Improved methods for the stereoselective synthesis of mannoheptosyl donors and their glycosides: Toward the synthesis of the trisaccharide repeating unit of the Campylobacter jejuni RM1221 capsular polysaccharide

Article abstract of DOI:10.1016/j.tet.2013.04.094

In view of the importance of 6-deoxymannoheptosides as structural units in the Campylobacter jejuni RM1221 capsular polysaccharide, the development of effective synthetic protocols for 4-O-6-S-α-cyanobenzylidene thio-d-mannoheptapyranoside donors carrying either 3-O-naphthylmethyl or 3-O-acetyl groups is described starting from d-mannose. In particular, tris(phenylthio)methyllithium is found to undergo highly stereoselective addition to a mannose-6-aldehyde in sharp contrast to the vinyl Grignard reagent whose reactions were essentially devoid of selectivity. A brief survey of coupling reactions with the two donors indicted the 3-O-acetyl system to be highly α-selective whereas the 3-O-naphthylmethyl congener was highly β-selective indicating that the presence of the seventh carbon atom in these donors is not detrimental to coupling selectivity in either instance.

Full text of DOI:10.1016/j.tet.2013.04.094

Tetrahedron 69 (2013) 5501e5510
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved methods for the stereoselective synthesis
of mannoheptosyl donors and their glycosides: toward the synthesis
of the trisaccharide repeating unit of the Campylobacter jejuni
RM1221 capsular polysaccharide
a
a,b,
*
ꢀ
Sebastien Picard , David Crich
a Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91190 Gif-sur-Yvette, France
b Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In view of the importance of 6-deoxymannoheptosides as structural units in the Campylobacter jejuni
Received 13 March 2013
Received in revised form 16 April 2013
Accepted 18 April 2013
RM1221 capsular polysaccharide, the development of effective synthetic protocols for 4-O-6-S-
nobenzylidene thio- -mannoheptapyranoside donors carrying either 3-O-naphthylmethyl or 3-O-acetyl
groups is described starting from -mannose. In particular, tris(phenylthio)methyllithium is found to
a-cya-
D
D
Available online 25 April 2013
undergo highly stereoselective addition to a mannose-6-aldehyde in sharp contrast to the vinyl Grignard
reagent whose reactions were essentially devoid of selectivity. A brief survey of coupling reactions with
Keywords:
Mannoheptosyl donors
the two donors indicted the 3-O-acetyl system to be highly
congener was highly -selective indicating that the presence of the seventh carbon atom in these donors
is not detrimental to coupling selectivity in either instance.
a-selective whereas the 3-O-naphthylmethyl
b
4-O-6-S-
Tris(phenylthio)methyllithium
-Selective glycosylation
a-Cyanobenzylidene
Ó 2013 Elsevier Ltd. All rights reserved.
b
Capsular polysaccharide
1. Introduction
The synthesis of the higher carbon sugars and their glycosides,
particularly the -glycero- -manno- and the -glycero-D-
b-
D
D
b
-L
manno-heptosides and their 6-deoxy congeners has been an area of
interest in our laboratory for some time with the emphasis on the
control of anomeric stereochemistry as influenced by the func-
tionality and stereochemistry at the 6-position.1,2 The 6-deoxy-
b-D-
mannoheptosides are of particular interest owing to the problems
posed by the need for a 4,6-O-benzylidene acetal or related func-
tion to control the anomeric stereochemistry3,4 and the need for
subsequent selective reductive cleavage of the C6eO6 bond, which
Fig. 1. Structure of capsular polysaccharide 1 from Campylobacter jejuni RM1221.
identified by Vinogradov et al.8 This polysaccharide has a linear
main chain comprised of a trisaccharide repeating unit that is made
up of two a- and one b-6-deoxy-D-manno-hepto-pyrannose resi-
is closely related to the problem of the synthesis of the b-D- and b-L-
rhamnopyranosides.2,5 A secondary but none the less important
problem from the practical standpoint in the development of an
efficient synthetic route is that of the introduction of the seventh
carbon with high levels of stereocontrol at the 6-position.1b,6 Our
current focus is on the glycosyl phosphosugars, which are present
in the cell walls and capsules of numerous bacteria,7 and in par-
ticular on the capsular polysaccharide 1 from Campylobacter jejuni
RM1221 (Fig. 1), the leading cause of human gastroenteritis,
dues, which are joined through a phosphodiester linkage. Having
established a method for the highly stereocontrolled synthesis of
the phosphodiester linkage,9 we turned our attention to the de-
velopment of improved methods for the preparation of the man-
noheptose unit, which we describe here.
2. Results and discussion
For the introduction of the seventh carbon we first investigated
a modification of a strategy developed earlier in the laboratory in
* Corresponding author. E-mail address: dcrich@chem.wayne.edu (D. Crich).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.094

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S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
the course of a block synthesis of multiple repeating units of the
Subsequent exposure of the reaction mixture to sodium borohy-
glycan from the Surface-Layer Glycoprotein from Bacillus ther-
dride afforded the diols 6, which were separated by silica gel
chromatography resulting in the isolation of 6-(L,D) and 6-(D,D) in
moaerophilus.1c Thus, starting from
a-
D-mannose pentaacetate, the
tetraol 2 was prepared in two steps using the commercially avail-
able odorless 2-methyl-5-tert-butylthiophenol (MbpSH) recom-
mended by Mallet et al.10,11 Subsequently, the tetraol 2 was
protected at the 3,4-O-position with butane-2,3-dione followed by
the highly regioselective benzylation at the 2-O-position using
Ley’s methodologies (Scheme 1) to give the thioglycoside 4.12
49% and 24% yield, respectively (Scheme 1).
Selective monobenzylation using dibutyltin oxide and benzyl
bromide of both isomers of 6 afforded the expected 7-O-benzyl-6-
ols 7 with excellent yield (Scheme 2).14 The unwanted 7-(
D,
D) di-
astereoisomer was salvaged by conversion to the 7-(L,D) isomer in
61% overall yield by triflation, displacement with 4-nitrobenzoate
Scheme 1. Synthesis of manno-hepto-pyrannosides 6-(L,D) and 6-(D,D).
A Swern oxidation on glycoside 4, followed by the addition in
situ of the vinyl Grignard reagent afforded the adduct 5 as an in-
and hydrolysis; the Mitsunobu protocol was not effective for this
conversion. Subsequently, a thioacetyl group was introduced at the
6-position with inversion of configuration also by a triflation and
displacement sequence in 79% yield. Hydrolysis of the bisacetal
function in the thioacetate 8 with aqueous TFA afforded the ex-
pected diol 10 in 77% yield and 9% of byproduct 9, resulting from
concomitant S- to O-acetyl migration, which we were unable to
suppress (Scheme 2).
separable 3:2 mixture of diastereoisomers 5-(L,D) and 5-(D,D) in 92%
yield. Despite previous reports of very high selectivity for the for-
mation of the L,D isomer in the closely related additions to the
corresponding methyl mannoside,6i we were unable to improve the
selectivity of this reaction thereby highlighting its susceptibility to
substituent effects and especially to the anomeric functionality
Scheme 2. Synthesis of the 6-deoxy-6-mercapto D,D-mannoheptoside 10.
(
a
-SMbp vs
a
-OMe). Continuing with the synthesis, the mixed di-
Deacetylation of 10 followed by attempted installation of the a-
astereomers of 5 were subjected to ozone at ꢀ78 ꢁC and quenched
with triphenylphosphine at that temperature, thereby enabling
cleavage of the alkene without oxidation of the thioglycoside.13
cyanobenzylidene acetal spanning O4 and S6, under conditions
previously optimized in the 6-deoxy-6-mercaptorhamnopyranoside
series,5 gave a complex mixture of unidentified products (Scheme 3).

S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
5503
Scheme 3. Synthesis of the cyanobenzylidene protected mannoheptoside 14.
Therefore 10 was selectively silylated at the 3-position by a TBDMS
group as reported by Yamasaki et al. in a cognate series,15 and the
acetyl removed with hydrazine to afford 13 in good yield. Finally, the
addition to methyl 2,3,4-tri-O-benzyl-
a
-
D
-mannopyrannoside,
and further reinforces above-mentioned dependence of the
stereoselectivity of additions to mannose-6-aldehydes on the
protecting group array and anomeric functionality.6o Fortunately,
it was discovered that treatment of the aldehyde obtained on
oxidation of 15 with the sterically hindered tris(phenylthio)
requisite 4-O-6-S-a-cyanobenzylidene system was built from 13 by
the standard two-step procedure involving orthoester exchange and
cyanation; after removal of the TBDMS group compound 14 was
obtained in 24% yield (Scheme 3), with the low yield apparently the
result of the instability of the silyl ether toward the conditions
employed for introduction of the cyanoacetal.
methyllithium reagent gave the (
exclusively and in excellent yield (Scheme 4).17 No evidence for
the formation of the (
) diastereoisomer was observed in the 1H
L,D)-isomer of the adduct 17
D,D
The poor selectivity in the transformation of 8 to 9 and the
overall inefficiency of this first synthesis of the thioglycoside 14
prompted the exploration and development of an alternative
strategy for the preparation of suitably protected 6-deoxy-6-
mercapto-D,D-mannoheptoside donors. Accordingly, tetraol 2
was converted to the thioglycoside 15 (Scheme 4) by adaptation
NMR spectrum of the crude reaction mixture. The excess orga-
nolithium reagent employed in order to achieve the high yield of
the adduct was readily recyclable in the form of tris(phenylthio)
methane following work-up and chromatographic purification.
Treatment of the tris(phenylthio)orthoester moiety in 17 with
a mixture of CuO and CuCl2 afforded the thiophenyl ester 18 and
Scheme 4. Stereoselective synthesis of the mannoheptoside 21.
of a standard protocol described in detail in the Supplementary
data.1b,16 Swern oxidation of 15 followed by the addition of the
vinyl Grignard reagent afforded 16 as an approximately 1:1
mixture of diastereoisomers, which contrasts with the 9:1
the methyl ester 19 in excellent combined yield, both of which
were reduced to the primary alcohol 20 without event. Selective
monobenzylation of 20 with dibutyltin oxide and benzyl bromide
then gave the expected 7-O-benzyl-6-ol 21 with excellent yield
(Scheme 4).14
(L,D):(D,D) ratio obtained by Oscarson et al. for the parallel

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S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
Attempted inversion of the 6-position of 21 by the thio-
removing the naphthylmethyl group with dichlorodicyanoquinone
in wet dichloromethane followed by acetylation (Scheme 6).
Mitsunobu protocol18 failed, but triflation followed displacement
with an appropriate nucleophile proved adequate for the task. The
choice of conditions for this inversion was nevertheless critical.
Thus, triflation followed by exposure to NH4SCN or AcSH/i-Pr2NEt
afforded the 3,6-dianhydro glycoside 22 in good yield with no in-
dication of the formation of the desired product 23 (Scheme 5). The
structure of 22 was confirmed by NOE correlations between H-1
and H-6. The formation of related 3,6-anhydrosugars has been
With an effective synthesis of the donors 27 and 28 in hand
model glycosylation reactions were conducted in order to de-
termine that the effectiveness of the cyanobenzylidene thioacetal
moiety as a stereocontrol agent in the mannoheptose series. Thus,
preactivation of the donor 28 with Ph2SO/Tf2O20 combination in
the presence of TTBP (Fig. 2) in dichloromethane at ꢀ78 ꢁC was
ꢀꢁ
previously observed by Kovac et al. and more recently by Lowary
et al. under DAST conditions.19 The use of Comin’s reagent for tri-
flation followed by treatment with potassium thioacetate afforded
the expected thioester 23 with a moderate 40% yield together with
7% of the elimination product 24. To avoid the formation of 24 the
final displacement was conducted with a mixture of potassium
thioacetate and thioacetic acid, when 23 was isolated in 76% yield
(Scheme 5).
Fig. 2. Structure of BSP and TTBP.
Scheme 5. Substitution of the heptanol 21.
The PMB group was selectively removed from 23 under acidic
condition at low temperature so as to prevent acetyl transfer,
resulting in the formation of 25 in 87% yield (Scheme 6). The in-
termediate thiol 26 was obtained by reduction of the thioester using
followed by addition of tert-butyl 6-hydroxyhexanoate,21 resulting
in the isolation of glycoside 29 in 96% yield with complete -se-
lectivity (Scheme 7). The very high degree of -selectivity observed
in this coupling process is consistent with that seen previously for
the 3-O-acyl-4,6-O-benzylidene protected mannosyl donors9,22 and
indicates that neither the presence of the seventh carbon nor of the
longer CeS bond is detrimental to stereoselectivity.
a
a
LiAlH4, and the 4-O-6-S-a-cyanobenzylidene system was introduced
in good yield by the usual two-step procedure of orthoester exchange
and cyanation.5 The 3-O-acetyl protected donor 28 was obtained by
Scheme 6. Synthesis of differentially protected mannoheptosyl donors 27 and 28.

S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
5505
were freshly distilled before use over CaH2 for CH2Cl2 or benzo-
phenone/Na for THF. Commercial ExtraDry AcrosealÒ quality tolu-
ene, MeOH and DMF, were used without further purification. 1H
NMR (500 and 300 MHz) and 13C NMR (125 and 75 MHz) spectra
were recorded at 298 K unless otherwise stated. Chemical shifts are
given in parts per million (d) and are referenced to the internal
solvent signal or to TMS used as an internal standard. Multiplicities
are given as follows: s (singlet), br s (broad singlet), d (doublet), t
(triplet), q (quadruplet), dd (doublet of doublet), ddd (doublet of
doublet of doublet), dt (doublet of triplet), m (multiplet). Coupling
constants J are given in Hertz. Carbon multiplicities were de-
termined by DEPT135 experiments. Diagnostic correlations were
Scheme 7.
a-Selective glycosylation with donor 28.
The 3-O-naphthylmethyl protected donor 27 was glycosylated
following preactivation with the BSP/Tf2O (Fig. 2) combination23 in
the presence of TTBP in dichloromethane at ꢀ50 ꢁC with three
model acceptors: 2-propanol, methyl rhamnoside 30, and methyl
glucoside 31. In each case completely
observed and the pure -mannoheptosides 32, 33, and 34 were
obtained by two-dimensional COSY, HSQC. Specific rotations were
ꢁC
measured at 589 nm; ½a D
ꢂ
is expressed in deg cm3 gꢀ1 dmꢀ1 and c
in g/100 cm3. Melting points were recorded in open capillary tubes
and are uncorrected. High resolution mass spectra (HMRS) were
recorded using electrospray ionization (ESI) or atmospheric pres-
sure chemical ionization (APCI).
b-selective couplings were
b
isolated in good yield, again indicating the lack of influence of the
seventh carbon on the glycosylation stereoselectivity (Scheme 8).
Scheme 8.
b-Selective glycosylation with donor 27.
3. Conclusion
4.1.1. (2-Methyl-5-tert-butylphenyl) 3,4-O-(20,30-dimethoxybutane-
20-30-diyl)-1-thia-
-mannopyranoside (3). To a solution of tetraol
a-D
The use of tris(phenylthiomethyl)lithium as nucleophile affords
extremely high stereoselectivity on addition to a mannopyranosyl
6-aldehyde in sharp contrast to the mixtures obtained with the less
hindered vinyl Grignard reagent. This high selectivity, coupled with
the use of the 3-O-naphthylmethyl protecting system enables the
2 (4 g, 11.67 mmol), in dry methanol (120 mL), was added butane-
2,3-dione (1.23 mL, 14 mmol), HC(OMe)3 (7.1 mL, 64.2 mmol), and
CSA (272 mg, 1.17 mmol). The reaction mixture was heated at reflux
for 8 h before being cooled to room temperature and quenched
with 20 mL of Et3N. The reaction mixture was concentrated under
reduced pressure and the crude product was purified on silica gel
(20% EtOAc in toluene) to give 3 (4.16 g, 78%) as a white powder.
efficient synthesis of the
28. Model coupling reactions to donors 27 and 28 proceed with
very high levels of - and -selectivity, respectively, indicating in
a- and b-selective mannoheptosyl 27 and
a
b
½
a 2D4
ꢂ
þ292.0 (c 1.0, CHCl3); mp 65 ꢁC; 1H NMR (500 MHz, CDCl3)
d:
both cases that the presence of the seventh carbon in the donors is
not in any way detrimental to the yield or selectivity of the coupling
reactions. Further progress on the synthesis of the C. jejuni capsular
polysaccharide will be reported in due course.
1.29 (s, 9H),1.32 (s, 3H),1.34 (s, 3H), 2.39 (s, 3H), 3.26 (s, 3H), 3.33 (s,
3H), 3.78 (d, J¼3.5 Hz, 2H), 4.11 (d, J¼10.0 Hz, 1H), 4.18 (t, J¼10.0 Hz,
1H), 4.22e4.25 (m, 1H), 4.26e4.31 (m, 1H), 5.50 (s, 1H), 7.14 (d,
J¼8.0 Hz, 1H), 7.22 (d, J¼8.0 Hz, 1H), 7.53 (s, 1H); 13C NMR (75 MHz,
CDCl3) d: 17.7, 17.8, 20.2, 31.1, 34.4, 47.9, 48.2, 61.2, 63.2, 68.7, 71.4,
4. Experimental section
4.1. General experimental
71.6, 97.4, 99.9, 100.5, 125.2, 130.0, 130.1, 131.9, 136.9, 136.9, 149.7;
ESIHRMS C23H36O7S calcd for [MþNa]þ: 479.2079, found 479.2093.
4.1.2. (2-Methyl-5-tert-butylphenyl) 2-O-benzyl-3,4-O-(20,30-dime-
thoxybutane-20-30-diyl)-1-thia-
a-D-mannopyranoside (4). To a chil-
All reactions were performed using oven dried glassware under
an atmosphere of argon. All purifications were performed on pre-
packed silica gel columns (50 mm). Reactions were monitored by
thin-layer chromatography on alumina backed silica gel plates (60
F254 aluminum) visualized by UV light and/or spraying with vanillin
(15%)þsulfuric acid (2.5%) in EtOH followed by heating. Solvents
led (ꢀ40 ꢁC) solution of 3 (7.42 g, 16.3 mmol) in dry DMF (160 mL)
was added benzyl bromide (2.13 mL,17.9 mmol) followed by 60% NaH
in mineral oil (1.31 g, 32.6 mmol). The reaction mixture was stirred
2 h at ꢀ40 ꢁC and 24 h at ꢀ5 ꢁC before it was quenched with saturated
aqueous NaHCO3 and then extracted with dichloromethane. The

5506
S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
combined organic layer was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The crude product was puri-
fied on silica gel (10% EtOAc in heptane to 20% EtOAc in heptane) to
J¼12.0 Hz, 1H), 4.97 (d, J¼12.0 Hz, 1H), 5.47 (s, 1H), 7.14 (d, J¼8.0 Hz,
1H), 7.23 (d, J¼8.0 Hz, 1H), 7.28 (d, J¼7.0 Hz, 1H), 7.34 (t, J¼7.0 Hz,
2H), 7.39 (d, J¼7.5 Hz, 2H), 7.44 (s, 1H); 13C NMR (75 MHz, CDCl3)
d:
give 4 (6.1 g, 69%) as a white powder: ½a D24
ꢂ
þ189.0 (c 1.0, CHCl3); mp
17.8, 20.2, 31.3, 34.5, 48.1, 63.3, 65.1, 68.7, 69.5, 73.1, 73.3, 77.2, 86.9,
99.8, 100.0, 125.3, 127.7, 128.0, 128.3, 129.0, 130.3, 131.9, 136.5, 138.4,
149.9. ESIHRMS C31H44O8S calcd for [MþNa]þ: 599.2655, found
599.2660.
56 ꢁC; 1H NMR (500 MHz, CDCl3)
d: 1.28 (s, 9H), 1.34 (s, 3H), 1.37 (s,
3H), 2.33 (s, 3H), 3.31 (s, 3H), 3.34 (s, 3H), 3.72e3.90 (m, 2H),
3.95e4.10 (m, 1H), 4.13 (dd, J¼9.5, 2.5 Hz, 1H), 4.24e4.33 (m, 2H),
4.68 (d, J¼12.0 Hz, 1H), 4.94 (d, J¼12.0 Hz, 1H), 5.42 (s, 1H), 7.13 (d,
J¼8.0 Hz, 1H), 7.21 (d, J¼8.0 Hz, 1H), 7.28 (d, J¼7.5 Hz, 1H), 7.33 (t,
J¼7.5 Hz, 2H), 7.43 (d, J¼7.5 Hz, 2H), 7.49 (s, 1H); 13C NMR (75 MHz,
4.1.4. (2-Methyl-5-tert-butylphenyl) 2,7-di-O-benzyl-3,4-O-(20,30-di-
methoxybutane-20-30-diyl)-
L
-glycero-1-thia-
a-D-mannoheptopyrano-
CDCl3)
d: 17.8, 20.2, 31.2, 31.3, 34.4, 47.9, 48.0, 61.6, 63.9, 69.4, 72.0,
side 7-(
L,
D
). A mixture of 6-( ) (2.8 g, 4.8 mmol) and n-Bu2SnO
L,D
73.1, 77.6, 87.1, 99.6, 100.0, 125.0, 127.6, 127.9, 128.3, 129.8, 130.1,
132.3, 136.6, 138.4, 149.7; ESIHRMS C30H42O7S calcd for [MþNa]þ:
569.2549, found 569.2546.
(1.45 g, 5.8 mmol) in dry toluene (50 mL) was heated 4 h at reflux.
The resulting clear solution was cooled to room temperature and
concentrated under reduced pressure. The residue was dissolved in
dry DMF (25 mL) and benzyl bromide (690 mL, 5.8 mmol) was added
4.1.3. (2-Methyl-5-tert-butylphenyl) 2-O-benzyl-3,4-O-(20,30-dime-
followed by the addition of CsF (1.46 g, 9.6 mmol). The reaction
mixture was stirred overnight at room temperature, diluted with
CH2Cl2, and filtrated through CeliteÒ. The filtrate was concentrated
under reduced pressure and the crude was purified on silica gel
thoxybutane-20-30-diyl)-
D
-glycero-1-thia-
a-D-mannoheptopyrano-
side (6-(
D,D)) and (2-methyl-5-tert-butylphenyl) 2-O-benzyl-3,4-O-
(20,30-dimethoxybutane-20-30-diyl)-
L
-glycero-1-thia-a-D-man-
noheptopyranoside (6-(
L,
D
)). To a chilled (ꢀ60 ꢁC) solution of oxalyl
(10% EtOAc in heptane) to give 7-(L,D) (3.14 g, 98%) as a clear viscous
chloride (2.64 mL, 30.75 mmol) in dry THF (25 mL) was added
a solution of DMSO (4.4 mL, 61.7 mmol) in dry THF (25 mL). The
reaction mixture was stirred 30 min at ꢀ60 ꢁC and then a solution
of 4 (6.7 g, 12.3 mmol) in dry THF (50 mL) was added. The reaction
mixture was stirred 5 h at ꢀ40 ꢁC and i-Pr2NEt was slowly added
(21.9 mL, 123 mmol). The reaction mixture was warmed to room
temperature and stirred 2 h at room temperature. The reaction
mixture was cooled at ꢀ78 ꢁC and a solution of vinyl magnesium
bromide (0.7 M in THF, 88.2 mL, 61.7 mmol) was slowly added. The
reaction mixture was stirred 2 h at ꢀ78 ꢁC, quenched with ethanol
(20 mL) and warmed to room temperature. Then, saturated aque-
ous NH4Cl was added, and then extracted with EtOAc. The com-
bined organic layer was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The crude was purified on
silica gel (10% EtOAc in heptane) to give 5 (6.5 g, 92%) as a 3:2
oil: ½a 2D4
ꢂ
þ212.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.30 (s,
9H), 1.34 (s, 3H), 1.39 (s, 3H), 2.18 (d, J¼7.5 Hz, 1H), 2.29 (s, 3H), 3.34
(s, 3H), 3.35 (s, 3H), 3.42 (dd, J¼9.5, 4.0 Hz, 1H), 3.51 (t, J¼9.0 Hz,
1H), 4.01 (s, 1H), 4.10e4.21 (m, 3H), 4.38 (d, J¼12.0 Hz, 1H), 4.44 (t,
J¼12.0 Hz, 1H), 4.51 (d, J¼10.5 Hz, 1H), 4.72 (d, J¼12.5 Hz, 1H), 4.96
(d, J¼12.5 Hz, 1H), 5.57 (s, 1H), 7.10 (d, J¼8.0 Hz, 1H), 7.19 (d,
J¼8.0 Hz, 1H), 7.22e7.37 (m, 8H), 7.43 (d, J¼7.0 Hz, 2H), 7.46 (s, 1H);
13C NMR (75 MHz, CDCl3)
d: 17.8, 20.1, 31.4, 34.5, 48.0, 48.1, 62.9,
67.6, 69.7, 71.5, 72.0, 73.1, 73.2, 77.6, 86.7, 99.7, 100.0, 124.3, 127.3,
127.5, 127.6, 128.0, 128.2, 128.3, 130.0, 133.3, 135.4, 138.1, 138.4,
149.8. ESIHRMS C38H50O8S calcd for [MþNa]þ: 689.3124, found
689.3121.
4.1.5. (2-Methyl-5-tert-butylphenyl) 6-S-acetyl-2,7-di-O-benzyl-3,4-
O-(20,30-dimethoxybutane-20-30-diyl)-
D-glycero-1,6-dithio-a-D-man-
mixture of diastereoisomers (
L,D
) and (
D
,D
). This mixture was dis-
noheptopyranoside (8). To a chilled (ꢀ40 ꢁC) solution of 7-(
L,D)
solved in dry CH2Cl2 (600 mL), cooled to ꢀ78 ꢁC, and ozone was
bubbled until see a blue color persisted. The reaction mixture was
purged with argon and Ph3P (16.1 g, 61.5 mmol) was added. The
reaction mixture was stirred 4 h at ꢀ78 ꢁC, warmed slowly to room
temperature and stirred overnight at room temperature. CH2Cl2
was removed under reduced pressure and the residue was dis-
solved in a mixture of dry CH2Cl2/MeOH (1:2, 210 mL), cooled at
ꢀ78 ꢁC and NaBH4 (2.33 g, 61.5 mmol) was added. The reaction was
stirred 1 h at ꢀ78 ꢁC, warmed to room temperature, stirred over-
night at room temperature, quenched with saturated aqueous
NaHCO3, and then extracted with CH2Cl2. The combined organic
layer was washed with brine, dried (MgSO4), and concentrated
under reduced pressure. The crude was purified on silica gel
(134 mg, 0.2 mmol) and methylimidazole (40 mL, 0.503 mmol) was
added Tf2O (freshly distilled over P2O5, 64 mL, 0.4 mmol). The re-
action mixture was stirred 10 min at ꢀ40 ꢁC, warmed at ꢀ10 ꢁC, and
stirred 10 min at ꢀ10 ꢁC before to be poured into cold 0.1 N HCl and
extracted with CH2Cl2. The combined organic layer was washed
with saturated aqueous NaHCO3 and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was dissolved in
dry DMF (2 mL) and then AcSK (91.4 mg, 0.8 mmol) was added. The
reaction mixture was stirred 6 h at room temperature, quenched
with saturated aqueous NaHCO3, and then extracted with CH2Cl2.
The combined organic layer was washed with brine, dried (MgSO4),
and concentrated under reduced pressure. The crude was purified
on silica gel (10% EtOAc in heptane) to give 8 (114 mg, 79%) as
(Gradient: 5%e20% EtOAc in toluene) to give 6-(
D
,
D
) (1.5 g, 24%) as
yellow viscous oil: ½a D24
ꢂ
þ162.6 (c 1.0, CHCl3); 1H NMR (500 MHz,
a white powder: ½a D27
ꢂ
þ195.5 (c 1.0, CHCl3); mp 51 ꢁC; 1H NMR
CDCl3) d: 1.33 (s, 3H), 1.34 (s, 9H), 1.36 (s, 3H), 2.29 (s, 3H), 2.32 (s,
(500 MHz, CDCl3)
d
: 1.29 (s, 9H), 1.34 (s, 3H), 1.37 (s, 3H), 2.11 (t,
3H), 3.19 (s, 3H), 3.32 (s, 3H), 3.56 (dd, J¼10.0, 7.5 Hz, 1H), 3.91 (dd,
J¼10.0, 7.0 Hz 1H), 3.98e4.02 (m, 2H), 4.37 (t, J¼7.0 Hz, 1H),
4.40e4.49 (m, 2H), 4.50 (d, J¼12.5 Hz, 1H), 4.56 (d, J¼12.5 Hz, 1H),
4.69 (d, J¼12.0 Hz, 1H), 4.91 (d, J¼12.0 Hz, 1H), 5.43 (s, 1H), 7.12 (d,
J¼8.0 Hz,1H), 7.22 (dd, J¼8.0, 2.0 Hz,1H), 7.24e7.34 (m, 8H), 7.43 (d,
J¼6.0 Hz,1H), 2.31 (s, 3H), 3.02 (d, J¼3.0 Hz,1H), 3.31 (s, 3H), 3.34 (s,
3H), 3.63e3.74 (m, 2H), 3.92e3.99 (m, 2H), 4.11 (d, J¼10.0 Hz, 1H),
4.25 (d, J¼9.5, 5.5 Hz, 1H), 4.38 (t, J¼10.0 Hz, 1H), 4.67 (t, J¼12.0 Hz,
1H), 4.97 (d, J¼12.0 Hz, 1H), 5.40 (s, 1H), 7.12 (d, J¼8.0 Hz, 1H), 7.21
(d, J¼8.0 Hz,1H), 7.28 (d, J¼7.0 Hz,1H), 7.34 (t, J¼7.0 Hz, 2H), 7.42 (d,
J¼7.5 Hz, 2H), 7.59 (d, J¼2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d:
J¼7.5 Hz, 2H), 7.47 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
: 17.8, 17.9,
17.8, 20.1, 30.6, 31.3, 34.6, 43.4, 48.0, 48.3, 65.3, 69.0, 69.8, 72.7, 72.9,
73.6, 78.2, 87.4, 99.8, 100.1, 124.5, 127.4, 127.5, 127.7, 127.8, 128.2,
128.9, 129.8, 133.6, 135.8, 138.3, 149.8, 194.2. ESIHRMS C40H52O8S2
calcd for [MþNa]þ: 747.3001, found 747.3008.
20.2, 31.3, 34.5, 48.1, 48.4, 63.2, 66.6, 69.3, 71.7, 73.2, 73.3, 77.6, 87.1,
100.0, 100.1, 125.1, 127.7, 127.9, 128.3, 129.2, 130.2, 132.5, 136.4,
138.3, 149.9. ESIHRMS C31H44O8S calcd for [MþNa]þ: 599.2655,
found 599.2649; and 6-(
L
,
D
) (3.1 g, 44%) as a white powder: ½a D25
ꢂ
þ212.7 (c 1.0, CHCl3); mp 53 ꢁC; 1H NMR (500 MHz, CDCl3)
d
: 1.29
4.1.6. (2-Methyl-5-tert-butylphenyl) 4-O-acetyl-2,7-di-O-benzyl-
D-
(s, 9H), 1.34 (s, 3H), 1.37 (s, 3H), 1.82 (dd, J¼7.0, 4.5 Hz, 1H), 2.32 (s,
3H), 2.33e2.34 (m, 1H), 3.34 (s, 3H), 3.35 (s, 3H), 3.53e3.61 (m, 2H),
3.92e4.02 (m, 2H), 4.11e4.17 (m, 2H), 4.44 (t, J¼10.0 Hz,1H), 4.68 (t,
glycero-1,6-dithio- -mannoheptopyranoside (9) and (2-methyl-5-
a-D
tert-butylphenyl) 6-S-acetyl-2,7-di-O-benzyl-D-glycero-1,6-dithio-a-
D
-mannoheptapyranoside (10). To a chilled (ꢀ20 ꢁC) solution of 8

S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
5507
(1.55 g, 2.14 mmol) was added a mixture of TFA/H2O (9:1, 4 mL). The
reaction mixture was stirred 10 min at ꢀ20 ꢁC, warmed at 0 ꢁC, and
stirred 2 h at 0 ꢁC. The reaction mixture was quenched with satu-
rated aqueous NaHCO3 and then extracted with CH2Cl2. The com-
bined organic layer was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The crude was purified on
silica gel (30% EtOAc in heptane) to give 9 (118.2 mg, 9%) as a clear
(d, J¼11.5 Hz, 1H), 5.50 (s, 1H), 7.14 (d, J¼8.0 Hz, 1H), 7.21 (d,
J¼8.0 Hz, 1H), 7.24e7.34 (m, 10H), 7.57 (s, 1H); 13C NMR (75 MHz,
CDCl3)
d: ꢀ4.6, ꢀ4.5, 18.2, 20.2, 25.9, 31.4, 34.5, 40.5, 69.2, 72.3, 72.9,
73.2, 73.7, 75.7, 80.5, 86.3, 124.9, 127.6, 127.7, 127.8, 128.3, 128.4,
129.5, 130.0, 132.8, 136.4, 137.8, 138.2, 149.7. ESIHRMS C38H54O5S2Si
calcd for [MþNa]þ: 705.3080, found 705.3089.
viscous oil: ½a 2D4
ꢂ
þ93.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d:
4.1.9. (2-Methyl-5-tert-butylphenyl) 2,7-di-O-benzyl-4-O-6-S-(1-
1.31 (s, 9H), 1.87 (d, J¼8.5 Hz, 1H), 2.11 (s, 3H), 2.36 (s, 3H), 2.46 (d,
J¼10.0 Hz, 1H), 3.25e3.29 (m, 1H), 3.50 (dd, J¼9.5, 7.5 Hz, 1H), 3.81
(dd, J¼9.5, 6.0 Hz, 1H), 3.88e3.91 (m, 1H), 4.02e4.07 (m, 1H),
4.42e4.46 (m, 1H), 4.48 (d, J¼12.5 Hz, 1H), 4.54 (d, J¼12.5 Hz, 1H),
4.64 (d, J¼12.0 Hz,1H), 4.73 (d, J¼12.0 Hz,1H), 5.39 (t, J¼9.5 Hz,1H),
5.56 (s, 1H), 7.15 (d, J¼8.0 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H), 7.24e7.36
cyano)benzylidene-
(14). To a room temperature solution of 13 (130 mg, 0.19 mmol) in
dry CH2Cl2 (0.2 mL) was added CSA (9 mg, 38 mol) followed by the
addition of PhC(OMe)3 (116 L, 0.95 mmol). The reaction mixture
D-glycero-1,6-dithio-a-D-mannohepto-pyranoside
m
m
was stirred overnight at room temperature, quenched with satu-
rated aqueous NaHCO3, and extracted with CH2Cl2. The combined
organic layer was dried (Na2SO4) and concentrated under reduced
pressure. The residue was dissolved in dry CH2Cl2 (2 mL), cold at
(m, 10H), 7.56 (s, 1H); 13C NMR (75 MHz, CDCl3)
d: 20.2, 21.0, 31.3,
34.5, 39.9, 71.0, 71.4, 71.6, 72.5, 73.1, 73.6, 80.0, 84.6, 125.0, 127.5,
127.6,127.7,127.8,128.1,128.3,128.6,129.4,130.2,132.3,136.4,137.3,
138.0, 149.8, 170.9; ESIHRMS C34H42O6S2 calcd for [MþNa]þ:
633.2321, found 633.2341; and 10 (1.01 g, 77%) as a clear viscous oil:
0
ꢁC, and TMSCN (191
addition of BF3eEt2O (24
m
L, 1.52 mmol) was added followed by the
mL, 0.19 mmol). The reaction mixture was
stirred 1 h at 0 ꢁC, warmed to room temperature, stirred 2 h at room
temperature, quenched with saturated aqueous NaHCO3, and then
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried (MgSO4), and concentrated under reduced pres-
sure. The residue was dissolved in dry THF (2 mL) and TBAF (1 M in
½
a 2D6
ꢂ
þ108.9 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.36 (s, 9H),
2.29 (s, 3H), 2.34 (s, 3H), 2.45 (d, J¼8.0 Hz, 1H), 3.08 (d, J¼3.5 Hz,
1H), 3.56 (dd, J¼10.0, 4.0 Hz, 1H), 3.82e3.88 (m, 1H), 3.95 (dd,
J¼10.5, 8.5 Hz, 1H), 4.03e4.10 (m, 2H), 4.27e4.33 (m, 2H), 4.58 (d,
J¼12.0 Hz, 1H), 4.62 (d, J¼12.0 Hz, 1H), 4.63 (d, J¼12.0 Hz, 1H), 4.73
(d, J¼12.0 Hz, 1H), 5.53 (s, 1H), 7.15 (d, J¼8.0 Hz, 1H), 7.23 (dd, J¼8.0,
2.0 Hz, 1H), 7.28e7.36 (m, 10H), 7.58 (s, 1H); 13C NMR (75 MHz,
THF, 380 mL, 0.38 mmol) was added. The mixture was stirred 1 h at
room temperature, quenched with saturated aqueous NaHCO3, and
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried (MgSO4), and concentrated under reduced pres-
sure. The crude was purified on silica gel (20% EtOAc in heptane) to
CDCl3) d: 20.2, 30.5, 31.4, 34.6, 44.0, 69.8, 70.0, 71.7, 72.2, 73.4, 74.5,
79.9, 85.6, 124.6, 127.7, 127.8, 128.0, 128.5, 128.7, 129.9, 133.3, 135.9,
137.5, 137.6, 149.8, 194.6; ESIHRMS C34H42O6S2 calcd for [MþNa]þ:
633.2321, found 633.2321.
give 14 (32 mg, 24%) as a clear viscous oil: ½a D24
þ147.6 (c 1.0,
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.30 (s, 9H), 2.28 (s, 3H), 2.39
(d, J¼9.0 Hz, 1H), 3.43 (dd, J¼10.0, 7.5 Hz, 1H), 3.73 (dd, J¼10.0,
3.0 Hz, 1H), 3.98e4.03 (m, 1H), 4.09e4.12 (m, 1H), 4.16 (td, J¼9.0,
3.5 Hz, 1H), 4.22e4.37 (m, 4H), 4.69 (d, J¼12.0 Hz, 1H), 4.77 (d,
J¼12.0 Hz, 1H), 5.60 (s, 1H), 7.08 (d, J¼8.0 Hz, 1H), 7.12 (d, J¼6.5 Hz,
1H), 7.19 (dd, J¼8.0, 2.0 Hz, 1H), 7.23e7.28 (m, 4H), 7.30e7.33 (m,
1H), 7.35e7.38 (m, 4H), 7.40 (d, J¼1.5 Hz, 1H), 7.42e7.44 (m, 3H),
4.1.7. (2-Methyl-5-tert-butylphenyl) 6-S-acetyl-2,7-di-O-benzyl-3-
O-tert-butyldimethylsilyl-D-glycero-1,6-dithio-a-D-mannoheptopyr-
anoside (12). To a cooled (0 ꢁC) solution of 10 (240 mg, 0.4 mmol)
and imidazole (69 mg, 1.0 mmol) in dry DMF (4 mL) was added
TBDMSCl (122 mg, 0.8 mmol). The reaction mixture was stirred
overnight at room temperature, quenched with saturated aqueous
NaHCO3, and then extracted with CH2Cl2. The combined organic
layer was washed with brine, dried (MgSO4), and concentrated
under reduced pressure. The crude was purified on silica gel (10%
EtOAc in heptane) to give 12 (271 mg, 94%) as a clear viscous oil:
7.74e7.76 (m, 2H); 13C NMR (75 MHz, CDCl3)
d: 20.0, 31.4, 34.6, 45.5,
67.6, 68.4, 69.1, 73.0, 73.3, 77.2, 78.1, 79.5, 79.7, 84.1, 115.9, 124.4,
125.7, 126.8, 127.3, 127.6, 128.1, 128.3, 128.7, 130.2, 132.4, 135.0,
135.5, 137.0, 137.5, 149.8. ESIHRMS C40H43NO5S2 calcd for [MþNa]þ:
704.2480, found 704.2495.
½
a 2D4
ꢂ
þ113.8 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 0.16 (s, 3H),
0.17 (s, 3H), 0.97 (s, 9H), 1.36 (s, 9H), 2.29 (s, 3H), 2.34 (s, 3H), 2.55
(d, J¼3.5 Hz, 1H), 3.55 (dd, J¼10.0, 5.0 Hz, 1H), 3.89e3.93 (m, 2H),
3.97 (t, J¼8.5 Hz, 1H), 4.17e4.30 (m, 2H), 4.35e4.39 (m, 1H), 4.57 (s,
2H), 4.67 (d, J¼12.0 Hz, 1H), 4.78 (d, J¼12.0 Hz, 1H), 5.45 (s, 1H), 7.14
(d, J¼8.0 Hz, 1H), 7.22 (d, J¼8.0 Hz, 1H), 7.24e7.34 (m, 10H), 7.60 (s,
4.1.10. (2-Methyl-5-tert-butylphenyl)
2-O-benzyl-4-O-(p-methox-
ybenzyl)-3-O-(2-naphtalenyl-methyl)-7-S-tris(thiophenol)-l-glycero-
1-thia-
a
-
D
-thiomannoheptopyranoside (17). To a chilled (ꢀ60 ꢁC)
solution of oxalyl chloride (820 mL, 9.5 mmol) in dry THF (8 mL) was
added a solution of DMSO (1.3 mL, 19 mmol) in dry THF (5 mL). The
reaction mixture was stirred 30 min at ꢀ60 ꢁC and then a solution
of 15 (2.63 g, 3.8 mmol) in dry THF (30 mL) was slowly added. The
reaction mixture was stirred 5 h at ꢀ40 ꢁC and i-Pr2NEt was slowly
added (5.4 mL, 30.4 mmol) at ꢀ60 ꢁC. The reaction mixture was
slowly warmed to room temperature and stirred 2 h at room
temperature. In another flask, to a cooled (ꢀ78 ꢁC) solution of
tris(thiophenol)methane (12.9 g, 38 mmol), in dry THF (40 mL), was
dropwise added a solution of n-BuLi (1.6 M in hexane, 23.8 mL,
38 mmol). The yellow suspension was stirred 90 min at ꢀ78 ꢁC and
the previous mixture from Swern reaction was slowly added by
cannula at ꢀ78 ꢁC. The reaction mixture was stirred, warmed
slowly to room temperature and stirred overnight at room tem-
perature. The reaction mixture was quenched with saturated
aqueous NH4Cl and then extracted with EtOAc. The combined or-
ganic layer was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. The crude was purified on silica gel
(5%e20% t-BuOMe in heptane) to give 17 (3.5 g, 90%) as a clear
1H); 13C NMR (75 MHz, CDCl3)
d: ꢀ4.5, 18.3, 20.2, 25.9, 30.5, 31.4,
34.6, 43.9, 69.3, 69.4, 73.0, 73.1, 73.6, 75.2, 81.0, 86.8, 124.6, 127.5,
127.6,127.7,128.3,128.4,129.1,129.8,133.6,136.0,137.9,138.3,149.7,
194.7; ESIHRMS C40H56O6S2Si calcd for [MþNa]þ: 747.3185, found
747.3205.
4.1.8. (2-Methyl-5-tert-butylphenyl) 2,7-di-O-benzyl-3-O-tert-bu-
tyldimethylsilyl- -glycero-1,6-dithio-a-D-mannohepto-pyranoside
D
(13). To a cooled (0 ꢁC) solution of 12 (153 mg, 0.21 mmol) in dry
THF (2 mL) was added hydrazine (28.7 mg, 0.32 mmol). The re-
action mixture was stirred 3 h at room temperature, diluted with
EtOAc, and washed with water. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The crude was
purified on silica gel (10% EtOAc in heptane) to give 13 (140 mg,
98%) as a clear viscous oil: ½a D24
ꢂ
þ84.4 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) d: 0.17 (s, 3H), 0.18 (s, 3H), 0.97 (s, 9H),1.31 (s, 9H),
1.90 (d, J¼9.0 Hz, 1H), 2.36 (s, 3H), 2.55 (s, 1H), 3.49e3.51 (m, 1H),
3.64 (dd, J¼9.5, 5.0 Hz, 1H), 3.92 (s, 1H), 3.96 (d, J¼8.0 Hz, 1H),
4.20e4.30 (m, 2H), 4.50e4.55 (m, 2H), 4.68 (d, J¼11.5 Hz, 1H), 4.79
viscous oil: ½a 2D4
ꢂ
þ116.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d:
1.15 (s, 9H), 2.24 (s, 3H), 3.28 (d, J¼11.0 Hz, 1H); 3.79 (s, 3H), 3.92

5508
S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
(dd, J¼9.5, 2.0 Hz, 1H), 3.99e4.02 (m, 1H), 4.08 (t, J¼9.5 Hz, 1H), 4.18
(d, J¼11.0 Hz,1H), 4.21 (d, J¼10.0 Hz,1H), 4.67e4.85 (m, 6H), 5.54 (s,
1H), 6.73 (d, J¼8.0 Hz, 2H), 6.87 (d, J¼8.0 Hz, 2H), 7.07 (d, J¼7.5 Hz,
1H), 7.11e7.16 (m, 7H), 7.22e7.30 (m, 6H), 7.32e7.35 (m, 2H),
7.43e7.55 (m, 9H), 7.60 (s, 1H), 7.71e7.75 (m, 1H), 7.77e7.85 (m,
J¼12.0 Hz, 1H), 4.72 (s, 2H), 4.93 (d, J¼10.5 Hz, 1H), 5.47 (s, 1H), 6.82
(d, J¼8.5 Hz, 2H), 7.12 (d, J¼8.0 Hz,1H), 7.23e7.37 (m, 9H), 7.46e7.51
(m, 3H), 7.76e7.79 (m, 1H), 7.81e7.86 (m, 3H); 13C NMR (75 MHz,
CDCl3) d: 20.1, 31.3, 34.4, 55.2, 65.1, 69.3, 72.3, 72.4, 74.1, 74.2, 75.1,
76.3, 84.1, 85.4, 113.8, 125.3, 125.8, 125.9, 126.0, 126.1, 126.5, 127.7,
127.9, 128.2, 128.4, 128.9, 129.7, 129.9, 130.3, 130.4, 132.0, 133.0,
133.3, 133.5, 134.6, 136.5, 137.8, 149.9, 159.3, 199.3. ESIHRMS
C44H50O7S calcd for [MþNa]þ: 745.3175, found 745.3178.
3H); 13C NMR (75 MHz, CDCl3)
d: 20.4, 31.3, 34.5, 55.3, 72.2, 72.3,
73.0, 75.1, 75.2, 77.2, 79.7, 80.1, 85.9, 113.5, 124.4, 125.9, 126.0, 126.5,
127.7,127.8,127.9,128.2,128.4,129.1,129.6,129.8,130.5,131.6,133.0,
133.3, 133.7, 135.7, 135.8, 137.0, 137.2, 138.2, 149.8, 159.3. ESIHRMS
C62H62O6S4 calcd for [MþNa]þ: 1053.3327, found 1053.3340.
4.1.13. (2-Methyl-5-tert-butylphenyl)
thoxybenzyl)-3-O-(2-naphtalenylmethyl)-
2,7-di-O-benzyl-4-O-(p-me-
-glycero-1-thia- -man-
L
a-D
4.1.11. S-Phenyl [(2-methyl-5-tert-butylphenyl) 2-O-benzyl-4-O-(p-
methoxybenzyl)-3-O-(2-naphtalenylmethyl)-L-glycero-1-thia-a-D-
mannoheptopyranosyl urinate] (18) and methyl [(2-methyl-5-tert-
butylphenyl) 2-O-benzyl-4-O-(p-methoxybenzyl)-3-O-(2-
noheptopyranoside (21). A mixture of 20 (1.40 g, 1.9 mmol) and n-
Bu2SnO (570 mg, 2.28 mmol), in dry toluene (20 mL), was heated
overnight at reflux. The resulting clear solution was cooled to room
temperature and then concentrated under reduced pressure. The
residue was dissolved in dry DMF (10 mL) and then CsF (578 mg,
naphtalenylmethyl)-L-glycero-1-thia-a-D-mannoheptopyranosyl uri-
nate] (19). To a solution of 17 (3.7 g, 3.6 mmol), in MeOH/H2O/
CH2Cl2 mixture (42 mL, 12:1:1), was added CuO (331 mg, 3.6 mmol)
and CuCl2 (1.94 g, 14.4 mmol). The reaction mixture was stirred 4 h
at room temperature, quenched with saturated aqueous NH4Cl, and
then extracted with CH2Cl2. The combined organic layer was
washed with brine, dried (MgSO4), and concentrated under re-
duced pressure. The crude was purified on silica gel (20% EtOAc in
petroleum ether) to give 18 (243 mg, 9%) as a yellow viscous oil:
3.8 mmol) and benzyl bromide (340 mL, 2.85 mmol) were added.
The reaction mixture was stirred 20 h at room temperature, diluted
with CH2Cl2, and filtrated through CeliteÒ. The filtrate was con-
centrated under reduced pressure. The crude was purified on silica
gel (20% EtOAc in heptane) to give 21 (1.5 g, 96%) as a clear viscous
a 24
oil: ½ ꢂD þ51.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.29 (s,
9H), 2.26 (s, 3H), 2.25 (d, J¼7.0 Hz, 1H), 3.40 (dd, J¼10.0, 4.5 Hz, 1H),
3.55 (t, J¼9.5 Hz, 1H), 3.78 (s, 3H), 3.97 (dd, J¼9.5, 2.5 Hz, 1H),
4.01e4.05 (m, 2H), 4.20e4.25 (m, 1H), 4.31 (t, J¼9.5 Hz,1H); 4.38 (d,
J¼12.0 Hz, 1H), 4.44 (d, J¼12.0 Hz, 1H), 4.68e4.82 (m, 5H), 4.94 (d,
J¼10.5 Hz, 1H), 5.57 (s, 1H), 6.82 (d, J¼8.5 Hz, 2H), 7.08 (d, J¼8.0 Hz,
1H), 7.17 (dd, J¼8.0, 1.5 Hz, 1H), 7.21e7.32 (m, 10H), 7.36e7.42 (m,
3H), 7.46e7.7.51 (m, 3H), 7.76e7.79 (m, 1H), 7.81e7.86 (m, 3H); 13C
½
a 2D4
ꢂ
þ32.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.16 (s, 9H),
2.21 (s, 3H), 3.18 (d, J¼10.5 Hz, 1H); 3.79 (s, 3H), 4.01 (dd, J¼9.5,
2.0 Hz, 1H), 4.05e4.07 (m, 1H), 4.27 (d, J¼9.5 Hz, 1H), 4.53 (d,
J¼9.5 Hz,1H), 4.62 (d, J¼10.5 Hz,1H), 4.68 (d, J¼10.5 Hz,1H), 4.72 (s,
2H), 4.79 (d, J¼12.0 Hz, 1H), 4.83 (d, J¼12.0 Hz, 1H), 4.96 (d,
J¼12.0 Hz, 1H), 5.52 (s, 1H), 6.84 (d, J¼8.0 Hz, 2H), 7.04e7.09 (m,
3H), 7.16 (d, J¼8.0 Hz, 1H), 7.23e7.37 (m, 11H), 7.46e7.51 (m, 3H),
NMR (75 MHz, CDCl3)
d
: 20.0, 31.4, 34.5, 55.2, 68.3, 72.2, 72.3 (ꢃ2),
72.8, 73.2, 74.0, 75.1, 76.5, 80.4, 85.2, 113.8, 124.3, 125.8, 125.9, 126.0,
126.4,127.5,127.6,127.7,127.9,128.1,128.3,128.4,129.7,129.9,130.6,
132.9, 133.2, 133.3, 133.6, 135.7, 137.9, 138.0, 149.7, 159.2, 199.3.
ESIHRMS C51H56O7S calcd for [MþNa]þ: 835.3644, found 835.3654.
7.78e7.80 (m, 1H), 7.81e7.87 (m, 3H); 13C NMR (75 MHz, CDCl3)
d:
20.2, 31.2, 34.4, 55.3, 72.4 (ꢃ2), 74.0, 74.2, 75.2, 76.3, 76.9, 80.3, 85.9,
113.5, 124.5, 125.8, 126.0, 126.2, 126.6, 127.0, 127.6, 127.7, 127.9,
128.0, 128.2, 128.5, 129.0, 129.1, 129.6, 129.9, 130.4, 132.9, 133.0,
133.3, 134.6, 135.5, 135.9, 137.8, 149.9, 159.3, 199.3. ESIHRMS
C50H52O7S2 calcd for [MþNa]þ: 851.3052, found 851.3097; and 19
4.1.14. (2-Methyl-5-tert-butylphenyl) 6-S-acetyl-2,7-di-O-benzyl-4-
O-(p-methoxybenzyl)-3-O-(2-naphtalenylmethyl)-D-glycero-1,6-
(2.18 g, 81%) as a clear viscous oil: ½a D25
ꢂ
þ52.9 (c 1.0, CHCl3); 1H NMR
dithio-
a
-D
-mannoheptopyranoside (23). To a cooled (ꢀ78 ꢁC) solu-
(500 MHz, CDCl3)
d
: 1.28 (s, 9H), 2.21 (s, 3H), 2.95 (d, J¼9.0 Hz, 1H);
tion of 21 (1.40 g,1.7 mmol) and Comin’s reagent (1.35 g, 3.45 mmol),
in dry THF (17 mL), was slowly added a solution of NaHMDS (1 M in
THF, 3.5 mL, 3.45 mmol). The reaction mixture was stirred at ꢀ78 ꢁC
until TLC showed completed reaction (w2 h) and then AcSH (1.2 mL,
17 mmol) was added followed by the addition of a solution of AcSK
(1.94 g, 17 mmol) in dry DMF (17 mL). The reaction mixture was
stirred overnight at room temperature, quenched with saturated
aqueous NaHCO3, and then extracted with t-BuOMe. The combined
organic layer was washed with water, brine, dried (MgSO4), and then
concentrated under reduced pressure (water bath at room temper-
ature). The crude was purified on silica gel (10%e20% t-BuOMe in
3.34 (s, 3H), 3.78 (s, 3H), 4.00 (dd, J¼7.5, 1.0 Hz, 1H), 4.02e4.03 (m,
1H), 4.26e4.32 (m, 2H), 4.53 (d, J¼9.0 Hz, 1H), 4.64e4.82 (m, 5H),
4.95 (d, J¼10.0 Hz, 1H), 5.59 (s, 1H), 6.82 (d, J¼8.5 Hz, 2H), 7.05 (d,
J¼7.5 Hz, 1H), 7.13 (d, J¼7.5 Hz, 1H), 7.22e7.30 (m, 7H), 7.34e7.37
(m, 2H), 7.46e7.49 (m, 3H), 7.75e7.78 (m, 1H), 7.81e7.86 (m, 3H);
13C NMR (75 MHz, CDCl3)
d: 19.9, 31.3, 34.5, 52.0, 55.2, 69.4, 72.3,
72.4, 74.1, 74.2, 75.2, 76.8, 80.3, 84.7, 113.8, 123.9, 125.6, 125.8, 125.9,
126.1,126.5,127.7,127.8,127.9,128.1,128.4,129.6,129.8,130.6,133.0,
133.1, 133.3, 134.7, 135.6, 137.8, 149.9, 159.2, 172.8. ESIHRMS
C45H50O8S calcd for [MþNa]þ: 773.3124, found 773.3153.
heptane) to give 23 (1.12 g, 76%) as a yellow viscous oil: ½a D25
þ71.0 (c
ꢂ
4.1.12. (2-Methyl-5-tert-butylphenyl)
ybenzyl)-3-O-(2-naphtalenyl-methyl)-
2-O-benzyl-4-O-(p-methox-
-glycero-1-thia- -man-
1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.33 (s, 9H), 2.25 (s, 3H), 2.27
L
a
-
D
(s, 3H), 3.52 (dd, J¼10.5 H, J¼6.5 Hz,1H), 3.76 (s, 3H), 3.85 (dd, J¼8.0,
2.5 Hz, 1H), 3.55 (dd, J¼10.0, 7.5 Hz, 1H), 3.99e4.02 (m, 1H),
4.26e4.33 (m, 2H), 4.45e4.54 (m, 3H), 4.64e4.85 (m, 6H), 5.43 (s,
1H), 6.84 (d, J¼8.5 Hz, 2H), 7.09 (d, J¼8.0 Hz,1H), 7.18e7.36 (m,13H),
7.45e7.49 (m, 3H), 7.56 (s,1H), 7.75e7.79 (m,1H), 7.80e7.86 (m, 3H);
noheptopyranoside (20). To a cooled (ꢀ78 ꢁC) solution of 19 (2.1 g,
2.8 mmol), in dry THF (30 mL), was added LiAlH4 (213 mg,
5.6 mmol). The reaction mixture was stirred 10 min at ꢀ78 ꢁC,
warmed to room temperature, and stirred 4 h at room temperature.
The reaction mixture was quenched with a Rochelle’s salt solution,
stirred 4 h at room temperature, and then extracted with EtOAc.
The combined organic layer was washed with brine, dried (MgSO4),
and concentrated under reduced pressure. The crude was purified
on silica gel (40% EtOAc in heptane) to give 20 (1.82 g, 90%) as
13C NMR (75 MHz, CDCl3)
d: 20.3, 30.6, 31.4, 34.6, 43.6, 55.3, 69.7,
72.0, 72.3, 73.0, 74.5, 75.3, 75.6, 77.2, 80.7, 86.0, 113.8, 124.6, 125.9,
126.1, 126.6, 127.4, 127.6, 127.7, 128.0, 128.1, 128.3, 128.4, 129.2, 129.8,
129.9, 130.8,133.0, 133.3,133.7, 135.7, 136.0, 138.1, 149.8,159.2,194.4.
ESIHRMS C53H58O7S2 calcd for [MþNa]þ: 893.3522, found 893.3546.
a clear viscous oil: ½a D24
ꢂ
þ58.6 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
: 1.29 (s, 9H), 1.76 (dd, J¼10.0, 6.0 Hz, 1H), 2.26 (s, 3H), 2.32
4.1.15. (2-Methyl-5-tert-butylphenyl) 6-S-acetyl-2,7-di-O-benzyl-3-
(d, J¼9.5 Hz,1H), 3.50e3.61 (m, 3H), 3.78 (s, 3H), 3.95e4.04 (m, 4H),
4.24 (d, J¼9.5 Hz, 1H); 4.68 (d, J¼10.5 Hz, 1H), 4.71 (d, J¼12.5 Hz,
1H), 4.74 (d, J¼12.5 Hz, 1H), 4.79 (d, J¼12.0 Hz, 1H), 4.83 (d,
O-(2-naphtalenylmethyl)-D-glycero-1,6-dithio-a-D-mannoheptopyr-
anoside (25). To a chilled (ꢀ35 ꢁC) solution of 23 (1.10 g,1.26 mmol),
in CH2Cl2 (25 mL), was slowly added a mixture of TFA/H2O (9:1,

S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
5509
2.5 mL). The reaction mixture was stirred 2 h at ꢀ35 ꢁC and 1 h at
ꢀ25 ꢁC. The reaction mixture was quenched with saturated aqueous
NaHCO3 and then extracted with CH2Cl2. The combined organic
layer was washed with brine, dried (MgSO4), and then concentrated
under reduced pressure (water bath at room temperature). The
crude was purified on silica gel (20% EtOAc in heptane) to give 25
with brine, dried (MgSO4), and concentrated under reduced pres-
sure. The crude was purified on silica gel (20% EtOAc in heptane) to
give 14 (204.1 mg, 82%). To a solution of 14 in dry CH2Cl2 (4 mL),
DMAP (4.5 mg, 36.5
mmol), i-Pr2NEt (127 mL, 0.73 mmol), and Ac2O
(70 L, 0.73 mmol) were added. The reaction mixture was stirred
m
4 h at room temperature, quenched with saturated aqueous
NaHCO3, and then extracted with CH2Cl2. The combined organic
layer was washed with brine, dried (MgSO4), and then concentrated
under reduced pressure. The crude was purified on silica gel (10%
EtOAc in heptane) to give 28 (210 mg, 97%) as a clear viscous oil:
(822 mg, 87%) as a clear viscous oil: ½a D26
ꢂ
þ62.0 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3) d: 1.33 (s, 9H), 2.26 (s, 3H), 2.27 (s, 3H), 2.81
(d, J¼3.5 Hz,1H), 3.54 (dd, J¼10.0, 5.0 Hz,1H), 3.73 (dd, J¼9.0, 3.0 Hz,
1H), 3.94 (dd, J¼10.5, 8.0 Hz, 1H), 4.02e4.04 (m, 1H), 4.30 (dd,
J¼10.0, 2.5 Hz, 1H), 4.34e4.40 (m, 2H), 4.57 (s, 2H), 4.59 (d,
J¼12.5 Hz, 1H), 4.67 (d, J¼12.5 Hz, 1H), 4.76 (d, J¼12.0 Hz, 1H), 4.79
(d, J¼12.0 Hz, 1H), 5.46 (d, J¼1.0 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 7.20
(dd, J¼8.0, 2.0 Hz, 1H), 7.23e7.34 (m, 10H), 7.44e7.49 (m, 3H), 7.56
½
a 2D6
ꢂ
þ132.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.29 (s, 9H),
2.00 (s, 3H), 2.28 (s, 3H), 3.43 (dd, J¼9.5, 7.5 Hz, 1H), 3.75 (dd,
J¼10.5 H, J¼3.5 Hz, 1H), 4.03e4.11 (m, 1H), 4.10e4.14 (m, 1H), 4.25
(dd, J¼12.0 Hz, 1H), 4.29 (dd, J¼12.0 Hz, 1H), 4.39 (t, J¼10.0 Hz, 1H),
4.59e4.65 (m, 2H), 4.72 (d, J¼12.5 Hz, 1H), 5.47 (dd, J¼10.0, 3.0 Hz,
1H), 5.57 (s, 1H), 7.08 (d, J¼8.0 Hz, 1H), 7.11e7.14 (m, 2H), 7.19 (dd,
J¼8.0, 1.5 Hz, 1H), 7.23e7.35 (m, 8H), 7.40e7.43 (m, 4H), 7.64e7.67
(d, J¼2.0 Hz, 1H), 7.79e7.85 (m, 4H); 13C NMR (75 MHz, CDCl3)
d:
20.2, 30.5, 31.4, 34.6, 43.9, 68.4, 69.3, 72.0, 72.4, 73.0, 75.2, 76.8, 79.6,
86.1, 124.5, 125.7, 125.9, 126.1, 126.6, 127.5, 127.6, 127.9, 128.2, 128.3,
128.8,129.8,133.0,133.2,133.5,135.4,135.8,137.8,137.9,149.8,194.6.
ESIHRMS C45H50O6S2 calcd for [MþNa]þ: 773.2947, found 773.2972.
(m, 2H); 13C NMR (75 MHz, CDCl3)
d: 20.0, 20.9, 31.4, 34.5, 45.5,
67.5, 69.0, 69.9, 73.0, 73.1, 74.8, 77.2, 79.0, 84.6, 116.1, 124.5, 125.4,
126.9, 127.3, 127.6, 128.2, 128.3, 128.5, 128.8, 130.0, 130.2, 132.3,
135.1, 135.6, 137.1, 137.4, 149.8, 170.2. ESIHRMS C42H45NO6S2 calcd
for [MþNa]þ: 746.2586, found 746.2582.
4.1.16. (2-Methyl-5-tert-butylphenyl) 2,7-di-O-benzyl-4-O,6-S-(1-
cyano)benzylidene-3-O-(2-naphtalenyl-methyl)-D-glycero-1,6-dithio-
a
-
D
-mannoheptopyranoside (27). To a cooled (ꢀ78 ꢁC) solution of
25 (200 mg, 0.26 mmol), in dry THF (2.6 mL), was slowly added
4.1.18. 5-tert-Butyloxycarbonylpentyl 3-O-acetyl-2,7-di-O-benzyl-4-
a solution of LiAlH4 (2 M in THF, 130
m
L, 0.26 mmol). The reaction
O,6-S-(1-cyano)benzylidene-D-glycero-1-thia-a-D-mannoheptopyr-
mixture was stirred 30 min at ꢀ78 ꢁC, warmed to room tempera-
ture, and stirred 1 h at room temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl and then extracted with t-
BuOMe. The combined organic layer was washed with brine, dried
(Na2SO4), and then concentrated under reduced pressure (water
bath at room temperature). The residue was dissolved in dry CH2Cl2
anoside (29). To a cooled (ꢀ78ꢁC)solution of28(140 mg, 0.19 mmol),
TTBP(125mg, 0.5 mmol), andPh2SO (47 mg, 0.23 mmol) indryCH2Cl2
(4.0 mL), was added Tf2O (freshly distilled over P2O5, 39
mL,
0.23 mmol). The orange mixture was stirred 1 h at ꢀ78 ꢁC and a so-
lution of tert-butyl 6-hydroxyhexanoate (57 mg, 0.3 mmol) in dry
CH2Cl2 (1.0 mL) was added. The reaction mixture was stirred 1 h at
ꢀ78 ꢁC, warmed to room temperature, and stirred 1 h at room tem-
perature. The reaction mixture was quenched with saturated aqueous
NaHCO3, and then extracted with CH2Cl2. The combined organic layer
was washed with brine, dried (MgSO4), and concentrated under re-
duced pressure. The crude was purified on silica gel (10% EtOAc in
(1 mL) and CSA (6 mg, 0.026 mmol) and PhC(OMe)3 (160
mL,
1.3 mmol) were added. The reaction mixture was stirred overnight
at room temperature, quenched with aqueous saturated NaHCO3,
and then extracted with CH2Cl2. The combined organic layer was
washed with brine, dried (Na2SO4), and then concentrated under
reduced pressure (water bath at room temperature) and dried
under strong vacuum. The residue was dissolved in dry CH2Cl2
heptane) to give 29 (140 mg, 96%) as a clear viscous oil: ½a D26
þ61.8 (c
ꢂ
1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 1.22e1.28 (m, 2H), 1.44 (s,
(3 mL), cooled at 0 ꢁC, and then TMSCN (326
added followed by the addition of BF3eEt2O (27
mL, 2.6 mmol) was
9H), 1.46e1.52 (m, 4H), 2.00 (s, 3H), 2.16 (t, J¼7.0 Hz, 2H), 3.29 (dt,
J¼9.0, 6.5 Hz, 1H), 3.60 (dt, J¼9.0, 6.5 Hz, 1H), 3.76 (dd, J¼10.0 H,
J¼3.0 Hz,1H), 3.82e3.87 (m, 2H), 3.94e3.98(m,1H), 4.04 (t, J¼10.0 Hz,
1H), 4.47e4.55 (m, 3H), 4.65 (d, J¼12.5 Hz, 1H), 4.68 (d, J¼12.5 Hz,1H),
4.76 (d, J¼1.0 Hz,1H), 5.41 (dd, J¼10.0, 3.0 Hz,1H), 7.24e7.36 (m,10H),
mL, 0.26 mmol). The
reaction mixture was stirred 2 h at 0 ꢁC, warmed to room tem-
perature and stirred 2 h at room temperature. The reaction mixture
was quenched with saturated aqueous NaHCO3 and then extracted
with CH2Cl2. The combined organic layer was washed with brine,
dried (MgSO4), and then concentrated under reduced pressure. The
crude was purified on silica gel (10% t-BuOMe in heptane) to give 4
7.39e7.44 (m, 3H), 7.63e7.66 (m, 2H); 13C NMR (75 MHz, CDCl3)
d:
21.0, 24.8, 25.5, 28.1, 28.9, 35.4, 45.8, 66.8, 67.2, 67.7, 70.1, 73.3, 73.6,
75.2, 76.2, 78.9, 80.0, 98.4 (1JCH¼168.5 Hz), 116.2, 125.3, 127.4, 127.7,
127.9, 128.0, 128.3, 128.4, 128.7, 129.9, 135.3, 137.4, 137.5, 170.1, 173.0.
ESIHRMS C41H59NO9S calcd for [MþNa]þ: 754.3026, found 754.3012.
(160 mg, 74%) as a clear viscous oil: ½a D26
ꢂ
þ113.5 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3)
d
: 1.28 (s, 9H), 2.19 (s, 3H), 3.46 (dd, J¼10.0,
7.5 Hz, 1H), 3.76 (dd, J¼10.0 H, J¼3.5 Hz, 1H), 4.03e4.11 (m, 3H),
4.23e4.32 (m, 3H), 4.71e4.84 (m, 5H), 5.54 (s, 1H), 7.05 (d, J¼8.0 Hz,
1H), 7.10e7.13 (m, 2H), 7.16 (dd, J¼8.0, 2.0 Hz, 1H), 7.20e7.32 (m,
6H), 7.35e7.47 (m, 6H), 7.35e7.47 (m, 9H), 7.68e7.74 (m, 5H),
4.1.19. General
b-glycosylation procedure. Into a Schlenk flask, to
a chilled (ꢀ50 ꢁC) solution of 27 (1.0 equiv), TTBP (5 equiv), and BSP
(1.1 equiv) in dry CH2Cl2 (0.5 M), was added Tf2O (freshly distilled
over P2O5, 1.2 equiv). The orange mixture was stirred 1 h at ꢀ50 ꢁC
and a solution of alcohol (1.5 equiv) in dry CH2Cl2 was added. The
reaction mixture was stirred 8 h at ꢀ50 ꢁC, quenched with satu-
rated aqueous NaHCO3, and then extracted with CH2Cl2. The com-
bined organic layer was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The crude product was pu-
rified on silica gel (eluent: EtOAc/heptane).
7.79e7.82 (m,1H); 13C NMR (75 MHz, CDCl3)
d: 20.2, 31.4, 34.5, 45.5,
67.7, 69.3, 73.0, 73.2, 73.3, 76.5, 77.3, 77.5, 79.2, 85.5, 116.1, 124.4,
125.6, 125.8, 125.9, 126.0, 126.5, 126.9, 127.3, 127.5, 127.6, 127.9,
128.1, 128.2, 128.3, 128.5, 128.7, 130.0, 130.1, 132.6, 133.0, 133.2,
135.4, 135.5, 137.5, 137.6, 149.8. ESIHRMS C51H51NO5S2 calcd for
[MþNa]þ: 844.3106, found 844.3110.
4.1.17. (2-Methyl-5-tert-butylphenyl) 3-O-acetyl-2,7-di-O-benzyl-4-
O,6-S-(1-cyano)benzylidene-
D
-glycero-1,6-dithio-
a
-
D
-man-
4.1.19.1. i-Propyl 2,7-di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-
noheptopyranoside (28). To a solution of 27 (300 mg, 0.365 mmol),
in a mixture of CH2Cl2/H2O (20:1, 4.2 mL), was added DDQ (100 mg,
0.44 mmol). The reaction mixture was stirred overnight at room
temperature, quenched with saturated aqueous NaHCO3, and then
extracted with CH2Cl2. The combined organic layer was washed
3-O-(2-naphtalenylmethyl)-D-glycero-6-thia-b-D-mannoheptopyr-
anoside (32). Prepared by the general procedure with a yield of 90%
as a clear viscous oil: ½a D26
ꢂ
þ12.9 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
: 1.13 (d, J¼6.0 Hz, 1H), 1.23 (d, J¼6.0 Hz, 1H), 3.53 (t,
J¼10.0 Hz, 1H), 3.60 (dd, J¼9.5, 3.0 Hz, 1H), 3.72 (dd, J¼10.0, 3.0 Hz,

5510
S. Picard, D. Crich / Tetrahedron 69 (2013) 5501e5510
1H), 3.80e3.86 (m, 2H), 3.92 (dd, J¼10.0, 5.0 Hz, 1H), 4.02e4.06 (m,
1H), 4.43 (s, 1H), 4.45 (d, J¼12.5 Hz, 1H), 4.50 (d, J¼12.5 Hz, 1H),
4.60e4.68 (m, 3H), 4.92 (d, J¼12.5 Hz, 1H), 5.01 (d, J¼12.5 Hz, 1H),
7.23e7.34 (m, 9H), 7.40e7.51 (m, 7H), 7.62 (s, 1H), 7.66e7.72 (m, 4H),
charge. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.04.094.
References and notes
7.79e7.82 (m,1H); 13C NMR (125 MHz, CDCl3)
d: 21.7, 23.4, 45.5, 67.2,
70.4, 71.8, 72.2, 73.4, 74.4, 75.4, 77.2, 77.9, 79.5, 99.8 (1JCH¼154.7 Hz),
116.0, 125.6, 125.8, 125.9, 126.0, 126.4, 127.5, 127.7, 127.8, 127.9, 128.0,
128.1, 128.4, 128.7, 128.8, 130.1, 133.0, 133.1, 135.5, 135.6, 137.5, 138.4.
ESIHRMS C43H43NO6S calcd for [MþNa]þ: 724.2709, found 724.2689.
1. (a) Crich, D.; Banerjee, A. Org. Lett. 2005, 7, 1395e1398; (b) Crich, D.; Banerjee,
A. J. Am. Chem. Soc. 2006, 128, 8078e8086; (c) Crich, D.; Li, M. J. Org. Chem. 2008,
73, 7003e7010.
2. For a review: Picard, S.; Crich, D. Chimia 2011, 65, 59e64.
3. Crich, D. Acc. Chem. Res. 2010, 43, 1144e1153.
4. Guinchard, X.; Picard, S.; Crich, D. In Modern Chemoselective Tools for the Syn-
thesis of Complex Bioactive Molecules; John Wiley & Sons: New Jersey, NJ, 2012;
pp 395e432.
4.1.19.2. Methyl 2,7-di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-
3-O-(2-naphtalenylmethyl)-
D
-glycero-6-thia-
b-D-mannoheptopyr-
5. Crich, D.; Li, L. J. Org. Chem. 2009, 74, 773e781.
€
ꢀ
6. (a) Oscarson, S. Carbohydr. Polym. 2001, 44, 305e311; (b) Gyorgydeak, Z.;
anoside-(1/4)-2,3-isopropylidene-
a-L
-rhamnopyranoside
ꢀ
Pelyvas, I. F. Monosaccharide Sugars-Chemical Synthesis by Chain Elongation,
(33). Prepared by the general procedure with a yield of 78% as
Degradation and Epimerization; Academic: San Diego, CA, 1998; (c) Brima-
combe, J. S.; Kabir, A. B. K. M. S. Carbohydr. Res. 1986, 152, 329e334 and ref-
erences therein; (d) Boons, G. J. P. H.; van der Marel, G. A.; van Boom, J. H.
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481e492; (o) Segerstedt, E.; Manerstedt, K.; Johansson, M.; Oscarson, S. J.
a clear viscous oil: ½a D24
ꢂ
ꢀ11.2 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
: 1.28 (s, 3H), 1.32 (d, J¼6.0 Hz, 3H), 1.35 (s, 3H), 3.41 (s, 3H),
3.44e3.51 (m, 2H), 3.61e3.65 (m, 2H), 3.76 (dd, J¼10.0, 6.5 Hz, 1H),
3.84 (dd, J¼10.0, 3.0 Hz, 1H), 3.98 (d, J¼2.5 Hz, 1H), 4.06e4.11 (m,
3H), 4.49 (m, 2H), 4.58 (t, J¼9.5 Hz, 1H), 4.63 (d, J¼12.5 Hz, 1H), 4.68
(d, J¼12.5 Hz, 1H), 4.83e4.86 (m, 3H), 4.91 (d, J¼12.0 Hz, 1H),
7.23e7.35 (m, 9H), 7.39e7.47 (m, 7H), 7.65e7.72 (m, 5H), 7.79e7.82
(m,1H); 13C NMR (75 MHz, CDCl3)
d: 17.8, 26.2, 28.0, 45.7, 54.9, 64.0,
67.4, 71.1, 72.0, 73.3, 74.6, 75.5, 76.0, 77.2, 77.8, 78.4, 79.5, 97.9
(1JCH¼167.6 Hz), 100.4 (1JCH¼157.7 Hz), 109.3, 116.1, 125.6, 125.7,
125.8, 126.0, 126.3, 127.5, 127.6, 127.8, 127.9,128.1, 128.4,128.7, 130.1,
132.9, 133.1, 135.4, 135.5, 137.3, 138.4. ESIHRMS C50H53NO10S calcd
for [MþNH4]þ: 877.3734, found 877.3740.
ꢂ
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4.1.19.3. Methyl 2,7-di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-
3-O-(2-naphtalenylmethyl)-
D
-glycero-6-thia-
b
-
D
-mannoheptopyr-
anoside-(1/6)-2,3,4-tri-O-benzoyl-
a-D -glucopyranoside
9. Crich, D.; Picard, S. J. Org. Chem. 2009, 74, 9576e9579.
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Collot, M.; Savreux, J.; Mallet, J.-M. Tetrahedron 2008, 64, 1523e1535.
11. See Supplementary data for details of synthesis.
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Perkin Trans. 1 1998, 3907e3911.
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Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Dekker: New York, NY,
1997; pp 69e86.
(34). Prepared by the general procedure with a yield of 87% as
a clear viscous oil: ½a D26
ꢂ
þ31.9 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) d: 3.47 (s, 3H), 3.50e3.55 (m, 2H), 3.59e3.64 (m, 2H), 3.78
(dd, J¼10.0, 5.5 Hz, 1H), 3.96e4.01 (m, 1H), 4.04e4.11 (m, 2H), 4.36
(d, J¼12.0 Hz, 1H), 4.40 (s, 1H), 4.62 (t, J¼9.5 Hz, 1H), 4.64 (d,
J¼12.5 Hz, 1H), 4.68 (d, J¼12.5 Hz, 1H), 4.98 (d, J¼12.5 Hz, 1H), 5.06
(d, J¼12.5 Hz,1H), 5.24e5.30 (m, 2H), 5.49 (t, J¼10.0 Hz,1H), 6.20 (t,
J¼9.5 Hz, 1H), 7.20e7.56 (m, 25H), 7.65e7.74 (m, 5H), 7.81e7.85 (m,
1H), 7.89 (d, J¼7.5 Hz, 2H), 7.93 (d, J¼7.5 Hz, 2H), 8.01 (d, J¼7.0 Hz,
2H); 13C NMR (125 MHz, CDCl3)
d: 45.5, 55.5, 67.0, 68.3, 68.7, 69.5,
15. Ishii, K.; Esumi, Y.; Iwasaki, Y.; Yamasaki, R. Eur. J. Org. Chem. 2004, 1214e1227.
16. Crich, D.; Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126, 15081e15086.
70.4, 70.5, 72.1, 72.2, 73.2, 74.8, 75.0, 76.8, 77.6, 79.5, 96.9
(1JCH¼171.9 Hz), 101.9 (1JCH¼156.1 Hz), 115.9, 125.6, 125.8, 125.9,
126.0, 126.5, 127.7, 127.9, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6,
128.7,128.1,129.3,129.7,129.8,129.9,130.1,133.0,133.1,133.4,133.6,
135.4, 137.6, 138.2, 165.4, 165.7, 165.8. ESIHRMS C68H61NO14S calcd
for [MþNH4]þ: 1165.4157, found 1165.4111.
ꢀ
17. Gavard, O.; Hersant, Y.; Alais, J.; Duverger, V.; Dilhas, A.; Bascou, A.; Bonnafe, D.
Eur. J. Org. Chem. 2003, 3603e3620.
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ꢀꢁ
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metry 2005, 16, 553e567.
ꢀ
20. Codee, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft, H. S.; van Boeckel,
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Supplementary data
Preparation and characterization of 2, 7-(
and 13C NMR spectra of all new compounds are available free of
L,D
), 15, 16, 22, 24, 1H
23. Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015e9020.