Synthesis of the C-glycoside of α-d-mannose-(1 → 6)-d-myo-inositol

Article abstract of DOI:10.1039/c3ob41337c

The dimannosylatedinositol pseudotrisaccharide phospholipid of the lipoarabinomannan (LAM) component of the mycobacterial cell wall has attracted interest as a therapeutic target because of its uniqueness to mycobacteria, its assembly at an early stage in LAM biosynthesis and the immunological activity of oligosaccharides containing this subunit. Accordingly, analogues of this pseudotrisaccharide, α-d-mannose-(1 → 2)-α-d-mannose-(1 → 6)-d-myo-inositol are of interest as mechanistic probes and drug leads. C-glycosides are of special interest because of their hydrolytic stability and conformational differences compared to O-glycosides. Herein, as a prelude to C-glycoside analogues of this pseudotrisaccharide, we describe the synthesis of the C-glycoside of α-d-mannose-(1 → 6)-d-myo-inositol. The synthetic strategy centers on the elaboration of a C1-linked glycal-inositol, the glycone segment of which is assembled via an oxocarbenium ion cyclization on a thioacetal-enol ether precursor that originates from glycone and aglycone components.

Full text of DOI:10.1039/c3ob41337c

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Synthesis of the C-glycoside of α-D-mannose-
(1 → 6)-D-myo-inositol†
Cite this: Org. Biomol. Chem., 2013, 11,
6952
Sunej Hans, Ahmad Altiti and David R. Mootoo*
The dimannosylatedinositol pseudotrisaccharide phospholipid of the lipoarabinomannan (LAM) com-
ponent of the mycobacterial cell wall has attracted interest as a therapeutic target because of its unique-
ness to mycobacteria, its assembly at an early stage in LAM biosynthesis and the immunological activity
of oligosaccharides containing this subunit. Accordingly, analogues of this pseudotrisaccharide, α-D-
mannose-(1 → 2)-α-D-mannose-(1 → 6)-D-myo-inositol are of interest as mechanistic probes and drug
leads. C-glycosides are of special interest because of their hydrolytic stability and conformational differ-
ences compared to O-glycosides. Herein, as a prelude to C-glycoside analogues of this pseudotrisaccha-
ride, we describe the synthesis of the C-glycoside of α-D-mannose-(1 → 6)-D-myo-inositol. The synthetic
strategy centers on the elaboration of a C1-linked glycal-inositol, the glycone segment of which is
assembled via an oxocarbenium ion cyclization on a thioacetal-enol ether precursor that originates from
“glycone” and “aglycone” components.
Received 29th June 2013,
Accepted 23rd August 2013
DOI: 10.1039/c3ob41337c
www.rsc.org/obc
isolated, and this presents and opportunity for rational drug
Introduction
design.9 C-glycoside analogues such as 3 that may act as hydro-
The resurgence of mycobacterial infections (M. tuberculosis lytically stable, bi-substrate mimetics of the transition state
and AIDS-associated M. avium) has been associated with leading to 2, are of interest as pharmaceutical leads and for
increasing populations of immunocompromised and home- enzyme studies.10–12 Small PIM fragments have also shown
less individuals.1,2 Of particular concern is the emergence of interesting immunomodulatory activities and their C-glyco-
M. tuberculosis strains that are resistant to many of the drugs sides may also find applications as probes of the underlying
that are used to treat tuberculosis.3 Consequently the develop- mechanisms.13–16 However, while the synthesis of O-glycoside
ment of new antimycobacterial agents is an active area of analogues is well documented, studies on C-glycosides thereof,
research.4,5 The mycobacterial cell wall contains numerous
components that are believed to be necessary for survival in
the host and is the site of action of established antimyco-
bacterial agents.6 The LAM subunit is composed of an outermost
arabinomannan segment linked to a phosphotidylinositol
mannoside (PIM) region. In addition to maintaining the struc-
tural integrity of the cell wall LAM has been implicated in the
suppression of immune responses thereby contributing to
pathogenesis and many of the clinical manifestations of tuber-
culosis.7 Accordingly, inhibition of the biosynthesis of LAM is
a potential therapeutic strategy and the pseudotrisaccharide
PIM2 2 an early stage intermediate is an attractive target
because it is unique to mycobacteria (Fig. 1).8 An α-mannose
transferase that catalyzes the synthesis of 2 from GDP-
mannose and the pseudodisaccharide 1 has recently been
Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10065,
USA. E-mail: dmootoo@hunter.cuny.edu; Fax: +1 212 772 5332;
Tel: +1 212 772 4356
†Electronic supplementary information (ESI) available: Copies of 1H, 13C and 2D
NMR spectra for 4 and 12–25. See DOI: 10.1039/c3ob41337c
Fig. 1 Biosynthesis and C-glycoside analogues of PIM2.
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are not.17–20 Herein, en route to structures like 3, we describe
the synthesis of 4, the C-glycoside of the core pseudodisaccha-
ride, α-D-mannose-(1 → 6)-D-myo-inositol.
Results and discussion
Our first approach to 4 followed the Beau α-C-manno-glycosida-
tion protocol of coupling the mannosyl sulfone 5 and 6-C-
formyl-myo-inositols like 6 (Scheme 1).21 Unfortunately this
approach was not successful, possibly because of the highly
hindered nature of the aldehyde partner. We therefore adopted
a C-glycosidation strategy that is based on de novo synthesis of
the glycone segment, and which we have used for
C-disaccharides.22–25 Thus, we envisaged that 4 could be fabri-
cated by elaboration of a C-linked glycal-inositol 8, which is
available via an oxocarbenium ion cyclization on thioacetal-
enol ether 7.
The synthesis of the requisite C-linked glycal-inositol 17
started from the known 1-phenylthio-1,2-O-isopropylidene
alcohol 1423 and the 6-C-branched myo-inositol acid 13
(Scheme 2). The latter was prepared from the known D-myo-ino-
sitol derivative 1026 using the Keck C-radical allylation methodo-
logy.27 Thus, alcohol 10 was converted to the thiocarbonate 11
and treatment of 11 with allyltributyltin in the presence of
AIBN gave the C-allyl derivative 12. Removal of ester and ketal
protecting groups in 12 provided the pentaol derivative,
which was protected as the penta-O-benzyl ether. Standard oxi-
dative processing of the alkene in the latter gave acid 13. With
acid 13 and alcohol 14 in hand DCC mediated esterification
was next attempted. However, 15 was obtained in low yield.
The Yamaguchi protocol was more successful, providing 15 in
86% yield.28 Reaction of 15 with the Tebbe reagent yielded 16
in 77% yield. The oxocarbenium ion cyclization on 16 was pro-
moted by methyl triflate to give 17 in 78% yield.
Scheme 2 Synthesis of C-linked glycal-inositol.
on 17 (Scheme 3). This led to a 3 : 1 mixture of 18 : 19, which was
more easily separated as the respective benzoates 20 and 21.
1H NMR analysis suggested that 20 was the α-C-altro-isomer in
6′
predominantly the
C
3′
conformation ( J4′,5′ = J5′,6′ = 6.9 Hz),
3′
and 21 was the β-C-allo-favoring the
C ( J4′,5′ = 3.9 Hz; J5′,6′ =
6′
Elaboration of C-glycal 17 to the desired α-C-mannoside
motif started with a hydroboration–borane oxidation sequence
6.9 Hz).29,30 We envisaged that the desired α-C-manno motif
could be obtained through configurational inversion at the C4′
position in 20 and towards this end 20 was next transformed
to alcohol 23. Thus, acetonide cleavage in 20 provided diol 22,
which was converted via the derived orthoacetate to
a
2 : 1 mixture of 23 and its regioisomer 24.31 As for the precur-
6′
sor 20, the desired isomer 23 was also found to favor the
C
3′
conformation ( J2′,3′ = J3′,4′ = 3.8 Hz; J4′,5′ = J5′,6′ = 7.5 Hz). Reac-
tion of 23 with trifluoromethanesulfonic anhydride and dry
dichloromethane at −20 to 10 °C afforded the triflate deriva-
tive. The crude product was treated with potassium nitrite in
DMF at 50 °C to give the desired alcohol 25 in 80% yield
over two steps.32 The manno configuration and the 3′C6′ confor-
mation of 25 was supported by J values ( J2′,3′ = J3′,4′ = 9.6 Hz;
J4′,5′ = J5′,6′ = 0 Hz) and H-2′/H-4′ and H-4′/H-7′ nOe’s. Straight-
forward removal of alcohol protecting groups in 25 provided
the target α-C-manno-pyranosyl-myo-inositol 4. By starting
with a myo-inositol precursor with orthogonal protecting
groups on the C1 and C2 alcohols, this synthesis can be
easily adapted to produce C-disaccharide derivatives of 25,
Scheme 1 Strategies for α-C-manno-pseudodisaccharides.
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Scheme 3 Transformation of C-linked glycal to α-C-mannos.
that are primed for incorporation into pseudo-trisaccharide were recorded using a Rudolph Autopol III or Jasco P-1020
mimetics of 3.
polarimeters with 10 or 5 cm cells (path lengths of 1 or
0.5 dm) respectively, and are given in units of 10−1 deg cm2 g
at 589 nm (sodium D-line). Infra-red spectra were obtained
using a Thermo Scientific Nicolet IS5 spectrometer as thin
film liquid samples between sodium chloride plates. Only
selected absorbances (νmax) are reported. NMR spectra were
recorded using either Varian Unity Plus 500, Bruker Ultra
Shield and Bruker Ultra Shield Plus instruments. Unless other-
wise noted, 1H and 13C spectra were recorded at 500 and
125 MHz respectively in CDCl3 or C6D6 solutions with residual
CHCl3 or C6H6 as internal standard (δH 7.27, 7.16 and δC 77.2,
128.4 ppm). Chemical shifts are quoted in ppm relative to tetra-
methylsilane (δH 0.00) and coupling constants ( J) are given
in hertz. First order approximations are employed throughout.
High resolution mass spectrometry was performed on an
Ultima Micromass Q-TOF or Waters Micromass LCT Premier
mass spectrometers.
Conclusions
In summary the C-glycoside of α-D-mannose-(1 → 6)-D-myo-
inositol 4 was prepared via a de novo synthesis of the “glycone”
segment, over ten steps from thioacetal 13 and the C-branched
inositol 14. This synthesis illustrates the feasibility of this strat-
egy for synthetically challenging α-C-mannosides. The method
is currently being applied to higher order saccharide mimetics
of PIM and to stereochemically diverse C-glycoinositols. These
results will be reported in due course.
Experimental
Solvents were purified by standard procedures or used from
commercial sources as appropriate. Petroleum ether refers to
the fraction of petroleum ether boiling between 40 and 60 °C.
Ether refers to diethyl ether. Unless otherwise stated thin layer
6-O-Phenylcarbonothioyl-2,3-O-(D-1′,7′,7′-trimethyl-[2.2.1]-
bicyclohept-2′-ylidene)-1,4,5-tris-O-pivaloyl-D-myo-inositol (11)
chromatography (TLC) was done on 0.25 mm thick precoated Phenyl chlorothionoformate (0.10 mL, 0.77 mmol) was added
silica gel 60 (HF-254, Whatman) aluminium sheets and flash dropwise to suspension of the alcohol 10 (196 mg,
a
column chromatography (FCC) was performed using Kieselgel 0.35 mmol) and DMAP (4 mg, 0.04 mmol), in dry toluene
60 (32–63 mesh, Scientific Adsorbents). Elution for FCC 10 mL at rt. Pyridine (0.14 mL, 1.75 mmol) was then added
usually employed a stepwise solvent polarity gradient, corre- and the resulting suspension was stirred for 2 h at rt. The reac-
lated with TLC mobility. Chromatograms were observed under tion mixture was then washed with 0.1 M HCl and saturated
UV (short and long wavelength) light, and/or were visualized aqueous NaHCO3, and the organic extract dried (Na2SO4) and
by heating plates that were dipped in a solution of ammonium(VI) concentrated in vacuo. FCC of the residue gave 11 (0.20 g,
1
molybdate tetrahydrate (12.5 g) and cerium(IV) sulfate tetra- 83%). Rf = 0.50 (10% ethyl acetate–petroleum ether); H NMR
1
hydrate (5.0 g) in 10% aqueous sulphuric acid (500 mL), or a (CDCl3) δ H NMR (CDCl3) δ 0.88 (s, 3H), 0.98 (s, 3H), 1.09 (s,
solution of 20% sulfuric acid in ethanol. Optical rotations ([α]D 3H), 1.25 (m, 28H), 1.45 (m, 2H), 1.74 (m, 2H), 1.91 (m, 2H),
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4.10 (t, 1H, J = 6.0 Hz, H-2/3), 4.65 (dd, 1H, J = 4.3, 6.4 Hz, (CDCl3) δ 30.3, 41.2, 71.4, 72.7, 73.1, 73.7, 74.5, 75.6, 77.2,
H-2/3), 5.25 (m, 3H, H-1, 4, 5), 6.31 (dd, 1H, J = 7.7, 10.7 Hz, 79.5, 81.5, 83.6, 117.6, 127.0–128.5 (several lines), 135.0, 138.1,
H-6), 7.00 (d, 2H, J = 8.0 Hz), 7.30 (t, 1H, J = 8.0 Hz), 7.42 (t, 138.5, 138.9, 139.2. HRMS (EI) m/z calcd for C44H47O5 (M + H)+
2H, J = 8.0 Hz); 13C NMR (CDCl3) δ 9.93, 20.2 (two signals), 655.3418, found 655.3421.
26.9, 27.0, 27.0, 27.1, 29.3, 38.8, 44.0, 45.1, 48.0, 69.4, 71.8,
A solution of the material from the previous step (1.53 g,
72.1, 72.2, 72.9, 79.0, 118.7, 121.7, 126.6, 129.5, 153.4, 176.5, 2.34 mmol) in 5 : 1 CH2Cl2–MeOH (72 mL) was cooled to
177.0, 177.6, 194.5. HRMS (EI) m/z calcd for C38H54O10NaS −78 °C. A stream of O3 in O2 was bubbled through the solution
(M + Na)+ 725.3334, found 725.3334.
until the starting material was not detectable by TLC. The
mixture was flushed with argon and then triphenylphosphine
(1.22 g, 4.68 mmol) was added. The mixture was warmed to rt,
stirred for 2 h, and concentrated in vacuo. The residue was
6-Deoxy-6-C-(3′-propenyl)-2,3-O-(D-1′,7′,7′-trimethyl-[2.2.1]-
bicyclohept-2′-ylidene)-1,4,5-tris-O-pivaloyl-D-myo-inositol (12)
A solution of 11 (167 mg, 0.24 mmol), allyltributyltin (0.22 mL, purified by FCC to provide the derived aldehyde (1.47 g, 96%):
0.72 mmol), AIBN (7.88 mg, 0.05 mmol) and toluene (3.5 mL) clear oil; Rf = 0.79 (30% ethyl acetate–petroleum ether); 1H
was heated at reflux for 18 h. The mixture was then evaporated NMR (CDCl3) δ 2.40–2.56 (m, 2H), 2.80–3.00 (m, 1H), 3.07 (dd,
under reduced pressure. FCC of the residue afforded 12 1H, J = 2.0, 11.2 Hz), 3.20 (dd, 1H, J = 9.0, 10.7 Hz), 3.37 (dd,
(0.85 g, 61%). Rf = 0.69 (10% ethyl acetate–petroleum ether); IR 1H, J = 2.2, 9.85 Hz), 4.07 (bt, 1H, J = 2.0 Hz), 4.08–4.19 (m,
1
ν 1734 cm−1; H NMR (CDCl3) δ 0.90 (s, 3H), 1.00 (s, 3H), 1.05 2H), 4.30 (d, 1H, J = 11.5 Hz), 4.50 (dd, 2H, J = 2.0, 10.7 Hz),
(s, 3H), 1.22 (s, 18H), 1.22 (m, 1H, buried under singlet), 1.28 4.75 (ABq, Δδ = 0.08, J = 11.8 Hz), 4.82 (d, 2H, J = 10.9 Hz), 8.87
(s, 9H), 1.44 (m, 2H), 1.70 (m, 2H), 1.90 (m, 2H), 2.25 (m, 2H, (d, 1H, J = 11.9 Hz), 8.88 (d, 1H, J = 10.7 Hz), 5.01 (d, 1H, J =
H-6′), 2.57 (m, 1H, H-6), 3.97 (t, 1H, J = 6.2 Hz, H-3), 4.45 (dd, 10.8 Hz), 7.20–7.50 (m, 25H), 9.55 (t, 1H, J = 2.6 Hz); 13C NMR
1H, J = 4.4, 5.3 Hz, H-2), 4.95 (m, 3H, H-1, 5, vCH), 5.08 (m, (CDCl3) δ 38.8, 44.2, 71.6, 72.8, 73.0, 74.0, 74.9, 75.6, 78.4,
2H, H-4, vCH), 5.65 (m, 1H, vCH); 13C NMR (CDCl3) δ 9.6, 81.2, 81.4, 83.3, 127.4, 127.5, 127.7, 127.7, 127.9, 128.0, 128.1,
20.2, 20.3, 26.9, 27.0, 27.1, 27.2, 29.2, 30.6, 38.1, 38.7, 38.8, 128.2, 128.2, 128.4, 128.4, 128.5, 128.5, 137.2, 138.0, 138.2,
38.9, 45.0, 45.1, 48.0, 51.7, 68.7, 69.7, 72.8, 73.7, 74.5, 118.1, 138.8, 138.9, 202.0.
119.0, 132.6, 177.0, 177.0, 177.5. HRMS (EI) m/z calcd for
A solution of aldehyde from the previous step (1.47 g,
2.23 mmol), in THF (22.3 mL) was cooled to 0 °C. Solutions of
2,3-dimethyl-2-butene (1.1 mL, 2 M in THF), aqueous 1 M
sodium biphosphate (2.20 mL, 2.20 mmol), and aqueous 1 M
sodium chlorate (2.20 mL, 2.20 mmol) were then sequentially
C34H54O8Na (M + Na)+ 613.3710, found 613.3712.
6-Deoxy-6-C-(2′-ethanoic acid)-1,2,3,4,5-O-penta-O-benzyl-D-
myo-inositol (13)
Sodium hydroxide (5.5 g, 0.14 mol) was added to the solution added. The reaction mixture was warmed to rt, stirred for 2 h,
of 12 (2.0 g, 3.4 mmol) in dry methanol (30 mL). The reaction then extracted with ethyl acetate. The organic phase was
mixture was heated at reflux for 3 h. Most of the volatiles were washed with brine, dried (Na2SO4), filtered and concentrated
then removed under reduced pressure. The residue was in vacuo. The residue was purified by FCC to give 13 (1.37 g,
1
diluted with water, neutralized with 1 M HCl and extracted 93%); Rf = 0.48 (30% ethyl acetate–petroleum ether); H NMR
with ethyl acetate. The organic phase was dried (Na2SO4) and (CDCl3) δ 2.68 (d, 2H, J = 4.9 Hz), 2.70–2.78 (m, 1H), 3.30–3.34
concentrated in vacuo. An approximately 2 M solution of HCl (dd, 1H, J = 1.9, 11.4 Hz), 3.38 (dd, 1H, J = 2.3, 9.8 Hz), 3.40
in methanol (200 mL) was added to the residue, the mixture (dd, 1H, J = 8.9, 10.9 Hz), 3.70–4.02 (m, 1H), 4.03–4.20 (m, 2H),
stirred for 16 h, then neutralized with methanolic NaOH and 4.37 (d, 1H, J = 11.4 Hz), 4.52 (d, 1H, J = 11.4 Hz), 4.60 (d, 1H,
evaporated in vacuo. The product was taken up in a mixture of J = 11.0 Hz), 4.61 (ABq, Δδ = 0.08, J = 8.3 Hz), 4.75–4.90 (m,
20% MeOH in CHCl3 and filtered through a short column of 3H), 5.00 (t, 2H, J = 10.9 Hz), 7.20–7.49 (m, 25H); 13C NMR
silica gel. The filtrate was evaporated in vacuo. To a solution (CDCl3) δ 23.9, 29.1, 32.0, 39.2, 67.7, 71.6, 72.8, 72.9, 73.8,
of the residue in dry DMF (15 mL) at 0 °C under an argon 75.0, 75.6, 77.8, 80.2, 81.3, 83.4, 108.0, 127.3, 127.5, 127.6,
atmosphere, was added NaH (2.1 g, 60% in mineral oil, 127.7, 127.7, 127.9, 127.9, 127.9, 128.0, 128.2, 128.4, 128.4,
52 mmol) and Bu4NI (0.54 g, 1.5 mmol). After 10 min BnBr 128.4, 128.4, 128.5, 137.6, 138.4, 138.4, 138.8, 139.0. HRMS
(5.7 mL, 48 mmol) was introduced and stirring continued for (ES) m/z calcd for C43H44O7Na (M + Na)+ 695.2985, found
an additional 0.5 h at rt. The reaction mixture was then diluted 695.2963.
with water, and extracted with ether. The organic layer was
washed with water, dried (Na2SO4) and concentrated in vacuo.
Thioacetal ester (15)
The residue was purified by FCC to give the penta-O-benzyl A mixture of acid 13 (0.38 g, 0.56 mmol), 2,4,6-trichlorobenzoyl
derivative (1.5 g, 68%): clear oil; Rf = 0.75 (10% ethyl acetate– chloride (0.09 mL, 0.56 mmol) and triethylamine (0.16 mL,
petroleum ether); IR ν 3433 (br), 1729, 1644 cm−1 1H NMR 1.13 mmol) in THF (30 mL) was stirred for 3.5 h at 0 °C. A
;
(CDCl3) δ 2.60 (m, 3H, H-6, 6′), 3.15 (dd, 1H, J = 1.7, 11.1 Hz, mixture of alcohol 14 (0.29 g, 0.56 mmol) and DMAP (89 mg,
H-1), 3.25–3.40 (m, 2H, H-3/4, 5), 4.10–4.25 (m, 2H, H-2, 3/4), 0.73 mmol) in toluene (15 mL) were added, and stirring con-
4.46 (ABq, 2H, Δδ = 0.02 ppm, J = 11.4 Hz, PhCH2), 4.68 tinued for 1 h. The mixture was then diluted with ether,
(m, 3H, PhCH), 4.85 (m, 3H, PhCH), 5.05 (m, 4H, vCH2, washed with saturated aqueous NaHCO3 and brine, dried
PhCH), 5.74 (m, 1H, vCH), 7.18–7.48 (m, 25H, ArH); 13C NMR (Na2SO4), filtered, and evaporated under reduced pressure.
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The residue was purified by FCC to give ester 15 (0.57 g, 86%): filtered and evaporated in vacuo. FCC of the residue provided
colorless oil; Rf = 0.58 (15% ethyl acetate–petroleum ether); IR 17 (0.35 g, 78%) as a light yellow oil. Rf (basic alumina) = 0.35
ν 1727 cm−1; H NMR (CDCl3) δ 1.02 (s, 9H), 1.37 (s, 3H), 1.44 (10% ethyl acetate–petroleum ether); H NMR (C6D6) δ 1.16 (s,
(s, 3H), 2.68–2.85 (m, 3H), 3.38 (dd, 1H, J = 2.3, 9.9 Hz), 9H, tBu), 1.23 (s, 3H, CH3), 1.32 (s, 3H, CH3), 2.70 (dd, 1H, J =
3.45–3.55 (m, 2H), 3.70–3.83 (m, 2H), 4.03–4.15 (m, 2H), 4.33 5.0, 14.3 Hz, H-7′a), 2.91 (dd, 1H, J = 3.1, J = 14.3 Hz, H-7′b),
(dd, 1H, J = 4.5, 6.7 Hz), 4.40 (d, 1H, J = 11.4 Hz), 4.48 (d, 1H, 2.97 (m, 1H, H-6), 3.39 (dd, 1H, J = 1.7, 12.0 Hz, H-1), 3.42 (dd,
J = 11.4 Hz), 4.52 (d, 1H, J = 10.9 Hz), 4.64 (d, 2H, J = 4.2 Hz), 1H, J = 2.0, 10.4 Hz, H-3), 3.64 (m, 1H, bdd, J = 2.5, 10.0 Hz,
4.75–4.85 (m, 3H), 4.90 (d, 1H, J = 10.8 Hz), 5.01 (d, 1H, J = H-2′), 3.69 (dd, 1H, J = 9.1, 10.0 Hz, H-5), 3.99 (dd, 1H, J = 4.2,
10.9 Hz), 5.23 (q, 1H, J = 5.0 Hz), 5.50 (d, 1H, J = 6.7 Hz), 11.0 Hz, H-1′a), 4.04 (dd, 1H, J = 5.5, 10.0 Hz, H-3′), 4.08 (bd,
7.15–7.73 (m, 40H); 13C NMR (CDCl3) δ 19.1, 26.0, 26.8, 27.3, 1H, J = 11.0 Hz), 4.21 (bt, 1H, J = 1.9 Hz, H-2), 4.24 (t, 1H, J =
31.5, 39.4, 62.1, 62.1, 71.7, 72.6, 72.8, 73.2, 73.7, 75.0, 75.4, 5.5 Hz, H-4′), 4.41 (t, 1H, J = 9.5 Hz, H-4), 4.46 (ABq, 2H, Δδ =
77.6, 79.4, 80.1, 81.3, 83.5, 84.9, 111.5, 127.6, 127.7, 127.7, 0.04 ppm, J = 11.1 Hz, PhCH2), 4.55 (ABq, 2H, Δδ = 0.04 ppm,
127.7, 127.8, 127.9, 127.9, 128.1, 128.3, 128.3, 128.4, 128.4, J = 11.9 Hz, PhCH2), 4.80 (apparent d, 1H, J = 10.9 Hz, PhCH),
128.4, 129.0, 132.0, 135.6, 135.6, 139.1, 172.0. HRMS (EI) m/z 4.92 (ABq, 2H, Δδ = 0.03 ppm, J = 12.1 Hz, PhCH2), 5.05 (m,
1
1
calcd for C72H78O10NaSiS (M
1185.4977.
+
Na)+ 1185.4977, found 3H, H-5′, PhCH2), 5.30 (apparent d, 1H, J = 11.3 Hz, PhCH),
7.00–7.28 (m, 21H, ArH), 7.31 (d, 2H, J = 1.2 Hz, ArH), 7.38 (d,
2H, J = 7.5 Hz, ArH), 7.46 (d, 4H, J = 7.5 Hz, ArH), 7.52 (d, 2H,
Thioacetal enol ether (16)
J = 7.3 Hz, ArH), 7.84 (dt, 4H, J = 1.4, 7.9 Hz, ArH); 13C NMR
To a mixture of ester 15 (1.35 g, 1.16 mmol), and pyridine (C6D6) δ 21.0, 27.2, 28.6, 30.2, 32.8, 42.6, 64.7, 70.7, 71.2, 72.9,
(0.10 mL) in anhydrous 3 : 1 toluene–THF (30 mL), was added, 74.2, 75.4, 76.0, 76.1, 77.2, 78.7, 80.4, 82.3, 83.5, 85.8, 98.9
under an argon atmosphere and at −78 °C, Tebbe reagent (C-5′), 109.5, 128.9–130.0 (several lines buried under C6D6),
(5.71 mL, 0.5 M in THF). The reaction mixture was warmed to 131.4, 135.0, 135.1, 137.4, 137.5, 140.6, 140.7, 141.2, 141.6,
rt, stirred at this temperature for 1 h, then slowly poured into 160.0 (C-6′). HRMS (EI) m/z calcd for C67H75O9Si (M + H)+
1 N aqueous NaOH at 0 °C. The resulting suspension was 1051.5174, found 1051.5159.
extracted with ether and the organic phase was washed with
6-Deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(2′,6′-anhydro-3′,4′-O-
brine, dried (Na2SO4), filtered and concentrated in vacuo. FCC
isopropylidene-1′-O-tert-butyldiphenylsilyl-7′-deoxy-D-glycero-D-
talo-heptitol-7′-C-yl)-D-myo-inositol (18) and 6-deoxy-1,2,3,4,5-
of the residue on basic alumina provided enol ether 16 (0.70 g,
77% based on recovered starting material) as a light yellow oil:
penta-O-benzyl-6-C-(2′,6′-anhydro-3′,4′-O-isopropylidene-1′-O-
Rf (basic alumina) = 0.45 (10% ethyl acetate–petroleum ether);
tert-butyldiphenylsilyl-7′-deoxy-L-glycero-L-allo-heptitol-7′-C-yl)-
1H NMR (C6D6) δ 1.16 (s, 9H), 1.40 (s, 3H), 1.51 (s, 3H),
D-myo-inositol (19)
2.61–3.00 (m, 3H), 3.47 (dd, 1H, J = 2.1, 10.0 Hz), 3.60 (dd, 1H,
J = 1.8, 11.3 Hz), 3.77 (t, 1H, J = 9.1 Hz), 4.06 (dd, 1H, J = 4.8, BH3·Me2S (1.3 mL, 1 M solution, 1.3 mmol) was added at 0 °C
10.8 Hz), 4.10–4.20 (m, 2H), 4.20–4.26 (m, 3H), 4.40 (t, 1H, J = to a solution of 17 (0.35 g, 0.33 mmol) in anhydrous THF
9.5 Hz), 4.45–4.55 (m, 6H), 4.56 (q, 1H, J = 4.6 Hz), 4.61–4.77 (15 mL) under an atmosphere of argon. The mixture was
(m, 2H), 4.80–5.11 (m, 5H), 5.26 (d, 1H, J = 11.4 Hz), 5.53 (s, warmed to rt and stirred for an additional 1 h, then recooled
1H), 5.90 (d, 1H, J = 6.3 Hz), 6.87–7.85 (m, 40H); 13C NMR to 0 °C and treated with a mixture of 3 N NaOH (2.4 mL) and
(C6D6) δ 19.7, 23.1, 26.5, 27.4, 27.5, 28.0, 30.4, 32.2, 34.8, 41.9, 30% aqueous H2O2 (2.4 mL) for 30 min. The mixture was then
62.7, 71.9, 73.2, 74.7, 74.9, 74.9, 75.9, 76.8, 79.1, 80.6, 80.7, diluted with ether and washed with saturated aqueous
82.5, 85.0, 86.0, 86.4, 112.5, 112.6, 127.9, 127.9, 128.0, 128.1, NaHCO3 and brine, dried (Na2SO4), filtered and evaporated
128.1, 128.1, 128.3, 128.5, 128.7, 128.7, 128.8, 128.8, 128.9, under reduced pressure. FCC of the residue provided an unse-
129.0, 129.0, 129.6, 130.6, 130.6, 132.0, 133.8, 135.4, 136.4, parated mixture of 18 : 19 (0.30 g, ca. ratio 3 : 1, 83%). Repeated
139.6, 139.7, 140.3, 140.3, 140.8, 160.8. HRMS (EI) m/z calcd FCC on the mixture provided samples of separated 18 and 19.
for C73H80O9NaSiS (M + Na)+ 1183.4184, found 1183.5188.
For 18: Rf = 0.25 (20% ethyl acetate–petroleum ether); [α]2D3–
13.3 (c 1.02, CHCl3); IR ν 3411 cm−1; 1H NMR (CDCl3) δ 1.05 (s,
9H, t-Bu), 1.34 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.75 (m, 1H,
H-7′), 1.87 (m, 1H, H-7′), 2.65 (m, 1H, H-6), 3.15 (m, 3H, H-1,
H-5, OH), 3.30 (dd, 1H, J = 2.1, 9.9 Hz, H-3), 3.44 (m, 1H, H-5′),
6-Deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(2′,6′-anhydro-5′,7′-
dideoxy-3,4-O-isopropylidene-1′-O-tert-butyldiphenylsilyl-L-
ribo-hept-5-enitol-7′-C-yl)-D-myo-inositol (17)
A mixture of enol ether 16 (0.49 g, 0.42 mmol), 2,6-di-tert- 3.57 (m, 1H, H-6′), 3.71 (dd, 1H, J = 4.8, 10.5 Hz, H-1′a), 3.78
butyl-4-methylpyridine (1.02 g, 5.0 mmol), and freshly acti- (dd, 1H, J = 6.7, 10.6 Hz, H-1′b), 3.89 (m, 2H, H-2′, H-4′), 4.05
vated, powdered 4 Å molecular sieves (1.47 g) in anhydrous (bs, 1H, H-2), 4.09 (t, 1H, J = 9.2 Hz, H-4), 4.26 (apparent d,
CH2Cl2 (20 mL), was stirred for 15 min, at rt, under an atmos- 1H, J = 11.3 Hz, PhCH), 4.31 (dd, 1H, J = 3.6, 6.10 Hz, H-3′),
phere of argon, then cooled to 0 °C. Methyl triflate (0.47 mL, 4.48 (apparent d, 1H, J = 11.2 Hz, PhCH), 4.64 (m, 3H, PhCH ×
4.2 mmol) was then introduced, and the mixture warmed to rt, 3), 4.72–4.89 (m, 3H, PhCH × 3), 4.94 (apparent d, 1H, J =
and stirred for an additional 18 h, at which time, triethylamine 12.0 Hz, PhCH), 4.96 (apparent d, 1H, J = 12.0 Hz, PhCH), 7.11
(1 mL) was added. The mixture was diluted with ether, washed (m, 3H, ArH), 7.20–7.50 (m, 28H, ArH), 7.65 (m, 4H, ArH);
with saturated aqueous NaHCO3 and brine, dried (Na2SO4), 13C NMR (CDCl3) δ 19.2, 25.8, 26.9, 28.0, 33.2, 37.7, 64.1, 71.9,
6956 | Org. Biomol. Chem., 2013, 11, 6952–6959
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72.6, 72.8, 73.5, 73.5, 73.6, 73.7, 74.8, 74.8, 75.4, 76.8, 80.3, 139.4, 165.8. HRMS (EI) m/z calcd for C74H81O11Si (M + H)+
81.5, 82.4, 83.3, 108.8, 127.3–128.6 (several signals), 129.8 (two 1173.5542, found 1173.5525.
signals), 133.3, 135.6, 137.1, 138.5, 138.6, 138.9, 138.9. HRMS
(EI) m/z calcd for C67H77O10Si (M + H)+ 1069.5280, found 1H NMR (CDCl3) δ 0.96 (s, 9H, t-Bu), 1.20 (s, 3H, CH3), 1.28 (s,
1069.5266. 3H, CH3), 1.82 (m, 1H, H-7′a), 1.94 (m, 1H, H-7′b), 2.58 (m, 1H,
For 21: Rf = 0.55 (20% ethyl acetate–petroleum ether);
For 19: Rf = 0.23 (20% ethyl acetate–petroleum ether); IR ν H-6), 3.18 (dd, 1H, J = 0.7, 11.5 Hz, H-1), 3.23 (dd, 1H, J = 2.1,
1
3455 cm−1; H NMR (CDCl3) δ 0.93 (s, 9H, t-Bu), 1.25 (s, 3H, 10.0 Hz, H-3), 3.44 (dd, 1H, J = 6.3, 7.8 Hz, H-2′), 3.52 (t, 1H,
CH3), 1.27 (s, 3H, CH3), 1.88 (m, 2H, H-7′), 2.58 (d, J = 8.3 Hz, J = 10.0 Hz, H-5), 3.64 (dd, 1H, J = 5.9, 11.3 Hz, H-1′a), 3.78
OH), 2.50 (m, 1H, H-6), 3.09 (d, J = 10.9 Hz, H-1), 3.27 (m, 3H, (bd, 1H, J = 10.0 Hz, H-1′b), 3.91 (t, 1H, J = 11.0 Hz, H-4), 3.95
H-2′, 3′, 3), 3.40 (t, J = 9.3 Hz, H-5), 3.60 (m, 2H, H-1′, 6′), 3.73 (dd, 1H, J = 4.8, 9.4 Hz, H-3′), 4.12 (bs, 1H, H-2), 4.17 (dt, 1H,
(bd, J = 11.2 Hz, H-1′), 3.87 (dd, J = 4.9, 9.3 Hz, H-3′), 4.00 (t, J = J = 2.9, 9.8 Hz, H-6′), 4.30 (apparent d, 1H, J = 11.0, PhCH), 4.42
9.6 Hz, H-4), 4.07 (bs, 1H, H-2), 4.26 (apparent d, J = 11.3 Hz, (ABq, 2H, J = 11.8 Hz, Δδ = 0.06 ppm, PhCH2), 4.54 (apparent
PhCH), 4.29 (t, J = 4.5 Hz, H-4′), 4.49 (m, 3H, PhCH × 3), 4.73 d, 1H, J = 10.9 Hz, PhCH), 4.58 (t, 1H, J = 4.3 Hz, H-4′), 4.63
(m, 4H, PhCH × 4), 4.88 (apparent d, J = 10.8, PhCH), 4.94 (apparent d, 1H, J = 10.8 Hz, PhCH), 4.72 (apparent d, 1H, J =
(apparent d, J = 11.3, PhCH), 7.10–7.30 (m, 28H, ArH), 7.60 (m, 11.0 Hz, PhCH), (s, 2H, PhCH2), 4.79 (m, 3H, PhCH × 3), 4.85
4H, ArH); 13C NMR (CDCl3) δ 19.5, 26.6, 27.1, 28.4, 22.1, 38.4, (partially buried dd, 1H, J = 3.9, 9.7 Hz, H-5′), 4.88 (apparent
64.5, 71.8 (2C), 72.8, 72.9 (two signals), 73.7, 75.0, d, 1H, J = 10.8, PhCH), 7.05–7.40 (m, 33H, ArH), 7.45 (t, 1H, J =
75.3 (2C), 75.8, 78.8, 79.9, 81.8, 82.7, 83.7, 110.0, 7.5, ArH), 7.62 (m, 4H, ArH); 7.78 (d, 2H, J = 7.8 Hz, ArH);
127.4–128.6 (several signals), 129.7 (two signals), 133.7, 133.8, 13C NMR (CDCl3) δ 19.5, 26.5, 27.2, 28.3, 29.8, 38.4, 64.5,
135.8, 135.9, 138.1, 138.8, 138.9, 139.1, 139.3. HRMS (EI) m/z 71.9, 72.8, 72.9 (two signals), 73.0, 73.2, 73.9, 74.7, 75.8,
calcd for C67H76O10NaSi (M
1091.5076.
+
Na)+ 1091.5105, found 79.0, 79.4, 81.1, 81.8, 81.9, 84.0, 110.4, 127.4–128.7 (several
signals), 129.8, 130.1, 130.2, 133.2, 133.6, 133.8, 135.8 (two
signals), 138.0, 139.0, 139.2, 139.3, 139.4, 166.0. HRMS (ES)
6-Deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(2′,6′-anhydro-5-O-
benzoyl-3′,4′-O-isopropylidene-1′-O-tert-butyldiphenylsilyl-7′-
deoxy-D-glycero-D-talo-heptitol-7′-C-yl)-D-myo-inositol (20) and
6-deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(2′,6′-anhydro-5-O-
benzoyl-3′,4′-O-isopropylidene-1′-O-tert-butyl-diphenylsilyl-7′-
deoxy-L-glycero-L-allo-heptitol-7′-C-yl)-D-myo-inositol (21)
m/z calcd for C74H80O11NaSi (M + Na)+ 1195.5368, found
1195.5410.
6-Deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(2′,6′-anhydro-5-O-
benzoyl-1′-O-tert butyldiphenylsilyl-7′-deoxy-L-glycero-L-allo-
heptitol-7′-C-yl)-D-myo-inositol (22)
A mixture of 18 and 19 (244 mg, 0.229 mmol) was dissolved in
CH2Cl2 (20 mL), and pyridine (0.055 mL, 0.675 mmol) and
benzoyl chloride (0.034 mL, 0.296 mmol) were added to the 5% Acetyl chloride in methanol (0.1 mL) was added to a solu-
reaction mixture. The reaction was monitored by TLC. The tion of 20 (206 mg, 0.176 mmol) in dry CH2Cl2 (15 mL). The
mixture was diluted with CH2Cl2, washed with saturated reaction mixture was stirred at rt for 20 min. The mixture was
aqueous NaHCO3 and brine, dried (Na2SO4), filtered and neutralized by addition of sodium methoxide. Removal of the
evaporated in vacuo. FCC of the residue provided recovered 19 volatiles under reduced pressure and FCC of the residue pro-
(30 mg, 12%), 20 (94 mg, 40% brsm), 21 (77 mg, 33% brsm), vided 22 (142 mg, 71%): IR ν 3443 cm−1; Rf = 0.54 (40% ethyl
1
and unseparated 20/21 (38 mg, 16% brsm).
acetate–petroleum ether); H NMR (CDCl3) δ 1.10 (s, 9H, t-Bu),
For 20: Rf = 0.63 (20% ethyl acetate–petroleum ether); IR ν 1.54 (m, 1H, H-7′a), 2.56 (m, 2H, H-6, 7′b), 2.67 (d, 1H, J =
1
1720 cm−1; H NMR (CDCl3) δ 1.11 (s, 9H, t-Bu), 1.28 (s, 3H, 3.1 Hz, OH), 2.93 (d, 1H, J = 4.0 Hz, OH), 3.17 (m, 2H, H-1, 5),
CH3), 1.49 (s, 3H, CH3), 1.62 (ddd, J = 2.1, 7.4, 12.8 Hz, 1H, 3.33 (dd, 1H, J = 2.3, J = 9.9 Hz, H-3), 3.80 (dd, 1H, J = 6.8,
H-7′a), 2.18 (dt, J = 1.8, 12.8 Hz, 1H, H-7′b), 2.67 (apparent q, 10.5 Hz, H-1′a), 3.83 (dd, 1H, J = 4.3, J = 10.5 Hz, H-1′b), 3.92
J = 11.1 Hz, 1H, H-6), 3.19 (m, 2H, H-1, H-5), 3.26 (dd, 1H, J = (m, 1H, H-2′), 4.02 (m, 1H, H-4′), 4.07 (m, 2H, H-2, 3′), 4.18 (t,
2.2, 9.9 Hz, H-3), 3.82 (dd, 1H, J = 4.1, 10.9 Hz, H-1′a), 3.89 (dd, 1H, J = 9.3 Hz, H-4), 4.32 (m, 2H, H-6′, PhCH), 4.51 (apparent
1H, J = 4.7, J = 10.9 Hz, H-1′b), 4.00 (q, 1H, J = 4.5 Hz, H-2′), d, 1H, J = 11.5 Hz, PhCH), 4.62 (m, 3H, PhCH × 3), 4.80 (m,
4.03 (bt, 1H, J = 2.0 Hz, H-2), 4.15 (t, 1H, J = 9.3 Hz, H-4), 4.23 3H, PhCH × 3), 5.03 (apparent d, 1H, J = 11.5 Hz, PhCH), 5.04
(t, 1H, J = 6.1 Hz, H-4′), 4.29 (m, 2H, H-6′, PhCH × 2), 4.35 (t, (apparent d, 1H, J = 11.5 Hz, PhCH), 5.15 (dd, 1H, J = 3.7, J =
1H, J = 5.1 Hz, H-3′), 4.46 (apparent d, 1H, J = 11.6 Hz, PhCH), 4.8 Hz, H-5′), 7.20–7.41 (m, 33H, ArH), 7.54 (t, 1H, J = 6.5 Hz,
4.60 (m, 3H, PhCH × 3), 4.75 (apparent d, 1H, J = 10.7 Hz, ArH), 7.68 (m, 4H, ArH), 7.95 (d, 2H, J = 7.0 Hz, ArH); 13C NMR
PhCH), 4.81 (s, 2H, PhCH2), 4.97 (apparent t, 2H, J = 9.6 Hz, (CDCl3) δ 19.2, 27.0, 30.0, 37.2, 65.1, 69.0, 69.2, 69.3, 71.4, 72.6
PhCH × 2), 5.22 (t, 1H, J = 6.9 Hz, H-5′), 7.09–7.40 (m, 33H, (two signals), 73.3, 73.5, 74.0, 75.4, 75.5, 81.4, 81.5, 81.8, 83.6,
ArH), 7.60 (t, 1H, J = 7.5 Hz, ArH), 7.75 (m, 4H, ArH), 7.95 (d, 127.5, 127.5, 127.7, 127.9, 128.0, 128.0, 128.1, 128.3, 128.3,
2H, J = 8.0 Hz, ArH); 13C NMR (CDCl3) δ 19.5, 26.4, 27.2, 27.9, 128.3, 128.4, 128.4, 129.9, 130.0, 132.8, 133.0 135.6, 135.7,
30.4, 37.8, 64.7, 71.5, 72.4, 72.5, 72.8, 72.9, 73.1, 73.5, 74.3, 135.7, 137.7, 138.5, 138.6, 138.7, 139.2, 166.0. HRMS (EI)
75.6, 81.0, 81.1, 81.6, 83.4, 109.5, 127.6–130.4 (several signals), m/z calcd for C71H77O11Si (M
+
H)+ 1133.5229, found
133.2, 133.6, 133.8, 135.9, 136.0, 138.2, 138.7, 138.9, 139.2, 1133.5215.
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6-Deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(3′-O-acetyl-2′,6′-anhydro-
5-O-benzoyl-1′-O-tert-butyldiphenylsilyl-7′-deoxy-L-glycero-L-
allo-heptitol-7′-C-yl)-D-myo-inositol (23) and 6-deoxy-1,2,3,4,5-
penta-O-benzyl-6-C-(4′-O-acetyl-2′,6′-anhydro-5-O-benzoyl-1′-O-
tert-butyldiphenylsilyl-7′-deoxy-L-glycero-L-allo-heptitol-7′-C-yl)-
D-myo-inositol (24)
6-Deoxy-1,2,3,4,5-penta-O-benzyl-6-C-(3′-O-acetyl-2′,6′-anhydro-
5-O-benzoyl-1′-O-tert-butyldiphenylsilyl-7′-deoxy-D-glycero-D-
manno-heptitol-7′-C-yl)-D-myo-inositol (25)
To a solution of 23 (0.025 g, 0.021 mmol), in CH2Cl2 (0.3 mL)
was added pyridine (0.03 mL) at −20 °C. Trifluoromethane-
sulfonic anhydride (0.007 mL, 0.021 mmol) in CH2Cl2 (0.5 mL)
was then added dropwise, and the mixture warmed to 10 °C
over 2 h. The solution was then diluted with CH2Cl2 and
washed with 1 M HCl, saturated aqueous NaHCO3, water and
brine. The organic phase was dried (Na2SO4) and concentrated
in vacuo at rt. KNO2 (0.020 g, 0.24 mmol) was added to a solu-
tion of the crude product in dry DMF (1 mL). After stirring at
50 °C for 6 h, the mixture was diluted with CH2Cl2 and washed
with brine. The organic phase was dried (MgSO4) and concen-
trated in vacuo. Purification of the residue by FCC afforded 25
(0.020 g, 80%): Rf = 0.10 (20% ethyl acetate–petroleum ether);
[α]D23 –23 (c 1.0, CHCl3); IR ν 3468, 1717 cm−1; 1H NMR (CDCl3)
δ 1.11 (s, 9H, t-Bu), 1.41 (m, 1H, H-7′a), 2.00 (s, 3H, CH3CO),
2.08 (m, 1H, H-7′b), 2.30 (d, 1H, J = 9.9 Hz, OH), 2.54 (m, 1H,
H-6), 3.12 (m, 2H, H-1, 5), 3.31 (dd, 1H, J = 2.1, 9.9 Hz, H-3),
3.51 (dd, 1H, J = 3.5, 11.3 Hz, H-1′a, 2′), 3.68 (m, 2H, H-1′b, 2),
3.86 (m, 1H, H-4′), 4.15 (m, 2H, H-2, 4), 4.26 (apparent d, 1H,
J = 11.6 Hz, PhCH), 4.65 (m, 5H, H-6′, PhCH × 4), 4.77 (apparent
d, 1H, 10.7 Hz, PhCH), 4.82 (s, 2H, PhCH2), 5.01 (apparent d,
1H, J = 10.7 Hz, PhCH), 5.03 (apparent d, 1H, J = 11.2 Hz,
PhCH), 5.28 (bs, 1H, H-5′), 5.49 (t, 1H, J = 9.6 Hz, H-3′),
7.16–7.48 (m, 33H, ArH), 7.55 (t, 1H, J = 7.41, ArH), 7.69 (dd,
2H, J = 1.1, 7.7 Hz, ArH), 7.71 (dd, 2H, J = 1.2, 7.8 Hz, ArH),
8.09 (d, 2H, J = 7.3 Hz, ArH); 13C NMR (CDCl3) δ 19.3 (C-Si),
21.0 (CH3), 26.7 [(CH3)3C], 28.1 (C-7′), 37.2 (C-6), 62.7 (C-1′),
69.7 (C-4′), 70.2 (C-3′), 71.0 (PhC), 71.2 (C-2′), 72.4 (C-2), 72.6
(PhC), 73.4 (PhC), 74.5 (PhC), 75.2 (C-5′, 6′), 75.4 (PhC), 80.6
(C-1), 81.3 (C-3, 5), 83.7 (C-4), 127.2–128.5 (several signals),
129.4, 129.5, 130.2, 133.0, 133.3, 133.5, 135.7, 135.8, 137.5,
138.5, 138.6, 138.9, 139.2 (all Ar), 166.0 (CvO), 171.4 (CvO).
HRMS (ES) m/z calcd for C73H78O12NaSi (M + Na)+ 1197.5160,
found 1197.5167.
A solution of 22 (0.041 g, 0.036 mmol) in dry benzene (6 mL)
and triethyl orthoacetate (6 mL) was treated with CSA (1.1 mg)
at rt for 1 h. Triethylamine (3 mL) was then added and the
mixture diluted with water and extracted with ethyl acetate.
The organic phase was washed with saturated aqueous
NaHCO3, water and brine, dried (Na2SO4) and concentrated
under reduced pressure. The residue was dissolved in
CH2Cl2 (10 mL) and treated with 80% aqueous acetic
acid (20 mL). The mixture was stirred at rt for 35 min, then
diluted with toluene and evaporated under reduced pressure.
FCC of the residue afforded 23 (0.027 g, 64%) and 24 (0.014 g,
33%).
For 23: Rf = 0.17 (20% ethyl acetate–petroleum ether); IR ν
3443, 1730 cm−1; 1H NMR (CDCl3) δ 1.10 (s, 9H, t-Bu), 1.66 (m,
1H, H-7′a), 2.00 (s, 3H, CH3CO), 2.20 (dd, 1H, J = 6.4, 10.4 Hz,
H-7′b), 2.63 (m, 1H, H-6), 3.18 (m, 2H, H-1, 5), 3.26 (dd, 1H, J =
2.2, 9.9 Hz, H-3), 3.76 (dd, 1H, J = 4.7, 10.9 Hz, H-1′b),
3.81 (dd, 1H, J = 6.0, 10.9 Hz, H-1′a), 3.99–4.17 (m, 4H, H-2, 4,
2′, 4′), 4.7 (m, 1H, PhCH, H-6′), 4.48 (apparent d, 1H, J =
11.4 Hz), 4.60 (m, 3H, PhCH), 4.7 (m, 3H, PhCH), 4.90 (m, 2H,
PhCH), 5.13 (t, 1H, J = 7.5 Hz, H-5′), 5.43 (t, 1H, J = 3.8 Hz,
H-3′), 7.18–7.46 (m, 33H, ArH), 7.51 (t, J = 7.5 Hz, 1H,
ArH), 7.68 (m, 4H, ArH), 7.86 (d, 2H, J = J = 7.8 Hz, ArH); 13C
NMR (500 MHz, CDCl3) δ 19.2, 21.1, 26.8, 30.6, 37.3, 62.4,
68.9, 71.1, 71.4, 72.6, 72.7, 72.8, 73.2, 73.3, 74.5, 74.7,
75.5, 81.0, 81.2, 81.4, 83.3, 127.2, 127.5, 127.6, 127.7, 127.7,
127.8, 127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 129.8, 129.9,
133.2, 135.6, 135.7, 138.0, 139.1, 166.5, 170.2. HRMS (ES) m/z
calcd for C73H78O12NaSi (M
1197.5205.
+
Na)+ 1197.5160, found
For 24: Rf = 0.20 (20% ethyl acetate–petroleum ether); IR ν
3452, 1726 cm−1; 1H NMR (CDCl3) δ 0.97 (s, 9H, t-Bu), 1.45 (m,
1H, H-7′a), 1.86 (s, 3H, CH3CO), 2.06 (bs, 1H, OH), 2.32 (t, 1H,
J = 12.2 Hz, H-7′b), 2.50 (m, 1H, H-6), 3.07 (m, 2H, H-1, 5), 3.17
(dd, 1H, J = 2.2, 9.9 Hz, H-3), 3.72 (m, 1H, CH2-1′), 3.88 (m, 1H,
H-2′), 3.94 (bs, 1H, H-2), 4.02 (t, 1H, J = 9.3 Hz, H-4), 4.14
(apparent d, 1H, J = 11.4 Hz, 1H, PhCH), 4.22 (m, 1H, H-3′),
4.27 (m, 1H, H-6′), 4.35 (apparent d, 1H, J = 11.4 Hz, PhCH),
4.50 (m, 3H, PhCH), 4.68 (m, 3H, PhCH), 4.91 (m, 2H, PhCH),
5.13, (t, 1H, J = 5.10, H5′), 5.30 (dd, 1H, J = 3.6, 6.3 Hz,
H-4′), 7.10–7.30 (m, 33H, ArH), 7.46 (t, 1H, J = 7.5 Hz, ArH),
7.62 (m, 4H, ArH), 7.80 (d, 2H, J = 7.8 Hz, ArH); 13C
NMR (500 MHz, CDCl3) δ 19.4, 21.1, 27.1, 29.8, 37.7, 63.9,
67.1, 71.1, 71.5, 72.2, 72.6, 72.7, 72.8, 73.5, 75.0, 75.6,
81.1, 81.2, 81.6, 83.6, 127.8–128.6 (several lines), 129.8,
129.9, 130.0, 130.1, 133.1, 133.2, 133.4, 135.8, 135.9,
138.0, 138.7, 138.8, 139.1, 139.3, 166.5, 170.2. HRMS (ES) m/z
6-Deoxy-6-C-(2′,6′-anhydro-7′-deoxy-D-glycero-D-manno-heptitol-
7′-C-yl)-D-myo-inositol [C-glycoside of α-D-mannose-(1 → 6)-D-
myo-inositol] (4)
A mixture of 25 (0.008 g, 0.01 mmol) and NaOMe (ca. 5 mg,
0.01 mmol) in methanol (5 mL) was stirred at rt for 30 min.
The solvent was then removed under reduced pressure and
THF (1 mL) and TBAF (0.012 mL of a 1 M solution in THF,
0.012 mmol) were added to the residue. The mixture was
stirred for 5 h at rt, then diluted with saturated aqueous
NaHCO3 and extracted with ether. The organic phase was
dried (Na2SO4) and concentrated in vacuo. FCC of the residue
afforded a homogeneous material (0.0040 g) as a colorless oil:
Rf = 0.21 (2% methanol–ethyl acetate). A mixture of this
product, 20% Pd on carbon (0.0123 g), and methanol (1 mL)
was stirred under an atmosphere of hydrogen (balloon), for
12 h. The mixture was then purged with argon and filtered
through Celite. The filtrate was concentrated in vacuo, and the
calcd for C73H78O12NaSi (M
1197.5188.
+
Na)+ 1197.5160, found
6958 | Org. Biomol. Chem., 2013, 11, 6952–6959
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Paper
residue purified by FCC to give 4 (0.002 g, 87%); Rf = 0.12 (40% 15 N. A. Parlane, B. J. Compton, C. M. Hayman, G. F. Painter,
methanol–CH2Cl2); [α]1D9 6 (c 0.2, H2O); 1H NMR (600 MHz,
D2O, external standard: Me4NBr) δ 1.70 (m, 1H, H-7′a), 1.90
R. J. Basaraba, A. Heiser and B. M. Buddle, Vaccine, 2012,
30, 580–588.
(m, 1H, H-6), 2.18, (bt, 1H, J = 13.8 Hz, H-7′b), 3.20 (t, 1H, J = 16 S. Front, M.-L. Bourigault, S. Rose, S. Noria,
9.1 Hz, H-5), 3.46 (bd, 1H, J = 10.0 Hz, H-3), 3.55–3.78 (m, 5H),
3.83 (m, 2H), 3.92 (bd, 1H, J = 1.5 Hz), 3.99 (bd, 1H, J = 2.4
V. F. Quesniaux and O. R. Martin, Bioconjugate Chem.,
2013, 24, 72–84.
Hz), 4.25 (bd, 1H, J = 8.4 Hz, H-6′); 13C NMR (150 MHz, D2O) δ 17 To the best of our knowledge the synthesis of C-pseudo-
29.1 (C-7′), 41.7 (C-6), 63.8 (C-1′), 69.9, 73.1, 73.5, 73.6, 74.4,
75.2 (C-5), 75.7, 76.0, 76.5 (C-3), 79.3; HRMS (ES) m/z calcd for
C13H24O10Na (M + Na)+ 363.1267, found 363.1267.
disaccharide 4 has not been previously reported. For syn-
thetic studies on the O-pseudodisaccharide and analogues:
C. J. J. Elie, R. Verduyn, C. E. Dreef, D. M. Brounts,
G. A. van der Marel and J. H. van Boom, Tetrahedron, 1990,
46, 8243–8254 and ref. 17–19.
Acknowledgements
18 S. Boonyarattanakalin, X. Liu, M. Michieletti, B. Lepenies
and P. H. Seeberger, J. Am. Chem. Soc., 2008, 130, 16791–
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19 P. S. Patil and S. C. Hung, Org. Lett., 2010, 12, 2618–2621.
20 B. Fraser-Reid, S. R. Chaudhuri, K. N. Jayaprakash, J. Lu
and C. V. S. Ramamurty, J. Org. Chem., 2008, 73, 9732–
9743.
This publication was made possible by a Research Center in
Minority Institutions Program grant from the National Insti-
tute of Health Disparities (MD007599) of the National Insti-
tutes of Health (NIH). Support from the PSC-CUNY Research
Program is also acknowledged.
21 L. M. Mikkelsen, S. L. Krintel, J. Jiménez-Barbero and
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22 R. W. Denton, X. Cheng, K. A. Tony, A. Dilhas,
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