Total syntheses of the proposed structure for ieodoglucomides A and B

Article abstract of DOI:10.1021/jo400041p

The first enantioselective total synthesis of new glycolipopeptides, ieodoglucomides A and B, has been accomplished along with synthetic elaboration to their C14-epimers starting from d-glucose using β-glycosylation and Grubbs olefin cross-metathesis reactions as the key steps. The present synthetic study has indicated the ambiguity in proposed absolute stereochemistry for the natural product.

Full text of DOI:10.1021/jo400041p

Article
pubs.acs.org/joc
Total Syntheses of the Proposed Structure for Ieodoglucomides A
and B
Chada Raji Reddy,* Enukonda Jithender, and Kothakonda Rajendra Prasad
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: The first enantioselective total synthesis of new
glycolipopeptides, ieodoglucomides A and B, has been
accomplished along with synthetic elaboration to their C14-
epimers starting from D-glucose using β-glycosylation and
Grubbs olefin cross-metathesis reactions as the key steps. The
present synthetic study has indicated the ambiguity in
proposed absolute stereochemistry for the natural product.
acid and L-valine via a β-glycosylation reaction precursor
alcohol. Other required olefins 4 and 5 would be easily
prepared from the commercially available 7-octenoic acid and
the related amino acids (L-alanine or glycine).
First Generation Strategy. Our initial synthetic expedition
toward ieodoglucomide A and B began with the preparation of
desired alcohol 7, a precursor for glycosylation reaction from L-
valine, which was initially converted to the epoxide 6 using
literature procedures in three-steps.3 A copper-catalyzed ring-
opening of the epoxide 6 with the Grignard reagent, generated
from 6-bromo-1-hexene and magnesium in THF, furnished the
alcohol 7 in 78% yield with 96% ee (Scheme 2).4,5
The sugar precursor for glycosylation reaction toward the
olefin 3a was achieved from D-glucose (Scheme 3). First, D-
glucose was transformed to the allyl glycoside 8 via a three-step
sequence.6 Next esterification of 8 with succinic anhydride in
the presence of pyridine followed by benzylation of the
resulting free-carboxylic acid using BnBr/Cs2CO3 in acetoni-
trile at 45 °C provided the succinate derivative 9 in 80% yield
over two steps. Palladium-mediated deallylation of 9 using
PdCl2/AcOH7 offered the desired sugar lactol 10 in 83% yield.
After having prepared both the precursors, glycosylation of 10
with the alcohol 7 was performed to produce the olefin 3a with
exclusive β-anomeric selectivity. This was accomplished under
Schmidt condensation8 reaction conditions of lactol 10 in the
presence of trimethylsilyltriflate (TMSOTf) at −15 °C, with
the alcohol 7 as its perbenzoylated α-trichloroacetimidate ester
(prepared using CCl3CN/DBU in dichloromethane).
INTRODUCTION
■
Ieodoglucomide A (1) and B (2) are two unique glycopeptides
isolated from a marine-derived bacterium Bacillus licheniformis
(strain 09IDYM23) in 2012 by Shin et al.1 The preliminary
biological evaluation revealed that natural products 1 and 2
were found to exhibit moderate antimicrobial activity against
Gram-positive, Gram-negative bacteria and fungi. Further
studies on the cytotoxicity against six human cancer cell lines
indicated that ieodoglucomide B (2) exhibited cancer cell
growth inhibition against lung cancer (NCI-H23) and stomach
cancer (NUGC-3) cell lines with GI50 values of 25.18 and 17.78
μg/mL, respectively. Structurally, ieodoglucomides A and B
possess a C30 and C29 skeleton, respectively, with a glycolipid
backbone, which is an unprecedented component of any
natural product. In addition, their structures have represented
the unique features consisting of an amino acid (L-alanine for 1
and glycine for 2), a new fatty acid (14-hydroxy-15-
methylhexadecanoic acid), a sugar (β-D-glucose) and a succinic
acid unit. The absolute stereochemistry of 1 and 2 was
determined by Marfey’s method for the amino acid, Mosher’s
method for C14 of 14-hydroxy-15-methylhexadecanoic acid
and comparison of specific rotation as well as Rf value with an
authentic compound for β-D-glucose. The interesting bio-
activities together with the distinctive structural framework
have prompted us to undertake the total synthesis of
ieodoglucomides A and B. As part of our continuing studies
toward the total synthesis of bioactive molecules,2 we describe
herein the first total syntheses of 1 and 2 as well as their C14-
epimers.
Olefins 4 and 5 were easily prepared via amide formation
between the 7-octenoic acid and amino benzyl ester 11
(obtained from L-alanine) or 12 (from glycine), under standard
reaction conditions (EDCI/HOBt/DIPEA in dichlorome-
thane) (Scheme 4).
RESULTS AND DISCUSSION
■
According to our retrosynthetic analysis (Scheme 1),
ieodoglucomides A and B were envisioned through a
convergent process involving construction of the complete
carbon skeleton through an intermolecular metathesis reaction
of a sugar-linked olefin 3a or 3b and an amino acid-appended
olefin 4 (for 1) and 5 (for 2). Synthesis of the olefin 3 was
anticipated starting from readily available D-glucose, succinic
Having both the fragments, now the stage was set for the
cross-metathesis reaction (Scheme 5). To our delight, the
Received: January 9, 2013
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthesis of Ieodoglucomide A and B
a
glucose in a two-step sequence involving acetylation followed
by selective removal of the anomeric acetyl group.11
Subsequent treatment of the hemiacetal 17 with trichloroace-
tonitrile in the presence of DBU in dichloromethane for 3 h
afforded the thermodynamically stable α-trichloroacetimidate,
which was immediately subjected to TMSOTf-promoted
glycosylation12 with the alcohol 7 to provide the corresponding
β-glycoside 18 in 67% yield over two steps. The next task was
to introduce the requisite succinyl group on to the sugar to give
the metathesis precursor 3b. Removal of the acetyl groups of
glycoside 18 was achieved using the Zemplen method (0.02 M
NaOMe/MeOH) to get the tetraol 19 in 78% yield.13
Conversion of 19 to the compound 3b with a free 4-hydroxyl
group was carried out in a three-step sequence involving (i) 4,6-
O-benzylidene formation (1,3-dioxane) with benzaldehyde
dimethyl acetal/CSA to give 20 in 95% yield, (ii) benzylation
of the remaining two hydroxyl groups using NaH/BnBr in
DMF, followed by (iii) regioselective reductive ring-opening by
treatment with LiAlH4 in the presence of AlCl3 provided the
desired 21 in 67% yield.14 Installation of the succinyl group was
achieved via esterification of 21 with succinic anhydride/
pyridine followed by benzylation of the resulting free-carboxylic
acid using BnBr/Cs2CO3 in acetonitrile to provide the
succinate derivative 3b in 83% yield. Next, exposure of the
alkene 3b to the key cross-metathesis (CM) with the olefin
partner 4 in the presence of G-II catalyst in dichloromethane at
reflux temperature delivered the fully protected glycopeptide 22
in 86% yield. Finally, hydrogenation of 22 using 10% Pd/C in
EtOH was successful in reduction of the double bond as well as
removal of all five benzyl groups in one pot to produce the
ieodoglucomide A (1) in 92% yield. Similarly, CM reaction of
Scheme 2. Synthesis of Alcohol 7
a
Reagents and conditions: (a) 6-Bromo-1-hexene, Mg, THF, CuI, −10
°C, 3 h, 78%.
intermolecular metathesis reaction between 3a and 4 proceeded
smoothly in the presence of Grubbs second generation (G-II)
catalyst9 in dichloromethane at reflux temperature to give the
fully protected glycopeptide 13 in 84% yield. Then, reduction
of the double bond, debenzylation and ethanolysis of the
benzoyl ester were planned in a one-pot operation under
hydrogenation reaction conditions using 10% Pd/C−H2 (g) in
EtOH in the presence of K2CO3 to obtain the target molecule
1. However, to our disappointment the above reaction provided
the desuccinyl glycopeptide 14, instead of the target molecule
1. Similarly, metathesis reaction between 3a and 5 provided the
glycopeptide 15, which upon treatment with hydrogenation
conditions gave 16, instead of the target molecule 2. All the
attempts for selective succinylation of the resulting primary
alcohol 14 or 16 gave an inseparable mixture of compounds.10
Second Generation Strategy. The above failure led us to
change our strategy to the one depicted in Scheme 6, wherein
no base-mediated solvolysis was involved after introducing the
succinyl group with suitable protecting groups on the sugar for
β-glycosylation reaction as well as for one-pot olefin reduction
and debenzylation. Thus, the revised approach for 1 and 2
commenced with the preparation of hemiacetal 17 from D-
a
Scheme 3. Synthesis of 3a
a
Reagents and conditions: (a) (i) Succinic anhydride, Py, rt, 12 h; (ii) BnBr, Cs2CO3, CH3CN, 45 °C, 6 h, 80% (two steps); (b) PdCl2, AcOH, H2O,
rt, 11 h, 83%; (c) (i) CCl3CN, DBU, CH2Cl2, rt, 3 h; (ii) 7, TMSOTf, CH2Cl2, −15 °C, 2 h, 65% (two steps).
B
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a
Scheme 4. Synthesis of 4 and 5
a
Reagents and conditions: (a) HOBt, EDCI, DIPEA, CH2Cl2, 0 °C to rt, 12 h, 4: 85%, 5: 87%.
a
Scheme 5
a
Reagents and conditions: (a) 4 for 13 or 5 for 15, benzoquinone, G-II, CH2Cl2, reflux, 5 h, 13: 84%, 15: 85%; (b) (i) 10% Pd/C, H2 (g) (1 atm),
EtOH, 2 h, rt; (ii) K2CO3, rt, 1 h, 14: 80%, 16: 82%.
a
Scheme 6. Synthesis of 1 and 2
a
Reagents and conditions: (a) (i) CCl3CN, DBU, CH2Cl2, rt, 3 h; (ii) 7, TMSOTf, CH2Cl2, −15 °C, 2 h, 67% (two steps); (b) NaOMe, MeOH, rt,
1 h, 78%; (c) PhCH(OMe)2, CH3CN, CSA, rt, 2 h, 95%; (d) (i) NaH, BnBr, DMF, 0 °C to rt, 3 h; (ii) LiAlH4, AlCl3, CH2Cl2, Et2O, 2 h, 67% (two
steps); (e) (i) succinic anhydride, Py, rt, 12 h; (ii) BnBr, Cs2CO3, CH3CN, 45 °C, 6 h, 83% (two steps); (f) 4 for 22 or 5 for 23, benzoquinone, G-
II, CH2Cl2, reflux, 5 h, 22: 86%, 23: 85%; (g) 10% Pd/C, H2 (g) (1 atm), EtOH, 6 h, rt, 1: 92%, 2: 90%.
3b with olefin 5 followed by hydrogenation of the resulting
alkene 23 delivered the ieodoglucomide B (2) in 90% yield.
All the spectroscopic data (1H, 13C NMR, mass and IR)
including NOE analysis for synthetic 1 and 2 were in full
agreement with those reported for the natural product. But, the
specific rotations were observed with the opposite sign as
[α]20D = −16.9 (c = 0.75, MeOH) for 1 and [α]20D = −8.9 (c =
0.80, MeOH) for 2, whereas for isolated compounds it was
+24 (c = 0.2, MeOH) for 2. This discrepancy prompted us to
analyze the absolute configuration assignment of the natural
product. The absolute stereochemistry of the natural
ieodoglucomides A and B was entirely on comparison with
the authentic samples except for the C14-hydroxyl group of 14-
hydroxy-15-methylhexadecanoic acid, wherein we found the
inconsistency between the given structure having “S”
configuration and the reported ΔδH (δS − δR) values obtained
for (S)- and (R)-MTPA esters.1 From these ΔδH values, the
reported as [α]23 = +22 (c = 0.2, MeOH) for 1 and [α]23
=
D
D
C
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a
Scheme 7. Synthesis of Alcohol 7a
a
Reagents and conditions: (a) n-BuLi, 1-heptyne, THF, −78 °C, 3 h, 95%; (b) MnO2, toluene, 50 °C, 2 h, 90%; c) (S,S)-Noyori catalyst, HCOOH,
Et3N, 10 h, rt, 80% (95% ee); (d) 1,3-diamino propane, KH, rt, 3 h, 78%; (e) Pd-CaCO3, EtOAc, 1 h, rt, 84%.
a
Scheme 8. Synthesis of 1a and 2a
a
Reagents and conditions: (a) (i) CCl3CN, DBU, CH2Cl2, rt, 3 h; (ii) 7a, TMSOTf, CH2Cl2, −15 °C, 2 h, 65% (two steps); (b) NaOMe, MeOH, rt,
1 h, 80%; (c) PhCH(OMe)2, CH3CN, CSA, rt, 2 h, 95%; (d) (i) NaH, BnBr, DMF, 0 °C to rt, 3 h; (ii) LiAlH4, AlCl3, CH2Cl2, Et2O, 2 h, 65% (two
steps); (e) (i) succinic anhydride, Py, rt, 12 h; (ii) BnBr, Cs2CO3, CH3CN, 45 °C, 6 h, 85% (two steps); (f) 4 for 33 or 5 for 34, benzoquinone, G-
II, CH2Cl2, reflux, 5 h, 33: 85%, 34: 87%; (g) 10% Pd/C, H2 (g) (1 atm), EtOH, 6 h, rt, 1a: 90%, 2a: 88%.
a
1
Table 1. Comparison of H and 13C NMR Data of Natural and Synthetic Ieodoglucomides
ieodoglucomide A
ieodoglucomide B
S-isomer (2)
position
16
NMR
1H
13C
1H
13C
natural
S-isomer (1)
R-isomer (1a)
natural
R-isomer (2a)
0.93 d (6.5)
18.3
0.93 d (6.4)
18.3
0.89 t (6.2)
18.7
0.93 d (7.0)
18.3
0.93 d (6.9)
18.3
0.90 t (6.2)
18.7
17
0.93 d (6.5)
18.7
0.93 d (6.4)
18.6
0.89 t (6.2)
18.8
0.93 d (7.0)
18.7
0.93 d (6.9)
18.6
0.90 t (6.2)
18.8
a
Signals of all the other positions are in accordance with the reported values for natural product.
absolute configuration at C14 in the natural product should be
“R”. On the basis of this observation, we decided to synthesize
ieodoglucomides A (1a) and B (2a) with the “R” configuration
at the C14 stereocenter (C14-epimers of 1 and 2).
mide (KAPA)-mediated alkyne zipper reaction, in which the
alkyne functionality shifted from the center to the terminus of a
chain to give the alkyne 27 in 78% yield,17 which upon
treatment under Lindlar’s hydrogenation conditions (5% Pd-
CaCO3 in EtOAc) provided the desired alcohol 7a in 84%
yield.
Having the alcohol 7a in hand, the stage was set for the
synthesis of the C14-epimer of 1 and 2 (Scheme 8). Thus,
glycosylation of the hemiacetal 17 with 7a was carried out via
the α-trichloroacetimidate followed by TMSOTf-mediated
glycosylation to afford the corresponding β-glycoside 28 in
65% yield. Compound 28 was transformed to the targeted C14-
epimers 1a and 2a through the intermediates 29 to 34,
following the similar sequence of reactions used for the
Toward the C14-epimers of ieodoglucomide A and B, first,
synthesis of the alcohol 7a was considered from readily
available isobutyraldehyde (Scheme 7). Addition of lithiated 1-
heptyne on to isobutyraldehyde produced the propargylic
alcohol 24 in 95% yield. Oxidation of the corresponding
alcohol with MnO2 in toluene at 50 °C for 2 h provided the
propargylic ketone 25 in 90% yield. Asymmetric reduction of
25 using the (S,S)-Noyori catalyst in the presence of HCOOH/
Et3N15 delivered the alcohol 26 in 80% yield with 95% ee.16
The alkynol 26 was subjected to potassium 3-aminopropyla-
D
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2846, 1218, 772 cm−1. Anal. Calcd for C11H22O: C, 77.58; H, 13.02.
Found: C, 77.29; H, 12.93.
conversion of 18 to 1 and 2. The obtained 1a and 2a were fully
characterized and found that the specific rotations for these
compounds were also observed with a “negative” sign as [α]20
(S)-2-Methyldec-9-en-3-yl 4-nitrobenzoate (7′). To a solution
of chiral alcohol 7 (100 mg, 0.6 mmol) in CH2Cl2 (5 mL), were added
p-nitrobenzoic acid (118 mg, 0.7 mmol), DCC (242 mg, 1.2 mmol)
and DMAP (catalytic), and the mixture was stirred for 2 h at room
temperature. The reaction mixture was filtered and evaporated, and
the crude was purified by silica gel column chromatography (2%
D
= −13.57 (c = 1.12, MeOH) for 1a and [α]20D = −7.25 (c = 0.8,
MeOH) for 2a. At this stage, comparison of H and 13C NMR
1
spectral data of all four synthetic compounds with the reported
data revealed that the data of synthetic 1 and 2 are in
accordance with the natural product, whereas 1a and 2a have a
slight difference at the C16 and C17 positions (Table 1). This
data suggests that the absolute configuration at the C14-
stereocenter is most likely “S” as proposed for the natural
products 1 and 2. To elucidate this, a direct comparison of
synthetic compound with the natural product sample is
essential. Considering the chemical reliability of the synthetic
products, confirmed by a range of analytical data, the
observation of opposite sign for specific rotation values
between the synthetic products and that reported for the
natural products may be due to the erroneously reported
specific rotation for the natural product.18,19
EtOAc in hexanes) to afford the ester product 7′ (171 mg, 91%) as a
1
yellow liquid: [α]20 = −16.42 (c = 0.95, CHCl3); H NMR (300
D
MHz, CDCl3) δ 8.30 (d, J = 9.0 Hz, 2H), 8.22 (d, J = 9.0 Hz, 2H),
5.85−5.70 (m, 1H), 5.09−4.98 (m, 2H), 4.96−4.87 (m, 1H), 2.08−
1.92 (m, 3H), 1.79−1.62 (m, 2H), 1.44−1.27 (m, 6H), 1.04−0.94 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 164.4, 150.3, 138.8, 136.0, 130.6,
123.4, 114.2, 80.4, 33.6, 31.4, 31.0, 28.9, 28.6, 25.4, 18.6, 17.5; IR
(KBr) υmax 3078, 2956, 2931, 1720, 1528, 1272, 1101, 718 cm−1. Anal.
Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.90; H,
7.91; N, 4.41.
Allyl 2,3,4-tri-O-benzoyl-6-O-(3-benzyloxycarbonylpropano-
yl)-α-D-glucopyranoside (9). 4-(N,N-Dimethylamino)-pyridine
(110 mg, 0.9 mmol) and succinic anhydride (1.38 g, 18.7 mmol)
were added to a stirred solution of the alcohol 8 (5.0 g, 9.3 mmol) in
dry pyridine (50 mL) at room temperature under a nitrogen
atmosphere. The reaction mixture was stirred for 12 h at room
temperature. Upon completion, the reaction mixture was concentrated
under reduced pressure, and the residue was dissolved in EtOAc (100
mL) and washed with 1 N HCl (50 mL) and brine (50 mL). The
organic phase was dried over Na2SO4 and concentrated in vacuo. The
obtained acid residue in acetonitrile (50 mL), cesium carbonate (6.1 g,
18.7 mmol) and benzyl bromide (3.2 g, 18.7 mmol) was stirred for 6 h
at 45 °C. The reaction mixture was cooled to room temperature,
diluted with EtOAc (100 mL), and washed with water (50 mL) and
brine (25 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue obtained was purified by column
chromatography on silica gel (30% EtOAc in hexanes) to afford
compound 9 (5.4 g, 80%) as a yellow liquid: [α]20D = +45.95 (c = 1.31,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 7.9 Hz, 2H), 7.92
(d, J = 7.4 Hz, 2H), 7.85 (d, J = 7.4 Hz, 2H), 7.54−7.46 (m, 2H),
7.44−7.23 (m, 12H), 6.17 (t, J = 9.4 Hz, 1H), 5.92−5.81 (m, 1H),
5.57 (t, J = 9.4 Hz, 1H), 5.40−5.26 (m, 3H), 5.18 (d, J = 10.4 Hz, 1H),
5.14 (s, 2H), 4.37−4.23 (m, 4H), 4.15−4.05 (m, 1H), 2.74−2.63 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 171.8, 171.7, 165.6, 165.2, 136.0,
135.7, 133.35, 133.30, 133.1, 133.0, 129.8, 129.7, 129.5, 129.1, 128.9,
128.8, 128.4, 128.3, 128.19, 128.15, 117.9, 95.1, 71.8, 70.3, 69.2, 68.9,
67.7, 66.4, 62.6, 29.0, 28.9; IR (KBr) υmax 3067, 3034, 2957, 2929,
1733, 1601, 1452, 1262, 1159, 1102, 1028, 711 cm−1; HRMS (m/z)
calcd for C41H38O12Na (M + Na)+ 745.2261, found 745.2252.
2,3,4-Tri-O-benzoyl-6-O-(3-benzyloxycarbonylpropanoyl)-D-
glucopyranoside (10). To a mixture of compound 9 (2.0 g, 2.7
mmol) in AcOH (20 mL) was added water (1 mL), NaOAc (522 mg,
6.3 mmol) and PdCl2 (585 mg, 3.3 mmol), and the mixture was stirred
for 11 h at room temperature. The reaction mixture was diluted with
EtOAc (50 mL) and washed with water (25 mL), saturated aq.
NaHCO3 (25 mL) and brine (25 mL). The organic phase was dried
over Na2SO4, filtered, and concentrated, and the resulting residue was
purified by flash column chromatography (40% EtOAc in hexanes) to
In summary, the efficient syntheses of ieodoglucomide A and
B along with their C14-epimers have been achieved on the basis
of the proposed structures. The synthetic sequence notably
features β-glycosylation and Grubbs olefin cross-metathesis
reactions as the key steps starting from D-glucose.
EXPERIMENTAL SECTION
■
General Methods. All solvents and reagents were purified by
standard techniques. All of the reactions were performed in oven-dried
round-bottom flasks. Crude products were purified by column
chromatography either on silica gel (60−120 mesh) or silica gel 90
C18-reversed phase (for fully deprotected compounds). Thin layer
chromatography plates were visualized by exposure to ultraviolet light
and/or to a methanolic acidic solution of p-anisaldehyde or an aqueous
solution of potassium permanganate (KMnO4) or an ethanolic
solution of ninhydrin followed by heating (<1 min) on a hot plate
(∼250 °C). Organic solutions were concentrated on a rotary
evaporator at 35−40 °C. FTIR spectra were recorded KBr thin films
(for liquids) and disks (for solids). Specific rotations were measured
with an automatic digital polarimeter at 20 °C. H and 13C NMR
1
spectra were recorded in CDCl3 and CD3OD solvent on 300, 400, and
500 MHz NMR spectrometers. Chemical shifts are reported in parts
1
per million (ppm). H NMR spectra were recorded at 300 or 500
MHz, and chemical shifts are referenced to either TMS (δ = 0.0) or
CD3OD (δ = 4.83). 13C NMR spectra were recorded at 75 or 100
MHz, and chemical shifts are referenced to internal CDCl3 (δ = 77.0)
or CD3OD (δ = 49.17). Coupling constants (J) are quoted in hertz
(Hz). HRMS were recorded on quadrupole time-of-flight (Q-TOF)
mass spectrometer equipped with an ESI source.
(S)-2-Methyldec-9-en-3-ol (7). To a solution of (R)-2-isopropy-
loxirane 6 (2.0 g, 23.2 mmol) in dry tetrahydrofuran (30 mL), cuprous
iodide (441 mg, 2.3 mmol) was added, and the mixture was cooled to
−10 °C. Hex-5-enylmagnesium bromide (1.5 M in tetrahydrofuran,
23.2 mL, 35.0 mmol) was added slowly at −10 °C. The reaction
mixture was allowed to warm to room temperature and stirred for 3 h.
Reaction mixture was cooled to 0 °C, quenched with saturated aq.
NH4Cl (50 mL), allowed to warm to room temperature and extracted
with EtOAc (2 × 50 mL). The combined organic layers were washed
with brine (25 mL), dried over Na2SO4, filtered and evaporated under
reduced pressure. The obtained crude was purified by silica gel column
chromatography (4% EtOAc in hexanes) to afford the desired alcohol
1
yield compound 10 (1.5 g, 83%) as a yellow viscous liquid: H NMR
(300 MHz, CDCl3) δ 8.07−7.79 (m, 6H), 7.59−7.22 (m, 14H), 6.30−
6.11 (m, 1H), 5.72 (br s, 1H), 5.65−5.47 (m, 1H), 5.41−5.24 (m,
1H), 5.13 (s, 2H), 4.64−4.50 (m, 1H), 4.38−4.21 (m, 2H), 3.86 (br s,
1H), 2.77−2.61 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 172.3, 171.9,
165.7, 165.3, 133.4, 133.3, 133.1, 133.0, 129.9, 129.86, 129.81, 129.6,
129.0, 128.9, 128.7, 128.5, 128.4, 128.29, 128.24, 128.1, 96.4, 95.8,
72.1, 70.0, 69.3, 67.3, 66.6, 62.7, 29.2, 28.9; IR (KBr) υmax 2921, 2852,
1729, 1451, 1262, 1219, 1098, 1069, 772, 710 cm−1; HRMS (m/z)
calcd for C38H34O12Na (M + Na)+ 705.1948, found 705.1940.
(3S)-2-Methyl-9-en-3-yl-2,3,4-tri-O-benzoyl-6-O-(3-benzy-
loxycarbonylpropanoyl)-β-D-glucopyranoside (3a). To a mixture
of compound 10 (1.0 g, 1.4 mmol) in CH2Cl2 (15 mL), was added
trichloroacetonitrile (2.1 g, 14.6 mmol) and DBU (30 μL). The
7 (3.0 g, 78%) as a colorless liquid: [α]20 = −20.26 (c = 0.54,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.87−5.76 (m, 1H), 5.00 (d,
J = 17.4 Hz, 1H), 4.93 (d, J = 9.9 Hz, 1H), 3.38−3.32 (m, 1H), 2.10−
2.01 (m, 2H), 1.70−1.59 (m, 1H), 1.54−1.27 (m, 8H), 0.96−0.85 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 139.0, 114.1, 76.6, 34.0, 33.7,
33.4, 29.1, 28.8, 25.8, 18.8, 17.0; IR (KBr) υmax 3392, 3031, 2922,
E
dx.doi.org/10.1021/jo400041p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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1
mixture was stirred at room temperature for 3 h and then concentrated
under reduced pressure. The resulting residue was purified by flash
column chromatography (30% EtOAc in hexanes) to yield the imidate
derivative as a yellow liquid. The imidate and alcohol 7 (249 mg, 1.4
mmol) were coevaporated three times with toluene, dissolved in dry
CH2Cl2 (20 mL), and stirred over freshly activated 4 Å molecular
sieves for 30 min and then cooled to −15 °C. TMSOTf (18 μL, 0.08
mmol) was added, and the mixture was stirred for 2 h at −15 °C. Then
triethylamine (0.1 mL) was added, stirring was continued for 10 min,
and the mixture was filtered and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
[α]20 = −11.92 (c = 0.92, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.94 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H), 7.81 (d, J = 7.7 Hz,
2H), 7.49 (t, J = 6.9 Hz, 2H), 7.43−7.23 (m, 17H), 6.02 (d, J = 6.2 Hz,
1H), 5.83 (t, J = 9.7 Hz, 1H), 5.54−5.46 (m, 2H), 5.40−5.27 (m, 3H),
5.21−5.15 (m, 1H), 5.13 (s, 2H), 4.78 (d, J = 7.7 Hz, 1H), 4.68−4.61
(m, 1H), 4.33−4.27 (m, 2H), 3.96−3.90 (m, 1H), 3.44−3.37 (m, 1H),
2.69−2.57 (m, 4H), 2.22−2.14 (m, 2H), 2.04−1.91 (m, 2H), 1.78−
1.69 (m, 1H), 1.68−1.50 (m, 8H), 1.39 (d, J = 6.9 Hz, 3H), 1.36−1.23
(m, 8H), 0.73 (d, J = 6.7 Hz, 3H), 0.66 (d, J = 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.0, 172.6, 171.8, 171.7, 165.7, 165.2, 164.9,
135.7, 135.2, 133.4, 133.1, 133.0, 130.3, 130.1, 129.7, 129.67, 129.65,
129.3, 128.7, 128.57, 128.53, 128.3, 128.2, 128.0, 101.2, 85.8, 72.9,
72.0, 71.6, 69.7, 67.0, 66.4, 63.0, 47.9, 36.4, 32.4, 30.8, 30.6, 29.66,
29.60, 29.3, 29.0, 28.83, 28.80, 25.5, 24.8, 18.4, 17.6, 17.3; IR (KBr)
υmax 3383, 3065, 2929, 2855, 1735, 1665, 1453, 1278, 1261, 1157,
1099, 772, 710 cm−1; HRMS (m/z) calcd for C65H75NO15Na (M +
Na)+ 1132.5034, found 1132.5022.
Compound 14. To the compound 13 (50 mg, 0.04 mmol)
dissolved in methanol (10 mL), was added 10% Pd on carbon catalyst
(5 mg, 10% w/w), and the mixture was stirred in a hydrogen
atmosphere for 2 h at room temperature. The hydrogen gas was
removed, potassium carbonate (18.6 mg, 0.13 mmol) was added, and
then the mixture was stirred for 1 h at room temperature, filtered and
concentrated under reduced pressure. The resulting crude was purified
by Silica gel 90 C18-reversed phase column chromatography (3:2
(20% EtOAc in hexanes) to afford compound 3a (794 mg, 65%) as a
1
yellow liquid: [α]20 = −14.06 (c = 0.32, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.94 (d, J = 8.0, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.81
(d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.0 Hz, 2H), 7.44−7.31 (m, 9H),
7.30−7.23 (m, 3H), 5.87−5.75 (m, 2H), 5.55−5.46 (m, 2H), 5.13 (s,
2H), 4.99 (d, J = 17.0 Hz, 1H), 4.92 (d, J = 9.5 Hz, 1H), 4.78 (d, J =
8.0 Hz, 1H), 4.34−4.28 (m, 2H), 3.96−3.89 (m, 1H), 3.43−3.37 (m,
1H), 2.70−2.58 (m, 4H), 2.08−2.00 (m, 2H), 1.78−1.69 (m, 1H),
1.53−1.23 (m, 8H), 0.73 (d, J = 6.5 Hz, 3H), 0.65 (d, J = 6.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 171.8, 171.7, 165.7, 165.2, 164.9, 139.1,
135.7, 133.4, 133.1, 133.0, 129.7, 129.67, 129.63, 129.3, 128.7, 128.5,
128.3, 128.2, 114.0, 101.1, 72.9, 72.0, 71.6, 69.7, 66.4, 63.0, 33.7, 30.9,
30.7, 29.1, 29.0, 28.8, 25.2, 17.5, 17.3; IR (KBr) υmax 3067, 2930, 2856,
1734, 1601, 1452, 1280, 1262, 1157, 1097, 772, 710 cm−1; HRMS (m/
z) calcd for C49H54O12Na (M + Na)+ 857.3513, found 857.3509.
(S)-Benzyl 2-oct-7-enamidopropanoate (4). To a solution of
11 (1.5 g, 7.0 mmol) in CH2Cl2 (10 mL) was added DIPEA (1.36 g,
10.5 mmol) at 0 °C, and the mixture was stirred for 30 min. Separately
the oct-7-enoic acid (500 mg, 3.5 mmol) in CH2Cl2 (10 mL), HOBt
(475 mg, 3.5 mmol) was added at 0 °C and stirred for 10 min. Then
EDCI (1.3 g, 7.0 mmol) was added, and the mixture was stirred for 30
min at 0 °C. The above prepared amine solution was added to the
reaction mixture at 0 °C, allowed to warm to room temperature and
stirred for 12 h. The reaction mixture was diluted with CH2Cl2 (25
mL) and washed with 1 N HCl (10 mL), followed by saturated aq.
NaHCO3 (20 mL) and brine (20 mL). The combined organic layers
were dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue obtained was purified by silica gel column
MeOH:H2O) to afford the compound 14 (18.7 mg, 80%) as a yellow
liquid: [α]20 = −20.53 (c = 0.75, CH3OH); H NMR (500 MHz,
1
D
CD3OD) δ 4.38−4.29 (m, 2H), 3.85 (dd, J = 5.9, 11.9 Hz, 1H), 3.72−
3.66 (m, 1H), 3.52−3.47 (m, 1H), 3.38−3.29 (m, 2H), 3.26−3.15 (m,
2H), 2.22 (t, J = 6.9 Hz, 2H), 1.95−1.86 (m, 1H), 1.65−1.57 (m, 2H),
1.55−1.42 (m, 2H), 1.37 (dd, J = 6.9 Hz, 3H), 1.35−1.24 (m, 18H),
0.97−0.90 (m, 6H); 13C NMR (75 MHz, CD3OD) δ 176.0, 104.1,
85.4, 78.4, 77.9, 75.7, 72.0, 63.2, 49.4, 37.1, 33.2, 32.1, 31.1, 31.0, 30.9,
30.7, 30.5, 27.1, 26.8, 18.7, 18.4, 18.3; IR (KBr) υmax 3690, 2926, 2862,
1647, 1371, 1219, 1054, 1033, 772 cm−1; HRMS (m/z) calcd for
C26H49NO9Na (M + Na)+ 542.3305, found 542.3303.
Compound 15. Compound 15 was obtained from 3a (100 mg,
0.11 mmol) and 5 (69.3 mg, 0.23 mmol) by using the procedure
described for compound 13, which gave the product as a yellow liquid
chromatography (20% EtOAc in hexanes) to give 4 (906 mg, 85%) as
(111 mg, 85%): [α]20 = −20.02 (c = 0.80, CHCl3); H NMR (500
1
1
a yellow colored liquid: [α]20 = −3.02 (c = 1.02, CHCl3); H NMR
D
D
MHz, CDCl3) δ 7.94 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H),
7.81 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 6.9 Hz, 2H), 7.44−7.30 (m, 14H),
7.29−7.24 (m, 3H), 5.99 (br s, 1H), 5.83 (t, J = 9.9 Hz, 1H), 5.54−
5.46 (m, 2H), 5.40−5.27 (m, 2H), 5.18 (s, 2H), 5.13 (s, 2H), 4.78 (d,
J = 7.7 Hz, 1H), 4.30 (d, J = 3.9 Hz, 2H), 4.07 (d, J = 4.9 Hz, 2H),
3.96−3.90 (m, 1H), 3.44−3.38 (m, 1H), 2.68−2.57 (m, 4H), 2.22 (t, J
= 6.9 Hz, 2H), 2.03−1.92 (m, 2H), 1.78−1.69 (m, 1H), 1.68−1.40 (m,
8H), 1.38−1.23 (m, 8H), 0.74 (d, J = 6.9 Hz, 3H), 0.66 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 173.3, 171.8, 171.7, 169.9, 165.7,
165.2, 164.9, 135.8, 135.7, 133.4, 133.1, 133.0, 130.3, 130.1, 129.7,
129.67, 129.65, 129.3, 128.7, 128.59, 128.53, 128.39, 128.33 128.2,
101.1, 85.8, 72.9, 72.0, 71.6, 69.7, 67.1, 66.4, 63.1, 41.2, 36.3, 32.4,
30.8, 30.6, 29.5, 29.3, 29.0, 28.8, 28.6, 27.1, 25.5, 24.8, 17.6, 17.3; IR
(KBr) υmax 3372, 2928, 2855, 1736, 1452, 1260, 1097, 772, 710 cm−1;
HRMS (m/z) calcd for C64H73NO15Na (M + Na)+ 1118.4878, found
1118.4899.
(500 MHz, CDCl3) δ 7.40−7.30 (m, 5H), 6.00 (d, J = 4.9 Hz, 1H),
5.84−5.74 (m, 1H), 5.20 (d, J = 12.3 Hz, 1H), 5.15 (d, J = 12.3 Hz,
1H), 4.99 (d, J = 17.3 Hz, 1H), 4.93 (d, J = 9.8 Hz, 1H), 4.69−4.61
(m, 1H), 2.19 (t, J = 7.4 Hz, 2H), 2.07−2.01 (m, 2H), 1.67−1.60 (m,
2H), 1.44−1.29 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 173.0, 172.6,
138.7, 135.2, 128.5, 128.4, 128.0, 114.3, 67.1, 47.9, 36.4, 33.5, 28.6,
28.5, 25.3, 18.5; IR (KBr) υmax 3291, 2929, 1744, 1647, 1539, 1157,
910, 772 cm−1; HRMS (m/z) calcd for C18H26NO3 (M + H)+
304.1907, found 304.1906.
Benzyl 2-oct-7-enamidoacetate (5). Compound 5 was prepared
from oct-7-enoic acid (500 mg, 3.5 mmol) and 12 (1.4 g, 7.0 mmol)
by using the procedure described for amide 4, yielding 5 (885 mg,
1
87%) as a yellow liquid: H NMR (500 MHz, CDCl3) δ 7.40−7.29
(m, 5H), 5.99 (br s, 1H), 5.84−5.73 (m, 1H), 5.18 (s, 2H), 4.98 (d, J
= 17.3 Hz, 1H), 4.93 (d, J = 9.8 Hz, 1H), 4.08 (d, J = 4.9 Hz, 2H), 2.23
(t, J = 7.4 Hz, 2H), 2.07−2.01 (m, 2H), 1.68−1.61 (m, 2H), 1.45−
1.30 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 173.1, 169.9, 138.7,
135.0, 128.59, 128.51, 128.3, 114.3, 67.1, 41.3, 36.2, 33.4, 28.6, 28.5,
25.3; IR (KBr) υmax 3300, 2929, 1749, 1654, 1539, 1184 cm−1; HRMS
(m/z) calcd for C17H24NO3 (M + H)+ 290.1751, found 290.1749.
Compound 13. To a solution of 3a (100 mg, 0.11 mmol) and 4
(72.6 mg, 0.23 mmol) in dry CH2Cl2 (20 mL), was added
benzoquinone (3 mg, 0.02 mmol) in dry CH2Cl2 (1 mL). After
stirring for 10 min Grubb’s second generation (G-II) catalyst (5.0 mg,
5 mol %) was added to the resulting mixture, and the mixture was
refluxed for 5 h. The reaction mixture was cooled to room temperature
and filtered over Celite. The filtrate was concentrated in vacuo, and the
resulting crude was purified by silica gel column chromatography (30%
EtOAc in hexanes) to afford 13 (111 mg, 84%) as a yellow liquid:
Compound 16. Compound 16 was prepared from 15 (50 mg, 0.04
mmol) by using the procedure described for the preparation of 14,
yielding 16 (18.9 mg, 82%) as a yellow liquid: [α]20 = −16.04 (c =
D
0.96, CH3OH); 1H NMR (500 MHz, CD3OD) δ 4.31 (d, J = 7.9 Hz,
1H), 3.89−3.82 (m, 3H), 3.70 (dd, J = 6.9, 11.9 Hz, 1H), 3.52−3.47
(m, 1H), 3.38−3.29 (m, 2H), 3.26−3.16 (m, 2H), 2.25 (t, J = 6.9 Hz,
2H), 1.95−1.86 (m, 1H), 1.66−1.59 (m, 2H), 1.55−1.42 (m, 2H),
1.36−1.25 (m, 18H), 0.97−0.91 (m, 6H); 13C NMR (75 MHz,
CD3OD) δ 176.8, 104.1, 85.4, 78.4, 77.8, 75.7, 72.0, 63.2, 42.7, 37.1,
32.2, 32.1, 31.1, 31.0, 30.9, 30.7, 30.5, 27.1, 26.8, 18.7, 18.3; IR (KBr)
υmax 3668, 3386, 2940, 2866, 1647, 1371, 1219, 1054, 1032, 772 cm−1;
HRMS (m/z) calcd for C25H47NO9Na (M + Na)+ 528.3149, found
528.3181.
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dx.doi.org/10.1021/jo400041p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3S)-2-Methyl-9-en-3-yl-2,3,4,6-tetra-O-acetyl-β-D-glucopyr-
anoside (18). Compound 18 was prepared from 17 (3.0 g, 8.6 mmol)
and 7 (1.5 g, 8.6 mmol) by using the procedure described for the
mixture was filtered through a pad of Celite, and the filtrate was
washed with 1 M HCl (20 mL), followed by water (20 mL) and brine
(20 mL). The organic layer was dried over Na2SO4 and evaporated in
vacuo. The resulting crude was purified by flash chromatography (20%
EtOAc in hexanes) to afford 21 (960 mg, 67%) as a white solid: mp
71−74 °C; [α]20D = −27.50 (c = 0.64, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.40−7.23 (m, 15H), 5.88−5.75 (m, 1H), 5.05−4.97 (m,
3H), 4.89−4.77 (m, 2H), 4.75−4.68 (m, 2H), 4.65−4.59 (m, 1H),
4.49 (d, J = 7.5 Hz, 1H), 3.90−3.83 (m, 1H), 3.72−3.61 (m, 2H),
3.57−3.50 (m, 1H), 3.48−3.36 (m, 3H), 2.09−1.98 (m, 2H), 1.92−
1.81 (m, 1H), 1.57−1.37 (m, 2H), 1.35−1.18 (m, 6H), 0.97−0.87 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 139.0, 138.5, 138.4, 137.9, 128.6,
128.3, 128.2, 128.0, 127.8, 127.7, 127.5, 114.2, 102.3, 84.6, 84.2, 82.1,
77.8, 75.6, 74.9, 74.8, 74.4, 62.2, 33.7, 31.1, 30.9, 29.5, 28.7, 25.4, 18.6,
17.6; IR (KBr) υmax 3387, 3031, 2925, 2856, 1454, 1375, 1070, 736,
697 cm−1; HRMS (m/z) calcd for C38H50O6Na (M + Na)+ 625.3499,
found 625.3492.
preparation of 3a, yielding the title compound 18 (2.8 g, 67%) as a
1
white solid: mp 84−86 °C; [α]20 = −14.06 (c = 0.32, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 5.89−5.68 (m, 1H), 5.25−5.12 (m, 1H),
5.11−4.85 (m, 3H), 4.50 (d, J = 7.9 Hz, 1H), 4.26−4.00 (m, 3H),
3.72−3.59 (m, 1H), 3.39−3.28 (m, 1H), 2.15−1.91 (m, 14H), 1.86−
1.70 (m, 1H), 1.69−1.18 (m, 8H), 0.89−0.80 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 170.6, 170.3, 169.4, 169.2, 138.9, 114.1, 100.8, 85.7,
72.9, 71.6, 71.3, 68.6, 62.2, 33.6, 30.9, 30.7, 28.8, 24.7, 20.69, 20.66,
20.60, 17.7, 17.3; IR (KBr) υmax 2926, 2856, 1756, 1370, 1226, 1039,
772 cm−1; HRMS (m/z) calcd for C25H40O10Na (M + Na)+ 523.2513,
found 523.2498.
(3S)-2-Methyl-9-en-3-yl-β-D-glucopyranoside (19). A solution
of 18 (2.0 g) in anhydrous MeOH (20 mL) was treated with a catalytic
amount of NaOMe and stirred for 1 h, neutralized with Dowex H+
resin, filtered, and concentrated under reduced pressure, and the
resulting crude was purified by flash column chromatography on silica
gel (70% EtOAc in hexanes) to afford the compound 19 (1.0 g, 78%)
as a colorless liquid: [α]20D = −20.31 (c = 1.6, MeOH); 1H NMR (500
MHz, CD3OD) δ 5.88−5.76 (m, 1H), 4.99 (d, J = 17.2 Hz, 1H), 4.92
(d, J = 9.7 Hz, 1H), 4.30 (d, J = 7.9 Hz, 1H), 3.85 (dd, J = 1.8, 11.6
Hz, 1H), 3.68 (dd, J = 5.5, 12.1 Hz, 1H), 3.53−3.46 (m, 1H), 3.40−
3.28 (m, 2H), 3.26−3.15 (m, 2H), 2.09−2.03 (m, 2H), 1.96−1.87 (m,
1H), 1.56−1.47 (m, 2H), 1.45−1.27 (m, 6H), 0.92 (t, J = 7.4 Hz, 2 ×
3H); 13C NMR (75 MHz, CD3OD) δ 140.1, 114.7, 103.8, 85.1, 78.1,
77.6, 75.3, 71.7, 62.8, 34.8, 32.5, 31.4, 30.5, 30.0, 26.2, 18.6; IR (KBr)
υmax 3384, 2925, 2851, 1455, 1359, 1219, 772 cm−1; HRMS (m/z)
calcd for C17H32O6Na (M + Na)+ 355.2091, found 355.2090.
(3S)-2-Methyl-9-en-3-yl-4,6-O-benzylidine-β-D-glucopyrano-
side (20). Benzaldehyde dimethylacetal (824 mg, 5.4 mmol) and CSA
(189 mg, 0.81 mmol) were added to the tetrol 19 (900 mg, 2.7 mmol)
in acetonitrile (20 mL), and the mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with EtOAc (25
mL) and washed with saturated aq. NaHCO3 (10 mL) and brine (10
mL). The organic layer was dried over Na2SO4 and evaporated, and
the crude was purified by flash column chromatography (50% EtOAc
(3S)-2-Methyl-9-en-3-yl-2,3,4-tri-O-benzyl-6-O-(3-benzyloxy-
carbonylpropanoyl)-β-D-glucopyranoside (3b). Compound 3b
was obtained from 21 (500 mg, 0.8 mmol) by using the procedure
described for the preparation of 9, yielding 3b (545 mg, 83%) as a
1
white solid: mp 66−68 °C; [α]20 = −20.01 (c = 0.6, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.40−7.21 (m, 20H), 5.87−5.76 (m, 1H),
5.14 (s, 2H), 5.02−4.89 (m, 4H), 4.88−4.75 (m, 2H), 4.70 (d, J = 10.9
Hz, 1H), 4.56 (d, J = 10.9 Hz, 1H), 4.44−4.32 (m, 2H), 4.20 (dd, J =
4.9, 11.8 Hz, 1H), 3.65 (t, J = 8.6 Hz, 1H), 3.53−3.36 (m, 4H), 2.70−
2.63 (m, 4H), 2.09−2.02 (m, 2H), 1.92−1.80 (m, 1H), 1.57−1.37 (m,
2H), 1.37−1.16 (m, 6H), 0.99−0.91 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 171.9, 171.8, 139.1, 138.5, 138.4, 137.8, 135.7, 128.5, 128.4,
128.3, 128.26, 128.23, 128.17, 128.10, 127.9, 127.7, 127.5, 114.1,
102.4, 84.6, 84.0, 82.9, 77.7, 75.6, 74.9, 74.7, 72.4, 66.5, 63.6, 33.7,
31.1, 30.8, 29.5, 29.1, 29.0, 28.8, 28.7, 25.4, 18.4, 17.6; IR (KBr) υmax
3483, 2924, 2853, 1737, 1454, 1156, 1062, 772, 697 cm−1; HRMS (m/
z) calcd for C49H60O9Na (M + Na)+ 815.4129, found 815.4121.
Compound 22. Compound 22 was obtained from 3b (100 mg,
0.12 mmol) and 4 (76.5 mg, 0.25 mmol) by using the procedure
described for compound 13, to give 22 as a yellow liquid (115 mg,
1
86%): [α]20 = −14.88 (c = 0.86, CHCl3); H NMR (300 MHz,
D
in hexanes) to afford the diol 20 (1.08 g, 95%) as a white solid: mp
CDCl3) δ 7.42−7.23 (m, 25H), 6.04 (d, J = 6.2 Hz, 1H), 5.39−5.29
(m, 3H), 5.17 (s, 2H), 4.95 (d, J = 10.9 Hz, 2H), 4.88−4.75 (m, 2H),
4.73−4.53 (m, 4H), 4.45−4.32 (m, 2H), 4.20 (dd, J = 4.5, 11.5 Hz,
1H), 3.73−3.60 (m, 1H), 3.50−3.31 (m, 4H), 2.69−2.61 (m, 4H),
2.25−2.15 (m, 2H), 2.10−1.76 (m, 4H), 1.71−1.56 (m, 2H), 1.55−
1.45 (m, 1H), 1.39 (d, J = 7.1 Hz, 3H), 1.37−1.19 (m, 12H), 0.89 (t, J
= 6.2 Hz, 2 × 3H); 13C NMR (75 MHz, CDCl3) δ 173.0, 172.6, 172.4,
172.0, 138.5, 138.2, 135.6, 135.2, 130.8, 130.5, 129.9, 128.58, 128.50,
128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 103.2, 84.7, 84.0,
82.0, 77.1, 75.3, 74.9, 73.0, 70.1, 67.1, 66.5, 63.7, 47.9, 36.4, 32.5, 32.3,
31.2, 31.0, 29.6, 29.5, 29.2, 29.1, 28.9, 28.6, 25.4, 25.3, 18.5, 18.0, 17.8;
IR (KBr) υmax 2921, 2852, 1736, 1453, 1218, 1155, 1062, 772 cm−1;
HRMS (m/z) calcd for C65H81NO12Na (M + Na)+ 1090.5656, found
1090.5590.
1
103−105 °C; [α]20 = −25.23 (c = 1.28, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.53−7.46 (m, 2H), 7.41−7.33 (m, 3H), 5.90−5.74
(m, 1H), 5.54 (s, 1H), 5.05−4.91 (m, 2H), 4.43 (d, J = 7.7 Hz, 1H),
4.31 (dd, J = 4.9, 10.3 Hz, 1H), 3.86−3.74 (m, 2H), 3.61−3.38 (m,
4H), 2.76 (br s, 1H), 2.46 (br s, 1H), 2.10−2.00 (m, 2H), 1.97−1.83
(m, 1H), 1.68−1.24 (m, 8H), 0.90 (d, J = 6.7 Hz, 2 × 3H); 13C NMR
(75 MHz, CDCl3) δ 139.0, 136.9, 129.2, 128.2, 126.2, 114.1, 102.6,
101.8, 84.7, 80.5, 74.9, 73.1, 68.6, 66.2, 33.7, 30.7, 29.0, 28.8, 25.1,
17.9, 17.7; IR (KBr) υmax 3424, 2927, 2861, 1736, 1640, 1458, 1382,
1097, 1028, 990, 912, 770 cm−1; HRMS (m/z) calcd for C24H36O6Na
(M + Na)+ 443.2404, found 443.2401.
(3S)-2-Methyl-9-en-3-yl-2,3,4-tri-O-benzyl-β-D-glucopyrano-
side (21). To a solution of sodium hydride (60% oil suspension, 285
mg, 7.1 mmol) in DMF (10 mL), compound 20 (1.0 g, 2.3 mmol)
dissolved in DMF (10 mL) was added at 0 °C, and the mixture was
stirred for 45 min at the same temperature. Benzyl bromide (814 mg,
4.7 mmol) was added to the above mixture at 0 °C, and then it was
allowed to warm to room temperature, and stirring was continued for
3 h. The reaction mixture was quenched by adding ice cold water (20
mL), and the mixture was extracted with EtOAc (2 × 25 mL). The
combined organic layers were washed with brine (3 × 20 mL), dried
over Na2SO4 and concentrated under reduced pressure. The crude
obtained was purified by flash column chromatography (10% EtOAc in
hexanes) to afford dibenzylated compound as a yellow residue. The
residue in CH2Cl2:diethyl ether (1:1, 10 mL) was added to a solution
of lithium aluminum hydride (542 mg, 14.2 mmol) in CH2Cl2/diethyl
ether (1:1, 5.0 mL) at 0 °C under a nitrogen atmosphere. The reaction
mixture was warmed to 50 °C, and then a solution of AlCl3 (1.44 g,
10.9 mmol) in diethyl ether (10 mL) was added slowly. The mixture
was stirred for 2 h at the same temperature and then cooled to 0 °C;
EtOAc (10 mL) and water (10 mL) were added slowly. The resulting
Compound 23. Compound 23 was prepared from 3b (100 mg,
0.12 mmol) and 5 (72.9 mg, 0.25 mmol) by using the procedure
described for compound 13, giving 23 as a yellow liquid (113 mg,
1
85%): [α]20 = −11.14 (c = 0.88, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 7.44−7.23 (m, 25H), 5.98 (br s, 1H), 5.41−5.27 (m, 2H),
5.20−5.17 (m, 2H), 5.12 (s, 2H), 4.98−4.91 (m, 2H), 4.88−4.76 (m,
2H), 4.70 (d, J = 10.9 Hz, 1H), 4.56 (d, J = 10.7 Hz, 1H), 4.44−4.43
(m, 2H), 4.20 (dd, J = 4.7, 11.7 Hz, 1H), 4.11−4.04 (m, 3H), 3.65 (t, J
= 8.6 Hz, 1H), 3.53−3.36 (m, 3H), 2.71−2.58 (m, 4H), 2.28−2.18 (m,
2H), 2.10−1.81 (m, 3H), 1.78−1.57 (m, 4H), 1.55−1.19 (m, 12 H),
0.89 (t, J = 6.2 Hz, 2 × 3H); 13C NMR (75 MHz, CDCl3) δ 173.3,
172.4, 172.0, 170.0, 138.5, 138.2, 135.6, 130.5, 129.9, 129.4, 128.6,
128.5, 128.34, 128.30, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 103.2,
84.8, 84.0, 81.9, 77.1, 75.3, 74.9, 73.0, 70.0, 67.1, 66.5, 63.7, 41.2, 36.2,
32.5, 32.3, 31.2, 31.0, 29.6, 29.5, 29.2, 29.0, 28.9, 28.6, 25.4, 25.3, 18.0,
17.8; IR (KBr) υmax 3348, 2923, 2853, 1737, 1656, 1455, 1218, 1063,
772 cm−1; HRMS (m/z) calcd for C64H79NO12Na (M + Na)+
1076.5500, found 1076.5542.
G
dx.doi.org/10.1021/jo400041p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Compound 1. 10% Pd on carbon (5 mg, 10% w/w) was added to
a solution of compound 22 (50 mg) in methanol (10 mL), and the
mixture was stirred in a hydrogen atmosphere for 6 h at room
temperature. The reaction mixture was filtered and concentrated under
brine (50 mL). The organic layer was dried over Na2SO4, filtered, and
evaporated, and the crude product was purified by silica gel column
chromatography (2% EtOAc in hexanes) to afford the chiral alcohol
26 (6.4 g, 80%) as a yellow liquid: [α]20D = +0.75 (c = 1.07, CHCl3);
1H NMR (300 MHz, CDCl3) δ 4.20−4.12 (m, 1H), 2.21 (td, J = 1.5,
6.7 Hz, 2H), 1.91−1.73 (m, 1H), 1.57−1.46 (m, 2H), 1.43−1.25 (m,
4H), 1.09−0.95 (m, 6H), 0.90 (t, J = 6.7 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 86.2, 79.7, 68.1, 34.6, 31.0, 28.3, 22.1, 18.6, 18.0, 17.3,
13.9; IR (KBr) υmax 3392, 2958, 2927, 2856, 1736, 1462, 1379, 1260,
1022, 800 cm−1. Anal. Calcd for C11H20O: C, 78.51; H, 11.98. Found:
C, 78.80; H, 12.02.
(S)-2-Methyldec-4-yn-3-yl-4-nitrobenzoate (26′). To a sol-
ution of chiral alkynol 26 (100 mg, 0.5 mmol) in CH2Cl2 (5 mL) were
added p-nitrobenzoic acid (119 mg, 0.7 mmol), DCC (245 mg, 1.1
mmol) and DMAP (catalytic), and the mixture was stirred for 2 h at
room temperature. The reaction mixture was filtered and evaporated,
and the crude was purified by silica gel column chromatography (2%
EtOAc in hexanes) to afford the ester product 26′ (179 mg, 95%) as a
yellow liquid: [α]20D = +4.76 (c = 1.05, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 8.33−8.27 (m, 2H), 8.26−8.21 (m, 2H), 5.49−5.45 (m,
1H), 2.23 (td, J = 2.2, 6.7 Hz, 2H), 2.18−2.07 (m, 1H), 1.56−1.46 (m,
2H), 1.42−1.24 (m, 4H), 1.13−1.04 (m, 6H), 0.88 (t, J = 6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 163.7, 150.5, 135.7, 130.7, 123.4, 87.7,
75.5, 71.1, 32.7, 30.9, 28.1, 22.0, 18.6, 18.2, 17.6, 13.9; IR (KBr) υmax
2962, 2932, 2867, 2234, 1729, 1531, 1345, 1267, 1099, 970, 719, 629
cm−1. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found:
C, 68.38; H, 7.33; N, 4.42.
(R)-2-Methyldec-9-yn-3-ol (27). Potassium hydride (35%
suspension in mineral oil, 14.2 g, 125.0 mmol) was weighed in an
oven-dried round bottomed flask, washed with diethyl ether (3 × 25
mL) under a nitrogen atmosphere, and dried under a vacuum for 15
min. To this was added slowly 1,3-diaminopropane (125 mL) at room
temperature, and the mixture was stirred for 1 h. Then, the alkynol 26
(6.0 g, 35.7 mmol) was added dropwise to the above mixture at 0 °C,
and it was allowed to stir for 2 h at room temperature. After
completion of the reaction (monitored by TLC), the mixture was
cooled to 0 °C and quenched by slow addition of crushed ice. The
aqueous layer was extracted with EtOAc (2 × 100 mL). The combined
organic layers were washed with 1 N HCl (50 mL), brine (50 mL) and
dried over Na2SO4. The organic layers were evaporated under reduced
pressure, and the residue was purified by silica gel column
reduced pressure to afford compound 1 (26.6 mg, 92%) as a yellow
1
liquid: [α]20 = −16.93 (c = 0.75, CH3OH); H NMR (500 MHz,
D
CD3OD) δ 4.44 (d, J = 11.4 Hz, 1H), 4.37 (dd, J = 6.9, 13.9 Hz, 1H),
4.29 (d, J = 7.4 Hz, 1H), 4.19 (dd, J = 6.4, 11.9 Hz, 1H), 3.46−3.39
(m, 2H), 3.37−3.25 (m, 2H), 3.19 (t, J = 7.9 Hz, 1H), 2.66−2.57 (m,
4H), 2.22 (t, J = 7.4 Hz, 2H), 1.92−1.84 (m, 1H), 1.65−1.57 (m, 2H),
1.51−1.44 (m, 2H), 1.38 (d, J = 6.9 Hz, 3H), 1.36−1.24 (m, 18H),
0.93 (d, J = 6.4 Hz, 2 × 3H); 13C NMR (75 MHz, CD3OD) δ 176.5,
176.2, 176.0, 174.0, 104.1, 85.6, 78.1, 75.5, 75.1, 72.0, 65.2, 49.1, 36.9,
32.3, 32.2, 30.9, 30.8, 30.6, 30.4, 30.2, 29.9, 27.0, 26.6, 18.6, 18.3, 17.8;
IR (KBr) υmax 3690, 2926, 2862, 1647, 1371, 1219, 1054, 1033, 772
cm−1; HRMS (m/z) calcd for C30H53NO12Na (M + Na)+ 642.3465,
found 642.3521.
Compound 2. Compound 2 was obtained as a yellow liquid from
23 (50 mg) by using the procedure described for the preparation of 1,
1
yielding 2 (25.8 mg, 90%): [α]20 = −8.98 (c = 0.88, CH3OH); H
D
NMR (500 MHz, CD3OD) δ 4.44 (d, J = 11.4 Hz, 1H), 4.30 (d, J =
7.9 Hz, 1H), 4.18 (dd, J = 6.4, 11.9 Hz, 1H), 3.89 (s, 2H), 3.46−3.39
(m, 2H), 3.37−3.24 (m, 2H), 3.19 (t, J = 8.4 Hz, 1H), 2.67−2.57 (m,
4H), 2.25 (t, J = 7.4 Hz, 2H), 1.92−1.83 (m, 1H), 1.67−1.58 (m, 2H),
1.51−1.42 (m, 2H), 1.39−1.21 (m, 18H), 0.93 (d, J = 6.4 Hz, 2 ×
3H); 13C NMR (75 MHz, CD3OD) δ 176.9, 176.0, 174.1, 173.5,
104.1, 85.6, 78.1, 75.5, 75.1, 72.0, 65.2, 42.0, 36.9, 32.3, 32.2, 30.9,
30.8, 30.6, 30.4, 30.2, 29.9, 27.0, 26.6, 18.6, 18.3; IR (KBr) υmax 3668,
3386, 2940, 2866, 1647, 1371, 1219, 1054, 1032, 772 cm−1; HRMS
(m/z) calcd for C29H51NO12Na (M + Na)+ 628.3303, found 628.3306.
2-Methyldec-4-yn-3-ol (24). To a solution of 1-heptyne (7.3 g,
76.4 mmol) in dry tetrahydrofuran (100 mL) was added n-BuLi (28
mL, 2.5 M solution in hexane, 69.4 mmol) at −78 °C slowly under
nitrogen. Then the reaction mixture was stirred at the same
temperature for 1 h. Isobutyraldehyde (5.0 g, 69.4 mmol) in dry
tetrahydrofuran (50 mL) was added slowly to the above mixture at
−78 °C. The mixture was stirred for 1 h at the same temperature, and
then it was quenched by adding saturated aq. NH4Cl (100 mL). The
mixture was allowed to warm to room temperature, and then it was
extracted with EtOAc (2 × 100 mL). The combined organic layers
were washed with brine (50 mL), dried over Na2SO4 and evaporated
under a vacuum. The crude obtained was purified by silica gel column
chromatography (2% EtOAc in hexanes) to afford the racemic alcohol
chromatography (4% EtOAc in hexanes) to give 27 (4.6 g, 78%) as
1
a yellow liquid: [α]20 = +15.61 (c = 0.98, CHCl3); H NMR (300
D
1
24 (11.0 g, 95%) as a yellow liquid: H NMR (300 MHz, CDCl3) δ
MHz, CDCl3) δ 3.42−3.30 (m, 1H), 2.20 (td, J = 2.6, 6.9 Hz, 2H),
1.95 (t, J = 2.8 Hz, 1H), 1.75−1.23 (m, 9H), 0.96−0.87 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 84.5, 76.5, 68.1, 33.8, 33.4, 28.7, 28.3, 25.4,
18.7, 18.2, 17.0; IR (KBr) υmax 3308, 2935, 2863, 2115, 1463, 1220,
990, 772, 629 cm−1. Anal. Calcd for C11H20O: C, 78.51; H, 11.98.
Found: C, 78.30; H, 11.94.
(R)-2-Methyldec-9-en-3-ol (7a). Compound 27 (4.0 g, 2.3
mmol) was treated with Lindlar’s catalyst (5% Pd/CaCO3) (10% w/
w, 200 mg) and quinoline (0.1 mL) in EtOAc (50 mL). The reaction
mixture was purged with hydrogen several times and stirred under a
hydrogen atmosphere. After 1 h, the reaction mixture was filtered and
concentrated. The crude product was purified by flash column
chromatography (5% EtOAc in hexanes) to afford the desired product
7a (3.4 g, 84%) as a colorless liquid: [α]20D = +17.09 (c = 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 5.91−5.73 (m, 1H), 5.08−4.89 (m,
2H), 3.43− 3.31 (m, 1H), 2.14−1.98 (m, 2H), 1.75−1.58 (m, 1H),
1.56−1.22 (m, 8H), 0.95−0.88 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 138.9, 114.0, 76.5, 33.9, 33.6, 33.3, 29.1, 28.8, 25.8, 18.7, 17.0; IR
(KBr) υmax 3392, 3067, 2921, 2856, 1258, 1219, 772 cm−1. Anal. Calcd
for C11H22O: C, 77.58; H, 13.02. Found: C, 77.78; H, 12.98.
(3R)-2-Methyl-9-en-3-yl-2,3,4,6-tetra-O-acetyl-β-D-glucopyr-
anoside (28). Compound 28 was prepared from 17 (3.0 g, 8.6 mmol)
and 7a (1.2 g, 6.8 mmol) by using the procedure described for the
preparation of 3a, yielding 28 (2.8 g, 65%) as a white solid: mp 88−90
°C; [α]20D = −11.65 (c = 0.85, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 5.88−5.72 (m, 1H), 5.24−5.14 (m, 1H), 5.08 (d, J = 9.8 Hz, 1H),
5.04−4.98 (m, 1H), 4.97−4.93 (m, 1H), 4.92−4.89 (m, 1H), 4.51 (d, J
4.22−4.07 (m, 1H), 2.21 (td, J = 1.5, 6.7 Hz, 2H), 1.91−1.78 (m, 1H),
1.57−1.45 (m, 2H), 1.43−1.23 (m, 4H), 1.03−0.95 (m, 6H), 0.90 (t, J
= 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 85.9, 79.7, 67.9, 34.5,
30.9, 28.3, 22.0, 18.5, 18.0, 17.2, 13.8; IR (KBr) υmax 3424, 2956, 2923,
2852, 1736, 1219, 772 cm−1. Anal. Calcd for C11H20O: C, 78.51; H,
11.98. Found: C, 78.34; H, 11.94.
2-Methyldec-4-yn-3-one (25). To a solution of alcohol 24 (10.0
g, 59.5 mmol) in toluene (100 mL) was added activated manganese-
(IV) oxide (41.4 g, 476.1 mmol) at room temperature. The mixture
was heated to 50 °C and stirred for 2 h (monitored by TLC). The
reaction mixture was cooled to room temperature, filtered and
evaporated. The crude was purified by flash column chromatography
(2% EtOAc in hexanes) to get the ketone 25 (8.9 g, 90%) as a yellow
residue: 1H NMR (300 MHz, CDCl3) δ 2.61 (septet, J = 6.9 Hz, 1H),
2.38 (t, J = 6.9 Hz, 2H), 1.60 (quintet, J = 7.1 Hz, 2H), 1.46−1.26 (m,
4H), 1.18 (d, J = 6.9 Hz, 6H), 0.91 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 192.0, 94.8, 79.5, 42.7, 30.7, 27.2, 21.8, 18.6 (2), 17.7,
13.6; IR (KBr) υmax 2958, 2927, 2856, 1736, 1379, 1260, 1022, 800
cm−1. Anal. Calcd for C11H18O: C, 79.46; H, 10.91. Found: C, 79.71;
H, 10.95.
(S)-2-Methyldec-4-yn-3-ol (26). To the ketone 25 (8.0 g, 48.1
mmol) in CH2Cl2 (15 mL), were added formic acid (40 mL),
triethylamine (40 mL) and (S,S)-Noyori asymmetric hydrogenation
catalyst (746 mg, 2.5 mol %). The resulting mixture was stirred at
room temperature for 10 h, diluted with EtOAc (200 mL), and washed
with water (100 mL) followed by saturated aq. NaHCO3 (50 mL) and
H
dx.doi.org/10.1021/jo400041p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 7.5 Hz, 1H), 4.26−4.18 (m, 1H), 4.17−4.08 (m, 1H), 3.70−3.62 (m,
1H), 3.38−3.29 (m, 1H), 2.10−1.98 (m, 14H), 1.86−1.67 (m, 1H),
1.59−1.22 (m, 8H), 0.90−0.81 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 170.6, 170.3, 169.4, 169.2, 139.0, 114.1, 100.8, 85.8, 72.9, 71.6, 71.4,
68.6, 62.2, 33.7, 30.9, 30.8, 29.0, 28.8, 25.1, 20.68, 20.60, 17.8, 17.3; IR
(KBr) υmax 2926, 2856, 1756, 1370, 1226, 1039, 772 cm−1; HRMS (m/
z) calcd for C25H40O10Na (M + Na)+ 523.2513, found 523.2498.
(3R)-2-Methyl-9-en-3-yl-β-D-glucopyranoside (29). Com-
pound 29 was obtained from 28 (2.0 g, 4.0 mmol) by using the
Compound 33. The compound 33 was obtained from the reaction
of 32 (100 mg, 0.12 mmol) with 4 (76.5 mg, 0.25 mmol) following the
procedure described for compound 13, affording 33 as a yellow liquid
1
(119 mg, 85%): [α]20D= −13.00 (c = 1.0, CHCl3); H NMR (300
MHz, CDCl3) δ 7.42−7.23 (m, 25H), 6.05 (d, J = 6.2 Hz, 1H), 5.40−
5.28 (m, 2H), 5.20−5.15 (m, 3H), 5.12 (s, 2H), 4.95 (d, J = 10.9 Hz,
1H), 4.88−4.75 (m, 2H), 4.73−4.53 (m, 3H), 4.45−4.32 (m, 2H),
4.20 (dd, J = 4.5, 11.5 Hz, 1H), 3.73−3.60 (m, 1H), 3.53−3.36 (m,
4H), 2.70−2.60 (m, 4H), 2.25−2.15 (m, 2H), 2.10−1.76 (m, 4H),
1.71−1.56 (m, 2H), 1.55−1.45 (m, 1H), 1.40 (d, J = 7.1 Hz, 3H),
1.37−1.19 (m, 12H), 0.89 (t, J = 6.2 Hz, 2 × 3H); 13C NMR (75
MHz, CDCl3) δ 173.0, 172.5, 171.9, 171.8, 138.4, 137.8, 135.7, 135.2,
130.4, 129.9, 128.57, 128.50, 128.39, 128.30, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 127.5, 102.3, 84.8, 84.0, 82.2, 77.6, 75.5, 74.8, 74.7,
72.4, 67.1, 66.4, 63.3, 47.9, 36.4, 32.5, 32.3, 31.1, 30.8, 29.6, 29.4, 29.2,
29.0, 28.9, 28.7, 25.6, 25.3, 18.5, 18.4, 17.6; IR (KBr) υmax 2921, 2852,
1736, 1650, 1453, 1349, 1218, 1155, 1062, 772 cm−1; HRMS (m/z)
calcd for C65H81NO12Na (M + Na)+ 1090.5656, found 1090.5590.
Compound 34. The compound 34 was prepared from 32 (100
mg, 0.12 mmol) and 5 (72.9 mg, 0.25 mmol) by using the procedure
described for compound 13, giving 34 as a yellow liquid (120 mg,
87%): [α]20D= −15.50 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.42−7.20 (m, 25H), 5.98 (br s, 1H), 5.40−5.27 (m, 2H), 5.20−5.17
(m, 2H), 5.12 (s, 2H), 4.98−4.91 (m, 2H), 4.88−4.76 (m, 2H), 4.70
(d, J = 10.9 Hz, 1H), 4.56 (d, J = 10.7 Hz, 1H), 4.44−4.43 (m, 2H),
4.20 (dd, J = 4.7, 11.7 Hz, 1H), 4.11−4.04 (m, 3H), 3.65 (t, J = 8.6 Hz,
1H), 3.53−3.36 (m, 3H), 2.69−2.60 (m, 4H), 2.28−2.18 (m, 2H),
2.10−1.81 (m, 4H), 1.78−1.57 (m, 3H), 1.55−1.19 (m, 12H), 0.89 (t,
J = 6.2 Hz, 2 × 3H); 13C NMR (75 MHz, CDCl3) δ 173.1, 171.9,
171.8, 169.9, 138.7, 138.5, 138.4, 135.7, 135.0, 130.4, 129.9, 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5,
102.3, 84.8, 84.0, 82.2, 77.7, 75.5, 74.8, 74.7, 72.4, 67.1, 66.4, 63.3,
41.3, 36.3, 33.4, 32.5, 32.3, 31.2, 30.9, 29.5, 29.4, 29.2, 29.0, 28.9, 28.7,
28.6, 28.5, 25.6, 25.3, 18.4, 17.6; IR (KBr) υmax 2921, 2851, 1739,
1654, 1455, 1355, 1215, 1172, 1083, 1009, 772 cm−1; HRMS (m/z)
calcd for C64H79NO12Na (M + Na)+ 1076.5500, found 1076.5542.
Compound 1a. Compound 1a was obtained from 33 (30 mg, 0.02
mmol) following the procedure described for the preparation of 1,
yielding 1a (15.6 mg, 90%) as a yellow liquid: [α]20D= −13.57 (c =
1.12, CH3OH); 1H NMR (500 MHz, CD3OD) δ 4.43 (d, J = 11.6 Hz,
1H), 4.36 (dd, J = 7.1, 14.3 Hz, 1H), 4.28 (d, J = 7.1 Hz, 1H), 4.20
(dd, J = 6.2, 11.6 Hz, 1H), 3.46−3.38 (m, 2H), 3.37−3.23 (m, 2H),
3.17 (t, J = 8.0 Hz, 1H), 2.64−2.57 (m, 4H), 2.22 (t, J = 7.1 Hz, 2H),
1.94−1.84 (m, 1H), 1.65−1.57 (m, 2H), 1.54−1.45 (m, 2H), 1.38 (d, J
= 7.1 Hz, 3H), 1.36−1.26 (m, 18H), 0.89 (t, J = 6.2 Hz, 6H); 13C
NMR (75 MHz, CD3OD) δ 176.1, 174.4, 174.1, 104.1, 85.9, 78.2,
75.5, 75.2, 72.2, 65.2, 49.1, 37.2, 32.8, 31.9, 30.9, 30.8, 30.6, 30.4, 27.1,
26.7, 18.8, 18.7 (2); IR (KBr) υmax 3690, 2926, 2862, 1647, 1371,
1219, 1054, 1033, 772 cm−1; HRMS (m/z) calcd for C30H53NO12Na
(M + Na)+ 642.3500, found 642.3521.
procedure described for the preparation of 19, yielding 29 (1.06 g,
1
80%) as a colorless liquid: [α]20 = −13.13 (c = 1.15, MeOH); H
D
NMR (500 MHz, CD3OD) δ 5.88−5.76 (m, 1H), 4.99 (d, J = 17.2 Hz,
1H), 4.92 (d, J = 9.7 Hz, 1H), 4.30 (d, J = 7.9 Hz, 1H), 3.85 (dd, J =
1.8, 11.6 Hz, 1H), 3.68 (dd, J = 5.5, 12.1 Hz, 1H), 3.53−3.46 (m, 1H),
3.37 (t, J = 8.8 Hz, 1H), 3.34−3.28 (m, 1H), 3.26−3.15 (m, 2H),
2.09−2.02 (m, 2H), 1.96−1.87 (m, 1H), 1.56−1.47 (m, 2H), 1.45−
1.27 (m, 6H), 0.92 (t, J = 7.4 Hz, 6H); 13C NMR (75 MHz, CD3OD)
δ 140.1, 114.7, 103.8, 85.1, 78.1, 77.6, 75.3, 71.7, 62.8, 34.8, 32.5, 31.4,
30.5, 30.0, 26.2, 18.6; IR (KBr) υmax 3384, 2925, 2851, 1455, 1359,
1219, 772 cm−1; HRMS (m/z) calcd for C17H32O6Na (M + Na)+
355.2091, found 355.2090.
(3R)-2-Methyl-9-en-3-yl-4,6-O-benzylidine-β-D-glucopyrano-
side (30). Compound 30 was obtained from 29 (800 mg, 2.4 mmol)
following the procedure described for the preparation of 20, yielding
the acetal 30 (961 mg, 95%) as a white solid: mp 96−98 °C; [α]20
=
D
−33.20 (c = 1.01, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.53−7.46
(m, 2H), 7.42−7.33 (m, 3H), 5.89−5.73 (m, 1H), 5.53 (s, 1H), 5.05−
4.91 (m, 2H), 4.42 (d, J = 7.5 Hz, 1H), 4.31 (dd, J = 4.9, 10.3 Hz, 1H),
3.87−3.72 (m, 2H), 3.61−3.37 (m, 4H), 2.75 (br s, 1H), 2.47 (br s,
1H), 2.11−2.00 (m, 2H), 1.95−1.81 (m, 1H), 1.56−1.23 (m, 8H),
0.93−0.85 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 138.9, 137.0,
129.1, 128.2, 126.2, 114.3, 102.4, 101.8, 84.6, 80.7, 74.8, 73.1, 68.7,
66.2, 33.6, 31.2, 30.3, 29.3, 28.7, 25.3, 18.1, 17.9; IR (KBr) υmax 3424,
2927, 2861, 1736, 1640, 1458, 1382, 1097, 1028, 990, 912, 770 cm−1;
HRMS (m/z) calcd for C24H37O6 (M + H)+ 421.2584, found
421.2582.
(3R)-2-Methyl-9-en-3-yl-2,3,4-tri-O-benzyl-β-D-glucopyrano-
side (31). Compound 31 was obtained from 30 (850 mg, 2.0 mmol)
following the procedure described for preparation of 21, yielding 31
(792 mg, 65%) as a white solid: mp 71−74 °C; [α]20D = −12.77 (c =
1
1.3, CHCl3); H NMR (300 MHz, CDCl3) δ 7.40−7.23 (m, 15H),
5.86−5.69 (m, 1H), 5.02−4.90 (m, 3H), 4.89−4.77 (m, 2H), 4.75−
4.68 (m, 2H), 4.65−4.59 (m, 1H), 4.47 (d, J = 7.5 Hz, 1H), 3.91−3.79
(m, 1H), 3.72−3.61 (m, 2H), 3.57−3.48 (m, 1H), 3.47−3.29 (m, 3H),
2.06−1.93 (m, 2H), 1.92−1.81 (m, 1H), 1.57−1.37 (m, 2H), 1.35−
1.18 (m, 6H), 0.97−0.87 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
139.0, 138.5, 138.4, 137.9, 128.4, 128.3, 128.2, 128.0, 127.8, 127.7,
127.5, 114.1, 102.3, 84.7, 84.0, 82.3, 77.8, 75.6, 74.9, 74.8, 74.5, 62.2,
33.7, 31.1, 30.9, 29.5, 28.7, 25.4, 18.6, 17.6; IR (KBr) υmax 3387, 3031,
2925, 2856, 1454, 1375, 1070, 736, 697 cm−1; HRMS (m/z) calcd for
C38H50O6Na (M + Na)+ 625.3499, found 625.3492.
(3R)-2-Methyl-9-en-3-yl-2,3,4-tri-O-benzyl-6-O-(3-benzylox-
ycarbonylpropanoyl)-β-D-glucopyranoside (32). Compound 32
was obtained from 31 (600 mg, 0.8 mmol) by using the procedure
described for the preparation of 9, yielding 32 (671 mg, 85%) as a
Compound 2a. Compound 2a was obtained from 34 (25 mg, 0.02
mmol) following the procedure described for the preparation of 1,
yielding 2a (12.6 mg, 88%) as a yellow liquid: [α]20D= −7.25 (c = 0.8,
CH3OH); 1H NMR (500 MHz, CD3OD) δ 4.43 (d, J = 11.6 Hz, 1H),
4.29 (d, J = 7.1 Hz, 1H), 4.20 (dd, J = 7.1, 11.6 Hz, 1H), 3.84 (s, 2H),
3.45−3.38 (m, 2H), 3.38−3.24 (m, 2H), 3.18 (t, J = 8.0 Hz, 1H),
2.64−2.56 (m, 4H), 2.25 (t, J = 8.0 Hz, 2H), 1.93−1.85 (m, 1H),
1.66−1.54 (m, 2H), 1.54−1.46 (m, 2H), 1.39−1.26 (m, 18H), 0.90 (t,
J = 6.2 Hz, 2 × 3H); 13C NMR (75 MHz, CD3OD) δ 176.3, 176.2,
174.6, 173.5, 104.1, 85.8, 78.2, 75.5, 75.2, 72.1, 65.1, 41.8, 37.2, 32.7,
31.8, 31.8, 31.2, 30.9, 30.8, 30.6, 30.5, 27.0, 26.7, 18.8, 18.7; IR (KBr)
υmax 3668, 3386, 2940, 2866, 1647, 1371, 1219, 1054, 1032, 772 cm−1;
HRMS (m/z) calcd for C29H52NO12 (M + H)+ 606.3484, found
606.3488.
1
white solid: mp 66−68 °C; [α]20D= −16.13 (c = 1.5, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.40−7.21 (m, 20H), 5.85−5.69 (m, 1H),
5.12 (s, 2H), 5.02−4.89 (m, 4H), 4.88−4.75 (m, 2H), 4.70 (d, J = 10.9
Hz, 1H), 4.56 (d, J = 10.9 Hz, 1H), 4.44−4.32 (m, 2H), 4.20 (dd, J =
4.9, 11.8 Hz, 1H), 3.65 (t, J = 8.6 Hz, 1H), 3.53−3.36 (m, 4H), 2.68−
2.60 (m, 4H), 2.05−1.93 (m, 2H), 1.92−1.80 (m, 1H), 1.57−1.37 (m,
2H), 1.37−1.16 (m, 6H), 0.95−0.83 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 171.9, 171.8, 139.0, 138.5, 138.4, 137.8, 135.7, 128.5, 128.4,
128.3, 128.26, 128.23, 128.17, 128.10, 127.9, 127.7, 127.5, 114.1,
102.4, 84.8, 84.0, 82.9, 77.7, 75.6, 74.9, 74.7, 72.4, 66.5, 63.4, 33.7,
31.1, 30.8, 29.5, 29.1, 29.0, 28.9, 28.7, 25.5, 18.4, 17.6; IR (KBr) υmax
3060, 3032, 2929, 2857, 1740, 1454, 1354, 1214, 1155, 1069, 772, 698
cm−1; HRMS (m/z) calcd for C49H64NO9 (M + NH4)+ 810.4576,
found 810.4550.
Compound 86 and 1710 were prepared from D-glucose according to
the literature procedure. The spectral data of 8 and 17 were in full
agreement with the literature data.
I
dx.doi.org/10.1021/jo400041p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds,
368−373.
COSY, HMBC, HSQC and ROESY spectra of 2 and 2a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: rajireddy@iict.res.in.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the Council of Scientific and
Industrial Research (CSIR)-New Delhi for research funding
under the ORIGIN program of the 12th five year plan. The
authors would like to thank Prof. Hee Jae Shin for providing
information about the natural product data. E.J. thanks the
CSIR-New Delhi for a senior research fellowship. The authors
are also thankful to the reviewers of this manuscript for their
valuable suggestions.
(16) The enantiomeric excess of (S)-2-methyldec-4-yn-3-ol (26) was
determined by converting it to p-nitrobenzoate derivative 26′ under
DCC/DMAP reaction conditions using p-nitrobenzoic acid. Chiral
HPLC: Chiral pack column (I 250 × 4.6 mm, 5 μ), mobile phase 3%
isopropanol in hexanes, flow rate 1 mL/min, λ 210 nm. Retention time
(min): 8.0 (97.7%), 9.14 (2.3%).
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