Synthesis of C(27)-C(38) fragment of aflastatin A

Article abstract of DOI:10.1016/j.tet.2012.12.065

Efforts at finding out a strategy for the synthesis of the densely hydroxylated C(27)-C(48) fragment of aflastatin A have been described. The initial studies dealing with alkyne-epoxide coupling using a linear polyol epoxide resulted in a debenzylative cycloetherification leading to a C-arabinoside derivative. This problem has been addressed by applying an epoxide pendant on a furanosyl unit. With the model alkyne, the epoxide-alkyne coupling proceeded smoothly. Subsequently, following a sequence of [Pd]-mediated alkynone cycloisomerization/stereoselective hydroboration-oxidation, the synthesis of the central C(27)-C(38) fragment has been executed. When employed, the original C(33)-C(48) alkyne, the coupling and the cycloisomerizations are facile. However, the resulting glycals are unstable, thus warranting a revision in our approach.

Full text of DOI:10.1016/j.tet.2012.12.065

Tetrahedron 69 (2013) 1830e1840
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of C(27)eC(38) fragment of aflastatin A
*
Sachin B. Narute, C.V. Ramana
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 October 2012
Received in revised form 14 December 2012
Accepted 26 December 2012
Available online 3 January 2013
Efforts at finding out a strategy for the synthesis of the densely hydroxylated C(27)eC(48) fragment of
aflastatin A have been described. The initial studies dealing with alkyneeepoxide coupling using a linear
polyol epoxide resulted in a debenzylative cycloetherification leading to a C-arabinoside derivative. This
problem has been addressed by applying an epoxide pendant on a furanosyl unit. With the model alkyne,
the epoxideealkyne coupling proceeded smoothly. Subsequently, following a sequence of [Pd]-mediated
alkynone cycloisomerization/stereoselective hydroborationeoxidation, the synthesis of the central
C(27)eC(38) fragment has been executed. When employed, the original C(33)eC(48) alkyne, the cou-
pling and the cycloisomerizations are facile. However, the resulting glycals are unstable, thus warranting
a revision in our approach.
Keywords:
Aflastatin
Epoxideealkyne coupling
u
-Alkynone cycloisomerization
Ó 2013 Elsevier Ltd. All rights reserved.
Palladium catalysis
Hydroboration
1. Introduction
Aflatoxins are the naturally occurring mycotoxins produced by
Aspergillus fungi such as Aspergillus flavus and Aspergillus para-
siticus.1 These fungi are the contaminants in a wide variety of food
and feeds and the aflatoxins are the most significant environmental
carcinogens in mammals.2 The rapid development of drug resistant
strains of Aspergillus fungi is a major concern, which warranted the
discovery of novel specific inhibitors for the aflatoxin production.3
In 1996, Sakuda and co-workers reported the isolation of aflastatin
A (1)4 and revealed it as a potent and specific inhibitor for aflatoxin
biosynthesis, which worked without notably affecting the growth
of A. parasiticus from Streptomyces sp. MRI142.5 The putative
structure of aflastatin A has been proposed by the Sakuda group
with the help of chemical degradation and intensive NMR studies.6
However, the same group has revised its structure, as shown in
Fig. 1 in 2007.7 Aflastatin A (1) is an architecturally complex polyol
natural product, which comprises a tetramic acid derivative with
a highly oxygenated long alkyl side chain, as well as a densely
functionalized tetrahydropyran ring. The presence of 29 contiguous
stereogenic centers demonstrates the complexity of this molecule
from a synthetic point of view.
Fig. 1. Structure of aflastatin A (1) and the targeted C(26)eC(48) fragment 2.
over part of the molecule, i.e., the fully functionalized tetrahy-
dropyran moiety remain untouched by the synthetic community
due to its complex structural outlay. Inspired by the challenges
associated with the construction of the tetrahydropyran unit with
requisite stereochemistry, as well as our interest in the synthesis of
polyol natural products and cycloisomerization on sugar building
blocks,10 aflastatin A has been selected for the synthetic exercise.
Our initial success in this regard was constructing the central tet-
The stereochemical and structural complexity coupled with
potent inhibitory activity makes aflastatin A an attractive target for
total synthesis. The groups of Evans8 and McDonald9 have reported
the synthesis of the C(9)eC(27) fragment. The synthesis of the left
rahydropyran unit, employing
stereoselective hydroborationeoxidation, which have been amply
u-alkynone cycloisomerization and
* Corresponding author. Tel.: þ91 20 2590 2577; fax: þ91 20 2590 2629; e-mail
address: vr.chepuri@ncl.res.in (C.V. Ramana).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.065

S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
1831
applied to synthesize the C(31)eC(48) fragment of aflastatin A.11 In
continuation, our next concern was the construction of the C(26)e
C(48) fragment with a keen interest to look at the applicability of
a metal mediated cycloisomerization on a densely functionalized
polyol template. Herein, we document our efforts in this direction,
The terminal 1,2-diol was then selectively protected as the penty-
lidene ketal 15 by treatment of tetraol 11 at 0 ꢀC with H2SO4 in 3-
pentanone. The formation of dipentylidene ketal 14 as the side-
product was found to be temperature and time dependent. The
benzylation of the two free hydroxyl groups in compound 15, fol-
lowed by acid hydrolysis of resulting compound 16, afforded the
diol 17 in good yields. Next, the treatment of diol 17 with benzoyl
chloride followed by methanesulfonyl chloride delivered com-
pound 19, which, upon exposure to lithium hydroxide, resulted in
the key epoxide building block 20 in 78% yield. Spectral and ana-
lytical data of 20 were in good agreement with the assigned
structure. The characteristic methine protons of the oxirane ring
were found to resonate as two dd at 1.94 and 2.22 ppm in the 1H
NMR spectrum.
Having the required epoxide 20 in hand, the next concern was
its opening with the alkyne 6. In our earlier report dealing with the
synthesis of the C(31)e(C48) fragment, the easily accessible alkyne
21 has been used for the optimization studies. However, in that
case, the epoxide used was the simple ethylene oxide. As the syn-
thesis of key alkyne 6 involves a sequence of 12 linear steps,11 our
initial intention was to use the alkyne 21 for optimizing the se-
quence and then proceed with the alkyne 6 in order to arrive at the
desired objective. The attempted epoxide opening reaction with
alkyne 21 using n-BuLi and BF$Et2O failed to give the required
product 22 (Scheme 2). Under various reaction conditions explored
(Table 1), this reaction led to either formation of the epoxide-
rearranged product 23 or isolation of trace amounts of the re-
which reveals the applicability and the limitations of the key
u-
alkynone cycloisomerization and hydroborationeoxidation in the
synthesis of the above-mentioned fragment of aflastatin A.
2. Result and discussions
Fig. 2 reveals the salient features of our retrosynthetic discon-
nections for constructing the protected C(26)eC(48) fragment 2. The
key reaction in this regard was an
u-alkynone cyclo-
isomerization11,12 and a face selective hydroborationeoxidaton13
that addresses the construction of the central tetrahydropyran
core. The keyalkynone intermediate 4 would be assembled from the
TBS ether 5, which in turn, could be synthesized by addition of the
alkyne 6 to epoxide 7.14 In our earlier report, we have documented
the synthesis of key alkyne 6 from
chemical details of the epoxide fragment 7 led us to identify the
glucoheptanoic- -lactone, where the configuration of the hydroxyl
D
-ribose.11 Inspection of stereo-
a-D-
g
groups at C(2)eC(5) matches perfectly with the stereochemistry of
the hydroxyl groups at C(27)eC(30) in aflastatin A. The stereo-
chemistry at C(6) of a-D-glucoheptanoic-g-lactone can be inverted
during the formation of key epoxide 7, the functional unit that was
opted for, in order to address the C(32)eC(33) bond formation.
Fig. 2. Retrosynthetic disconnections for C(26)eC(48) fragment of aflastatin A.
The synthesis of the epoxide 7 was commenced through the
quired product 22. The rearranged product 23 was expected to be
formed by BF3$Et2O mediated debenzylative cycloetherification,
a commonly encountered problem when the reacting groups are in
a 1,4-position.16 Compound 23 was converted to the corresponding
acetate 24 for the purpose of characterization.
Since improving the yield of requisite product 22 proved diffi-
cult, we next intended to use an epoxide that had been appended
on a furanoside unit so that the chances of intramolecular epoxide
opening could be reduced. According to the revised tactic, the ep-
oxide 25 was selected as a suitable precursor for the next synthetic
preparation of triol 9 using the reported procedures from
a-D-
glucoheptanoic-
g
-lactone.15 The benzylation of triol 9 using NaH
and benzyl bromide in DMF at room temperature gave the tribenzyl
derivative 10 (Scheme 1). Our initial attempts to selectively hy-
drolyze the terminal acetonide of compound 10 under various
conditions met with the isolation of the three possible hydrolysis
products 11e13 in varying amounts. This led us to attempt the
hydrolysis of both the acetonide groups followed by selective
protection of the terminal diol unit. Thus, the treatment of 10 with
0.8% H2SO4 in methanol gave the tetraol 11 in quantitative yields.
exercise. Epoxide 25 was equipped from D-glucose by the literature

1832
S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
Scheme 1. Synthesis of epoxide fragment 20.
alkynone cycloisomerization employing Pd(OAc)2 in anhydrous
methanol to afford anomeric mixture of glycals 29- and 29- in
a
b
a 4:1 proportion and in 64% collective yield. Both the anomers were
separated by column chromatography and were proceeded in-
dependently for hydroborationeoxidation and acetylation to get
the required products (30-a, 61% yield and 30-b, 53% yield). The
assigned structures were confirmed with the help of extensive
NMR studies. The proton connectivities were fixed with the help of
the COSY spectrum and the stereochemistry of anomeric center
was established by NOESY correlations. For example, the anomeric
C(37)eOMe of 30-
a showed NOE with C(33)eH whereas in 30-b,
Scheme 2. Attempts for alkyneeepoxide cross-coupling reaction.
a similar NOE effect was not observed (Fig. 3).
After having executed successfully the synthesis of the
C(27)eC(38) fragment, the next eventual synthetic goal was the
assembly of the C(27)eC(48) fragment, utilizing the epoxide 25 and
the key alkyne 6 as the starting points. The opening of the epoxide
25 with alkyne 6 proceeded smoothly and provided 31 (Scheme 4).
The benzylation of free eOH in 31 followed by TBS deprotection of
the resulting compound 32 gave the alkynol fragment 33 in good
yields. The alkynol thus obtained was converted to an alkynone 34
by oxidation, employing IBX in ethyl acetate under reflux condi-
tions. The assigned structure of alkynone 34 was established with
the help of spectral and analytical techniques. The presence of
signals in 1H and 13C NMR was consistent with the allocated
structure. Finally, HRMS spectral data also secured the structure of
alkynone 34.
Table 1
Reaction conditions and results for alkyneeepoxide cross-coupling reaction
Sr. no. Reagents used Temperature Results
1
2
3
n-BuLi (2 equiv), BF3$Et2O (3 equiv)
n-BuLi (2 equiv), BF3$Et2O (2 equiv)
n-BuLi (1 equiv), BF3$Et2O (1.1 equiv) ꢁ78 ꢀC
ꢁ78 ꢀC
ꢁ78 ꢀC
72% (23)
68% (23)
64% (23) and
3% (22)
S.M. recovered
S.M. recovered
S.M. recovered
S.M. recovered
S.M. recovered
S.M. recovered
S.M. recovered
S.M. recovered
4
5
6
7
8
9
10
11
n-BuLi (1 equiv)
ꢁ78 ꢀC to rt
n-BuLi (1 equiv), CuCN (2 equiv)
n-BuMgBr (2 equiv), CuCN (3 equiv)
n-BuMgBr (2 equiv), CuI (3 equiv)
n-BuLi (2 equiv), MgBr2 (2 equiv)
n-BuLi (2 equiv), ZnI2 (2 equiv)
n-BuLi (2 equiv), ZnTf2 (1 equiv)
n-BuLi (2 equiv), ScTf3 (1 equiv)
ꢁ40 ꢀC
ꢁ40 ꢀC to rt
ꢁ40 ꢀC to rt
0 ꢀC to rt
0
0
0
ꢀC to rt
ꢀC to rt
ꢀC to rt
The glycals 35-
a and 35-b were obtained in 56% yield (a/
b
¼3:1 proportion) by alkynone cycloisomerization of 34 in
presence of Pd(OAc)2 in MeOH at room temperature. Both the
anomers were separable by column chromatography. However
the characterization of these compounds proved a demanding
task. Both the compounds were found to be unstable during NMR
analysis and were hydrolyzed easily to give the dicarbonyl com-
pound 36 as was evident from the presence of characteristic
signals in 1H and 13C NMR spectra. In 1H NMR, the absence of
procedures17 and treated with alkyne 21 using n-BuLi and BF3$Et2O
at ꢁ78 ꢀC in THF to procure compound 26 in 79% yield (Scheme 3).
The protection of the resulting alcohol 26 as its benzyl ether 27
followed by TBS deprotection delivered the alkynol intermediate 28
in good yields. The crude alkynone obtained from the oxidation of
alkynol 28 using IBX in refluxing ethyl acetate was subjected for

S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
1833
Scheme 3. Synthesis of C(27)eC(38) fragment.
compounds may not be stable enough to do hydro-
borationeoxidation. After these disappointing results, the alkynone
was subjected for sequential cycloisomerization, hydro-
borationeoxidation, and acetylation as done earlier in the previous
report (Scheme 5);11 but regrettably we ended up with the for-
mation of an intractable mixture of compounds. The consistent
results obtained even with various other boranes explored led to
a conclusion that construction of the key tetrahydropyran unit
should be placed in the early stages of the synthetic program.
Fig. 3. Characteristic NOEs in 30-a and 30-b.
Scheme 4. Synthesis of alkynone 34 by using oxirane opening reaction.
singlet corresponding to eOMe at z3.33 ppm (in 35-
a
and 35-
b
)
3. Conclusion
and the presence of signals at
d
2.44 (dd, J¼4.7, 17.5 Hz, 1H), 2.53
(dd, J¼5.6, 17.5 Hz, 1H), 2.58e2.70 (m, 1H), 2.72e2.89 (m, 1H),
3.05 (dd, J¼7.5, 17.6 Hz, 1H), and 3.85 (dd, J¼3.4, 6.1 Hz, 1H)
clearly indicated that the dihydropyran was completely hydro-
lyzed into dione 36. Also the presence of two carbonyl carbons at
205.8 and 210.3 ppm in the 13C NMR spectrum further supported
the assigned structure of 36. After quick analysis of the freshly
In conclusion, the synthesis of the C(27)eC(38) fragment of
aflastatin A has been executed by employing the
u-alkynone
cycloisomerization and stereoselective hydroborationeoxidation
as focal transformations. Apart from this, the Yamaguchi oxirane
opening reaction also played a significant role in CeC bond for-
mation by coupling the epoxide and alkyne fragments. Also, we
have attempted the synthesis of the C(27)eC(48) fragment by uti-
lizing the same protocol. Though achieving the desired fragment
proved difficult, our studies in that direction have opened a new
door for the construction of fully functionalized tetrahydropyran
unit. Further studies aiming to develop a convergent approach that
involves the construction of the key tetrahydropyran unit with
minimum number of carbons and subsequent chain elongations are
in progress and will be reported in due course.
prepared samples of 35-
analytical data for 35- whereas 35-
stable compared to 35-
, making the data difficult to record. 1H
and 13C NMR spectra of 35-
always showed the peaks of dione
36 along with 35-
Our attempts involving the direct hydroborationeoxidation and
acetylation of freshly prepared 35- and 35- led to formation of
a complex reaction mixture (Scheme 5), which indicates that the
a
and 35-
b
, we were able to get the
a
b was found to be very un-
a
b
b
.
a
b

1834
S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
Scheme 5. Attempted synthesis of C(27)eC(48) fragment.
4. Experimental section
4.1. General
0.45; [
a
]
25 þ10.2 (c 2.9, CHCl3); IR (CHCl3): 3011, 2928, 1089 cmꢁ1
;
D
1H NMR (CDCl3, 400 MHz):
d 1.30 (s, 3H), 1.38 (s, 3H), 1.40 (s, 3H),
1.41 (s, 3H), 3.63e3.66 (m, 1H), 3.68e3.70 (m, 1H), 3.79e3.83 (m,
2H), 3.86 (dd, J¼2.3, 8.5 Hz, 1H), 3.88 (dt, J¼2.0, 8.4 Hz, 1H),
4.04e4.10 (m, 2H), 4.23e4.28 (m, 1H), 4.36 (dd, J¼2.0, 11.3 Hz, 1H),
4.52 (dd, J¼1.5, 12.3 Hz, 1H), 4.56 (d, J¼1.5 Hz, 1H), 4.62 (br d,
J¼12.3 Hz, 1H), 4.71 (dd, J¼1.6, 11.3 Hz, 1H), 4.84 (dd, J¼2.1, 11.8 Hz,
Air and/or moisture sensitive reactions were carried out in an-
hydrous solvents under an atmosphere of argon in oven-dried
glassware. All anhydrous solvents were distilled prior to use:
dichloromethane and DMF from CaH2; methanol from Mg cake;
THF on Na/benzophenone; triethylamine and pyridine over KOH;
acetic anhydride from sodium acetate. Commercial reagents were
used without purification. Column chromatography was carried out
by using Spectrochem silica gel. Optical rotations were determined
1H), 7.21e7.37 (m, 15H); 13C NMR (CDCl3, 100 MHz):
d 19.2 (q), 25.1
(q), 26.9 (q), 29.4 (q), 67.4 (t), 67.43 (t), 69.7 (d), 70.6 (d), 71.2 (t),
73.3 (t), 73.4 (d), 74.0 (t), 74.4 (d), 76.5 (d), 98.6 (s),109.1 (s),127.1 (d,
3C), 127.4 (d, 2C), 127.6 (d, 2C), 127.7 (d, 2C), 128.1 (d, 2C), 128.2 (d,
2C), 128.24 (d, 2C), 138.3 (s), 138.34 (s), 139.1 (s); HRMS (MALDI-
TOF) calcd for C34H42O7 ([MþNa]þ) 585.2829, found 585.2813.
on a Jasco DIP-370 digital polarimeter. Specific optical rotations [
a]
D
are given in 10ꢁ1 deg cm2 gꢁ1 1H and 13C NMR spectroscopy
.
measurements were carried out on Bruker AC 200 MHz or Bruker
DRX 400 MHz spectrometers, and TMS was used as an internal
standard. 1H and 13C NMR chemical shifts are reported in parts per
4.3. Acetonide hydrolysis of 10
Pyridinium p-toluenesulfonate (50 mg) was added to a solution
of compound 10 (1.0 g) in methanol (10 mL) at 0 ꢀC and the reaction
mixture was stirred at same temperature for 1 h. The TLC showed
formation of new three slower moving spots along with starting
material. Therefore reaction mixture was basified with triethyl-
amine and solvent was evaporated under reduced pressure to get
a mixture of 11e13, which was separated by column chromatog-
raphy (100e200 mesh silica gel, 2:8 to 9:11 ethyl acetate/petroleum
ether) to procure pure compounds 11 (211 mg, 37%), 12 (141 mg,
23%), 13 (107 mg, 17%), and starting material 10 (338 mg, all yields
are based on starting material recovered).
million (ppm) downfield from chloroform-d (
d
¼7.25) or TMS and
coupling constants (J) are reported in hertz (Hz). The following
abbreviations are used to designate signal multiplicity: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, and br¼broad. The
multiplicity of 13C NMR signals was assigned with the help of DEPT
spectra and the abbreviations used: s¼singlet, d¼doublet,
t¼triplet, and q¼quartet, represent C (quaternary), CH, CH2, and
CH3, respectively. Mass spectroscopy was carried out on PI QStar
Pulsar (Hybrid Quadrupole-TOF LC/MS/MS) and 4800 plus MALDI
TOF/TOF Applied Biosystem spectrometer.
4.2. (4S,5R,6R)-5-(Benzyloxy)-4-((S)-1,2-bis(benzyloxy)ethyl)-
6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-1,3-
dioxane (10)
4.3.1. Characterization data of 11. Rf (70% EtOAc/petroleum ether)
25
0.12; [
a
]
þ9.1 (c 1.6, CHCl3); IR (CHCl3): 3460, 3010, 2918, 1452,
D
1089 cmꢁ1; 1H NMR (CDCl3, 500 MHz):
d 2.95 (br s, 1H), 3.10 (br s,
1H), 3.39 (br s, 1H), 3.46 (br s, 1H), 3.62 (br s, 1H), 3.64e3.75 (m,
3H), 3.72 (dd, J¼4.5, 10.5 Hz, 1H), 3.73e3.75 (m, 1H), 3.83 (dd, J¼3.3,
10.5 Hz, 1H), 3.95 (t, J¼6.6 Hz, 1H), 4.02 (t, J¼2.8 Hz, 1H), 4.40 (d,
J¼11.5 Hz, 1H), 4.52 (d, J¼11.7 Hz, 2H), 4.56 (d, J¼12.1 Hz, 1H), 4.66
(d, J¼11.5 Hz, 1H), 4.69 (d, J¼11.5 Hz, 1H), 7.24e7.34 (m, 15H); 13C
At 0 ꢀC, a solution of triol 9 (10 g, 34.2 mmol) and benzyl bro-
mide (12.6 mL, 106 mmol) in anhydrous DMF (100 mL) was treated
with sodium hydride (5.47 g, 60% oil emulsion, 137 mmol) and
stirred at room temperature for 6 h. The reaction mixture was
cooled and the excess NaH was quenched by adding cold water. The
reaction mixture was partitioned between ethyl acetate (250 mL)
and water (100 mL). The separated organic layer was washed with
water (4ꢂ100 mL), brine (100 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The resulting crude product was
purified by column chromatography (230e400 mesh silica gel,
1.5:8.5 ethyl acetate/petroleum ether) to obtain compound 10
(16.8 g, 87%) as pale yellow syrup. Rf (15% EtOAc/petroleum ether)
NMR (CDCl3, 125 MHz): d 63.7 (t), 69.2 (t), 71.6 (d), 71.7 (t), 72.3 (d),
73.5 (t), 73.6 (d), 74.6 (t), 76.4 (d), 78.0 (d), 127.7 (d), 127.7 (d), 127.8
(d, 2C), 127.9 (d, 3C), 128.0 (d, 2C), 128.4 (d, 4C), 128.5 (d, 2C), 137.9
(s), 137.95 (s), 137.97 (s); HRMS (MALDI-TOF) calcd for C28H34O7
([MþNa]þ) 505.2203, found 505.2184.
4.3.2. Characterization data of 12. Rf (60% EtOAc/petroleum ether)
25
0.51; [
a
]
ꢁ2.1 (c 1.4, CHCl3); IR (CHCl3): 3440, 2998, 2910,
D

S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
1835
1110 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
d
1.38 (s, 3H), 1.39 (s, 3H),
127.9 (d, 2C), 128.4 (d, 2C), 128.42 (d, 2C), 128.5 (d, 2C), 138.1 (s),
138.17 (s), 138.19 (s); HRMS (MALDI-TOF) calcd for C33H42O7
([MþNa]þ) 573.2829, found 573.2790.
3.58 (dd, J¼3.8, 10.7 Hz, 1H), 3.66e3.71 (m, 4H), 3.82 (s, 1H), 3.87
(dd, J¼1.8, 10.7 Hz, 1H), 3.91 (ddd, J¼1.8, 3.4, 9.1 Hz, 1H), 4.09 (dd,
J¼1.0, 9.1 Hz, 1H), 4.40 (d, J¼11.4 Hz, 1H), 4.54 (d, J¼12.2 Hz, 1H),
4.60 (d, J¼12.2 Hz, 1H), 4.68 (d, J¼11.4 Hz, 1H), 4.73 (d, J¼12.0 Hz,
1H), 4.83 (d, J¼11.4 Hz, 1H), 7.24e7.34 (m, 15H); 13C NMR (CDCl3,
4.5.2. Characterization data of 14. Rf (15% EtOAc/petroleum ether)
25
0.25; [
a
]
þ15.7 (c 1.0, CHCl3); IR (CHCl3): 3011, 2916, 1092 cmꢁ1
;
D
100 MHz):
d
19.1 (q), 29.4 (q), 63.9 (t), 67.6 (t), 68.7 (d), 69.4 (d), 71.0
1H NMR (CDCl3, 400 MHz):
d 0.79e0.92 (m, 12H),1.54e1.66 (m, 6H),
(t), 71.1 (d), 73.37 (t), 73.38 (d), 73.6 (t), 76.5 (d), 98.8 (s), 127.5 (d),
127.6 (d), 127.66 (d, 3C), 127.67 (d, 2C), 127.8 (d, 2C), 128.3 (d, 2C),
128.34 (d, 2C), 128.4 (d, 2C), 138.3 (s), 138.4 (s), 138.7 (s); HRMS
(MALDI-TOF) calcd for C31H38O7 ([MþNa]þ) 545.2516, found
545.2519.
1.71e1.81 (m, 2H), 3.67 (dd, J¼3.4, 10.6 Hz, 1H), 3.72 (br d, J¼8.5 Hz,
1H), 3.77e3.84 (m, 3H), 3.89 (ddd, J¼2.1, 3.2. 9.1 Hz, 1H), 4.06 (dd,
J¼1.0, 9.1 Hz, 1H), 4.09 (dd, J¼6.5, 8.3 Hz, 1H), 4.25 (dt, J¼6.2, 8.3 Hz,
1H), 4.35 (d, J¼11.4 Hz, 1H), 4.52 (d, J¼12.3 Hz, 1H), 4.58 (d,
J¼13.0 Hz, 1H), 4.61 (d, J¼12.3 Hz, 1H), 4.73 (d, J¼11.5 Hz, 1H), 4.87
(d, J¼12.1 Hz, 1H), 7.23e7.35 (m, 15H); 13C NMR (CDCl3, 100 MHz):
4.3.3. Characterization data of 13. Rf (60% EtOAc/petroleum ether)
d 7.1 (q), 8.1 (q), 8.15 (q), 8.3 (q), 21.1 (t), 29.0 (t), 29.7 (t), 30.7 (t),
25
0.62; [
a
]
þ9.4 (c 0.6, CHCl3); IR (CHCl3): 3410, 2995, 2928,
67.6 (t), 68.3 (t), 69.7 (d), 70.0 (d), 71.2 (t), 73.4 (t), 73.8 (t), 73.9 (d),
74.0 (d), 76.6 (d), 101.9 (s), 113.1 (s), 126.7 (d, 2C), 127.0 (d), 127.5 (d),
127.52 (d), 127.6 (d, 2C), 127.8 (d, 2C), 128.1 (d, 2C), 128.3 (d, 4C),
138.3 (s), 138.5 (s), 139.4 (s); HRMS (MALDI-TOF) calcd for C38H50O7
([MþNa]þ) 641.3455, found 641.3453.
D
1065 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
d
1.34 (s, 3H), 1.40 (s, 3H),
2.92 (d, J¼6.1 Hz, 1H), 2.97 (br s, 1H), 3.64 (dt, J¼3.6, 7.8 Hz, 1H),
3.71e3.75 (m, 2H), 3.85 (dd, J¼3.2, 10.5 Hz, 1H), 3.93e3.98 (m, 2H),
4.03 (t, J¼2.5 Hz, 1H), 4.07e4.10 (m, 2H), 4.44 (d, J¼11.7 Hz, 1H),
3.54e3.56 (m, 3H), 4.72 (d, J¼11.3 Hz, 1H), 4.73 (d, J¼11.7 Hz, 1H),
7.28e7.35 (m, 15H); 13C NMR (CDCl3, 100 MHz):
d
25.3 (q), 26.8 (q),
4.6. (R)-2,2-Diethyl-4-((1R,2R,3S,4S)-1,2,3,4,5-pentakis
67.3 (t), 69.4 (t), 71.8 (t), 73.1 (d), 73.5 (t), 74.7 (t), 75.3 (d), 75.4 (d),
76.2 (d), 78.0 (d), 109.5 (s), 127.7 (d, 4C), 127.8 (d, 3C), 127.9 (d, 2C),
128.37 (d, 2C),128.4 (d, 2C), 128.42 (d, 2C), 138.0 (s), 138.1 (s), 138.12
(s); HRMS (MALDI-TOF) calcd for C31H38O7 ([MþNa]þ) 545.2516,
found 545.2532.
(benzyloxy)pentyl)-1,3-dioxolane (16)
To a solution of diol 15 (4 g, 7.3 mmol) in anhydrous DMF
(40 mL) was added benzyl bromide (1.8 mL, 15.3 mmol) at room
temperature and the reaction mixture was cooled to 0 ꢀC. To this,
sodium hydride (871 mg, 21.8 mmol) was added portion wise. After
complete addition, reaction mixture was allowed to stir at room
temperature for 4 h. The reaction mixture was cooled and the ex-
cess NaH was quenched by adding cold water. The reaction mixture
was partitioned between ethyl acetate (100 mL) and water (50 mL).
The separated organic layer was washed with water (4ꢂ50 mL),
brine (50 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude was purified by column chromatography
(230e400 mesh silica gel, 1:4 ethyl acetate/petroleum ether) to
4.4. (2R,3R,4S,5S,6S)-4,6,7-Tris(benzyloxy)heptane-1,2,3,5-
tetraol (11)
To a solution of compound 10 (15 g, 26.6 mmol) in methanol
(150 mL) was added 0.8% solution of H2SO4 in methanol (15 mL)
and stirring was continued for 8 h at room temperature. After
completion of the reaction, as indicated by TLC, the contents were
cooled in an ice bath and neutralized with solid K2CO3. The reaction
mixture was filtered through Celite pad and the filtrate was evap-
orated under reduced pressure. The crude was purified by column
chromatography (100e200 mesh silica gel, 9:11 ethyl acetate/pe-
troleum ether) to afford tetrol 11 (10.8 g, 84% yield) as colorless
gum.
obtain 16 (4.9 g, 92%) as pale yellow syrup. Rf (20% EtOAc/petroleum
25
ether) 0.60; [
a]
þ2.9 (c 1.7, CHCl3); IR (CHCl3): 3021, 2917, 1448,
D
1131 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d
0.85 (t, J¼7.5 Hz, 3H), 0.86
(t, J¼7.5 Hz, 3H), 1.53e1.64 (m, 4H), 3.73 (dd, J¼5.1, 10.0 Hz, 1H),
3.77e3.82 (m, 2H), 3.83e3.88 (m, 2H), 3.92 (t, J¼4.7 Hz, 1H), 3.96
(dd, J¼6.3, 7.9 Hz, 1H), 4.04 (dd, J¼4.6, 6.3 Hz, 1H), 4.10 (dt, J¼5.6,
8.0 Hz, 1H), 4.45 (d, J¼11.9 Hz, 1H), 4.51 (d, J¼12.1 Hz, 1H), 4.55 (d,
J¼12.1 Hz, 1H), 4.59 (d, J¼11.6 Hz, 1H), 4.62 (d, J¼11.4 Hz, 1H),
4.65e4.74 (m, 3H), 4.76 (d, J¼11.4 Hz, 1H), 7.24e7.33 (m, 25H); 13C
4.5. Selective protection of terminal diol
To an ice-cold solution of tetrol 11 (5 g, 10.4 mmol) in 3-
pentanone (50 mL), were added five drops of concentrated H2SO4
and stirring was continued at same temperature for next 3 h [for-
mation of dipentylidene derivative 14 was also observed if the
temperature increases above 5 ꢀC]. After complete consumption of
starting material, the reaction mixture was basified by triethyl-
amine (2 mL) and the solvent was evaporated under reduced
pressure. The resulting crude was purified by column chromatog-
raphy (230e400 mesh silica gel, 3:7 ethyl acetate/petroleum ether)
to isolate pure product 15 (4.9 g, 86%) as pale yellow gum.
NMR (CDCl3, 100 MHz):
d 8.3 (q, 2C), 28.5 (t), 29.5 (t), 66.7 (t), 69.7
(t), 71.9 (t), 73.3 (t), 74.0 (t), 74.4 (t), 75.2 (t), 76.8 (d), 79.4 (d), 79.5
(d), 79.7 (d), 80.5 (d), 112.2 (s), 127.4 (d, 3C), 127.5 (d, 4C), 127.6 (d,
2C), 127.7 (d, 2C), 127.9 (d, 2C), 128.0 (d, 2C), 128.2 (d, 4C), 128.23 (d,
4C), 128.3 (d, 2C), 138.3 (s), 138.5 (s), 138.54 (s), 138.6 (s), 138.8 (s);
HRMS (MALDI-TOF) calcd for C47H54O7 ([MþNa]þ) 753.3768, found
753.3756.
4.7. (2R,3R,4S,5S,6S)-3,4,5,6,7-Pentakis(benzyloxy)heptane-1,2-
diol (17)
4.5.1. Characterization data of 15. Rf (15% EtOAc/petroleum ether)
25
0.71; [
a
]
D
þ9.4 (c 0.6, CHCl3); IR (CHCl3): 3396, 3009, 2891,
To a solution of compound 16 (4.5 g, 6.7 mmol) in methanol
(50 mL) was added 0.8% solution of H2SO4 in methanol (5 mL) and
stirred for 6 h before neutralizing with solid K2CO3. The contents
were filtered through Celite bed and the filtrate was evaporated
under reduced pressure. The residue was purified by column
chromatography (230e400 mesh silica gel, 3:7 ethyl acetate/pe-
1121 cmꢁ1
;
1H NMR (CDCl3, 500 MHz):
d
0.89 (t, J¼7.5 Hz, 6H),
1.59e1.65 (m, 4H), 2.90 (d, J¼6.9 Hz,1H), 2.96 (d, J¼4.8 Hz,1H), 3.63
(ddd, J¼3.4, 4.6, 7.9 Hz, 1H), 3.70e3.72 (m, 1H), 3.73 (dd, J¼4.6,
10.5 Hz, 1H), 3.85 (dd, J¼3.3, 10.5 Hz, 1H), 3.89 (dd, J¼5.9, 7.9 Hz,
1H), 3.94 (dt, J¼2.3, 7.3 Hz, 1H), 4.06 (t, J¼2.5 Hz, 1H), 4.07e4.11 (m,
1H), 4.14 (dd, J¼6.3, 7.9 Hz, 1H), 4.41 (d, J¼11.6 Hz, 1H), 4.54 (d,
J¼11.3 Hz, 1H), 4.56 (br s, 2H), 4.73 (d, J¼11.6 Hz, 1H), 7.27e7.34 (m,
troleum ether) to afford 17 (3.3 g, 82%) as colorless gum. Rf (30%
25
EtOAc/petroleum ether) 0.26; [
a
]
D
þ2.9 (c 1.1, CHCl3); IR (CHCl3):
15H); 13C NMR (CDCl3, 125 MHz):
d
8.1 (q), 8.3 (q), 29.1 (t), 29.6 (t),
3398, 3012, 2921, 1451, 1102 cmꢁ1
3.59 (dd, J¼4.3, 11.4 Hz, 1H), 3.66 (dd, J¼3.2, 11.4 Hz, 1H),
3.70e3.73 (m, 2H), 3.79 (dd, J¼4.1, 7.6 Hz, 1H), 3.84 (dd, J¼3.5,
;
1H NMR (CDCl3, 400 MHz):
68.1 (t), 69.4 (t), 71.8 (t), 73.3 (d), 73.6 (t), 74.8 (t), 75.5 (d), 75.9 (d),
76.4 (d), 78.1 (d), 113.2 (s), 127.7 (d, 4C), 127.8 (d, 2C), 127.86 (d),
d

1836
S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
10.3 Hz, 1H), 3.86e3.90 (m, 2H), 4.06 (t, J¼4.3 Hz, 1H), 4.47 (d,
J¼12.0 Hz, 1H), 4.50e4. 57 (m, 6H), 4.68 (br d, J¼11.7 Hz, 2H), 4.77
(d, J¼11.2 Hz, 1H), 7.24e7.31 (m, 25H); 13C NMR (CDCl3, 100 MHz):
20 mL) at 0 ꢀC. After 30 min stirring at 0 ꢀC, the reaction mixture
was stirred for next 7 h at room temperature. The reaction mixture
was concentrated under reduced pressure and the residue ob-
tained was purified by column chromatography (230e400 mesh
d
63.6 (t), 69.5 (t), 71.8 (d), 72.0 (t), 73.3 (t), 73.4 (t), 74.0 (t, 2C), 76.5
(d), 78.2 (d), 78.6 (d), 78.9 (d), 127.5 (d), 127.6 (d, 2C), 127.6 (d, 2C),
127.7 (d, 2C), 127.8 (d), 127.9 (d), 128.0 (d, 2C), 128.1 (d, 2C), 128.3 (d,
6C), 128.35 (d, 2C), 128.4 (d, 4C), 137.7 (s), 137.8 (s), 138.2 (s, 2C),
138.5 (s); HRMS (MALDI-TOF) calcd for C42H46O7 ([MþNa]þ)
685.3142, found 685.3163.
silica gel, 1.5:8.5 ethyl acetate/petroleum ether) to obtain 20 (1.2 g,
25
79%) as a colorless gum. Rf (20% EtOAc/petroleum ether) 0.64; [a]
D
ꢁ27.2 (c 1.5, CHCl3); IR (CHCl3): 3055, 2921, 1131 cmꢁ1
;
1H NMR
(CDCl3, 400 MHz):
d
1.94 (dd, J¼2.4, 4.8 Hz, 1H), 2.22 (dd, J¼4.0,
4.8 Hz, 1H), 3.06e3.11 (m, 2H), 3.63 (dd, J¼5.2, 9.7 Hz, 1H), 3.70
(dt, J¼3.5, 5.2 Hz, 1H), 3.76 (dd, J¼3.1, 7.0 Hz, 1H), 3.85 (dd, J¼5.2,
9.7 Hz, 1H), 4.18 (dd, J¼3.5, 7.0 Hz, 1H), 4.40e4.46 (m, 3H), 4.53 (d,
J¼12.0 Hz, 1H), 4.54 (d, J¼11.7 Hz, 1H), 4.59 (br d, J¼11.6 Hz, 1H),
4.75 (d, J¼11.3 Hz, 1H), 4.77 (d, J¼11.6 Hz, 1H), 4.85 (br d,
J¼12.0 Hz, 2H), 7.22e7.36 (m, 25H); 13C NMR (CDCl3, 100 MHz):
4.8. (2R,3R,4S,5S,6S)-3,4,5,6,7-Pentakis(benzyloxy)-2-
hydroxyheptyl benzoate (18)
At 0 ꢀC, a solution of diol 17 (3 g, 4.5 mmol) and Et3N (0.76 mL,
5.4 mmol) in anhydrous CH2Cl2 (30 mL) was added benzoyl chloride
(0.5 mL, 4.5 mmol) and the contents stirred at the same tempera-
ture for 2.5 h. Then reaction mixture was partitioned between
CH2Cl2 (100 mL) and water (60 mL). The organic layer was sepa-
rated, washed with brine (50 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue obtained was purified by col-
umn chromatography (230e400 mesh silica gel, 1:4 ethyl acetate/
d
42.4 (t), 53.3 (d), 67.5 (t), 71.8 (t), 72.0 (t), 73.4 (t), 74.5 (t), 74.8
(t), 78.9 (d), 79.7 (d), 80.1 (d), 80.6 (d), 127.3 (d, 2C), 127.4 (d, 2C),
127.6 (d), 127.7 (d, 2C), 127.8 (d, 2C), 127.9 (d, 2C), 128.1 (d, 2C),
128.2 (d, 2C), 128.25 (d, 4C), 128.3 (d, 2C), 128.4 (d, 2C), 128.6 (d,
2C), 138.1 (s), 138.13 (s), 138.3 (s), 138.6 (s), 138.9 (s); HRMS
(MALDI-TOF) calcd for C42H44O6 ([MþNa]þ) 667.3036, found
667.3065.
petroleum ether) to procure 18 (2.9 g, 83%) as colorless syrup. Rf
25
(15% EtOAc/petroleum ether) 0.45; [
a]
þ6.4 (c 1.4, CHCl3). IR
4.11. Addition of alkyne 21 to the epoxide 20
D
(CHCl3): 3421, 2998, 2912, 1732, 1083 cmꢁ1
400 MHz):
;
1H NMR (CDCl3,
d
3.72e3.77 (m, 2H), 3.87 (dd, J¼3.1, 10.2 Hz, 1H),
At ꢁ78 ꢀC, a solution of alkyne 21 (493 mg, 0.9 mmol) in an-
hydrous THF (6 mL) was treated with n-BuLi (0.2 mL, 1.6 M in
hexane, 0.3 mmol) and stirred for 20 min and then introduced
a solution of BF3$Et2O (48 mg, 0.3 mmol) and stirred at ꢁ78 ꢀC for
20 min. To this, a solution of epoxide 20 (200 mg, 0.3 mmol) in
anhydrous THF (2 mL) was added slowly at ꢁ78 ꢀC and the contents
were stirred for 2.5 h at the same temperature. Reaction mixture
was quenched by adding saturated sodium bicarbonate (1 mL) and
partitioned between ethyl acetate (80 mL) and water (20 mL). The
organic layer was washed with brine (20 mL), dried over sodium
sulfate, and evaporated under reduced pressure. The crude com-
pound was purified by column chromatography (silica 230e400
mesh, 25% ethyl acetate in petroleum ether) to afford compound 22
(11 mg, 3% yield) as colorless syrup and compound 23 (112 mg, 64%
yield) as pale yellow gum.
3.89e3.99 (m, 2H), 4.04e4.13 (m, 2H), 4.35 (dd, J¼5.7, 11.6 Hz, 1H),
4.44e4.54 (m, 6H), 4.62 (br s, 2H), 4.69 (d, J¼11.6 Hz, 1H), 4.71 (d,
J¼11.4 Hz,1H), 4.78 (d, J¼11.4 Hz,1H), 7.22e7.32 (m, 25H), 7.39e7.42
(m, 2H), 7.53e7.55 (m, 1H), 7.99e8.07 (m, 2H); 13C NMR (CDCl3,
100 MHz): d 66.3 (t), 69.5 (t), 70.4 (d), 72.0 (t), 73.2 (t), 73.4 (t), 74.1
(t), 74.2 (t), 76.6 (d), 78.3 (d), 78.5 (d), 78.9 (d),127.5 (d),127.6 (d, 2C),
127.7 (d, 3C), 127.8 (d, 2C), 128.1 (d, 2C), 128.14 (d, 2C), 128.3 (d, 6C),
128.4 (d, 7C), 129.7 (d, 2C), 130.1 (d), 132.9 (d, 2C), 137.6 (s), 137.8
(s, 2C), 138.1 (s), 138.2 (s), 138.5 (s), 166.6 (s); HRMS (MALDI-TOF)
calcd for C49H50O8 ([MþNa]þ) 789.3404, found 789.3425.
4.9. (2R,3S,4R,5S,6S)-3,4,5,6,7-Pentakis(benzyloxy)-2-((methyl
sulfonyl)oxy)heptylbenzoate (19)
At 0 ꢀC, a solution of compound 18 (2.5 g, 3.3 mmol) and Et3N
(0.6 mL, 4.2 mmol) in anhydrous CH2Cl2 (30 mL) was treated with
methanesulfonyl chloride (0.3 mL, 3.6 mmol) and the contents
were stirred at room temperature for 2.5 h. The crude product
isolated after the usual aqueous workup was purified by column
chromatography (230e400 mesh silica gel, 1.5:8.5 ethyl acetate/
4.11.1. Characterization data of 22. Rf (15% EtOAc/petroleum ether)
25
0.33; [
a
]
D
þ27.1 (c 2.2, CHCl3); IR (CHCl3): 3398, 3013, 2912, 1441,
1086 cmꢁ1; 1H NMR (CDCl3, 500 MHz):
d 0.05 (s, 6H), 0.85 (s, 9H),
2.24 (ddd, J¼1.9, 5.7, 16.5 Hz, 1H), 2.52 (ddd, J¼1.9, 7.7, 16.5 Hz, 1H),
2.63 (br s, 1H), 3.55 (dd, J¼5.2, 10.0 Hz, 1H), 3.60 (dd, J¼2.8, 10.0 Hz,
1H), 3.75 (dd, J¼4.5, 10.1 Hz, 1H), 3.77e3.82 (m, 3H), 3.91e3.95 (m,
3H), 4.01 (dd, J¼3.0, 7.4 Hz, 1H), 4.04 (ddd, J¼3.0, 5.2, 8.2 Hz, 1H),
4.42e4.6 (m, 4H), 4.47e4.59 (m, 5H), 4.66 (d, J¼11.6 Hz,1H), 4.68 (d,
J¼12.0 Hz, 1H), 4.69 (d, J¼11.6 Hz, 1H), 4.75 (d, J¼11.5 Hz, 1H), 4.76
(d, J¼11.4 Hz, 1H), 4.77 (d, J¼11.2 Hz, 1H), 4.80 (d, J¼12.0 Hz, 1H),
4.90 (d, J¼11.5 Hz, 1H), 7.21e7.34 (m, 40H); 13C NMR (CDCl3,
petroleum ether) to afford 19 (2.1 g, 78%) as colorless gum. Rf (5%
25
EtOAc/toluene) 0.70; [
a
]
þ17.5 (c 2.3, CHCl3); IR (CHCl3): 3011,
2913, 1461, 1121 cmꢁ1
;
1DH NMR (CDCl3, 500 MHz):
d 2.74 (s, 3H),
3.71 (dd, J¼6.1, 11.4 Hz, 1H), 3.85e3.90 (m, 3H), 3.96 (t, J¼5.1 Hz,
1H), 4.16 (dd, J¼2.8, 5.9 Hz, 1H), 4.50 (br d, J¼11.2 Hz, 3H), 4.58 (dd,
J¼8.3, 12.7 Hz, 1H), 4.65e4.69 (m, 6H), 4.72 (dd, J¼2.4, 12.7 Hz, 1H),
4.75 (d, J¼11.4 Hz, 1H), 5.20 (dt, J¼2.4, 8.3 Hz, 1H), 7.15e7.32 (m,
25H), 7.42 (t, J¼7.8 Hz, 2H), 7.54e7.57 (m, 1H), 8.02e8.03 (m, 2H);
125 MHz):
d
ꢁ5.0 (q), ꢁ4.3 (q),18.0 (s), 25.8 (q, 3C), 69.5 (d), 69.8 (t),
70.8 (t), 71.1 (d), 71.9 (t, 2C), 72.3 (d), 73.2 (t), 73.3 (t), 73.5 (t), 74.4
(t, 2C), 74.7 (t), 74.9 (t), 78.0 (d), 78.8 (s), 79.1 (d), 79.4 (d), 80.1 (d),
81.7 (d), 84.6 (s), 127.3 (d), 127.4 (d, 2C), 127.5 (d, 2C), 127.54 (d),
127.6 (d, 2C), 127.7 (d, 6C), 127.8 (d, 2C), 128.0 (d, 2C), 128.02 (d, 2C),
128.1 (d, 4C), 128.16 (d, 2C), 128.19 (d, 2C), 128.26 (d, 5C), 128.3 (d,
7C), 137.9 (s), 138.2 (s, 2C), 138.3 (s), 138.4 (s), 138.43 (s), 138.6 (s),
138.7 (s); HRMS (MALDI-TOF) calcd for C75H86O10Si ([MþNa]þ)
1197.5888, found 1197.5919.
13C NMR (CDCl3, 125 MHz):
d 38.4 (q), 63.7 (t), 69.4 (t), 72.1 (t), 73.3
(t), 73.8 (t), 74.9 (t), 75.0 (t), 78.3 (d), 78.7 (d), 79.5 (d), 80.3 (d), 81.3
(d), 127.5 (d), 127.6 (d), 127.63 (d), 127.7 (d, 3C), 127.8 (d, 3C), 128.1
(d, 2C), 128.2 (d), 128.22 (d, 4C), 128.3 (d, 2C), 128.32 (d, 5C), 128.4
(d, 2C), 129.0 (d), 129.7 (d), 129.72 (d, 2C), 133.1 (d), 137.7 (s), 137.8
(s), 138.1 (s), 138.2 (s), 138.3 (s), 138.4 (s), 166.1 (s); HRMS (MALDI-
TOF) calcd for C50H52O10S ([MþNa]þ) 867.3179, found 867.3156.
4.10. (S)-2-((1R,2S,3S,4S)-1,2,3,4,5-Pentakis(benzyloxy)pentyl)
oxirane (20)
4.11.2. Characterization data of 23. Rf (15% EtOAc/petroleum ether)
25
0.18; [
a
]
þ37.2 (c 6.4, CHCl3); IR (CHCl3): 3427, 3022, 2913,
D
1127 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
d
3.62 (dd, J¼4.2, 11.7 Hz,
Solid lithium hydroxide (300 mg, 7.1 mmol) was added to
a solution of compound 19 (2 g, 2.4 mmol) in THF/MeOH (7:3,
1H), 3.67 (dd, J¼5.6, 10.7 Hz, 1H), 3.73 (dd, J¼3.1, 11.7 Hz, 1H), 3.87
(dd, J¼1.9, 10.7 Hz, 1H), 3.99e4.08 (m, 4H), 4.14 (dd, J¼3.1, 9.1 Hz,

S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
1837
1H), 4.39 (d, J¼11.4 Hz, 1H), 4.46 (d, J¼11.9 Hz, 1H), 4.49 (d,
J¼11.4 Hz, 1H), 4.50e4.56 (m, 4H), 4.78 (d, J¼11.5 Hz, 1H),
7.20e7.33 (m, 20H); 13C NMR (CDCl3, 100 MHz):
63.1 (t), 70.9 (t),
4.14. tert-Butyldimethyl(((2R,3S,4S,8S)-1,3,4,8-
tetrakis(benzyloxy)-8-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)oct-5-yn-2-yl)
d
71.6 (t), 71.7 (t), 72.5 (t), 73.4 (t), 75.8 (d), 80.3 (d), 81.7 (d), 82.5 (d),
85.1 (d), 127.4 (d, 2C), 127.5 (d, 4C), 127.6 (d, 2C), 127.9 (d, 4C), 128.2
(d, 4C), 128.5 (d, 4C), 137.2 (s), 137.5 (s), 138.4 (s), 138.7 (s); HRMS
(MALDI-TOF) calcd for C35H38O6 ([MþNa]þ) 577.2566, found
577.2577.
oxy)silane (27)
To a solution alcohol 26 (1 g, 1.2 mmol) in anhydrous DMF
(15 mL) was added benzyl bromide (0.16 mL, 1.3 mmol) at room
temperature and the reaction mixture was cooled to 0 ꢀC. To this,
sodium hydride (97 mg, 60% oil emulsion, 2.4 mmol) was added
portion wise. After complete addition, reaction mixture was
allowed to stir at room temperature for 6 h. Reaction mixture was
quenched and partitioned between ethyl acetate (80 mL) and
water (30 mL). The separated organic layer was washed with water
(4ꢂ30 mL), brine (30 mL), dried over sodium sulfate, and con-
centrated under reduced pressure. The crude was purified by col-
umn chromatography (230e400 mesh silica gel, 1.5:8.5 ethyl
4.12. ((2R,3R,4S,5S)-3,4-Bis(benzyloxy)-5-((S)-1,2-
bis(benzyloxy)ethyl)tetrahydrofuran-2-yl)methylacetate (24)
To a solution of compound 23 (80 mg, 0.2 mmol) in pyridine
(1 mL), acetic anhydride (1 mL) was added slowly at 0 ꢀC. The
contents were stirred for 3 h at room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL), washed with water
(5 mL), brine (5 mL), dried over sodium sulfate, and concentrated
under reduced pressure. The residue was purified by column
chromatography (230e400 mesh silica gel, 1.5:8.5 ethyl acetate/
acetate/petroleum ether) to obtain compound 27 (903 mg, 81%) as
25
pale yellow syrup. Rf (20% EtOAc/petroleum ether) 0.61; [
a
;
]
1DH
þ23.1 (c 1.6, CHCl3); IR (CHCl3): 3028, 2913, 1451, 1093 cmꢁ1
NMR (CDCl3, 400 MHz): d 0.01 (s, 3H), 0.02 (s, 3H), 0.82 (s, 9H), 1.33
petroleum ether) to procure compound 24 (79 mg, 91%) as colorless
(s, 3H), 1.44 (s, 3H), 2.46 (ddd, J¼1.6, 6.3, 17.1 Hz, 1H), 2.57 (ddd,
J¼1.7, 4.3, 17.1 Hz, 1H), 3.56 (dd, J¼4.8, 9.9 Hz, 1H), 3.61 (dd, J¼3.0,
9.9 Hz, 1H), 3.80 (dd, J¼4.3, 6.3 Hz, 1H), 3.92 (dt, J¼4.7, 6.6 Hz, 1H),
4.00e4.04 (m, 2H), 4.40e4.49 (m, 6H), 4.60e4.66 (m, 3H), 4.71 (d,
J¼11.9 Hz, 1H), 4.78 (d, J¼11.5 Hz, 1H), 4.83 (d, J¼11.9 Hz, 1H), 4.92
(d, J¼11.9 Hz, 1H), 5.99 (d, J¼4.0 Hz, 1H), 7.22e7.36 (m, 25H); 13C
25
gum. Rf (20% EtOAc/petroleum ether) 0.55; [
a]
þ33.1 (c 3.4,
D
CHCl3); IR (CHCl3): 3022, 2931, 1731, 1461, 1112 cmꢁ1
(CDCl3, 400 MHz):
;
1H NMR
d
2.00 (s, 3H), 3.70 (dd, J¼5.6, 10.6 Hz, 1H),
3.84e3.91 (m, 2H), 4.03e4.06 (m, 1H), 4.09e4.13 (m, 4H), 4.19 (dd,
J¼3.3, 9.0 Hz, 1H), 4.42e4.53 (m, 5H), 4.59 (br s, 2H), 4.81 (d,
J¼11.4 Hz, 1H), 7.24e7.34 (m, 20H); 13C NMR (CDCl3, 100 MHz):
NMR (CDCl3, 100 MHz):
d
ꢁ4.9 (q), ꢁ4.3 (q), 18.0 (s), 21.6 (t), 25.9
d
20.8 (q), 64.6 (t), 71.0 (t), 71.4 (t), 71.7 (t), 72.5 (t), 73.3 (t), 76.0 (d),
(q, 3C), 26.6 (q), 27.0 (q), 70.6 (t), 71.00 (d), 71.7 (t), 72.0 (t), 72.2
(d), 72.9 (t), 73.2 (t), 74.3 (t), 76.5 (d), 78.0 (s), 81.7 (d), 82.3 (d),
82.4 (d), 82.6 (d), 84.3 (s), 105.1 (d), 112.0 (s), 127.3 (d, 2C), 127.35
(d), 127.4 (d), 127.7 (d, 4C), 127.8 (d, 2C), 127.9 (d, 2C), 127.95 (d, 2C),
128.0 (d), 128.1 (d, 2C), 128.13 (d, 2C), 128.2 (d, 2C), 128.24 (d, 2C),
128.5 (d, 2C), 137.1 (s), 138.0 (s), 138.4 (s), 138.8 (s), 138.9 (s); HRMS
(MALDI-TOF) calcd for C56H68O9Si ([MþNa]þ) 935.4531, found
935.4512.
80.5 (d), 81.9 (d), 82.0 (d), 83.0 (d), 127.4 (d, 2C), 127.6 (d, 8C), 127.7
(d),127.9 (d),128.2 (d, 4C),128.4 (d, 2C),128.5 (d, 2C),137.5 (s),137.7
(s), 138.6 (s), 138.8 (s), 170.7 (s); HRMS (MALDI-TOF) calcd for
C37H40O7 ([MþNa]þ) 619.2672, found 619.2660.
4.13. (1S,5S,6S,7R)-5,6,8-Tris(benzyloxy)-1-((3aR,5R,6S,6aR)-6-
(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-7-((tert-butyldimethylsilyl)oxy)oct-3-yn-1-ol (26)
A solution of alkyne 21 (2.72 g, 5.1 mmol) in anhydrous THF
(20 mL) was treated with n-BuLi (3.2 mL,1.6 M in hexane, 5.1 mmol)
at ꢁ78 ꢀC for 20 min and then BF3$Et2O (680 mg, 4.8 mmol) was
added. Stirring was continued at ꢁ78 ꢀC for 20 min then to this,
a solution of epoxide 25 (50Z0 mg, 1.7 mmol) in anhydrous THF
(3 mL) was added slowly at ꢁ78 ꢀC and the contents were stirred
for 2 h at the same temperature. Reaction mixture was quenched by
adding saturated sodium bicarbonate (2 mL) and extracted with
ethyl acetate (100 mL) and water (40 mL). The organic layer was
washed with brine (40 mL), dried over sodium sulfate, and evap-
orated under reduced pressure. The crude was purified by column
chromatography (silica 230e400 mesh, 1:4 ethyl acetate/petro-
leum ether) to afford compound 26 (1.1 g, 79%) as pale yellow thick
4.15. (2R,3R,4S,8S)-1,3,4,8-Tetrakis(benzyloxy)-8-((3aR,5R,6-
S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)oct-5-yn-2-ol (28)
To an ice cooled solution of TBS ether 27 (900 mg, 1.0 mmol) in
anhydrous THF (10 mL) was added a solution of TBAF (386 mg,
1.5 mmol) in anhydrous THF (2 mL) under argon atmosphere and
allowed to stir at room temperature for 4 h. Reaction mixture was
concentrated and the residue was purified by column chroma-
tography (230e400 mesh silica gel, 1:4 ethyl acetate/petroleum
ether) to afford compound 28 (601 mg, 76% yield) as a colorless
25
gum. Rf (20% ethyl acetate/petroleum ether) 0.28; [
a
]
þ30.6 (c
D
1.0, CHCl3); IR (CHCl3): 3442, 3038, 2943, 1451, 1081 cmꢁ1; 1H NMR
(CDCl3, 500 MHz):
1.32 (s, 3H), 1.44 (s, 3H), 2.43 (dd, J¼6.1,
oil. Rf (25% EtOAc/petroleum ether) 0.32; [
a
]
25 þ19.1 (c 1.9, CHCl3);
d
D
IR (CHCl3): 3468, 3021, 2931,1099 cmꢁ1; 1H NMR (CDCl3, 500 MHz):
17.1 Hz, 1H), 2.53 (dd, J¼3.3, 17.1 Hz, 1H), 2.65 (br s, 1H), 3.59 (dd,
J¼5.7, 9.6 Hz, 1H), 3.65 (dd, J¼2.8, 9.6 Hz, 1H), 3.76 (dd, J¼3.6,
7.5 Hz, 1H), 3.91 (dt, J¼3.6, 6.5 Hz, 1H), 3.95 (br s, 1H), 4.00 (d,
J¼3.6 Hz, 1H), 4.40e4.42 (m, 2H), 4.47 (d, J¼11.8 Hz, 1H), 4.48 (d,
J¼11.7 Hz, 1H), 4.51 (d, J¼11.8 Hz, 1H), 4.52e4.54 (m, 1H),
4.57e4.64 (m, 3H), 4.70 (d, J¼11.6 Hz, 1H), 4.79 (d, J¼11.6 Hz, 1H),
4.86 (d, J¼12.2 Hz, 1H), 4.88 (d, J¼11.6 Hz, 1H), 5.99 (d, J¼3.9 Hz,
d
ꢁ0.01 (s, 3H), 0.01 (s, 3H), 0.80 (s, 9H), 1.32 (s, 3H), 1.42 (s, 3H),
2.50 (dd, J¼5.8, 16.8 Hz, 1H), 2.60 (dd, J¼7.1, 16.8 Hz, 1H), 3.52 (dd,
J¼5.0, 10.1 Hz, 1H), 3.58 (dd, J¼2.7, 10.1 Hz, 1H), 3.79 (dd, J¼4.2,
6.5 Hz, 1H), 3.97e3.99 (m, 2H), 4.08 (dd, J¼6.2, 10.9 Hz, 1H), 4.34 (t,
J¼3.8 Hz, 1H), 4.42e4.53 (m, 5H), 4.63e4.73 (m, 3H), 4.81 (d,
J¼11.9 Hz, 1H), 4.90 (d, J¼11.6 Hz, 1H), 6.00 (d, J¼3.8 Hz, 1H),
7.23e7.36 (m, 20H); 13C NMR (CDCl3, 125 MHz):
d
ꢁ5.0 (q), ꢁ4.3 (q),
1H), 7.20e7.37 (m, 25H); 13C NMR (CDCl3, 125 MHz):
d 21.6 (t), 26.5
18.0 (s), 23.9 (t), 25.8 (q, 3C), 26.4 (q), 26.9 (q), 68.9 (d), 70.8 (t), 71.0
(d), 71.8 (t, 2C), 72.2 (d), 73.2 (t), 74.3 (t), 78.8 (s), 80.5 (d), 81.4 (d),
82.3 (d), 83.1 (d), 83.9 (s), 104.9 (d), 111.9 (s), 127.3 (d, 2C), 127.5 (d),
127.7 (d, 2C), 127.8 (d, 2C), 127.9 (d, 2C), 128.1 (d, 2C), 128.13 (d, 2C),
128.2 (d, 2C), 128.3 (d, 3C),128.7 (d, 2C), 136.6 (s), 137.9 (s), 138.4 (s),
138.7 (s); HRMS (MALDI-TOF) calcd for C49H62O9Si ([MþNa]þ)
845.4061, found 845.3998.
(q), 26.9 (q), 70.8 (d), 70.82 (t), 70.9 (t), 71.4 (d), 71.7 (t), 73.0 (t),
73.3 (t), 73.9 (t), 76.4 (d), 77.6 (s), 80.5 (d), 82.1 (d), 82.3 (d), 82.7
(d), 84.7 (s), 105.1 (d), 112.0 (s), 127.3 (d), 127.5 (d), 127.6 (d), 127.7
(d, 3C), 127.8 (d, 2C), 127.83 (d, 4C), 128.0 (d, 3C), 128.16 (d, 2C),
128.2 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 128.5 (d, 2C), 137.0 (s),
137.8 (s), 138.0 (s), 138.5 (s), 138.8 (s); ESI-MS: m/z 821.43
([MþNa]þ).

1838
S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
4.16. Pd-mediated cycloisomerization
reduced pressure and the residual material was extracted with
diethyl ether (5 mL). The organic layer was washed water (2 mL),
dried over sodium sulfate, and concentrated under reduced pres-
sure. The crude compound was dissolved in 1 mL anhydrous CH2Cl2
and treated with pyridine (0.5 mL) followed by acetic anhydride
(0.5 mL). The contents were stirred at room temperature for 5 h. The
reaction mixture was concentrated under reduced pressure and
traces of solvents were removed by co-evaporation with toluene
(3ꢂ10 mL). Residue was purified by column chromatography
(230e400 mesh silica gel, 1:4 ethyl acetate/petroleum ether) to
IBX (52 mg, 0.2 mmol) was added to a solution of an alcohol 28
(100 mg, 0.1 mmol) in ethyl acetate (10 mL) at room temperature
and stirring was continued at reflux temperature for 3 h. After the
complete consumption of starting material, the reaction mixture
was cooled in ice bath, filtered through Celite bed, washed with
ethyl acetate, and the combined filtrate was evaporated under re-
duced pressure. The residual crude ketone (91 mg) was dissolved in
anhydrous methanol (10 mL) and the solution was degassed by
passing argon for 45 min. To this, Pd(OAc)2 (5 mg, 22.8
m
mol) was
procure compound 30-
a (32 mg, 66% yield) as colorless gum. Rf (20%
added and stirred for 2.5 h. After consumption of starting material,
the reaction mixture was filtered through Celite bed and the filtrate
was concentrated under reduced pressure. The resulting crude
material was purified by column chromatography (230e400 mesh
EtOAc/petroleum ether) 0.40; [
a
]
25 ꢁ16.9 (c 0.7, CHCl3); IR (CHCl3):
D
3011, 2933,1721,1450,1092 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d
1.28
(s, 6H),1.47e1.49 (m,1H),1.78e1.81 (m,1H),1.93 (s, 3H), 3.16 (s, 3H),
3.33 (d, J¼6.5 Hz,1H), 3.45 (d, J¼10.1 Hz,1H), 3.63 (d, J¼10.1 Hz,1H),
3.78e3.90 (m, 2H), 3.95 (dd, J¼2.8, 6.8 Hz,1H), 4.07 (d, J¼2.8 Hz,1H),
4.37e4.38 (m, 1H), 4.40 (d, J¼11.0 Hz, 1H), 4.43 (d, J¼11.7 Hz, 1H),
4.49 (d, J¼12.5 Hz, 1H), 4.52 (d, J¼3.7 Hz, 1H), 4.53e4.60 (m, 3H),
4.61e4.66 (m, 2H), 4.72 (d, J¼12.1 Hz, 1H), 4.91 (d, J¼11.4 Hz, 1H),
5.13 (t, J¼10.0 Hz, 1H), 5.94 (d, J¼3.9 Hz, 1H), 7.20e7.36 (m, 20H),
7.45e7.49 (m, 2H), 7.53e7.56 (m, 1H), 7.64e7.70 (m, 2H); 13C NMR
silica gel, 1:4 ethyl acetate/petroleum ether) to obtain 29-
a (52 mg,
53% yield) and 29- (13 mg, 14% yield) as colorless gums.
b
4.16.1. Characterization data of 29-
a
. Rf (15% EtOAc/petroleum
25
ether) 0.46; [
a]
D
þ9.2 (c 0.7, CHCl3); IR (CHCl3): 3019, 2928, 1455,
1096 cmꢁ1 1H NMR (CDCl3, 400 MHz):
;
d 1.31 (s, 3H), 1.43 (s, 3H),
2.19e2.35 (m, 2H), 3.09 (s, 3H), 3.45 (d, J¼10.3 Hz, 1H), 3.71 (d,
J¼10.3 Hz, 1H), 3.90 (d, J¼3.7 Hz, 1H), 3.95 (dt, J¼4.6, 7.7 Hz, 1H),
4.04 (dd, J¼1.8, 4.1 Hz, 1H), 4.24 (dd, J¼3.8, 7.4 Hz, 1H), 4.29 (d,
J¼12.2 Hz, 1H), 4.44 (m, 2H), 4.50 (d, J¼11.7 Hz, 1H), 4.53e4.57 (m,
3H), 4.60e4.63 (m, 3H), 4.65 (d, J¼12.2 Hz, 1H), 4.87 (d, J¼11.4 Hz,
1H), 4.90 (br s, 1H), 5.95 (d, J¼4.0 Hz, 1H), 7.15e7.36 (m, 25H); 13C
(CDCl3, 100 MHz): d 21.1 (q), 26.2 (q), 26.7 (q), 33.5 (t), 50.1 (q), 67.1
(t), 70.0 (d), 71.0 (t), 71.6 (d), 71.7 (t), 72.5 (t), 73.4 (t), 74.7 (d), 75.0
(t), 75.4 (d), 77.1 (d), 81.7 (d), 82.3 (d), 83.3 (d), 100.5 (s), 105.2 (d),
111.4 (s), 127.2 (d, 2C), 127.5 (d, 4C), 127.7 (d, 4C), 127.9 (d, 2C), 128.0
(d, 2C), 128.2 (d, 4C), 128.24 (d, 3C), 128.5 (d, 4C), 137.2 (s), 137.6 (s),
138.1 (s), 139.0 (s), 139.2 (s), 169.9 (s); HRMS (MALDI-TOF) calcd for
C53H60O12 ([MþNa]þ) 911.3983, found 911.3994.
NMR (CDCl3,100 MHz): d 26.5 (q), 26.9 (q), 36.0 (t), 48.7 (q), 64.7 (t),
70.7 (d), 70.8 (t), 71.8 (t), 72.4 (d), 73.3 (t), 73.5 (t), 74.9 (t), 75.3 (d),
82.1 (d), 82.7 (d), 83.2 (d), 100.4 (d), 101.6 (s), 105.1 (d), 111.8 (s),
127.1 (d), 127.2 (d, 2C), 127.3 (d, 2C), 127.6 (d, 2C), 127.8 (d), 127.9 (d,
3C), 128.0 (d, 2C), 128.1 (d, 2C), 128.2 (d, 2C), 128.3 (d, 2C), 128.32 (d,
2C),128.4 (d, 2C), 128.5 (d, 2C),137.2 (s), 137.6 (s), 138.6 (s), 138.8 (s),
139.1 (s), 146.8 (s); HRMS (MALDI-TOF) calcd for C51H56O10
([MþNa]þ) 851.3771, found 851.3724.
4.18. (2R,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-2-((S)-2-(benzyloxy)-
2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro
[2,3-d][1,3]dioxol-5-yl)ethyl)-6-((benzyloxy)methyl)-6-
methoxytetrahydro-2H-pyran-3-yl acetate (30-b)
Following the above procedure the hydroboration of 29-
(21 mg, 25 mol) followed by acetylation gave 30- (14 mg, 63%
yield) as pale yellow gum. Rf (20% EtOAc/petroleum ether) 0.42;
b
m
b
4.16.2. Characterization data of 29-
b
. Rf (15% EtOAc/petroleum
25
25
ether) 0.42; [
a]
ꢁ8.5 (c 0.6, CHCl3); IR (CHCl3): 3014, 2923, 1451,
[a
]
ꢁ29.4 (c 0.6, CHCl3); IR (CHCl3): 3010, 2919, 1726, 1452,
D
D
1109 cmꢁ1 1H NMR (CDCl3, 500 MHz):
;
d
1.33 (s, 3H), 1.46 (s, 3H),
1087 cmꢁ1 1H NMR (CDCl3, 400 MHz):
; d 1.28 (s, 3H), 1.38 (s, 3H),
2.18 (dd, J¼8.7, 14.3 Hz, 1H), 2.28 (dd, J¼2.9, 14.3 Hz, 1H), 3.34 (s,
3H), 3.67 (d, J¼10.0 Hz, 1H), 3.87e3.89 (m, 2H), 3.92 (d, J¼3.4 Hz,
1H), 4.01 (d, J¼4.1 Hz, 1H), 4.05 (dt, J¼3.4, 8.2 Hz, 1H), 4.24 (dd,
J¼3.4, 7.7 Hz, 1H), 4.43 (d, J¼12.0 Hz, 1H), 4.46 (d, J¼11.8 Hz, 1H),
4.48 (d, J¼12.0 Hz, 1H), 4.52 (d, J¼12.3 Hz, 1H), 4.54 (d, J¼12.1 Hz,
1H), 4.61e4.64 (m, 3H), 4.67 (d, J¼11.1 Hz, 1H), 4.69 (d, J¼11.4 Hz,
1H), 4.82 (d, J¼11.1 Hz, 1H), 4.86 (d, J¼4.8 Hz, 1H), 6.01 (d, J¼4.1 Hz,
1.45e1.49 (m, 2H), 1.92 (s, 3H), 3.22e3.31 (m, 1H), 3.38 (s, 3H), 3.49
(d, J¼10.8 Hz, 1H), 3.56 (br d, J¼10.9 Hz, 1H), 3.87e3.90 (m, 2H),
4.04 (d, J¼3.1 Hz, 1H), 4.10 (d, J¼3.1 Hz, 1H), 4.22 (d, J¼12.4 Hz, 1H),
4.33 (dd, J¼3.1, 8.4 Hz, 1H), 4.40 (d, J¼12.4 Hz, 1H), 4.44e4.48 (m,
3H), 4.51e4.54 (m, 3H), 4.71 (d, J¼11.5 Hz, 1H), 4.74 (d, J¼11.5 Hz,
1H), 4.88 (d, J¼11.9 Hz, 1H), 5.22 (t, J¼9.1 Hz, 1H), 5.95 (d, J¼3.9 Hz,
1H), 7.16e7.24 (m, 10H), 7.27e7.31 (m, 13 H), 7.41e7.43 (m, 2H); 13C
1H), 7.16e7.39 (m, 25H); 13C NMR (CDCl3, 125 MHz):
d
26.5 (q), 26.9
NMR (CDCl3,100 MHz): d 21.1 (q), 26.2 (q), 26.7 (q), 32.3 (t), 48.5 (q),
(q), 36.1 (t), 50.0 (q), 69.0 (t), 70.4 (t), 71.6 (t), 72.4 (t), 73.3 (t), 73.5
(t), 73.9 (d), 76.0 (d), 81.9 (d), 82.1 (d), 83.3 (d), 98.1 (d), 100.4 (s),
105.1 (d), 111.8 (s), 127.2 (d), 127.4 (d), 127.5 (d), 127.6 (d, 3C), 127.9
(d, 5C), 128.0 (d), 128.1 (d, 4C), 128.2 (d, 6C), 128.3 (d, 2C), 128.5 (d,
2C), 137.0 (s), 137.9 (s), 138.1 (s), 138.8 (s), 139.0 (s), 149.8 (s); HRMS
(MALDI-TOF) calcd for C51H56O10 ([MþNa]þ) 851.3771, found
851.3724.
65.2 (t), 67.1 (d), 71.6 (t), 71.62 (t), 71.7 (d), 72.1 (t), 73.4 (t), 74.8 (d),
74.9 (t), 75.5 (d), 78.4 (d), 81.4 (d), 82.2 (d), 83.6 (d), 101.1 (s), 105.1
(d), 111.2 (s), 127.2 (d, 2C), 127.4 (d, 2C), 127.9 (d), 127.95 (d, 3C),
128.1 (d, 3C), 128.1 (d), 128.3 (d, 3C), 128.4 (d, 4C), 128.5 (d), 131.9
(d), 132.0 (d, 2C), 132.1 (d, 2C), 137.0 (s), 137.7 (s), 138.5 (s), 138.8 (s),
139.2 (s), 170.0 (s); HRMS (MALDI-TOF) calcd for C53H60O12
([MþNa]þ) 911.3983, found 911.3994.
4.17. (2R,3R,4S,5S,6S)-4,5-Bis(benzyloxy)-2-((S)-2-(benzyloxy)-
2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro
[2,3-d][1,3]dioxol-5-yl)ethyl)-6-((benzyloxy)methyl)-6-
4.19. (1S,5S,6S,7R,9R)-5,6,9-Tris(benzyloxy)-1-((3aR,5R,6S,6aR)-
6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-7-((tert-butyldimethylsilyl)oxy)octadec-3-yn-1-ol (31)
methoxytetrahydro-2H-pyran-3-yl acetate (30-a)
A solution of alkyne 6 (3.44 g, 5.1 mmol) in anhydrous THF
(30 mL) was treated with n-BuLi (3.2 mL,1.6 M in hexane, 5.1 mmol)
at ꢁ78 ꢀC for 20 min and then with BF3$Et2O (680 mg, 4.8 mmol) for
20 min. To this, a solution of epoxide 25 (500 mg, 1.7 mmol) in
anhydrous THF (3 mL) was added slowly at ꢁ78 ꢀC and the contents
were stirred for 2 h at same temperature. Reaction mixture was
quenched by adding saturated sodium bicarbonate (5 mL) and
To an ice cooled solution of compound 29-
in anhydrous THF (3 mL) was added neat BH3$DMS (15.4
a
(45 mg, 54.3
m
mol)
mL,
163 mmol) and stirring was continued at room temperature for 3 h.
Then reaction mixture was cooled to 0 ꢀC, treated with 3 N NaOH
(0.5 mL) followed by 30% H2O2 (0.5 mL) and stirred at room tem-
perature for 8 h. The reaction mixture was concentrated under

S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
1839
extracted with ethyl acetate (150 mL) and water (70 mL). The or-
3458, 3014, 2923, 1451, 1129 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
ganic layer was washed with brine (60 mL), dried over sodium
sulfate, and evaporated under reduced pressure. The crude was
purified by column chromatography (silica 230e400 mesh, 1:3
ethyl acetate/petroleum ether) to afford compound 31 (1.35 g, 82%)
d
0.88 (t, J¼4.4 Hz, 3H), 1.25 (br s, 14H), 1.32 (s, 3H), 1.43 (s, 3H),
1.50e1.57 (m, 3H), 1.76e1.91 (m, 1H), 2.41e2.47 (m, 1H), 2.53 (ddd,
J¼2.1, 4.2, 17.1 Hz, 1H), 3.56 (dd, J¼3.7, 6.5 Hz, 1H), 3.58e3.61 (m,
1H), 3.91e3,95 (m, 2H), 4.00 (br d, J¼3.3 Hz,1H), 4.36e4.49 (m, 5H),
4.57 (br d, J¼11.5 Hz, 1H), 4.61e4.72 (m, 4H), 4.79 (d, J¼11.1 Hz, 1H),
4.85 (d, J¼12.1 Hz,1H), 4.91 (d, J¼11.7 Hz,1H), 5.99 (d, J¼4.0 Hz,1H),
as colorless gum. Rf (15% EtOAc/petroleum ether) 0.38; [
a]
25 þ7.5 (c
D
0.6, CHCl3); IR (CHCl3): 3471, 3009, 2918, 1439, 1101 cmꢁ1; 1H NMR
(CDCl3, 400 MHz):
d
ꢁ0.01 (s, 6H), 0.82 (s, 9H), 0.86 (t, J¼4.8 Hz, 3H),
7.19e7.37 (m, 25H); 13C NMR (CDCl3, 100 MHz):
d 14.1 (q), 21.7 (t),
1.24 (br s, 14H), 1.31 (s, 3H), 1.42 (s, 3H), 1.46e1.51 (m, 2H),
1.69e1.75 (m, 1H), 1.95e2.08 (m, 1H), 2.48 (ddd, J¼1.6, 6.0, 16.7 Hz,
1H), 2.60 (ddd, J¼1.7, 6.9,16.7 Hz,1H), 3.17 (br s,1H), 3.65 (dd, J¼2.0,
7.6 Hz, 1H), 3.73 (t, J¼5.1 Hz, 1H), 3.96e4.17 (m, 3H), 4.26e4.35 (m,
2H), 4.39e4.54 (m, 4H), 4.62e4.71 (m, 3H), 3.74e4.84 (m, 2H), 6.00
(d, J¼3.8 Hz, 1H), 7.19e7.38 (m, 20H); 13C NMR (CDCl3, 100 MHz):
22.7 (t), 24.6 (t), 26.5 (q), 26.9 (q), 29.3 (t), 29.5 (t), 29.6 (t), 29.9 (t),
31.9 (t), 33.4 (t), 36.6 (t), 70.4 (t), 70.7 (t), 71.1 (d), 71.7 (t), 71.8 (d),
73.1 (t), 74.2 (t), 76.6 (d), 77.9 (s), 80.2 (d), 82.2 (d), 82.4 (d), 82.6 (d),
83.4 (d), 84.5 (s), 105.1 (d), 112.0 (s), 127.3 (d), 127.5 (d, 2C), 127.7 (d,
3C), 127.8 (d, 2C), 127.84 (d, 4C), 128.0 (d, 2C), 128.2 (d, 5C), 128.3 (d,
2C),128.4 (d, 2C),128.5 (d, 2C),137.0 (s),138.0 (s),138.1 (s), 138.6 (s),
138.8 (s); HRMS (MALDI-TOF) calcd for C60H74O9 ([MþNa]þ)
961.5231, found 961.5281.
d
ꢁ4.5 (q), ꢁ4.3 (q), 14.1 (q), 17.9 (s), 22.7 (t, 2C), 23.9 (t), 25.3 (t),
25.9 (q), 25.91 (q), 26.0 (q), 26.4 (q), 26.9 (q), 29.3 (t), 29.6 (t, 2C),
29.7 (t), 29.9 (t), 31.9 (t), 68.9 (d), 70.7 (t), 71.9 (t), 74.2 (t), 74.5 (t),
75.8 (d), 76.3 (d), 77.2 (d), 77.4 (s), 80.4 (d), 82.3 (d), 83.3 (d), 84.1
(d), 85.1 (s), 105.0 (d), 112.0 (s), 127.3 (d, 2C), 127.6 (d), 127.8 (d, 4C),
127.9 (d, 3C),128.2 (d, 5C),128.3 (d, 3C),128.7 (d, 2C),136.6 (s),137.8
(s), 139.0 (s), 139.1 (s); HRMS (MALDI-TOF) calcd for C59H82O9Si
([MþNa]þ) 985.5626, found 985.5698.
4.22. (1S,5S,6S,9R)-1,5,6,9-Tetrakis(benzyloxy)-1-((3aR,5R,6-
S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)octadec-3-yn-7-one (34)
To a solution of alcohol 33 (100 mg, 106
mmol) in ethyl acetate
(10 mL) was added IBX (45 mg, 160 mol) at room temperature and
m
4.20. tert-Butyldimethyl(((1S,5S,6S,7R,9R)-1,5,6,9-tetrakis
(benzyloxy)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)octadec-3-yn-
7-yl)oxy)silane (32)
stirred at reflux temperature for 3 h. After the complete con-
sumption of starting material, the reaction mixture was cooled in
ice bath, filtered through Celite bed, washed with ethyl acetate, and
the combined filtrate evaporated under reduced pressure. The
crude compound was purified by column chromatography
(100e200 mesh silica gel, 1.5:8.5 ethyl acetate/petroleum ether) to
To a solution of alcohol 31 (1 g, 1.0 mmol) in anhydrous DMF
(15 mL) was added benzyl bromide (0.14 mL, 1.1 mmol) at room
temperature and then sodium hydride (83 mg, 60% oil emulsion,
2.1 mmol) at 0 ꢀC. Usual workup followed by purification by column
chromatography (230e400 mesh silica gel, 1:4 ethyl acetate/pe-
troleum ether) gave 32 (893 mg, 82%) as pale yellow syrup. Rf (15%
procure pure product 34 (94 mg, 94%) as colorless syrup. Rf (25%
25
EtOAc/petroleum ether) 0.44; [
a
]
D
þ7.4 (c 0.7, CHCl3); IR (CHCl3):
3011, 2919, 1722, 1085 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
d 0.88 (t,
J¼6.0 Hz, 3H), 1.23 (br s, 16H), 1.33 (s, 3H), 1.44 (s, 3H), 2.39e2.52
(m, 3H), 2.72e3.10 (m, 1H), 3.87e4.06 (m, 4H), 4.36e4.47 (m, 6H),
4.51e4.64 (m, 4H), 4.72 (d, J¼11.9 Hz, 1H), 4.75 (d, J¼11.7 Hz, 1H),
4.78 (d, J¼11.7 Hz, 1H), 6.00 (d, J¼4.1 Hz, 1H), 7.23e7.36 (m, 25H);
EtOAc/petroleum ether) 0.51; [
a
]
25 þ10.1 (c 3.2, CHCl3); IR (CHCl3):
D
3032, 2911, 1453, 1098 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d
ꢁ0.03 (s,
3H), ꢁ0.01 (s, 3H), 0.80 (s, 9H), 0.84 (t, J¼4.6 Hz, 3H),1.21 (br s,14H),
1.29 (s, 3H), 1.42 (s, 3H), 1.51e1.72 (m, 3H), 1.98e2.05 (m, 1H), 2.38
(ddd, J¼1.7, 6.2, 17.2 Hz, 1H), 2.51 (ddd, J¼1.9, 4.2, 17.2 Hz, 1H),
3.53e3.63 (m, 1H), 3.70 (t, J¼5.1 Hz, 1H), 3.85e3.89 (m, 1H),
3.95e3.99 (m, 2H), 4.26e4.42 (m, 6H), 4.58 (d, J¼3.6 Hz, 1H), 4.60
(d, J¼4.2 Hz,1H), 4.63 (d, J¼11.6 Hz,1H), 4.65 (d, J¼11.5 Hz, 1H), 4.72
(d, J¼10.7 Hz, 1H), 4.75 (d, J¼11.5 Hz, 1H), 4.80 (d, J¼11.5 Hz, 1H),
5.96 (d, J¼4.0 Hz, 1H), 7.15e7.32 (m, 25H); 13C NMR (CDCl3,
13C NMR (CDCl3, 100 MHz):
d 14.1 (q), 21.6 (t, 2C), 22.7 (t), 25.2 (t),
26.5 (q), 26.9 (q), 29.3 (t), 29.6 (t), 29.7 (t), 31.9 (t), 34.5 (t), 44.4 (t),
69.9 (d), 70.6 (t), 71.6 (t), 71.7 (t), 73.0 (t), 73.1 (t), 74.9 (d), 76.4 (d),
77.3 (s), 82.1 (d), 82.3 (d), 82.6 (d), 85.2 (s), 85.7 (d), 105.1 (d), 112.0
(s), 127.4 (d, 2C), 127.7 (d, 3C), 127.8 (d, 2C), 127.9 (d, 2C), 128.0 (d,
4C), 128.2 (d, 5C), 128.3 (s, 5C), 128.5 (d, 2C), 137.0 (s), 137.3 (s),
137.34 (s), 138.7 (s), 138.8 (s), 208.0 (s); HRMS (MALDI-TOF) calcd
for C60H72O9 ([MþNa]þ) 959.5074, found 959.5085.
100 MHz):
d
ꢁ4.5 (q), ꢁ4.2 (q),14.1 (q), 21.5 (t), 22.7 (t), 25.3 (t), 25.9
(q, 2C), 26.0 (q), 26.6 (q), 27.0 (q), 29.3 (t), 29.6 (t), 29.7 (t), 29.9 (t),
31.9 (t), 34.5 (t), 37.2 (t), 70.1 (d), 70.6 (d), 70.7 (t), 71.7 (t), 72.9 (t),
74.2 (t), 75.5 (t), 76.3 (d), 76.4 (d), 78.7 (s), 82.3 (d), 82.4 (d), 82.5 (d),
84.0 (s), 84.2 (d), 105.1 (d),112.0 (s), 127.2 (d), 127.3 (d, 2C),127.5 (d),
127.7 (d, 2C), 127.8 (d, 5C), 127.9 (d, 2C), 128.0 (d, 2C), 128.1 (d, 4C),
128.2 (d, 2C), 128.3 (d, 2C), 128.5 (d, 2C), 137.1 (s), 137.9 (s), 138.8 (s),
139.1 (s), 139.14 (s); HRMS (MALDI-TOF) calcd for C66H88O9Si
([MþNa]þ) 1075.6096, found 1075.6082.
4.23. Pd-mediated cycloisomerization
To a solution of alcohol 33 (100 mg, 0.1 mmol) in ethyl acetate
(10 mL) was added IBX (45 mg, 0.2 mmol) at room temperature and
stirred at reflux temperature for 3 h. After the complete con-
sumption of starting material, the reaction mixture was cooled in
ice bath, filtered through Celite bed, and the filtrate was evaporated
under reduced pressure. The residual crude ketone 34 (96 mg,
102
solution was degassed by passing argon gas for 45 min. To this,
Pd(OAc)2 (7 mg, 31 mol) was added and stirred for 2.5 h. After
mmol) was dissolved in anhydrous methanol (15 mL) and the
4.21. (1S,5S,6R,7R,9R)-1,5,6,9-Tetrakis(benzyloxy)-1-((3aR,5R,6-
S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]di-
oxol-5-yl)octadec-3-yn-7-ol (33)
m
consumption of starting material, the reaction mixture was filtered
through Celite bed and the filtrate was concentrated under reduced
pressure. The resulting crude compound was purified by column
chromatography (230e400 mesh silica gel, 1:3 ethyl acetate/pe-
To an ice cooled solution of TBS ether 32 (900 mg, 0.8 mmol) in
anhydrous THF (10 mL) was added a solution of TBAF (335 mg,
1.3 mmol) in anhydrous THF (2 mL) under argon atmosphere and
allowed to stir at room temperature for 4 h. Reaction mixture was
concentrated and residue was purified by column chromatography
(230e400 mesh silica gel, 1:3 ethyl acetate/petroleum ether) to
troleum ether) to procure compounds 35-a (55 mg, 55% yield) and
35- (18 mg, 18% yield) as colorless gums.
b
4.23.1. Characterization data of 35-
ether) 0.34; 1H NMR (CDCl3, 400 MHz):
(br s, 14H), 1.26e1.28 (m, 2H), 1.32 (s, 3H), 1.37e1.40 (m, 2H), 1.47
a. Rf (25% EtOAc/petroleum
afford compound 33 (601 mg, 75% yield) as a colorless gum. Rf (25%
d
0.87 (t, J¼6.2 Hz, 3H), 1.24
25
EtOAc/petroleum ether) 0.39; [
a]
þ8.5 (c 2.9, CHCl3); IR (CHCl3):
D

1840
S.B. Narute, C.V. Ramana / Tetrahedron 69 (2013) 1830e1840
(s, 3H), 2.23e2.34 (m, 2H), 3.29 (s, 3H), 3.75e3.84 (m, 2H),
3.95e4.03 (m, 2H), 4.21 (dd, J¼1.8, 5.9 Hz, 2H), 4.30e4.34 (m, 2H),
4.37e4.43 (m, 2H), 4.49 (br s, 2H), 4.53e4.59 (m, 2H), 4.61e4.64
(m, 2H), 4.78 (d, J¼11.3 Hz, 1H), 4.87 (d, J¼4.7 Hz, 1H), 5.99 (d,
J¼4.0 Hz, 1H), 7.19e7.23 (m, 13H), 7.27e7.35 (m, 12H); 13C NMR
Supplementary data
NMR spectra. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.12.065.
(CDCl3, 100 MHz): d 14.1 (q), 22.7 (t), 26.5 (q), 26.9 (q), 29.1 (t), 29.4
(t), 29.6 (t), 29.63 (t), 29.7 (t), 29.72 (t), 30.0 (t), 31.9 (t), 36.0 (t),
48.6 (q), 70.7 (t), 71.3 (t), 71.8 (t), 73.4 (t), 74.1 (t), 75.3 (d), 75.8 (d,
2C), 77.2 (d), 82.3 (d), 82.7 (d), 83.2 (d), 99.9 (d), 103.2 (s), 105.1 (d),
111.7 (s), 126.8 (d), 127.0 (d), 127.1 (d), 127.2 (d, 2C), 127.24 (d), 127.3
(d), 127.5 (d), 127.6 (d), 127.7 (d, 2C), 127.75 (d), 127.8 (d), 127.9 (d),
128.03 (d), 128.1 (d, 2C), 128.2 (d, 4C), 128.3 (d), 128.4 (d), 128.41
(d), 128.5 (d), 138.0 (s), 138.8 (s), 139.0 (s), 139.1 (s), 139.4 (s), 151.9
(s); HRMS (MALDI-TOF) calcd for C61H76O10 ([MþNa]þ) 991.5336,
found 991.5309.
References and notes
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5. (a) Ono, M.; Sakuda, S.; Suzuki, A.; Isogai, A. J. Antibiot. 1997, 50, 111e118; (b)
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Antibiot. 1998, 51, 1019e1028.
4.24. (1S,5S,6S,9R)-1,5,6,9-Tetrakis(benzyloxy)-1-((3aR,5R,6-
S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)octadecane-3,7-dione (36)
6. Ikeda, H.; Matsumori, N.; Ono, M.; Suzuki, A.; Isogai, A.; Nagasawa, H.; Sakuda,
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During the spectral (NMR) analysis both 35-
a and 35-b were
hydrolyzed in to dicarbonyl compound (36). Rf (30% EtOAc/petro-
leum ether) 0.31; [
a
]
D
25 ꢁ24.7 (c 1.3, CHCl3); IR (CHCl3): 3031, 2938,
1723, 1716, 1451, 1092 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
d
0.89 (t,
10. (a) Ramana, C. V.; Patel, P.; Gonnade, R. G. Tetrahedron Lett. 2007, 48, 4771e4774;
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Tetrahedron 2009, 65, 9819e9832; (e) Ramana, C. V.; Mallik, R.; Sahoo, G.
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13. (a) Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc., Chem. Commun. 1986,
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1992, 887e893.
J¼6.3 Hz, 3H), 1.25e1.31 (br m, 16H), 1.34 (s, 3H), 1.49 (s, 3H),
2.25e2.40 (m, 1H), 2.44 (dd, J¼4.7, 17.5 Hz, 1H), 2.53 (dd, J¼5.6,
17.5 Hz, 1H), 2.58e2.70 (m, 1H), 2.72e2.89 (m, 1H), 3.05 (dd, J¼7.5,
17.6 Hz, 1H), 3.85 (dd, J¼3.4, 6.1 Hz, 1H), 3.92e4.03 (m, 2H),
4.18e4.23 (m, 1H), 4.31e4.41 (m, 3H), 4.43e4.50 (m, 3H), 4.51e4.54
(m, 1H), 4.56e4.63 (m, 3H), 4.64e4.67 (m, 1H), 4.70e4.85 (m, 2H),
6.1 (d, J¼3.9 Hz, 1H), 7.20e7.39 (m, 25H); 13C NMR (CDCl3,
100 MHz): d 14.1 (q), 22.7 (t, 2C), 25.2 (t), 26.4 (q), 26.8 (q), 29.3 (t),
29.6 (t), 29.7 (t), 31.9 (t), 34.3 (t), 44.6 (t), 45.1 (t), 45.2 (t), 71.4 (t),
71.6 (t), 72.6 (t), 73.0 (t), 73.9 (t), 74.5 (d), 75.1 (d), 75.8 (d), 77.2 (d),
81.8 (d), 83.1 (d), 86.0 (d), 105.2 (d), 111.8 (s), 127.0 (d), 127.3 (d),
127.4 (d), 127.7 (d), 127.8 (d, 4C), 127.9 (d, 3C), 128.0 (d), 128.1 (d),
128.2 (d), 128.24 (d, 4C), 128.4 (d, 2C), 128.6 (d, 3C), 129.0 (d), 129.7
(d), 136.8 (s), 137.4 (s), 138.0 (s), 138.7 (s), 138.8 (s), 205.8 (s), 210.3
(s); HRMS (MALDI-TOF) calcd for C60H74O10 ([MþNa]þ) 977.5180,
found 977.5149.
16. Selected papers on debenzylative cycloetherification: (a) Gray, G. R.; Hartman,
F. C.; Barker, R. J. Org. Chem. 1965, 30, 2020e2024; (b) Martin, O. R.; Yang, F.; Xie,
F. Tetrahedron Lett. 1995, 36, 47e50; (c) Yang, B.-H.; Jiang, J.-Q.; Ma, K.; Wu,
H.-M. Tetrahedron Lett. 1995, 36, 2831e2834; (d) Reddy, L. V. R.; Roy, A. D.; Roy,
Acknowledgements
We thank the Ministry of Science and Technology for funding
through the Department of Science and Technology under the
Green Chemistry Program (No. SR/S5/GC-20/2007). S.B.N. thanks
CSIR, New Delhi for the financial assistance in the form of a research
fellowship.
ꢀ
R.; Shaw, A. K. Chem. Commun. 2006, 3444e3446; (e) Cribiu, R.; Cumpstey, I.
Chem. Commun. 2008, 1246e1248; (f) Thota, V. N.; Gervay-Hague, J.; Kulkarni,
S. S. Org. Biomol. Chem. 2012, 10, 8132e8139.
17. Hung, S.-C.; Lu, X.-A.; Lee, J.-C.; Chang, M. D.-T.; Fang, S.-.L.; Fan, T.-C.; Zuluetaa,
M. M. L.; Zhonga, Y.-Q. Org. Biomol. Chem. 2012, 10, 760e772.