcd. for C10H22O3Si [M + Na]+ 241.1235; found 241.1241.
(R)-[(3R,4S)-4-(4-Methoxybenzyloxy)pent-1-en-3-yl] 3-(tert-Butyl-
dimethylsilyloxy)butanoate (21): To a stirred solution of 8 (0.20 g,
0.88 mmol) in THF (2 mL) was added Et3N (0.37 mL, 2.63 mmol)
followed by 2,4,6-trichlorobenzoyl chloride (0.27 mL, 1.75 mmol)
after 10 min at 0 °C under a N2 atmosphere, and the mixture was
stirred at room temperature for 2 h. The reaction mixture was fil-
tered and evaporated, and the resulting product was dissolved in
toluene (1 mL). To this mixture was added DMAP (0.27 g,
2.19 mmol) and alcohol 7 (0.21 g, 0.96 mmol) in toluene (1 mL) at
0 °C under a N2 atmosphere, and the mixture was stirred at room
15.6, –4.5, –4.8 ppm. IR (neat): ν = 2934, 2858, 1614, 1513, 1464,
˜
1375, 1301, 1249, 1173, 1092, 1037, 925, 835 cm–1. HRMS (ESI):
calcd. for C19H32O3Si [M + Na]+ 359.2018; found 359.2024.
(4R,5S,E)-2-Tosylethyl 4-(tert-Butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)hex-2-enoate (6): To a mixture of alkene 22 (1.48 g,
4.40 mmol), 50% aq. NMO (2.06 mL, 8.81 mmol) in acetone/water
(4:1, 6 mL) was added a catalytic amount of OsO4 (0.02 m in tolu-
2418
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2414–2421

Total Synthesis of Macrosphelide M from Diacetone Glucose
ene, 0.19 mL) at 0 °C, and the mixture was stirred at room tempera-
ture for 12 h. The reaction mixture was treated with aq. Na2SO3
(5 mL), acetone was removed under reduced pressure and extracted
with EtOAc (2ϫ30 mL). The organic phase was dried (Na2SO4),
concentrated, and purified by column chromatography (60–
120 mesh silica gel, 25% EtOAc in PE) to afford 23 (1.50 g, 92%)
as a colorless oil. To a stirred solution of diol 23 (1.50 g,
4.05 mmol) in acetone/water (5:1, 7.5 mL) at 0 °C was added
NaIO4 (1.04 g, 4.86 mmol), and the mixture was stirred to room
temperature for 1 h. Acetone was removed under reduced pressure,
and the residue was extracted with CHCl3 (15 mL), dried
(Na2SO4), and evaporated to give aldehyde 24 as a colorless oil. To
a solution of (p-toulenesulfonylethoxycarbonylmethylene)tri-
phenylphosphorane (4.07 g, 8.11 mmol) in benzene (10 mL) at re-
flux was added aldehyde 24 in benzene (5 mL), and the mixture
was stirred for 5 h. Benzene was evaporated under reduced pres-
sure, and the residue was purified by column chromatography
(cis/trans isomers 6a/6 in 1:4). First eluted (60–120 mesh silica gel,
9% EtOAc in PE) was 6a (0.41 g, 18%) as a colorless oil. Second
eluted (60–120 mesh silica gel, 10% EtOAc in PE) was 6 (1.60 g,
70%) as a colorless oil. Data for 6a: [α]2D7 = +5.8 (c = 0.28, CHCl3).
1H NMR (300 MHz, CDCl3, 295 K): δ = 7.72 (d, J = 8.3 Hz, 2 H,
Ar-H), 7.29 (d, J = 8.3 Hz, 2 H, Ar-H), 7.20 (d, J = 8.7 Hz, 2 H,
Ar-H), 6.80 (d, J = 8.7 Hz, 2 H, Ar-H), 6.10 (dd, J = 8.3, 11.1 Hz,
1 H, CH=CH), 5.41 (dd, J = 1.1, 11.1 Hz, 1 H, CH=CH), 5.39 (m,
1 H, CHOTBS), 4.54 (d, J = 11.7 Hz, 1 H, OCHPMP), 4.47 (d, J
= 11.7 Hz, 1 H OCHЈPMP), 4.46–4.31 (m, 2 H, CH2OCO), 3.80
(s, 3 H, OCH3), 3.41–3.32 (m, 3 H, CHOPMB, CH2SO2), 2.45 (s,
3 H, CH3), 1.03 (d, J = 6.4 Hz, 3 H, CH3), 0.88 [s, 9 H, C(CH3)3],
0.06 (s, 3 H, CH3), 0.01 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3, 295 K): δ = 164.7, 158.9, 152.2, 144.9, 136.4, 131.0, 129.9
(2 C), 129.3 (2 C), 128.0 (2 C), 117.9, 113.5 (2 C), 77.6, 70.6, 70.5,
57.4, 55.2, 55.0, 25.7 (3 C), 21.6, 18.1, 15.7, –4.8 (2 C) ppm. IR
CHOTBS), 3.83–3.68 (m, 1 H, OCH), 3.46–3.40 (m, 2 H, CH2SO2),
2.46 (s, 3 H, CH3), 1.90 (br. s, 1 H, OH), 1.10 (d, J = 6.4 Hz, 3 H,
CH3), 0.92 [s, 9 H, C(CH3)3], 0.08 (s, 3 H, CH3), 0.04 (s, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = 165.2, 148.0, 145.0,
136.3, 129.9 (2 C), 128.1 (2 C), 121.0, 75.6, 70.1, 57.7, 55.0, 25.7 (3
C), 21.6, 18.1, 17.2, –4.6, –5.0 ppm. IR (neat): ν = 3515, 2933, 2892,
˜
2858, 1721, 1654, 1599, 1462, 1390, 1257, 1143, 1082, 1021, 981,
835 cm–1. HRMS (ESI): calcd. for C21H34O6SSi [M + Na]+
465.1743; found 465.1760.
(4R,5S,E)-2-Tosylethyl 5-(Acryloyloxy)-4-(tert-butyldimethyl
silyloxy)hex-2-enoate (26): To a stirred solution of 25 (1.11 g,
2.51 mmol) in CH2Cl2 (11 mL) was added DIPEA (1.74 mL,
10.05 mmol) followed by acrolyl chloride (0.24 mL, 3.01 mmol) at
0 °C. A catalytic amount of DMAP was added to the reaction mix-
ture, which was then stirred at room temperature for 40 min. Water
(10 mL) was added, and the organics were extracted with CH2Cl2
(20 mL). The solution was washed with brine (8 mL) and dried
(Na2SO4). The solvent was evaporated under reduced pressure, and
the residue was purified by column chromatography (60–120 mesh
silica gel, 12% EtOAc in PE) to afford 26 (1.18 g, 94%) as a light
yellow oil. [α]2D7 = –13.2 (c = 0.35, CHCl3). 1H NMR (300 MHz,
CDCl3, 295 K): δ = 7.81 (d, J = 8.3 Hz, 2 H, Ar-H), 7.37 (d, J =
8.3 Hz, 2 H, Ar-H), 6.70 (dd, J = 4.2, 15.5 Hz, 1 H, CH=CH), 6.39
(dd, J = 1.1, 17.0 Hz, 1 H, =CH2), 6.08 (dd, J = 10.6, 17.4 Hz, 1
H, CH=CH2), 5.87–5.80 (m, 2 H, CH=CH, =CH2), 4.90 (qd, J =
2.6, 6.4 Hz, 1 H, CHOCO), 4.52–4.35 (m, 3 H, CH2OCO,
CHOTBS), 3.47–3.37 (m, 2 H, CH2SO2), 2.47 (s, 3 H, CH3), 1.15
(d, J = 6.4 Hz, 3 H, CH3), 0.92 [s, 9 H, C(CH3)3], 0.04 (s, 3 H,
CH3), 0.00 (s, 3 H, CH3) ppm. 13C NMR (50 MHz, CDCl3, 295 K):
δ = 165.4, 165.2, 147.9, 144.9, 136.4, 131.0, 129.9 (2 C), 128.4, 128.1
(2 C), 120.8, 73.1, 72.5, 57.8, 55.1, 25.7 (3 C), 21.6, 18.2, 13.5, –4.7,
–5.0 ppm. IR (neat): ν = 2935, 2858, 1723, 1653, 1403, 1321, 1262,
˜
1194, 1145, 1066, 1030, 979, 834 cm–1. HRMS (ESI): calcd. for
C24H36O7SSi [M + Na]+ 519.1848; found 519.1838.
(neat): ν = 2925, 1750, 1604, 1510, 1309, 1248, 1145, 1088,
˜
815 cm–1. HRMS (ESI): calcd. for C29H42O7SSi [M + Na]+
585.2318; found 585.2320. Data for 6: [α]2D7 = –4.3 (c = 0.45,
CHCl3). 1H NMR (300 MHz, CDCl3, 295 K): δ = 7.77 (d, J =
8.3 Hz, 2 H, Ar-H), 7.33 (d, J = 8.3 Hz, 2 H, Ar-H), 7.21 (d, J =
8.7 Hz, 2 H, Ar-H), 6.85 (dd, J = 4.5, 15.9 Hz, 1 H, CH=CH), 6.83
(d, J = 8.7 Hz, 2 H, Ar-H), 5.80 (dd, J = 1.5, 15.9 Hz, 1 H,
CH=CH), 4.55–4.36 (m, 4 H, CH2OCO, OCH2PMP), 4.28–4.22
(m, 1 H, CHOTBS), 3.81 (s, 3 H, OCH3), 3.52–3.36 (m, 3 H,
CHOPMB, CH2SO2), 2.46 (s, 3 H, CH3), 1.11 (d, J = 6.4 Hz, 3 H,
CH3), 0.93 [s, 9 H, C(CH3)3], 0.07 (s, 3 H, CH3), 0.02 (s, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3, 295 K): δ = 165.6, 159.1, 150.1,
144.9, 136.3, 130.4, 129.9 (2 C), 129.2 (2 C), 128.1 (2 C), 119.8,
113.7 (2 C), 77.5, 74.6, 70.9, 57.7, 55.2, 55.1, 25.8 (3 C), 21.6, 18.1,
(4R,5S,E)-5-(Acryloyloxy)-4-(tert-butyldimethylsilyloxy)hex-2-enoic
Acid (4): To a solution of 26 (1.18 g, 2.38 mmol) in benzene (4 mL)
was added DBN (0.29 g, 2.38 mmol) in benzene (2 mL) at room
temperature, and the mixture was stirred for 12 h. Then ether/water
(1:1, 4 mL) was added to the reaction mixture. The water layer was
acidified with aq. 1 n HCl and extracted with EtOAc (2ϫ20 mL).
The organic layer was dried (Na2SO4) and evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (60–120 mesh silica gel, 30 % EtOAc in PE) to afford 4
(0.48 g, 64%) as a colorless oil. [α]2D7 = –33.1 (c = 0.20, CHCl3). 1H
NMR (300 MHz, CDCl3, 295 K): δ = 7.02 (dd, J = 4.2, 15.5 Hz, 1
H, CH=CH), 6.42 (dd, J = 1.1, 17.4 Hz, 1 H, =CH2), 6.15–6.03
(m, 2 H, CH=CH2, CH=CH), 5.85 (dd, J = 1.1, 10.6 Hz, 1 H,
=CH2), 4.99 (qd, J = 3.0, 6.4 Hz, 1 H, CHOCO), 4.53 (m, 1 H,
CHOTBS), 1.20 (d, J = 6.4 Hz, 3 H, CH3), 0.94 [s, 9 H, C(CH3)3],
0.06 (s, 3 H, CH3), 0.04 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3, 295 K): δ = 170.8, 165.5, 149.2, 131.1, 128.5, 121.4, 73.3,
15.4, –4.7, –4.8 ppm. IR (neat): ν = 2934, 2857, 1722, 1647, 1513,
˜
1462, 1383, 1250, 1144, 1089, 1032, 829 cm–1. HRMS (ESI): calcd.
for C29H42O7SSi [M + Na]+ 585.2318; found 585.2319.
(4R,5S,E)-2-Tosylethyl 4-(tert-Butyldimethylsilyloxy)-5-hydroxy-
hex-2-enoate (25): To a stirred solution of 6 (1.60 g, 2.85 mmol) in
CH2Cl2/H2O (19:1, 8 mL) at 0 °C was added DDQ (0.71 g,
3.13 mmol), and the mixture was stirred to room temperature for
30 min. The reaction mixture was treated with satd. aq. NaHCO3
(1 mL), dried (Na2SO4), and filtered through Celite by using
CHCl3. The solvent was evaporated, and the residue was purified
by column chromatography (60–120 mesh silica gel, 25% EtOAc in
72.6, 25.7 (3 C), 18.2, 13.7, –4.7, –5.0 ppm. IR (neat): ν = 3436,
˜
2932, 2858, 1725, 1702, 1657, 1465, 1409, 1295, 1262, 1194, 1160,
1065, 1035, 982, 837 cm–1. HRMS (ESI): calcd. for C15H26O5Si [M
+ Na]+ 337.1447; found 337.1450.
(4R,5S,E)-{(R)-4-[(3R,4S)-4-(4-Methoxybenzyloxy)pent-1-en-3-
yloxy]-4-oxobutan-2-yl} 5-(Acryloyloxy)-4-(tert-butyldimethyl
silyloxy)hex-2-enoate (3): To a stirred solution of 4 (0.05 g,
PE) to give 25 (1.11 g, 88%) as a colorless oil. [α]2D7 = –22.0 (c =
1
0.20, CHCl3). H NMR (300 MHz, CDCl3, 295 K): δ = 7.80 (d, J 0.16 mmol) in THF (1 mL) was added Et3N (0.07 mL, 0.48 mmol)
= 8.3 Hz, 2 H, Ar-H), 7.36 (d, J = 8.3 Hz, 2 H, Ar-H), 6.78 (dd, J followed by 2,4,6-trichlorobenzoyl chloride (0.05 mL, 0.32 mmol)
= 4.9, 15.9 Hz, 1 H, CH=CH), 5.76 (d, J = 1.5, 15.9 Hz, 1 H, at 0 °C under a N2 atmosphere, and the mixture was stirred at room
CH=CH), 4.54–4.36 (m, 2 H, CH2OCO), 4.18–4.11 (m, 1 H, temperature for 2 h. The reaction mixture was filtered, and the fil-
Eur. J. Org. Chem. 2012, 2414–2421
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2419

G. V. M. Sharma, P. S. Reddy
FULL PAPER
trate was evaporated. The resulting anhydride was dissolved in tolu-
ene (1 mL). To this mixture was added DMAP (0.05 g, 0.40 mmol)
followed by a solution of alcohol 5 (0.06 g, 0.18 mL) in toluene
(1 mL) at 0 °C under a N2 atmosphere, and the mixture was stirred
at room temperature for 6 h. The reaction mixture was filtered
through Celite, and the filtrate was evaporated. The crude residue
was purified by column chromatography (60–120 mesh silica gel,
for 3 h. Sat. aq. NaHCO3 solution (5 mL) was added and extracted
with CHCl3 (2ϫ15 mL). The combined organic layers were washed
with water (5 mL) and brine (5 mL) and dried (Na2SO4). The sol-
vent was evaporated under reduced pressure, and the residue was
purified by column chromatography (60–120 mesh silica gel, 1.3%
MeOH in CHCl3) to afford 1 (0.004 g, 67%) as a pale yellow oil.
[α]2D2 = +8.9 (c = 0.15, EtOH) {ref.[2] [α]2D2 = +5.5 (c = 0.30, EtOH)}.
7% ethyl acetate in PE) to give 3 (0.06 g, 62%) as a colorless syrup. 1H NMR (500 MHz, [D6]acetone, 295 K): δ = 7.04 (dd, J = 3.5,
[α]2D7 = +11.9 (c = 0.15, CHCl3). 1H NMR (300 MHz, CDCl3,
295 K): δ = 7.18 (d, J = 8.5 Hz, 2 H, Ar-H), 6.83 (dd, J = 4.3,
16.0 Hz, 1 H, CH=CH), 6.81 (d, J = 8.5 Hz, 2 H, Ar-H), 6.40 (dd,
J = 1.5, 17.2 Hz, 1 H, =CH2), 6.08 (dd, J = 10.4, 17.4 Hz, 1 H,
CH=CH2), 5.97 (dd, J = 1.7, 15.5 Hz, 1 H, =CH2), 5.87–5.71 (m,
15.5 Hz, 1 H, CH=CH), 6.47 (dd, J = 8.5, 16.2 Hz, 1 H, CH=CH),
6.08 (dd, J = 1.4, 15.5 Hz, 1 H, CH=CH), 5.89 (dd, J = 0.4,
16.2 Hz, 1 H, CH=CH), 5.28 (dqd, J = 4.2, 6.3, 10.6 Hz, 1 H,
CHOCO), 5.18 (ddd, J = 3.5, 4.9, 8.5 Hz, 1 H, CHOCO), 5.12 (d,
J = 2.8, 6.3 Hz, 1 H, CHOCO), 4.56 (d, J = 4.2 Hz, 1 H, OH),
2 H, CH=CH2, CH=CH), 5.41–5.19 (m, 4 H, =CH2, 2 CHOCO), 4.47 (br. s, 1 H, CHOH), 4.15 (d, J = 4.9 Hz, 1 H, OH), 3.90 (qdd,
5.0–4.89 (m, 1 H, CHOCO), 4.53–4.39 (m, 3 H, OCH2PMP, J = 4.9, 5.6, 6.3 Hz, 1 H, CHOH), 2.89 (dd, J = 3.5, 14.8 Hz, 1 H,
CHOTBS), 3.78 (s, 3 H, OCH3), 3.61–3.52 (m, 1 H, CHOPMB),
2.73 (dd, J = 7.0, 15.5 Hz, 1 H, CH), 2.55 (qd, J = 6.4, 15.5 Hz, 1
CH), 2.51 (dd, J = 10.6, 14.8 Hz, 1 H, CHЈ), 1.39 (d, J = 6.3 Hz,
3 H, CH3), 1.36 (d, J = 6.3 Hz, 3 H, CH3), 1.14 (d, J = 6.3 Hz, 3
H, CHЈ), 1.37 (d, J = 6.2 Hz, 3 H, CH3), 1.16 (d, J = 6.4 Hz, 3 H, H, CH3) ppm. 13C NMR (75 MHz, [D6]acetone, 295 K): δ =
CH3), 1.12 (d, J = 6.4 Hz, 3 H, CH3), 0.92 [s, 9 H, C(CH3)3], 0.04 169.08, 166.20, 164.72, 147.23, 144.40, 126.15, 122.92, 78.19, 75.24,
(s, 3 H, CH3), 0.01 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
295 K): δ = 169.2, 165.5, 165.2, 159.1, 146.8, 132.8, 131.0, 130.4,
129.2 (2 C), 128.5, 122.1, 118.3, 113.7 (2 C), 76.4, 75.4, 73.3, 72.7,
70.8, 67.6, 55.2, 41.1, 25.7 (3 C), 19.8, 18.2, 15.5, 13.5, –4.7,
75.11, 68.98, 68.49, 42.10, 20.07, 19.11, 17.94 ppm. IR (neat): ν =
˜
3450, 2926, 1716, 1650, 1644, 1272 cm–1. HRMS (ESI): calcd. for
C16H22O8 [M + Na]+ 365.1212; found 365.1209.
–5.0 ppm. IR (neat): ν = 2927, 2857, 1728, 1617, 1513, 1460, 1376,
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra for all com-
pounds.
˜
1254, 1188, 1063, 982, 835 cm–1. HRMS (ESI): calcd. for
C32H48O9Si [M + Na]+ 627.2965; found 627.2975.
(2R,6R,7E,11S,12R,13E)-12-(tert-Butyldimethylsilyloxy)-6-[(S)-1-
(4-methoxybenzyloxy)ethyl]-2,11-dimethyl-1,5,10-trioxacyclopenta-
deca-7,13-diene-4,9,15-trione (27): To a solution of 3 (0.05 g,
0.08 mmol) in dry CH2Cl2 (50 mL) was added Grubbs second gen-
eration catalyst (5 mol-%), and the mixture was stirred at reflux for
18 h under a N2 atmosphere. Most of the solvent was then distilled
off, and the concentrated solution was left to stir at room tempera-
ture for 2 h under a flow of air to decompose the catalyst. The
reaction mixture was evaporated to dryness to give a brown residue,
which was purified by column chromatography (60–120 mesh silica
gel, 9% EtOAc in PE) to afford compound 27 (0.028 g, 74% of
yield; based on 20% starting material [eluted first at 7% EtOAc in
PE] recovery) as a yellow solid. M.p. 67–69 °C. [α]2D7 = +1.0 (c =
Acknowledgments
The authors are thankful to the Council of Scientific and Industrial
Research, New Delhi, India, for financial support (MLP-0010C).
P.S.R. thanks the University Grants Commission (UGC), New
Delhi, India, for the award of a research fellowship.
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0.10, CHCl3). H NMR (300 MHz, CDCl3, 295 K): δ = 7.23 (d, J
= 8.7 Hz, 2 H, Ar-H), 7.03 (dd, J = 3.8, 15.5 Hz, 1 H, CH=CH),
6.86 (d, J = 8.7 Hz, 2 H, Ar-H), 6.40 (dd, J = 8.3, 15.7 Hz, 1 H,
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˜
1657, 1615, 1517, 1466, 1382, 1254, 1093, 1036, 983, 837 cm–1
.
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[14] The authors thank Prof. T. Yamada for providing the 1H NMR
and 13C NMR spectra of the natural product.
Received: November 4, 2011
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Published Online: March 12, 2012
Eur. J. Org. Chem. 2012, 2414–2421
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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