A Mitsunobu route to C-glycosides

Article abstract of DOI:10.1016/j.tet.2009.08.024

C-Glycosides were successfully prepared via dehydrative alkylation under Mitsunobu conditions, using substituted sulfonyl methanes as nucleophiles. The materials prepared were converted to useful C-glycoside intermediates. An application of this approach

Full text of DOI:10.1016/j.tet.2009.08.024

Tetrahedron 65 (2009) 8468–8477
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A Mitsunobu route to C-glycosides
*
Paolo Pasetto , Matthew C. Walczak
AMRI, Department of Medicinal Chemistry, 26 Corporate Circle, Albany, NY 12212, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2009
Received in revised form 6 August 2009
Accepted 7 August 2009
Available online 13 August 2009
C-Glycosides were successfully prepared via dehydrative alkylation under Mitsunobu conditions, using
substituted sulfonyl methanes as nucleophiles. The materials prepared were converted to useful C-gly-
coside intermediates. An application of this approach toward the synthesis of C-glycolipids is presented.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
pyranose (1) with 2 under Mitsunobu conditions with tribu-
tylphosphine provided the
b-C-glucoside product 3 in 84% yield,
C-Glycosides have attracted much attention as analogs of O-
glycosides, in which the hydrolytically labile acetal moiety of the
carbohydrate is replaced by a functionality that is resistant to
metabolic processing. A variety of C-glycosides, both synthetic and
naturally occurring, display interesting pharmaceutical properties.
This resulted in an intense effort by the scientific community in
developing synthetic strategies to C-glycosides.1
Our synthetic approach to C-glycosides involves the use of the
Mitsunobu reaction. The classical Mitsunobu reaction is a well-
established method to condense an alcohol with a carboxylic acid.
The utility of this reaction has been extended to the use of several
heteroatom nucleophiles.2 A dehydrative alkylation of bis-sulfones,
mediated by the redox couple triphenylphoshine and DEAD, was
described by Falck and co-workers.3 Similarly, a few other examples
of carbon nucleophiles employed in C-alkylation under Mitsunobu
conditions have been reported.4 The chain elongation of primary
alcohols of carbohydrates employing bis(2,2,2-trifluoroethyl)-
malonate as a nucleophile under Mitsunobu conditions was de-
scribed.5 However, when attempts were made to extend the
methodology toward reaction at the anomeric position, no formation
of C-alkylation product was observed.6
using 1.5 equiv of reagents (Scheme 1). The
b
-stereochemistry of 3
was easily assigned by 1H NMR, which showed the anomeric proton
as a doublet centered at 4.11 ppm with a coupling constant 3J¼9.9 Hz.
To extend the utility of this approach to the synthesis of C-glycosides,
a screening of potential nucleophiles was investigated. Thus, con-
densation of nucleophile 47 with 1 provided the
b
-C-glucoside
product 5 as a single diastereomer in 62% yield when 5 equiv of the
reagents was employed. The -stereochemistry of 5 was ascertained
b
also in this case by the coupling constant 3J¼9.7 Hz measured for the
signal corresponding to the anomeric proton (a doublet of doublets,
which resonated at 3.97 ppm and which presented a smaller cou-
pling 3J¼1.5 Hz with the proton located on the exocyclic carbon).
Diethyl(phenylsulfonyl)methylphosphonate (6)8 was found to be
another successful nucleophile that gave the C-glucoside 7 as a single
diastereomer in 39% yield (using 1.5 equiv of reagents). At this stage
the stereochemistry at the anomeric center could not be established
due to spectral overlap of diagnostic 1H NMR signals. The
b-stereo-
chemistry of 7 was unambiguously confirmed later on when 7 was
converted to compound 46.
We now report our recent discovery that C-glycosides can be
efficiently prepared by condensing a partially protected carbohy-
drate with a C-nucleophile under Mitsunobu conditions.
2. Results and discussion
Inspired by Falck’s report,3 we investigated the use of bis(phenyl-
sulfonyl)methane (2) as a possible nucleophile in the synthesis of
C-glycosides. Thus reaction of 2,3,4,6-tetra-O-benzyl-a-D-gluco-
* Corresponding author. Tel.: þ1 518 512 2000; fax: þ1 518 512 2079.
E-mail address: paolo.pasetto@amriglobal.com (P. Pasetto).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.024

P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
8469
(Phenylsulfonyl)acetonitrile (4) was chosen for optimization
studies, because of the lower yield obtained compared with the
bis(phenylsulfonyl)methane (2) and the absence of byproducts
(Table 1). Initially, several reaction conditions were explored by
screening different solvents and reagents, but maintaining the
same concentration (0.18 M starting material 1) and using 1.5 equiv
of the reagents (entries 1–8). The employment of different azo re-
agents resulted in no dramatic changes in the yields (entries 1–3).
The use of tributylphosphine appeared to be crucial: whenever
triphenylphosphine was employed the reaction failed9 (entries 4
and 5). Also, solvents other than benzene were tested, with gen-
erally a negative effect in the yield (entries 6–8). Having de-
termined the optimal reagents and solvent (entry 3) the reaction
conditions were further investigated, and the reaction’s yield im-
proved as the excess of reagents was increased (entries 9 and 10).
The use of the sterically less hindered Me3P did not result in im-
provement of the yield (entry 11). Entries 12–14 describe the effect
on yields that different reagents had on the condensation of 1 with
bis(phenylsulfonyl)methane (2) under Mitsunobu conditions. As
a confirmation of the results obtained for the nucleophile 4, the
yield appeared to be negatively affected by the use of triphenyl-
phosphine (entry 12), while no substantial change in the yield was
observed by employing either TMAD or DEAD (entries 13 and 14).
Similar optimization studies for the synthesis of 7 did not result in
substantial improvement in the yield (entries 15–19).
containing carbonyl groups were employed, competition between O-
and C-glycosylation was noticed (Scheme 2). The use of methyl
(phenylsulfonyl)acetate 8 as nucleophile afforded a 1/1.25 ratio of the
C-glucoside 9 versus the O-alkylation product 10. The
b anomer of 10
was largely prevalent over the , which amounted to 9% of the iso-
a
lated O-glucosylated product. On the contrary, the O-glucoside 13
was the only product observed when diethyl malonate (11) was
employed with no trace of the C-glycoside 12, in accordance to what
was previously reported for a fluorinated malonate ester.6 Also phe-
nylsulfonylacetone (14) gave the O-glucoside 16 as the sole product.
In all cases each epimer of 10 and the products 13 and 16 were ob-
served to be present as single isomers, but the E or Z configuration
could not be established by NMR studies. The O-/C-glycosylation ratio
appeared to be unaffected by the solvent used for the preparation of 9
and 10 (benzene, THF, DMF, and methylene chloride were tested).
Ambident nucleophiles were reported to afford competitive al-
kylation under Mitsunobu reaction.10 Indeed, when nucleophiles
Table 1
Optimization studies for dehydrative alkylation of 1 under Mitsunobu conditionsa
Entry
1
Nucleophile
Product
Reaction conditionsb
Yield (%)
26
4 (1.5 equiv)
5
TMAD (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
DEAD (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
ADDP (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
ADDP (1.5 equiv),
Ph3P (1.5 equiv), PhH
DEAD (1.5 equiv),
Ph3P (1.5 equiv), PhH
ADDP (1.5 equiv),
n-Bu3P (1.5 equiv), CH2Cl2
ADDP (1.5 equiv),
n-Bu3P (1.5 equiv), DMF
ADDP (1.5 equiv),
n-Bu3P (1.5 equiv), THF
ADDP (3 equiv),
n-Bu3P (3 equiv), PhH
ADDP (5 equiv),
n-Bu3P (5 equiv), PhH
ADDP (5 equiv),
Me3P (5 equiv), PhH
DEAD (1.5 equiv),
Ph3P (1.5 equiv), PhH
TMAD (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
DEAD (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
TMAD (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
ADDP (1.5 equiv),
n-Bu3P (1.5 equiv), PhH
ADDP (3 equiv),
2
4 (1.5 equiv)
4 (1.5 equiv)
4 (1.5 equiv)
4 (1.5 equiv)
4 (1.5 equiv)
4 (1.5 equiv)
4 (1.5 equiv)
4 (3 equiv)
5
5
5
5
5
5
5
5
5
5
3
3
3
7
7
7
7
7
27
35
0
3
Scheme 2.
4
5
0
Interestingly, both the prochiral nucleophiles 4 and 6 provided
the C-glucosides 5 and 7, respectively, as single diastereomers,
6
3
whose configurations at the carbon
a to the sulfone could not be
7
3
determined by NMR, whereas methyl (phenylsulfonyl)acetate (8)
gave 9 as a 5/4 mixture of epimers.
8
15
50
62
56
41
76
84
31
39
37
41
35
In our hands, the success of this reaction was limited to nucleo-
philes 2, 4, 6, and 8 while the use of nucleophiles 11, 14, and 17–23
(Fig. 1) resulted in no reaction with recovery of starting materials
for 17–23 and formation of O-alkylation products in the cases of 11
and 14 (vide supra).
9
10
11
12
13
14
15
16
17
18
19
4 (5 equiv)
4 (5 equiv)
2 (1.5 equiv)
2 (1.5 equiv)
2 (1.5 equiv)
6 (1.5 equiv)
6 (1.5 equiv)
6 (3 equiv)
Figure 1. Unreactive nucleophiles.
By analogy with the C-glucosides described so far, the C-galac-
tosides 25 and 26 were prepared under the same conditions
(Scheme 3). The product 26 resulted to be a 6/1 mixture of epimers
n-Bu3P (3 equiv), PhH
ADDP (5 equiv),
n-Bu3P (5 equiv), PhH
ADDP (5 equiv),
6 (5 equiv)
that was isolated in 42% yield. Also for the galactose series the b-
6 (5 equiv)
anomers were the only products isolated. The coupling constant
3J¼10.1 Hz indicated an axial arrangement of the anomeric proton
(4.42 ppm) of 25. The stereochemistry at the anomeric center of 26
was more conveniently assigned later, after the removal of the
Me3P (5 equiv), PhH
a
Abbreviations: ADDP: 1,10-(azodicarbonyl)dipiperidine; DEAD: diethyl azodi-
carboxylate; TMAD: N,N,N0,N0-tetramethylazodicarboxamide.
b
All reactions were run at room temperature overnight.

8470
P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
respectively. The coupling constant 3J¼9.3 Hz between the
anomeric proton of 30, centered at 3.46 ppm and the proton on
the endocyclic carbon confirmed the b-stereochemistry assigned to
the C-galactoside 26. These materials 28–31 represent useful in-
termediates that can be employed, via further functionalization, in
the preparation of more complex C-glycosides.
When the bis-sulfonyl derivative 3 was treated with either so-
dium amalgam or activated magnesium, the major product was 3218
along with the minor b
-methyl C-glycoside 3319 in a 2.4/1 ratio
Scheme 3.
(Scheme 5). The formation of 32 and 33 probably occurred via
a stepwise mechanism that involved a first desulfonylation of 3 to
obtain intermediate 27. A further desulfonylation would convert 27
to a methylene anion intermediate, which would provide either 32
sulfonyl group, since the mixture of epimers was converted to the
single isomer 30.
The C-glucoside products 3, 5, 7, and 9 were invariably the
isomers as it would be expected starting from the commercially
available 2,3,4,6-tetra-O-benzyl- -glucopyranose (1). No trace of
the anomer was observed, regardless of the nucleophile used and
the reaction conditions. Similarly, complete selectivity toward the
-product was observed when the electrophile in the Mitsunobu
step was the 2,3,4,6-tetra-O-benzyl- -galactopyranose (24) pur-
chased as a mixture of anomers ( w3/2). We can speculate that
the -phosphonium intermediate I would be more accessible to
a nucleophilic attack under an SN2 mechanism (Fig. 2). On the
contrary, the antiperiplanar approach of a nucleophile to the
phosphonium group in II would be less favorable because of steric
reasons. The discord of the ratio between the reagent and the
b-
by
tonation. Formation of
the desulfonylation step to obtain compounds 28–31, presumably
due to the presence of an electron-withdrawing group to the sul-
fone that stabilizes the intermediate carbanion. It may be possible
that -elimination does occur, followed by ring closure via Michael
b
-elimination and consequent ring opening20 or 33 by pro-
b-elimination products was not observed in
a-D
a
a
b
b
D
reaction. However, this alternate mechanism would most likely re-
a/b
sult in the formation of products 28–31 as anomeric mixtures.21
a
b
-
a/b
product may be explained by an equilibrium between the two
anomeric forms at some intermediate stage during the reaction.
Scheme 5.
The bis-sulfone 3 was unreactive as a nucleophile in all our ef-
forts at alkylation via deprotonation and treatment with either
benzyl, allyl or propargyl bromides. On the contrary, palladium
catalyzed allylation22 of 3 provided in excellent yield the C-glyco-
side 35, which was easily hydrogenated to 36 without affecting the
benzyl groups by employing palladium on alumina as catalyst
(Scheme 6). Desulfonylation with either sodium amalgam13 or ac-
tivated Mg14 afforded invariably a 2.5/1 mixture of 37 (E/Z¼5/1) and
38.23 Mercury mediated cyclization of 37, followed by in situ
Figure 2. Origin of a/b selectivity.
We then decided to investigate the synthetic utility of the ma-
terials we had synthesized. Mono-desulfonylation of 3 with alu-
minum amalgam11 (Scheme 4) proceeded in quantitative yield,
providing the C-glycoside 27 that can be employed in further
functionalization by taking advantage of the versatile sulfonyl
group.12 Desulfonylation of compounds 5, 7, 9, and 26 (Scheme 4)
could be achieved by treatment with either sodium amalgam13 or
activated magnesium.14 The ester 28 was isolated in excellent yield,
and with spectroscopic data in agreement with those reported.15
Desulfonylation of 5, 26, and 7 proceeded in all cases with good
yields as well, providing the C-glycosides 29,16 30, and 31,17
demercurization,24 afforded the -C-glucoside anomer 39.23
a
C-Glycolipids and their derivatives are important compounds
pursued for their interesting antiviral properties against HIV,25
malaria, and their anticancer activity.26,27 Our synthetic sequence
to the preparation of 39 was easily applied to the synthesis of the C-
glucolipid 45 (Scheme 6). Thus, the methyl carbonate 4028 was
prepared from the commercially available trans-2-decen-1-ol and
coupled with the bis-sulfone 3. Hydrogenation of 41, followed by
desulfonylation of 42 afforded 43 (E/Z¼2.3/1) and 44 in 3/1 ratio,
which were easily separated by column chromatography. Finally,
ring closure of 43 gave the a-C-glucolipid 45.
Olefination of 7 under Horner–Wadsworth–Emmons conditions
was unsuccessful with propionaldehyde and benzaldehyde, but
resulted in high yield of product 46 when paraformaldehyde was
employed29 (Scheme 7). At this stage it was possible to confirm the
b-stereochemistry assigned to compound 7 by measuring a coupling
constant 3J¼9.7 Hz for the doublet centered at 4.08 ppm and corre-
sponding to the anomeric proton of 46. The vinyl sulfone 46 could be
employed inthepreparation of avarietyofinteresting materials, since
it can easily undergo Michael type reactions and cycloadditions.30,31
Desulfonylation of 46 with sodium amalgam gave a mixture of four
easilyseparable products: the desired olefin 4732 (14%) along with the
major product 48 (E/Z¼2.7/1, 20%), and small amounts of 4923 (9%)
and 50 (8%). This last product 50 was likely formed by Michael addi-
tion of methanol to the vinyl sulfone 46, followed by desulfonylation
and b
-elimination.20 Mechanistically, products 48 and 49 could arise
from reduction of the double bond of 46, followed either by desul-
fonylation to obtain 49 or by desulfonylation/elimination to form 48.
Scheme 4.

P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
8471
Scheme 6.
4. Experimental section
4.1. General methods
Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. All nonaqueous reactions
were carried out under an atmosphere of dry nitrogen. NMR
spectra were obtained at 500 MHz for proton and 125 MHz for
carbon in deuterated solvents, using tetramethylsilane as an in-
ternal standard. The assignment of proton and carbon NMR peaks
was supported by routine COSY and HSQC spectra and for some
cases by NOESY spectra. Melting points were determined on a Mel-
Temp II melting point apparatus and were uncorrected. High res-
olution mass spectra were obtained on a Q-TOF mass spectrometer
using electrospray ionization. Thin layer chromatography analyses
were carried out on EMD TLC 60 F254 silica gel plates. Flash column
chromatography was carried out on ISCO, Inc. Combiflash Com-
panion, using ACS reagent grade solvents.
Scheme 7.
Complete conversion of 46 to the versatile synthetic intermediate 47
was achieved in excellent yield and with no traces of byproducts by
using zinc dust and saturated aqueous NH4Cl.33
4.2. General procedure for Mitsunobu reactions
To a stirred solution of the alcohol, phosphine, and nucleophile
in benzene at 0 ꢀC, under nitrogen atmosphere, was added the azo
reagent. After the reaction mixture was stirred at 0 ꢀC for 30 min,
the mixture was allowed to slowly warm to room temperature and
then stirred at room temperature overnight. The mixture was then
filtered, and the filtrate was concentrated under reduced pressure
to give the crude product. The residue was purified by column
chromatography.
3. Conclusions
The dehydrative alkylation of carbohydrates under Mitsunobu
conditions is a novel and efficient approach to the synthesis of C-
glycosides. This reaction is highly selective toward the
b anomer, with
no formation of product ever detected in the glucose and galactose
a
series. The C-glycosides obtained were easily converted into versatile
materials that can be employed as intermediates in the synthesis of
more complex C-glycosides with pharmacological properties.
In our hands, this strategy proved not to be generally applicable
to a wide variety of carbon nucleophiles previously reported suc-
cessful for the Mitsunobu reaction, but is limited to the four nu-
cleophiles 2, 4, 6, and 8.
The simple reaction conditions, the accessibility of the starting
materials, and the generally good yield obtained make the Mitsu-
nobu reaction an efficient tool for the synthesis of C-glycosides.
4.3. General desulfonylation procedure
4.3.1. Method A. A slurry of activated magnesium turnings in
MeOH was heated at 50 ꢀC. After a few minutes generation of hy-
drogen started and the sulfone or bis-sulfone starting material,
dissolved in THF, was added. The resulting mixture was stirred at
50 ꢀC and the reaction was monitored by TLC. If necessary, addi-
tional Mg was added to drive the reaction to completion. When
consumption of all starting material was detected, the reaction

8472
P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
mixture was cooled to room temperature, 1 N HCl was added
carefully, and the mixture was extracted with EtOAc. The organic
extracts were combined, dried (MgSO4), filtered, and concentrated
under reduced pressure to give the crude, which was purified by
column chromatography to afford the product(s).
column chromatography (silica gel, 0–50% EtOAc/heptane)
afforded 7 (1.74 g, 39%) as a colorless oil: 1H NMR (500 MHz,
CDCl3)
d
7.97–7.94 (m, 2H), 7.61–7.53 (m, 1H), 7.43 (t, J¼7.8 Hz,
2H), 7.35–7.21 (m, 18H), 7.20–7.11 (m, 2H), 4.94 (d, J¼11.6 Hz, 1H),
4.90 (d, J¼11.1 Hz, 1H), 4.86 (d, J¼11.2 Hz, 1H), 4.79 (d, J¼10.8 Hz,
1H), 4.75 (d, J¼11.6 Hz, 1H), 4.56 (d, J¼10.8 Hz, 1H), 4.39 (d,
J¼11.8 Hz, 1H), 4.34 (d, J¼11.8 Hz, 1H), 4.19 (t, J¼9.2 Hz, 1H), 4.17–
4.09 (m, 1H), 4.08–3.89 (m, 5H), 3.73 (t, J¼9.5 Hz, 1H), 3.63 (t,
J¼9.0 Hz, 1H), 3.59 (dd, J¼10.7, 3.2 Hz, 1H), 3.25 (dd, J¼10.7,
1.1 Hz, 1H), 3.18 (ddd, J¼9.6, 2.8, 1.5 Hz, 1H), 1.16 (t, J¼7.1 Hz, 3H),
4.3.2. Method B. To a solution of the sulfone or bis-sulfone starting
material in THF, MeOH and Na2HPO4 were added, followed by so-
dium amalgam (6 wt %) at room temperature. The mixture was
stirred until TLC analysis indicated complete consumption of
starting material and then 1 N HCl was added carefully. The mixture
was extracted with EtOAc and the organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure to
obtain a residue that was purified by column chromatography
when necessary.
1.10 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 139.4, 138.5,
138.3, 138.1, 137.9, 133.6, 129.7, 128.5, 128.4, 128.4, 128.4, 127.9,
127.8, 127.7, 127.6, 127.6, 127.5, 127.5, 87.5, 79.2, 78.4, 77.6, 76.6 (d,
JC–P¼4.6 Hz), 75.4, 75.1, 74.7, 73.2, 68.4, 64.6 (d, JC–P¼136.1 Hz),
63.6 (d, JC–P¼5.9 Hz), 62.6 (d, JC–P¼6.3 Hz), 16.3 (d, JC–P¼6.7 Hz),
16.2 (d, JC–P¼7.0 Hz); 31P NMR (202 MHz, CDCl3)
d 13.1; HRMS
4.4. Experimental procedures
(ESI), m/z calcd for [C45H51O10PSþNH4]þ: 832.3279; found
832.3284.
4.4.1. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-6-
(bis(phenylsulfonyl)methyl)tetrahydro-2H-pyran (3). The general
4.4.4. Methyl 2-(phenylsulfonyl)-2-((2R,3R,4S,5R,6R)-3,4,5-tris(ben-
zyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)acetate (9)
and (2R,3R,4S,5R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(1-
methoxy-2-(phenylsulfonyl)vinyloxy)tetrahydro-2H-pyran (10). The
general Mitsunobu procedure was followed, using 2,3,4,6-tetra-O-
Mitsunobu procedure was followed, using 2,3,4,6-tetra-O-benzyl-
a-
D-glucopyranose (1, 2.0 g, 3.7 mmol), tributylphosphine (1.38 mL,
5.6 mmol), bis(phenylsulfonyl)methane (2, 1.7 g, 5.6 mmol), and
DEAD (0.98 g, 5.6 mmol) in benzene (20 mL). Purification by column
chromatography (silica gel, 0–50% EtOAc/heptane) afforded 3
(2.54 g, 84%) as a white solid: mp 55–58 ꢀC; 1H NMR (500 MHz,
benzyl-a-D-glucopyranose (1, 120 mg, 0.22 mmol), tributylpho-
sphine (0.08 mL, 0.33 mmol), methyl (phenylsulfonyl)acetate (8,
71 mg, 0.33 mmol), and TMAD (60 mg, 0.34 mmol) in benzene
(3 mL). The two products 9 (white foam, 5/4 mixture of epimers,
50 mg, 31%) and 10 (colorless oil, 64 mg, 39%) were separated by
column chromatography (silica gel, 0–50% EtOAc/heptane). Com-
CDCl3)
d
7.92 (d, J¼8.1 Hz, 4H), 7.58 (t, J¼6.9 Hz, 2H), 7.47–7.25 (m,
22H), 7.21–7.14 (m, 2H), 5.07 (d, J¼11.8 Hz, 1H), 5.01 (s, 1H), 4.94 (d,
J¼11.1 Hz,1H), 4.86 (d, J¼11.8 Hz,1H), 4.85 (d, J¼11.1 Hz,1H), 4.79 (d,
J¼10.7 Hz, 1H), 4.62 (d, J¼10.7 Hz, 1H), 4.52 (d, J¼12.2 Hz, 1H), 4.40
(t, J¼9.4 Hz, 1H), 4.34 (d, J¼12.3 Hz, 1H), 4.11 (d, J¼9.9 Hz, 1H), 3.77
(t, J¼9.4 Hz, 1H), 3.62 (t, J¼9.0 Hz, 1H), 3.47 (dd, J¼12.1, 3.4 Hz, 1H),
pound 9: 1H NMR (500 MHz, CDCl3, mixture of epimers)
d 8.03–7.99
(m, 4H), 7.59–7.52 (m, 2H), 7.47–7.39 (m, 4H), 7.38–7.12 (m, 40H),
5.00 (d, J¼11.1 Hz, 1H), 4.95 (d, J¼11.2 Hz, 1H), 4.92 (d, J¼10.9 Hz,
1H), 4.85 (d, J¼10.9 Hz, 2H), 4.81–4.74 (m, 3H), 4.73 (d, J¼11.2 Hz,
1H), 4.62 (d, J¼10.8 Hz, 1H), 4.54 (d, J¼10.8 Hz, 1H), 4.52–4.45 (m,
3H), 4.44 (d, J¼1.0 Hz, 1H), 4.32 (d, J¼12.3 Hz, 1H), 4.27 (d, J¼9.5 Hz,
1H), 4.19 (d, J¼12.3 Hz, 1H), 4.03 (dd, J¼9.6, 1.1 Hz, 1H), 3.89 (t,
J¼9.5 Hz, 1H), 3.73–3.59 (m, 10H), 3.57 (dd, J¼11.8, 3.0 Hz, 1H), 3.48
(t, J¼9.1 Hz, 1H), 3.35 (dt, J¼9.7, 2.9 Hz, 1H), 3.24 (s, 3H), 3.16–3.09
(m, 1H), 3.00 (dd, J¼11.8, 1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3,
2.98–2.91 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 140.4, 138.5, 138.3,
138.2,138.1, 138.0,134.3, 134.1, 130.2,129.8,128.8,128.7, 128.5, 128.5,
128.4, 128.3, 127.9, 127.9, 127.8, 127.7, 127.6, 127.6, 127.4, 127.4, 87.6,
82.5, 80.4, 78.0, 77.5, 76.6, 75.5, 75.1, 74.9, 73.4, 67.6; HRMS (ESI), m/z
calcd for [C47H46O9S2þNH4]þ: 836.2922; found 836.2930.
4.4.2. 2-(Phenylsulfonyl)-2-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-
6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)acetonitrile (5). The
general Mitsunobu procedure was followed, using 2,3,4,6-tetra-O-
mixture of epimers)
d 163.8, 163.6, 139.2, 138.6, 138.5, 138.1, 138.0,
benzyl-
a
-
D
-glucopyranose (1, 100 mg, 0.184 mmol), tribu-
138.0, 137.9, 137.9, 137.8, 137.7, 133.8, 133.8, 130.1, 129.8, 128.6, 128.5,
128.4, 128.4, 128.3, 128.2, 127.9, 127.8, 127.8, 127.8, 127.7, 127.7, 127.7,
127.5, 127.4, 127.2, 127.2, 86.9, 86.9, 80.5, 79.7, 79.6, 78.2, 78.0, 77.6,
76.4, 76.0, 75.7, 75.6, 75.1, 75.0, 74.9, 74.8, 73.6, 73.5, 73.2, 70.0, 68.4,
67.6, 52.8, 52.6; HRMS (ESI), m/z calcd for [C43H44O9SþNH4]þ:
754.3044; found 754.3056. Compound 10: 1H NMR (500 MHz,
tylphosphine (0.23 mL, 0.92 mmol), phenylsulfonyl acetonitrile (4,
167 mg, 0.92 mmol), and 1,10-(azodicarbonyl)dipiperidine (232 mg,
0.92 mmol) in benzene (1 mL). Purification by column chroma-
tography (silica gel, 0–50% EtOAc/heptane) afforded 5 (80 mg, 62%)
as a colorless oil: 1H NMR (500 MHz, CDCl3)
d 7.97–7.94 (m, 2H),
7.63–7.57 (m, 1H), 7.49–7.43 (m, 2H), 7.38–7.24 (m, 16H), 7.24–7.21
(m, 2H), 7.21–7.16 (m, 2H), 4.96–4.92 (m, 2H), 4.86 (d, J¼11.1 Hz,
1H), 4.77 (d, J¼10.8 Hz, 1H), 4.61 (d, J¼10.8 Hz, 1H), 4.60 (d,
J¼11.5 Hz,1H), 4.38 (d, J¼12.2 Hz,1H), 4.21 (d, J¼1.5 Hz,1H), 4.20 (d,
J¼12.2 Hz, 1H), 3.97 (dd, J¼9.7, 1.5 Hz, 1H), 3.73 (t, J¼9.0 Hz, 1H),
3.67–3.60 (m, 2H), 3.44 (dd, J¼9.6, 8.9 Hz, 1H), 3.33 (ddd, J¼9.7, 3.5,
1.6 Hz, 1H), 3.19 (dd, J¼11.8, 1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
CDCl3, b anomer) d 8.03–7.96 (m, 2H), 7.41–7.24 (m, 21H), 7.21–7.15
(m, 2H), 5.33 (d, J¼7.5 Hz, 1H), 5.01 (s, 1H), 4.92 (d, J¼11.0 Hz, 1H),
4.84 (d, J¼10.8 Hz, 1H), 4.83–4.79 (m, 2H), 4.70 (d, J¼10.8 Hz, 1H),
4.59 (d, J¼10.9 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.1 Hz,
1H), 3.65 (s, 3H), 3.64–3.54 (m, 5H), 3.46 (ddd, J¼9.1, 4.6, 1.8 Hz,1H);
1H NMR (500 MHz, CDCl3,
NMR (125 MHz, CDCl3) d 164.0,144.1, 138.3,138.2,138.0,137.9, 132.2,
a
anomer)
d
5.88 (d, J¼3.4 Hz, 1H); 13C
d
138.3, 138.0, 137.9, 137.0, 137.0, 134.8, 129.9, 129.0, 129.0, 128.5,
128.6,128.5,128.4,128.4,128.5,128.2,128.0,127.9, 127.8, 127.8,127.7,
127.6, 127.6, 127.1, 97.4, 84.3, 84.2, 81.2, 77.2, 75.9, 75.7, 75.0, 74.8,
73.3, 68.5, 57.2; HRMS (ESI), m/z calcd for [C43H44O9SþNH4]þ:
754.3044; found 754.3026.
128.5, 128.5, 128.3, 128.2, 127.9, 127.9, 127.8, 127.7, 127.5, 127.4, 111.3,
86.4, 79.8, 77.9, 77.5, 75.7, 75.3, 75.1, 75.1, 73.4, 68.0, 59.2; HRMS
(ESI), m/z calcd for [C42H41NO7SþNH4]þ: 721.2942; found 721.2949.
4.4.3. Diethyl phenylsulfonyl((2R,3R,4S,5R,6R)-3,4,5-tris(benzy-
loxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)methyl-
phosphonate (7). The general Mitsunobu procedure was
4.4.5. Ethyl 3-ethoxy-3-((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
(benzyloxymethyl)tetrahydro-2H-pyran-2-yloxy)acrylate (13). The
general Mitsunobu procedure was followed, using 2,3,4,6-tetra-O-
followed, using 2,3,4,6-tetra-O-benzyl-
a
-
D
-glucopyranose (1,
benzyl-
sphine (34
a
-
D
-glucopyranose (1, 50 mg, 0.092 mmol), tributylpho-
L, 0.14 mmol), diethyl malonate (11, 22 mg, 0.14 mmol),
3.0 g, 5.55 mmol), tributylphosphine (2.1 mL, 8.32 mmol), diethyl
(phenylsulfonyl)methylphosphonate (6, 2.4 g, 8.32 mmol), and
ADDP (2.1 g, 8.32 mmol) in benzene (56 mL). Purification by
m
and TMAD (24 mg, 0.14 mmol) in benzene (0.5 mL). Purification by
column chromatography (silica gel, 0–50% EtOAc/heptane) afforded

P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
8473
13 (22 mg, 35%) as a white solid: mp 69–70 ꢀC; 1H NMR (500 MHz,
CDCl3)
4.55 (d, J¼11.8 Hz, 1H, major epimer), 4.38 (d, J¼11.9 Hz, 1H, major
epimer), 4.32–4.24 (m, 2H), 4.17 (d, J¼11.7 Hz, 1H, minor epimer),
3.99–3.94 (m, 2H), 3.87 (t, J¼9.4 Hz, 1H, major epimer), 3.69 (dd,
J¼10.0, 2.1 Hz, 1H, minor epimer), 3.62 (dd, J¼9.1, 2.5 Hz, 1H, major
epimer), 3.54 (dd, J¼9.2, 2.3 Hz, 1H, minor epimer), 3.48 (dd, J¼7.9,
5.2 Hz, 1H, major epimer), 3.43–3.38 (m, 1H, minor epimer), 3.28 (t,
J¼8.5 Hz, 1H, major epimer), 3.18 (dd, J¼9.3, 7.6 Hz, 1H, minor
epimer), 3.01 (dd, J¼9.0, 5.0 Hz, 1H, major epimer), 2.95 (dd, J¼9.4,
5.4 Hz, 1H, minor epimer); 13C NMR (125 MHz, CDCl3, major epi-
d
7.35–7.23 (m, 18H), 7.19–7.13 (m, 2H), 5.37 (d, J¼7.8 Hz,1H),
5.12 (d, J¼10.6 Hz, 1H), 4.96 (d, J¼11.0 Hz, 1H), 4.86–4.74 (m, 3H),
4.62–4.49 (m, 3H), 4.31 (s, 1H), 4.14–4.09 (m, 2H), 3.93 (q, J¼7.0 Hz,
2H), 3.80–3.60 (m, 5H), 3.53 (ddd, J¼9.4, 4.9, 1.9 Hz, 1H), 1.29 (t,
J¼7.0 Hz, 3H), 1.24 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
166.2, 165.5, 138.5, 138.4, 138.2, 138.1, 128.4, 128.4, 128.3, 128.3,
127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.6, 97.2, 84.6, 81.4, 77.5,
75.8, 75.6, 75.0, 73.4, 72.2, 68.7, 65.9, 59.1, 14.6, 13.9; HRMS (ESI), m/
z calcd for [C41H46O9þH]þ: 683.3215; found 683.3222.
mer)
d 138.6, 137.7, 137.7, 137.3, 137.0, 134.7, 129.9, 128.9, 128.8,
128.5, 128.5, 128.2, 128.2, 127.9, 127.9, 127.9, 127.6, 127.4, 111.2, 83.9,
4.4.6. (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-6-
(1-(phenylsulfonyl)prop-1-en-2-yloxy)tetrahydro-2H-pyran
(16). The general Mitsunobu procedure was followed, using
77.2, 75.5, 75.4, 74.6, 74.4, 73.3, 72.9, 72.1, 67.2, 59.2; 13C NMR
(125 MHz, CDCl3, minor epimer)
d 138.5, 138.1, 134.4, 130.8, 128.6,
128.5, 128.5, 128.3, 128.3, 128.1, 127.6, 113.9, 84.9, 78.0, 77.8, 75.3,
75.1, 73.6, 73.4, 67.7, 58.0; HRMS (ESI), m/z calcd for
[C42H41NO7SþNH4]þ: 721.2942; found 721.2951.
2,3,4,6-tetra-O-benzyl-a-D-glucopyranose (1, 200 mg, 0.37 mmol),
tributylphosphine (0.14 mL, 0.57 mmol), phenylsulfonylacetone
(14, 110 mg, 0.55 mmol), and TMAD (96 mg, 0.56 mmol) in benzene
(5 mL). Purification by column chromatography (silica gel, 0–50%
EtOAc/heptane) afforded the O-glucoside 16 (202 mg, contami-
4.4.9. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
6-(phenylsulfonylmethyl)tetrahydro-2H-pyran (27). To a solution of
3 (180 mg, 0.22 mmol) in THF (10 mL) was added aluminum foil
(250 mg, cut in small squares), followed by HgCl2 (2 wt % in H2O,
0.5 mL). The mixture was stirred for 20 h at room temperature and
then added directly to a short plug of silica gel and eluted with
EtOAc. The filtrate was concentrated and the residue purified by
column chromatography (silica gel, 0–40% EtOAc/heptane) to afford
27 (144 mg, quantitative yield) as a white solid: mp 110–111 ꢀC; 1H
nated with 11 wt % of 14, 67%): 1H NMR (500 MHz, CDCl3)
d 8.01–
7.93 (m, 2H), 7.43–7.23 (m, 21H), 7.22–7.16 (m, 2H), 5.67 (s,1H), 4.99
(d, J¼10.8 Hz, 1H), 4.94 (d, J¼10.8 Hz, 1H), 4.90 (d, J¼7.3 Hz, 1H),
4.84–4.79 (m, 2H), 4.75 (d, J¼10.8 Hz, 1H), 4.57 (d, J¼10.9 Hz, 1H),
4.47 (d, J¼12.0 Hz,1H), 4.40 (d, J¼12.1 Hz,1H), 3.64 (t, J¼8.9 Hz,1H),
3.60 (dd, J¼10.9, 1.6 Hz, 1H), 3.56–3.49 (m, 3H), 3.42 (ddd, J¼9.6,
5.2, 1.5 Hz, 1H), 2.01 (s, 3H).
NMR (500 MHz, CDCl3)
d 7.89–7.86 (m, 2H), 7.57–7.51 (m, 1H),
4.4.7. (2R,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxy-
methyl)-6-(bis(phenylsulfonyl)methyl)tetrahydro-2H-pyran
(25). The general Mitsunobu procedure was followed, using
7.47–7.40 (m, 2H), 7.36–7.20 (m, 18H), 7.16–7.08 (m, 2H), 4.89 (d,
J¼11.0 Hz, 1H), 4.88 (d, J¼11.3 Hz, 1H), 4.84 (d, J¼11.0 Hz, 1H), 4.76
(d, J¼10.8 Hz, 1H), 4.58 (d, J¼11.3 Hz, 1H), 4.52 (d, J¼10.8 Hz, 1H),
4.35 (d, J¼12.1 Hz, 1H), 4.27 (d, J¼12.1 Hz, 1H), 3.72 (td, J¼9.6,
1.5 Hz, 1H), 3.65 (t, J¼8.9 Hz, 1H), 3.59 (t, J¼9.4 Hz, 1H), 3.53 (dd,
J¼11.1, 3.4 Hz, 1H), 3.42 (dd, J¼14.7, 1.5 Hz, 1H), 3.24 (dd, J¼9.5,
2,3,4,6-tetra-O-benzyl-D-galactopyranose (24, 400 mg, 0.74 mmol),
tributylphosphine (0.27 mL, 1.11 mmol), bis(phenylsulfonyl)-
methane (2, 330 mg, 1.11 mmol), and TMAD (191 mg, 1.11 mmol)
in benzene (15 mL). Purification by column chromatography
(silica gel, 0–50% EtOAc/heptane) afforded 25 (440 mg, 73%) as
8.8 Hz, 1H), 3.22–3.14 (m, 3H); 13C NMR (125 MHz, CDCl3)
d 140.6,
138.2, 138.0, 137.9, 137.4, 133.3, 128.8, 128.6, 128.5, 128.4, 128.4,
128.3, 128.2, 128.1, 127.8, 127.8, 127.8, 127.8, 127.7, 127.7, 87.0, 79.3,
78.9, 77.7, 75.6, 75.0, 74.9, 74.5, 73.6, 68.2, 57.8; HRMS (ESI), m/z
calcd for [C41H42O7SþNH4]þ: 696.2989; found 696.3000.
a white solid: mp 61–63 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.01 (d,
J¼7.5 Hz, 2H), 7.90 (d, J¼7.4 Hz, 2H), 7.59 (t, J¼7.5 Hz, 1H), 7.47 (t,
J¼7.8 Hz, 2H), 7.44–7.20 (m, 21H), 7.01 (t, J¼7.9 Hz, 2H), 5.09 (d,
J¼11.1 Hz, 1H), 5.07 (d, J¼10.6 Hz, 1H), 5.01 (d, J¼1.0 Hz, 1H), 4.90
(d, J¼11.1 Hz, 1H), 4.83–4.75 (m, 2H), 4.69 (d, J¼11.6 Hz, 1H), 4.48
(d, J¼10.6 Hz, 1H), 4.42 (dd, J¼10.1, 1.0 Hz, 1H), 4.33 (d, J¼11.7 Hz,
1H), 4.11 (d, J¼11.7 Hz, 1H), 3.97 (d, J¼1.4 Hz, 1H), 3.60 (dd, J¼9.1,
2.4 Hz, 1H), 3.42 (t, J¼6.3 Hz, 1H), 3.19 (dd, J¼9.4, 7.6 Hz, 1H), 2.88
4.4.10. Methyl 2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyl-
oxymethyl)tetrahydro-2H-pyran-2-yl)acetate (28). The general
desulfonylation procedure (method B) was followed, using 9
(27 mg, 0.037 mmol), Na2HPO4 (15 mg, 0.11 mmol), and Na(Hg)
(6 wt %, 0.6 g) in THF (1 mL) and MeOH (2 mL). The reaction
mixture was stirred at room temperature for 1 h. Work up affor-
ded spectroscopically pure 28 (off-white gum, 21 mg, 96%) with-
out the need of further purification: 1H NMR (500 MHz, CDCl3)
(dd, J¼9.5, 5.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 140.1, 139.7,
138.7, 138.6, 138.0, 137.9, 134.0, 133.7, 131.6, 129.1, 128.9, 128.5,
128.5, 128.4, 128.4, 128.4, 127.9, 127.8, 127.8, 127.8, 127.7, 127.6,
127.6, 127.6, 85.3, 83.6, 78.1, 75.4, 75.3, 74.9, 74.5, 74.1, 73.5, 72.2,
67.7; HRMS (ESI), m/z calcd for [C47H46O9S2þNH4]þ: 836.2922;
found 836.2939.
d
7.34–7.24 (m, 18H), 7.19–7.15 (m, 2H), 4.94–4.90 (m, 2H), 4.87 (d,
J¼11.0 Hz, 1H), 4.81 (d, J¼10.8 Hz, 1H), 4.65–4.55 (m, 3H), 4.54–
4.49 (m, 1H), 3.78–3.71 (m, 2H), 3.71–3.68 (m, 2H), 3.65 (t,
J¼9.3 Hz, 1H), 3.60 (s, 3H), 3.46 (dt, J¼9.6, 3.0 Hz, 1H), 3.36 (t,
J¼9.2 Hz, 1H), 2.73 (dd, J¼15.3, 4.0 Hz, 1H), 2.48 (dd, J¼15.4, 8.1 Hz,
4.4.8. 2-(Phenylsulfonyl)-2-((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-
6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)acetonitrile (26). The
general Mitsunobu procedure was followed, using 2,3,4,6-tetra-O-
1H); 13C NMR (125 MHz, CDCl3)
d 171.4, 138.5, 138.2, 138.1, 138.0,
benzyl-
D
-galactose (24, 100 mg, 0.184 mmol), tributylphosphine
128.5, 128.4, 128.4, 128.3, 127.9, 127.9, 127.8, 127.8, 127.7, 127.7,
127.7, 127.6, 87.2, 81.3, 79.2, 78.5, 75.9, 75.6, 75.1, 75.0, 73.4, 68.7,
51.7, 37.5; HRMS (ESI), m/z calcd for [C37H40O7þNH4]þ: 614.3112;
found 614.3117.
(0.14 mL, 0.552 mmol), phenylsulfone acetonitrile (4, 100 mg,
0.552 mmol), and ADDP (139 mg, 0.552 mmol) in benzene (1 mL).
Purification by column chromatography (silica gel, 0–50% EtOAc/
heptane) afforded 26 (colorless oil, 6/1 mixture of epimers, 55 mg,
42%): 1H NMR (500 MHz, CDCl3, mixture of epimers)
d
7.93 (d,
4.4.11. 2-((2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)
J¼7.8 Hz, 2H, minor epimer), 7.89 (d, J¼7.7 Hz, 2H, major epimer),
7.54 (t, J¼7.4 Hz, 1H, major epimer), 7.48 (t, J¼7.4 Hz, 1H, minor
epimer), 7.42–7.20 (m, 22H), 5.09 (d, J¼10.7 Hz, 1H, minor epimer),
5.06 (d, J¼10.6 Hz, 1H, minor epimer), 4.98 (d, J¼11.5 Hz, 1H, major
epimer), 4.93 (d, J¼10.7 Hz, 1H, minor epimer), 4.88 (t, J¼11.1 Hz,
1H, major epimer), 4.73 (d, J¼11.7 Hz, 1H, major epimer), 4.63 (d,
J¼10.3 Hz, 1H, major epimer), 4.61 (d, J¼11.2 Hz, 1H, major epimer),
tetrahydro-2H-pyran-2-yl)acetonitrile (29). The general desulfony-
lation procedure (method A) was followed, using
5 (80 mg,
0.114 mmol), Mg (80 mg, 3.29) in MeOH (5 mL). The reaction mix-
ture was stirred at 50 ꢀC for 18 h. Work up, followed by column
chromatography (silica gel, 0–70% EtOAc/heptane) afforded 29
(45 mg, 70%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
d
7.38–7.25
(m,18H), 7.19–7.12 (m, 2H), 4.94 (d, J¼11.1 Hz, 2H), 4.93 (d, J¼11.1 Hz,

8474
P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
1H), 4.88 (d, J¼11.1 Hz, 1H), 4.81 (d, J¼10.8 Hz, 1H), 4.67–4.53 (m,
4H), 3.75–3.63 (m, 4H), 3.50–3.45 (m, 2H), 3.45–3.39 (m, 1H), 2.70
(dd, J¼16.8, 3.3 Hz, 1H), 2.52 (dd, J¼16.8, 6.1 Hz, 1H); 13C NMR
128.3, 128.3, 127.9, 127.9, 127.8, 127.7, 127.7, 127.5, 119.1, 81.4, 81.4,
78.4, 74.7, 73.3, 73.2, 71.2, 70.7, 70.4; HRMS (ESI), m/z calcd for
[C35H38O5þNa]þ: 561.2611; found 561.2618. Compound 33: mp 68–
(125 MHz, CDCl3)
d
138.3, 138.0, 137.9, 137.5, 128.7, 128.5, 128.5,
69 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.38–7.22 (m, 18H), 7.18–7.10 (m,
128.4, 128.2, 127.9, 127.9, 127.9, 127.8, 127.7, 127.6, 117.1, 86.8, 80.1,
79.4, 78.1, 75.6, 75.4, 75.1, 74.4, 73.6, 68.6, 21.1; HRMS (ESI), m/z calcd
for [C36H37NO5þNH4]þ: 581.3010; found 581.3012.
2H), 4.89 (s, 2H), 4.87 (d, J¼10.9 Hz, 1H), 4.81 (d, J¼10.8 Hz, 1H),
4.66 (d, J¼10.9 Hz, 1H), 4.61 (d, J¼12.3 Hz, 1H), 4.54 (d, J¼12.3 Hz,
1H), 4.53 (d, J¼10.8 Hz, 1H), 3.71 (dd, J¼10.7, 1.9 Hz, 1H), 3.69–3.63
(m, 2H), 3.59 (t, J¼9.4 Hz, 1H), 3.44 (ddd, J¼9.5, 4.5, 1.8 Hz, 1H), 3.39
(dq, J¼9.1, 6.2 Hz, 1H), 3.21 (t, J¼9.1 Hz, 1H), 1.32 (d, J¼6.2 Hz, 3H);
4.4.12. 2-((2S,3S,4R,5S,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)
tetrahydro-2H-pyran-2-yl)acetonitrile (30). The general desulfony-
lation procedure (method A) was followed, using 26 (35 mg,
0.050 mmol), Mg (40 mgꢁ3, added in 2 h intervals) in MeOH (4 mL)
and THF (2 mL). The reaction mixture was stirred at 50 ꢀC for 18 h.
Work up afforded spectroscopically pure 30 (colorless oil, 28 mg,
quantitative) without the need of further purification: 1H NMR
13C NMR (125 MHz, CDCl3)
d 138.7, 138.2, 138.2, 138.1, 128.4, 128.4,
128.4, 128.4, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6, 127.6, 87.1, 84.0,
78.8, 78.7, 75.6, 75.5, 75.3, 75.0, 73.5, 69.1, 18.2; HRMS (ESI), m/z
calcd for [C35H38O5þNH4]þ: 556.3057; found 556.3063.
4.4.15. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
6-(1,1-bis(phenylsulfonyl)but-3-enyl)tetrahydro-2H-pyran
(35). Palladium tetrakis triphenyl phosphine (75 mg, 0.06 mmol)
was added to a degassed solution of 3 (395 mg, 0.48 mmol) and
allyl methyl carbonate (34, 220 mg, 1.89 mmol) in THF (6 mL) and
the mixture was stirred at 55 ꢀC for 18 h. The mixture was then
cooled to room temperature and concentrated under reduced
pressure to give a residue that was purified by column chroma-
tography (silica gel, 0–40% EtOAc/heptane) to afford the product 35
(396 mg, 96%) as an off-white solid: mp 64–68 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
7.38–7.25 (m, 20H), 4.97 (d, J¼11.1 Hz, 1H), 4.93
(d, J¼11.6 Hz,1H), 4.76 (d, J¼11.7 Hz,1H), 4.68–4.58 (m, 3H), 4.49 (d,
J¼11.8 Hz, 1H), 4.43 (d, J¼11.8 Hz, 1H), 4.02 (d, J¼2.6 Hz, 1H), 3.75 (t,
J¼9.3 Hz, 1H), 3.64–3.54 (m, 4H), 3.46 (ddd, J¼9.3, 8.0, 3.2 Hz, 1H),
2.70 (dd, J¼16.8, 3.2 Hz, 1H), 2.46 (dd, J¼16.8, 7.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d 138.5, 137.9, 137.8, 137.8, 128.6, 128.5, 128.5,
128.3, 128.3, 128.1, 128.0, 127.9, 127.9, 127.8, 127.6, 127.6, 117.4, 84.3,
77.4, 77.2, 75.4, 75.1, 74.6, 73.6, 73.5, 72.1, 68.5, 21.3; HRMS (ESI), m/z
calcd for [C36H37NO5þNH4]þ: 581.3010; found 581.3021.
(500 MHz, CDCl3)
d
8.23 (d, J¼7.7 Hz, 2H), 8.18 (d, J¼7.7 Hz, 2H), 7.59
4.4.13. Diethyl ((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxyme-
thyl)tetrahydro-2H-pyran-2-yl)methylphosphonate (31). The general
desulfonylation procedure (method B) was followed, using 7 (230 mg,
0.28 mmol), Na2HPO4 (120 mg, 0.85 mmol), and Na(Hg) (6 wt %, 3 g)
in THF (5 mL) and MeOH (15 mL). The reaction mixture was stirred at
room temperature for 2 h. Work up, followed by column chroma-
tography (silica gel, 0–70% EtOAc/heptane) afforded 31 (182 mg, 96%)
(t, J¼7.4 Hz, 1H), 7.45–7.38 (m, 5H), 7.33–7.17 (m, 20H), 5.90 (dddd,
J¼15.1,10.2, 7.9, 4.8 Hz,1H), 5.06 (s, 2H), 5.01 (d, J¼10.2 Hz,1H), 4.89
(d, J¼10.8 Hz, 1H), 4.84 (d, J¼10.8 Hz, 1H), 4.79 (d, J¼11.0 Hz, 1H),
4.64 (d, J¼16.8 Hz, 1H), 4.59 (d, J¼11.0 Hz, 1H), 4.54 (t, J¼9.0 Hz, 1H),
4.27 (d, J¼9.9 Hz, 1H), 4.20 (d, J¼12.2 Hz, 1H), 4.14 (d, J¼12.2 Hz,
1H), 3.68 (t, J¼8.6 Hz, 1H), 3.54–3.46 (m, 2H), 3.26–3.20 (m, 2H),
3.01 (dd, J¼11.3, 4.8 Hz, 1H), 2.82 (dd, J¼16.2, 8.0 Hz, 1H); 13C NMR
as a white solid: mp 87–89 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.36–7.22
(125 MHz, CDCl3) d 141.2, 138.5, 138.3, 138.1, 138.0, 134.1, 133.6,
(m, 18H), 7.20–7.13 (m, 2H), 4.91 (d, J¼11.4 Hz, 1H), 4.90 (d, J¼11.0 Hz,
1H), 4.86 (d, J¼11.0 Hz, 1H), 4.82 (d, J¼10.8 Hz, 1H), 4.66 (d, J¼11.2 Hz,
1H), 4.58 (d, J¼11.0 Hz, 1H), 4.55 (d, J¼12.0 Hz, 1H), 4.50 (d, J¼12.0 Hz,
1H), 4.12–3.98 (m, 4H), 3.76–3.59 (m, 5H), 3.53–3.43 (m, 1H), 3.37–
3.33 (m, 1H), 2.27 (ddd, J¼19.8, 15.5, 2.3 Hz, 1H), 1.89 (td, J¼15.9,
9.6 Hz, 1H), 1.25 (t, J¼7.1 Hz, 3H), 1.24 (t, J¼7.1 Hz, 3H); 13C NMR
132.0,131.8,130.2,128.5,128.4,128.2,128.2,128.1,127.9,127.8,127.7,
127.6, 127.4, 127.4, 120.2, 96.1, 88.3, 79.7, 78.6, 77.5, 75.8, 74.6, 74.4,
73.1, 68.7, 33.4; HRMS (ESI), m/z calcd for [C50H50O9S2þNa]þ:
881.2788; found 881.2788.
4.4.16. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-6-
(125 MHz, CDCl3)
d
138.5, 138.1, 138.0, 138.0, 128.5, 128.4, 128.4, 128.4,
(1,1-bis(phenylsulfonyl)butyl)tetrahydro-2H-pyran
(36). Palladium
127.9, 127.9, 127.9, 127.8, 127.7, 127.7, 127.7, 127.6, 87.1 (d, JC–P¼2.6 Hz),
81.8 (d, JC–P¼13.9 Hz), 78.9, 78.3, 75.5, 75.0, 75.0, 74.8 (d, JC–P¼6.5 Hz),
73.5, 68.9, 61.7 (d, JC–P¼6.0 Hz), 61.5 (d, JC–P¼6.0 Hz), 28.6 (d, JC–
(5 wt % on alumina, 50 mg) was added to a solution of alkene 35
(120 mg, 0.14 mmol) in EtOAc (12 mL). The mixture was stirred
overnight under hydrogen (balloon pressure). The mixture was fil-
tered through CeliteÒ and concentrated to afford 36 (white solid,
118 mg, 98%) that was used in subsequent steps without further
¼142.4 Hz), 16.4 (d, JC–P¼5.9 Hz), 16.4 (d, JC–P¼6.2 Hz); 31P NMR
P
(202 MHz, CDCl3)
d
28.8; HRMS (ESI), m/z calcd for [C39H47O8PþH]þ:
675.3081; found 675.3089.
purification: mp 73–78 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.26–8.17
(m, 4H), 7.64 (t, J¼7.4 Hz, 1H), 7.53 (t, J¼7.8 Hz, 2H), 7.44–7.35 (m,
3H), 7.35–7.13 (m, 20H), 5.15 (d, J¼10.8 Hz, 1H), 5.05 (d, J¼10.8 Hz,
1H), 4.95 (d, J¼10.6 Hz, 1H), 4.92 (d, J¼10.6 Hz, 1H), 4.84 (d,
J¼10.9 Hz, 1H), 4.64 (d, J¼11.0 Hz, 1H), 4.52 (t, J¼9.2 Hz, 1H), 4.36 (d,
J¼10.0 Hz, 1H), 4.18 (d, J¼12.3 Hz, 1H), 4.08 (d, J¼12.3 Hz, 1H), 3.76
(t, J¼8.7 Hz, 1H), 3.57 (t, J¼9.3 Hz, 1H), 3.38 (ddd, J¼9.7, 4.1, 1.7 Hz,
1H), 3.31 (dd, J¼11.2, 1.7 Hz, 1H), 3.14 (dd, J¼11.2, 4.0 Hz, 1H), 2.64–
2.52 (m, 1H), 1.82–1.64 (m, 1H), 1.57–1.50 (m, 1H), 1.45 (t, J¼13.1 Hz,
4.4.14. (2R,3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-ol (32)
and (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-
methyltetrahydro-2H-pyran (33). The general desulfonylation pro-
cedure (method B) was followed, using 3 (210 mg, 0.26 mmol),
Na2HPO4 (120 mg, 0.85 mmol), and Na(Hg) (6 wt %, 3 g) in THF
(4 mL) and MeOH (12 mL). The reaction mixture was stirred at
room temperature for 2 h. Work up, followed by column chroma-
tography (silica gel, 0–50% EtOAc/heptane) afforded 32 (colorless
oil, 62 mg, 45%) and 33 (white solid, 26 mg, 19%). Desulfonylation of
3 following method A afforded the products 32 and 33 in the same
yields obtained with method B. Compound 32: 1H NMR (500 MHz,
1H), 0.14 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 141.3, 138.5,
138.3, 138.3, 138.1, 138.1, 134.0, 133.5, 131.9, 131.0, 128.6, 128.4, 128.4,
128.3, 128.2, 127.9, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.5, 127.3,
97.8, 88.8, 80.0, 79.1, 77.9, 76.6, 76.1, 74.7, 74.7, 73.0, 68.6, 30.5, 17.0,
13.1; HRMS (ESI), m/z calcd for [C50H52O9S2þNH4]þ: 878.3391;
found 878.3399.
CDCl3)
d
7.37–7.19 (m, 20H), 5.83 (ddd, J¼17.9, 10.4, 7.7 Hz, 1H), 5.28
(dd, J¼10.4, 1.3 Hz, 1H), 5.24 (ddd, J¼17.4, 1.5, 0.8 Hz, 1H), 4.81 (d,
J¼11.4 Hz, 1H), 4.68 (d, J¼11.4 Hz, 1H), 4.61 (d, J¼11.7 Hz, 1H), 4.58
(d, J¼11.5 Hz, 1H), 4.53 (d, J¼11.5 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H),
4.47 (d, J¼12.0 Hz, 1H), 4.39 (d, J¼11.7 Hz, 1H), 4.20–4.17 (m, 1H),
4.02 (dd, J¼9.8, 5.2 Hz, 1H), 3.76 (dd, J¼6.1, 3.7 Hz, 1H), 3.73 (dd,
J¼6.2, 3.7 Hz, 1H), 3.64–3.55 (m, 2H), 2.84 (br s, 1H); 13C NMR
4.4.17. (2R,3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)dec-6-en-2-ol (37)
and (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-
butyltetrahydro-2H-pyran (38). The general desulfonylation pro-
cedure (method B) was followed, using 36 (590 mg, 0.69 mmol),
Na2HPO4 (340 mg, 2.40 mmol), and Na(Hg) (6 wt %, 5 g) in THF
(125 MHz, CDCl3)
d 138.4, 138.4, 138.3, 138.1, 135.4, 128.4, 128.4,

P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
8475
(3 mL) and MeOH (15 mL). The reaction mixture was stirred at
room temperature for 2 h. Work up, followed by column chro-
matography (silica gel, 0–50% EtOAc/heptane) afforded 37 (col-
orless oil, 130 mg, 58%) and 38 (white solid, 51 mg, 23%).
4.84 (d, J¼10.8 Hz, 1H), 4.80 (d, J¼11.0 Hz, 1H), 4.62–4.50 (m, 2H),
4.24 (d, J¼9.9 Hz, 1H), 4.21 (d, J¼12.2 Hz, 1H), 4.12 (d, J¼12.2 Hz,
1H), 3.69 (t, J¼8.6 Hz, 1H), 3.46 (t, J¼9.3 Hz, 1H), 3.31–3.21 (m, 2H),
2.96 (dd, J¼11.1 Hz, 4.9, 1H), 2.77 (dd, J¼16.0, 8.3 Hz, 1H), 1.97–1.81
(m, 2H), 1.36–1.15 (m, J¼26.4, 12.2 Hz, 12H), 0.90 (t, J¼7.0 Hz, 3H);
Compound 37: 1H NMR (500 MHz, CDCl3, E isomer)
d 7.39–7.17 (m,
20H), 5.60 (dt, J¼15.5, 6.7 Hz, 1H), 5.41 (dd, J¼15.5, 8.4 Hz, 1H),
4.83 (d, J¼11.4 Hz, 1H), 4.69 (d, J¼11.4 Hz, 1H), 4.63–4.43 (m, 5H),
4.37 (d, J¼11.7 Hz, 1H), 4.15 (dd, J¼7.7, 6.2 Hz, 1H), 4.01 (dd, J¼9.3,
4.9 Hz, 1H), 3.75–3.71 (m, 2H), 3.62–3.55 (m, 2H), 2.01 (q,
J¼7.0 Hz, 2H), 1.42–1.35 (m, 2H), 0.90 (t, J¼7.4 Hz, 3H); 1H NMR
13C NMR (125 MHz, CDCl3)
d 141.5, 138.7, 138.3, 138.1, 138.0, 136.7,
133.9, 133.5, 133.0, 131.9, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8,
127.8, 127.8, 127.7, 127.7, 127.6, 127.4, 127.3, 121.0, 88.4, 79.7, 78.5,
77.6, 76.7, 75.9, 74.6, 74.2, 73.2, 68.9, 32.8, 31.9, 29.3, 29.3, 29.1, 29.0,
22.7, 14.1; HRMS (ESI), m/z calcd for [C57H64O9S2þNH4]þ: 974.4330;
found 974.4352.
(500 MHz, CDCl3, Z isomer, olefinic region)
d
5.67 (dt, J¼11.2,
7.3 Hz, 1H), 5.49 (dd, J¼11.0, 9.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3)
d
138.5, 138.5, 138.5, 138.1, 136.3, 128.5, 128.4, 128.3, 128.3,
4.4.20. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
6-(1,1-bis(phenylsulfonyl)decyl)tetrahydro-2H-pyran (42). By follow-
ing the procedure described for the preparation of 36, hydrogenation
of 41 (0.68 g, 0.71 mmol) using palladium (5 wt % on alumina,
136 mg) in EtOAc (14 mL) afforded 42 (0.527 g, 77%) as a colorless oil:
127.9, 127.8, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 81.6, 81.2, 78.5,
74.7, 73.3, 73.2, 71.3, 70.4, 70.2, 34.5, 22.3, 13.7; HRMS (ESI), m/z
calcd for [C38H44O5þNa]þ: 603.3081; found 603.3076. Compound
38: mp 91–92 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.37–7.23 (m, 18H),
7.21–7.14 (m, 2H), 4.90 (s, 2H), 4.87 (d, J¼10.9 Hz, 1H), 4.82 (d,
J¼10.8 Hz, 1H), 4.65 (d, J¼10.8 Hz, 1H), 4.63 (d, J¼12.1 Hz, 1H), 4.57
(d, J¼10.8 Hz, 1H), 4.56 (d, J¼12.3 Hz, 1H), 3.73 (dd, J¼10.9, 1.9 Hz,
1H), 3.71–3.65 (m, 2H), 3.60 (t, J¼9.4 Hz, 1H), 3.39 (ddd, J¼9.6, 4.4,
1.9 Hz, 1H), 3.27 (t, J¼9.0 Hz, 1H), 3.23 (td, J¼8.8, 2.3 Hz, 1H), 1.87–
1.76 (m, 1H), 1.58–1.41 (m, 2H), 1.40–1.24 (m, 3H), 0.89 (t, J¼7.2 Hz,
1H NMR (500 MHz, CDCl3)
d
8.28–8.13 (m, 4H), 7.63 (t, J¼7.4 Hz, 1H),
7.51 (t, J¼7.8 Hz, 2H), 7.41–7.35 (m, 3H), 7.34–7.19 (m, 18H), 7.17 (d,
J¼6.9 Hz, 2H), 5.16 (d, J¼10.9 Hz, 1H), 5.03 (d, J¼10.6 Hz, 1H), 4.95 (d,
J¼10.6 Hz,1H), 4.92 (d, J¼10.6 Hz,1H), 4.84 (d, J¼11.0 Hz, 1H), 4.64 (d,
J¼11.0 Hz, 1H), 4.52 (t, J¼9.2 Hz, 1H), 4.37 (d, J¼10.0 Hz, 1H), 4.18 (d,
J¼12.4 Hz, 1H), 4.07 (d, J¼12.4 Hz, 1H), 3.79 (t, J¼8.7 Hz, 1H), 3.57 (t,
J¼9.3 Hz, 1H), 3.39 (ddd, J¼9.7, 4.2, 1.9 Hz, 1H), 3.31 (dd, J¼11.2,
1.8 Hz, 1H), 3.12 (dd, J¼11.1, 3.9 Hz, 1H), 2.57 (br s, 1H), 1.70–1.57 (m,
1H), 1.52–1.38 (m, 2H), 1.36–1.15 (m, 7H), 1.10 (dt, J¼14.2, 7.0 Hz, 2H),
1.02–0.93 (m, 2H), 0.93–0.84 (m, 4H), 0.39–0.22 (m, 2H); 13C NMR
3H); 13C NMR (125 MHz, CDCl3)
d 138.7, 138.4, 138.2, 128.4, 128.4,
128.3, 128.0, 127.9, 127.8, 127.7, 127.7, 127.7, 127.6, 127.5, 87.4, 82.5,
79.3, 79.0, 78.8, 75.5, 75.3, 74.9, 73.4, 69.2, 31.4, 27.7, 22.7, 14.1;
HRMS (ESI), m/z calcd for [C38H44O5þNH4]þ: 598.3527; found
598.3529.
(125 MHz, CDCl3) d 141.4, 138.5, 138.4, 138.3, 138.2, 138.1, 133.9, 133.4,
131.9, 131.0, 128.6, 128.4, 128.2, 128.2, 128.0, 127.9, 127.7, 127.7, 127.7,
127.5, 127.4, 127.3, 98.0, 88.8, 80.0, 79.0, 77.9, 76.6, 76.1, 74.6, 73.0,
68.6, 31.9, 29.5, 29.5, 29.5, 29.4, 29.3, 23.7, 22.7, 14.2; HRMS (ESI), m/z
calcd for [C57H66O9S2þNH4]þ: 976.4487; found 976.4494.
4.4.18. (2R,3R,4R,5S,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-6-
butyltetrahydro-2H-pyran (39). Mercuric trifluoroacetate (0.3 M in
THF, 1 mL, 0.3 mmol) was added to a solution of alkene 37 (65 mg,
0.11 mmol) and the mixture was stirred for 1 h at room temperature.
After this time, K2CO3 (30 mg, 0.22 mmol) was added to the mixture
and stirred at room temperature for 3 h. The mixture was then
cooled to ꢂ78 ꢀC and BEt3 (1 M in THF, 0.2 mL, 0.2 mmol) was added,
followed by NaBH4 (15 mg, 0.40 mmol). After stirring at ꢂ78 ꢀC for
1 h, the mixture was allowed to warm to room temperature, stirred
for 1 h and then quenched with saturated aqueous ammonium
chloride, diluted with water, and extracted with EtOAc. The organic
extracts were combined, dried (MgSO4), filtered, and concentrated
under reduced pressure to give the crude product. The residue was
purified by column chromatography (silica gel, 0–30% EtOAc/hep-
tane) to afford the product 39 (34 mg, 53%) as a white solid: mp 67–
4.4.21. (2R,3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)heptadec-6-en-2-ol
(43) and (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-
6-undecyltetrahydro-2H-pyran (44). The general desulfonylation
procedure (method A) was followed, using 42 (400 mg, 0.417 mmol),
Mg (152 mg, 6.26 mmol) in MeOH (20 mL) and THF (20 mL). The
reaction mixture was stirred at 50 ꢀC for 4 h. Work up, followed by
column chromatography (silica gel, 0–30% EtOAc/heptane) afforded
43 (colorless oil, 150 mg, 53%) and 44 (colorless oil, 49 mg, 17%).
Compound 43: 1H NMR (500 MHz, CDCl3)
d 7.40–7.13 (m, 20H), 5.67
(dt, J¼11.0, 7.3 Hz, 1H, Z isomer), 5.60 (dt, J¼15.3, 6.7 Hz, 1H, E iso-
mer), 5.47 (dd, J¼11.0, 9.6 Hz, 1H, Z isomer), 5.40 (dd, J¼15.5, 8.4 Hz,
1H, E isomer), 4.83 (d, J¼11.4 Hz, 1H, E isomer), 4.80 (d, J¼11.4 Hz, 1H,
Z isomer), 4.70 (d, J¼11.3 Hz, 1H, Z isomer), 4.68 (d, J¼11.4 Hz, 1H, E
isomer), 4.65–4.46 (m, 5H), 4.38 (d, J¼11.7 Hz, 1H, Z isomer), 4.37 (d,
J¼11.8 Hz, 1H, E isomer), 4.19–4.12 (m, 1H), 4.05–3.98 (m, 1H), 3.77–
3.70 (m, 2H), 3.63–3.55 (m, 2H), 2.97 (d, J¼5.1 Hz, 1H, Z isomer), 2.87
(d, J¼5.5 Hz, 1H, E isomer), 2.08–1.98 (m, 2H), 1.39–1.12 (m, 16H),
68 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.39–7.21 (m, 18H), 7.18–7.09 (m,
2H), 4.93 (d, J¼10.9 Hz, 1H), 4.81 (d, J¼10.0 Hz, 1H), 4.79 (d,
J¼10.6 Hz, 1H), 4.68 (d, J¼11.6 Hz,1H), 4.62 (d, J¼12.1 Hz, 1H), 4.61 (d,
J¼11.7 Hz, 1H), 4.49 (d, J¼12.1 Hz, 1H), 4.46 (d, J¼10.6 Hz, 1H), 4.02
(ddd, J¼11.2, 5.5, 3.8 Hz, 1H), 3.79 (dd, J¼9.3, 8.3 Hz, 1H), 3.73 (dd,
J¼9.5, 5.7 Hz, 1H), 3.69 (dd, J¼10.5, 3.7 Hz, 1H), 3.65 (dd, J¼10.5,
1.8 Hz, 1H), 3.63–3.53 (m, 2H), 1.78–1.59 (m, 2H), 1.49–1.20 (m, 4H),
0.88 (t, J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 138.6, 138.5,
0.90 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
138.9, 138.4, 138.3,
138.5, 138.5, 138.4, 138.2, 138.1, 136.5, 135.6, 128.5, 128.4, 128.4, 128.3,
128.3, 128.2, 127.9, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.6, 127.5,
127.4, 127.0, 126.9, 81.9, 81.6, 81.2, 78.6, 78.4, 74.9, 74.7, 73.3, 73.2,
73.2, 71.3, 70.6, 70.5, 70.2, 70.2, 32.4, 31.9, 29.7, 29.7, 29.6, 29.5, 29.4,
29.4, 29.3, 29.1, 28.1, 22.7, 14.1; HRMS (ESI), m/z calcd for
[C45H58O5þNa]þ: 701.4176; found 701.4184. Compound 44: 1H NMR
138.1, 128.4, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6,
127.6, 82.7, 80.4, 78.3, 75.5, 75.1, 74.1, 73.5, 73.0, 70.9, 69.2, 27.6, 24.3,
22.5, 14.1; HRMS (ESI), m/z calcd for [C38H44O5þNH4]þ: 598.3527;
found 598.3532.
4.4.19. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
6-((E)-1,1-bis(phenylsulfonyl)undec-2-enyl)tetrahydro-2H-pyran
(41). By following the procedure described for the preparation of
35, allylation of 3 (1.0 g, 1.2 mmol) using carbonate 40 (0.65 g,
3.1 mmol) and palladium tetrakis triphenyl phosphine (0.141 g,
0.122 mmol) afforded 41 (0.9 g, 77%) as a colorless oil: 1H NMR
(500 MHz, CDCl3) d 7.38–7.22 (m, 18H), 7.20–7.14 (m, 2H), 4.89 (s,
2H), 4.87 (d, J¼10.9 Hz, 1H), 4.82 (d, J¼10.8 Hz, 1H), 4.64 (d,
J¼10.8 Hz, 1H), 4.63 (d, J¼12.2 Hz, 1H), 4.57 (d, J¼10.8 Hz, 1H), 4.56
(d, J¼12.3 Hz, 1H), 3.73 (dd, J¼10.9, 1.9 Hz, 1H), 3.71–3.65 (m, 2H),
3.60 (t, J¼9.4 Hz, 1H), 3.39 (ddd, J¼9.6, 4.4, 1.9 Hz, 1H), 3.27 (t,
J¼9.4 Hz,1H), 3.23 (dt, J¼9.4, 2.4 Hz,1H),1.84–1.76 (m,1H),1.54–1.40
(m, 2H), 1.31–1.22 (m, 17H), 0.88 (t, J¼7.0 Hz, 3H); 13C NMR
(500 MHz, CDCl3)
d
8.24 (d, J¼7.1 Hz, 2H), 8.16 (d, J¼7.8 Hz, 2H), 7.58
(t, J¼7.4 Hz, 1H), 7.49–7.35 (m, 5H), 7.34–7.15 (m, 20H), 5.50–5.37
(m, 1H), 5.07 (br s, 1H), 5.04–4.93 (m, 1H), 4.88 (d, J¼10.8 Hz, 1H),
(125 MHz, CDCl3)
d 138.7, 138.4, 138.3, 128.4, 128.4, 128.3, 128.0,
127.9, 127.8, 127.7, 127.7, 127.7, 127.6, 127.5, 87.4, 82.5, 79.3, 79.0, 78.8,

8476
P. Pasetto, M.C. Walczak / Tetrahedron 65 (2009) 8468–8477
75.5, 75.3, 74.9, 73.4, 69.2, 31.9, 31.8, 29.7, 29.7, 29.7, 29.6, 29.4, 25.5,
22.7, 14.1; HRMS (ESI), m/z calcd for [C45H58O5þNa]þ: 701.4176;
found 701.4177.
86.8, 82.5, 80.2, 78.8, 78.2, 75.6, 75.1, 75.0, 73.5, 69.0; HRMS (ESI),
m/z calcd for [C36H38O5þNH4]þ: 568.3057; found 568.3068.
4.4.25. (2R,3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)oct-6-en-2-ol
(48),
4.4.22. (2R,3R,4R,5S,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
6-undecyltetrahydro-2H-pyran (45). By following the procedure
described for the preparation of 39, cyclization of 43 (50 mg,
0.074 mmol) using mercuric trifluoroacetate (0.3 M in THF, 0.7 mL,
0.2 mmol), K2CO3 (21 mg, 0.150 mmol), BEt3 (1 M THF, 0.13 mL,
0.132 mmol), and NaBH4 (10 mg, 0.266 mmol) afforded the product
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-ethyl-
tetrahydro-2H-pyran (49), and (2R,3R,4R,5S,E)-1,3,4,5-tetrakis(benzyl-
oxy)-8-methoxyoct-6-en-2-ol (50). The general desulfonylation
procedure (method B) was followed, using 46 (385 mg, 0.56 mmol),
Na2HPO4 (240 mg, 1.7 mmol), and Na(Hg) (6 wt %, 5 g) in THF (6 mL)
and MeOH (20 mL). The reaction mixture was stirred at room tem-
perature for 2 h. Work up, followed by column chromatography
(silica gel, 0–50% EtOAc/heptane) afforded 47 (78 mg, 14%) and 48
(colorless oil, 110 mg, 20%), 49 (white solid, 29 mg, 9%), and 50
(colorless oil, 46 mg, 8%). Compound 48: 1H NMR (500 MHz, CDCl3)
45 (52 mg, 51%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
d 6.88–
6.73 (m, 18H), 6.66–6.61 (m, 2H), 4.45 (d, J¼10.9 Hz, 1H), 4.33 (d,
J¼9.9 Hz, 1H), 4.31 (d, J¼10.6 Hz, 1H), 4.19 (d, J¼11.7 Hz, 1H), 4.14 (d,
J¼12.1 Hz, 1H), 4.13 (d, J¼11.7 Hz, 1H), 4.00 (d, J¼12.5 Hz, 1H), 3.98
(d, J¼11.1 Hz, 1H), 3.56–3.50 (m, 1H), 3.33–3.28 (m, 1H), 3.24 (dd,
J¼9.5, 5.7 Hz, 1H), 3.20 (dd, J¼10.5, 3.7 Hz, 1H), 3.16 (dd, J¼10.5,
1.8 Hz, 1H), 3.14–3.09 (m, 1H), 3.09–3.04 (m, 1H), 1.26–1.18 (m, 1H),
1.18–1.09 (m, 1H), 1.01–0.90 (m, 1H), 0.87–0.70 (m, 17H), 0.40 (t,
d
7.36–7.15 (m, 20H), 5.83–5.74 (m, 1H, Z isomer), 5.60 (dq, J¼15.1,
6.4 Hz,1H, E isomer), 5.50 (ddd, J¼11.3, 9.6,1.8 Hz,1H, Z isomer), 5.42
(ddd, J¼15.4, 8.3, 1.6 Hz, 1H, E isomer), 4.92–4.79 (m, 1H), 4.74–4.66
(m, 1H), 4.63–4.56 (m, 2H), 4.55–4.44 (m, 3H), 4.42–4.31 (m, 1H), 4.13
(dd, J¼8.2, 5.8 Hz, 1H), 4.06–3.95 (m, 1H), 3.80–3.66 (m, 2H), 3.63–
3.48 (m, 2H), 3.45–3.32 (m, 1H, Z isomer), 2.91 (d, J¼5.4 Hz, 1H, Z
isomer), 2.84 (d, J¼5.5 Hz, 1H, E isomer), 1.70 (dd, J¼6.4, 1.5 Hz, 3H, E
isomer), 1.59 (dd, J¼7.0, 1.8 Hz, 3H, Z isomer); 13C NMR (125 MHz,
J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 138.9, 138.4, 138.3,
138.1, 128.4, 128.4, 128.3, 128.0, 128.0, 127.8, 127.7, 127.7, 127.6, 127.6,
82.7, 80.4, 78.3, 75.5, 75.1, 74.1, 73.5, 73.0, 70.9, 69.2, 31.9, 29.7, 29.7,
29.6, 29.6, 29.5, 29.4, 25.4, 24.6, 22.7, 14.1; HRMS (ESI), m/z calcd for
[C45H58O5þNH4]þ: 696.4623; found 696.4631.
CDCl3, E isomer) d 138.6, 138.5, 138.5, 138.1, 130.8, 128.5, 128.4, 128.3,
128.3, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 127.5, 127.4, 81.5, 81.1,
4.4.23. (2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
78.5, 74.7, 73.3, 73.2, 71.3, 70.5, 70.2, 17.9; 13C NMR (125 MHz, CDCl3,
6-(1-(phenylsulfonyl)vinyl)tetrahydro-2H-pyran (46). To
a
stirred
Z isomer) d 81.7, 78.5, 74.8, 74.7, 73.2, 71.3, 70.2,13.8; HRMS (ESI), m/z
solution of 7 (570 mg, 0.70 mmol) in THF (20 mL) at 0 ꢀC, was added
KOt-Bu. The mixture was stirred at 0 ꢀC for 15 min and then para-
formaldehyde (80 mg, 2.67 mmol) was added in one portion. The ice
bath was removed and the reaction mixture was allowed to warm to
room temperature. Within 30 min, TLC analysis indicated complete
consumption of starting material. The mixture was diluted with
EtOAc and washed with brine. The organic layer was dried (MgSO4),
filtered, and concentrated under reduced pressure and the resulting
residue was purified by column chromatography (silica gel, 0–30%
EtOAc/heptane) to obtain 46 (439 mg, 91%) as a white solid: mp
calcd for [C36H40O5þNa]þ: 575.2768; found 570.2776. Compound 49:
mp 76–77 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.38–7.23 (m, 19H), 7.20–
7.14 (m, 2H), 4.90 (s, 2H), 4.88 (d, J¼10.8 Hz, 1H), 4.82 (d, J¼10.8 Hz,
1H), 4.64 (d, J¼10.8 Hz, 1H), 4.63 (d, J¼12.3 Hz, 1H), 4.57 (d,
J¼10.8 Hz, 1H), 4.56 (d, J¼12.3 Hz, 1H), 3.74 (dd, J¼10.9, 2.0 Hz, 1H),
3.71–3.66 (m, 2H), 3.61 (t, J¼9.4 Hz,1H), 3.40 (ddd, J¼9.6, 4.4, 2.0 Hz,
1H), 3.29 (t, J¼9.1 Hz, 1H), 3.18 (dt, J¼9.0, 2.7 Hz, 1H), 1.90 (dqd,
J¼15.0, 7.5, 2.8 Hz, 1H), 1.55–1.45 (m, 1H), 1.00 (t, J¼7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 138.7, 138.4, 138.2, 128.4, 128.4, 128.3, 128.0,
127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.5, 87.4, 82.2, 80.4, 79.0, 78.8,
75.5, 75.3, 75.0, 73.5, 69.2, 24.7, 9.9; HRMS (ESI), m/z calcd for
[C36H40O5þNH4]þ: 570.3214; found 570.3219. Compound 50: 1H
118–119 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.95–7.87 (m, 2H), 7.53–
7.43 (m, 1H), 7.40–7.16 (m, 20H), 7.16–7.08 (m, 2H), 6.64 (s, 1H), 6.05
(s, 1H), 4.89 (d, J¼11.1 Hz, 1H), 4.86 (d, J¼11.1 Hz, 1H), 4.80 (d,
J¼10.8 Hz, 1H), 4.78 (d, J¼10.6 Hz, 1H), 4.67 (d, J¼10.7 Hz, 1H), 4.53
(d, J¼10.8 Hz, 1H), 4.38 (d, J¼12.1 Hz, 1H), 4.31 (d, J¼12.1 Hz, 1H),
4.08 (d, J¼9.7 Hz, 1H), 4.04–3.94 (m, 1H), 3.71–3.59 (m, 2H), 3.46
(dd, J¼10.7, 4.4 Hz,1H), 3.34 (dd, J¼10.7,1.6 Hz,1H), 3.25 (ddd, J¼9.2,
NMR (500 MHz, CDCl3) d 7.35–7.20 (m, 20H), 5.75–5.64 (m, 2H), 4.79
(d, J¼11.4 Hz,1H), 4.68 (d, J¼11.4 Hz,1H), 4.61 (d, J¼11.7 Hz,1H), 4.59
(d, J¼11.5 Hz,1H), 4.52 (d, J¼11.5 Hz,1H), 4.50 (d, J¼12.0 Hz, 1H), 4.47
(d, J¼11.9 Hz, 1H), 4.39 (d, J¼11.7 Hz, 1H), 4.20 (t, J¼6.2 Hz, 1H), 4.05–
3.97 (m, 1H), 3.87 (d, J¼4.4 Hz, 2H), 3.76–3.71 (m, 2H), 3.63–3.56 (m,
2H), 3.29 (s, 3H), 2.82 (d, J¼5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
4.2, 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 147.2, 140.7, 138.5,
138.0, 138.0, 137.8, 133.1, 129.4, 128.6, 128.6, 128.4, 128.4, 128.4,
128.2, 127.9, 127.8, 127.8, 127.6, 127.6, 127.5, 86.9, 79.8, 79.3, 78.3,
77.7, 75.6, 75.1, 74.8, 73.2, 68.8; HRMS (ESI), m/z calcd for
[C42H42O7SþNH4]þ: 708.2989; found 708.2993.
d 138.4, 138.3, 138.3, 138.1, 131.1, 120.0, 128.5, 128.4, 128.3, 128.3,
127.9, 127.9, 127.7, 127.7, 127.6, 127.5, 81.4, 80.3, 78.3, 74.7, 73.4, 73.2,
72.4, 71.2, 70.8, 70.4, 58.0; HRMS (ESI), m/z calcd for [C37H42O6þH]þ:
583.3054; found 583.3053.
4.4.24. (2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
Acknowledgements
6-vinyltetrahydro-2H-pyran (47). To
a solution of 46 (58 mg,
0.08 mmol) in THF (1.5 mL) was added Zn dust (400 mg), followed
by a saturated solution of NH4Cl (2 mL). The mixture was stirred at
room temperature for 18 h and then diluted with EtOAc, washed
with brine, dried (MgSO4), filtered, and concentrated under re-
duced pressure to obtain spectroscopically pure 47 (white solid,
39 mg, 89%) without the need of further purification: mp 81–82 ꢀC;
We are grateful to Prof. Richard W. Franck of Hunter
CollegedCUNY for helpful discussions and suggestions. We also
thank Dr. Polivina Jolicia F. Gauuan and the AMRI Publication
Committee for reviewing the manuscript.
Supplementary data
1H NMR (500 MHz, CDCl3)
d 7.37–7.21 (m, 18H), 7.19–7.12 (m, 2H),
1H and 13C NMR spectra of all compounds prepared. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2009.08.024.
5.97 (ddd, J¼17.1, 10.5, 6.4 Hz, 1H), 5.46 (d, J¼17.3 Hz, 1H), 5.29 (d,
J¼10.6 Hz, 1H), 4.92 (d, J¼11.1 Hz, 1H), 4.87 (d, J¼11.1 Hz, 1H), 4.82
(d, J¼10.8 Hz, 1H), 4.75 (d, J¼10.6 Hz, 1H), 4.65 (d, J¼10.1 Hz, 1H),
4.63 (d, J¼11.7 Hz, 1H), 4.57 (d, J¼10.7 Hz, 1H), 4.55 (d, J¼12.2 Hz,
1H), 3.77 (dd, J¼9.6, 6.5 Hz, 1H), 3.75–3.68 (m, 3H), 3.65 (t,
J¼9.3 Hz, 1H), 3.48 (ddd, J¼9.5, 3.7, 2.4 Hz, 1H), 3.34 (t, J¼9.2 Hz,
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138.7, 138.2, 138.2, 138.0, 135.3,
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