Synthesis of L-ido-configured six- and seven-membered carba-sugars

Article abstract of DOI:10.1055/s-2007-965899

Ring-closing olefin metathesis has been successfully applied to the modular construction of L-ido-configured six- and seven-membered carba-sugars. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965899

PAPER
523
Synthesis of L-ido-Configured Six- and Seven-Membered Carba-Sugars
Synthesis of
L-id
.
-Configured
V
Six- and
S
even-M
.
embered Ca
R
rba-Sugars amana,* Siddhartha R. Chaudhuri, Mukund K. Gurjar
National Chemical Laboratory, Pune-411 008, India
Fax +91(20)25902629; E-mail: vr.chepuri@ncl.res.in
Received 6 September 2006; revised 13 November 2006
OR
O
Abstract: Ring-closing olefin metathesis has been successfully
applied to the modular construction of L-ido-configured six- and
seven-membered carba-sugars.
O
MeO
O
RO
HO
RO
OMe
OMe
O
O
Key words: allylations, carbocycles, carbohydrates, metathesis,
radical reactions
OMe
MeO
MeO
O
O
OH
O
O
RO
MeO
RO
O
O
MeO
OMe
L-Iduronic acid, one of the naturally available L-sugars, is
the major component of the three glycosaminoglycans he-
parin, heparan sulfate, and dermatan sulfate. It is well es-
tablished that low-molecular-weight heparin analogue 11
(Figure 1) is a better anticoagulant than the heparin poly-
mer that has been marketed2 for several decades. The flex-
ibility of the pyranose ring of L-iduronic acid to adopt
either a chair 4C1/1C4 or a 2S0 skew boat conformation has
been accentuated as a critical factor in the biology of hep-
arin. Recently, Sinaÿ and co-workers3 synthesized methy-
RO
1 (R = SO3H)
OH
OH
HO
HO
HO
OH
OH
OH
HO
OH
HO
2
3
Figure 1 Antithrombin-binding synthetic pentasaccharide 1 and de-
signed L-ido-configured carba-sugars 2 and 3
lated antifactor Xa pentasaccharide
1
(Figure 1)
containing three possible conformationally locked forms
2
of L-iduronic acid and showed that the S0-conformer
(Scheme 1); the required stereochemistry of L-ido-carba-
cycles is carried at C5 of 5. Construction of another olefin
of different length at the C1 terminal, followed by RCM
should give the required medium-sized L-ido-configured
carbacycles.7
plays a critical role in the activation of antithrombin by
heparin and its analogues. The importance of conforma-
tionally flexible L-iduronic acid analogues as well as the
greater metabolic stability and conformational flexibility
of carba analogues of the sugars (carba- or pseudo-sugars)
compared to their oxygen analogues motivated us to de-
sign a project on the synthesis of methylated antifactor Xa
pentasaccharide analogues containing carba-L-iduronic
acid (of varying ring sizes).
As shown in Scheme 1, treatment of 5 with lithium alumi-
num hydride, benzylation, and deisopropylidenation gave
lactol 8. Upon treatment with sodium borohydride fol-
lowed by the addition of 2,2-dimethoxypropane, 8 gave
easily separable 1,2- and 2,4-isopropylidene derivatives 9
and 10. Diene 12 was obtained in 61% overall yield from
benzyl derivative 11 after a sequence of deisopropylide-
nation, dimesylation, and elimination,8 without any
purification of the intermediates. The key RCM reaction
of 12 was quite facile when Grubbs’ catalyst
[Ru(=CHPh)Cl2(PCy3)2] was used, and afforded the pseu-
do-glycal 13 in excellent yield. Pseudo-glycal 13 is char-
acterized by two peaks at d 124.5 and 130.6 (C=C) in its
Several groups have reported the synthesis of six-mem-
bered L-ido-configured carba-sugars by a variety of meth-
ods.4 However, synthetic efforts towards the selective
construction of L-ido-configured medium-size carbacy-
cles are scarce. Sinaÿ and co-workers4h reported the for-
mation of an eight-membered carba-L-idose derivative as
the minor product along with the corresponding major D-
gluco analogue. Herein, we describe a flexible method for
the synthesis of L-ido-configured carbacycles 2 and 3
(Figure 1) in which ring-closing metathesis (RCM) is the
key reaction.
1
13C NMR spectrum. In the H NMR spectrum, the ob-
served J(3,4) of 2.7 Hz indicated a pseudo-diequatorial re-
lation between H–C3 and H–C4. The assigned L-xylo
configuration of 13 was confirmed by its NOESY spec-
trum, where a weak NOE interaction was found between
H–C3 and H–C6 and no NOE interaction between H–C3
and H–C5.
Our intended strategy was based on our observation5 that
radical allylation of 5-chloro-5-deoxy-1,2-isopropy-
lidene-L-idofuranurono-6,3-lactone (4)6 results in reten-
tion of configuration, exclusively giving 5 in 92% yield
As observed with the carba-3,4,6-tri-O-benzyl-D-glucal,9
dihydroxylation of 13 also occurred exclusively anti to the
3-OBn group, and the corresponding carba-b-L-idopyra-
nose derivative 15 was obtained in good yield after acety-
SYNTHESIS 2007, No. 4, pp 0523–0528
Advanced online publication: 22.01.2007
DOI: 10.1055/s-2007-965899; Art ID: T13706SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7

524
C. V. Ramana et al.
PAPER
H
H
H
H
Cl
O
O
O
O
O
b)
c)
a)
O
O
O
O
Ref 5
O
HO
BnO
O
O
O
O
O
O
HO
BnO
4
5
6
7
d)
BnO
BnO
OBn
BnO
OBn
OH
OBn
H
O
f)
e)
+
OH
O
O
O
10
O
OBn
O
OH
O
BnO
HO
BnO
OH
11
8
9
g)
OBn
6
BnO
OR
OH
OH
1
BnO
BnO
BnO
5
h)
k)
i)
2
BnO
OR
HO
OBn
12
OBn
OBn
OH
13
14 R = H
2
j)
15 R = Ac
Scheme 1 Reagents and conditions: (a) AllSnBu3, AIBN, benzene, reflux, 10 h, 92%; (b) LAH, THF, 0 °C to r.t., 1 h, 90%; (c) NaH, BnBr,
DMF, 0 °C to r.t., 2 h, 88%; (d) 6 M HCl, THF–H2O (5:1), 70 °C, 3 h, 74%; (e) i. NaBH4, THF–H2O (3:1), 0 °C, 10 min, ii. 2,2-dimethoxypro-
pane, CH2Cl2, PTSA, r.t., 1 h, 65% (9), 14% (10); (f) NaH, BnBr, DMF, 0 °C to r.t., 3 h, 70%; (g) i. 0.8% H2SO4, MeOH, r.t., 5 h; ii. MsCl,
Et3N, CH2Cl2, 0 °C to r.t., 0.5 h; iii. NaI, MEK, reflux, 6 h, 61% (3 steps); (h) [Ru(=CHPh)Cl2(PCy3)2] (5 mol%), CH2Cl2, r.t., 6 h, 91%; (i)
OsO4, K3[Fe(CN)6], K2CO3, t-BuOH–H2O (1:1), r.t.; (j) Ac2O, py, r.t., 65% (two steps); (k) H2,10% Pd/C, MeOH, 91%.
lation of the intermediate diol, whereas hydrogenation of (C=C) in the 13C NMR spectrum. The observed J(3,4) of
the intermediate diol 14 provided the carba-b-L-idopyra- 9.5 Hz and J(4,5) of 4.8 Hz indicate a diaxial relation be-
nose 2.10 The trans-diequatorial relation between H–C2 tween H–C3 and H–C4, and an axial–pseudoaxial relation
and H–C3 and between H–C3 and H–C4 and the 1C4 con- between H–C4 and H–C5. The L-ido configuration as-
formation of diacetate 15 in acetone-d6 solution was signed to 18 was confirmed by NOE experiments, where
deduced from the observed coupling constants a strong NOE interaction was found between H–C3 and
1
J(2,3) = J(3,4) = 3.9 Hz and J(4,5) = 3.4 Hz in the H H–C5/H–C6.
NMR spectrum.
The syn-dihydroxylation reaction of 18 in the presence of
After having gained easy access to carba-b-L-idopyra- osmium tetroxide and N-methylmorpholine N-oxide in a
nose, we next focused our attention on the synthesis of the tetrahydrofuran–water mixture (1:1) at room temperature
corresponding seven-membered carbacycle. Treatment of for five hours resulted in the formation of diol 19
1
8 with excess methylene(triphenyl)phosphorane and sub- (Scheme 2). Compound 19 was characterized by its H
sequent benzylation and RCM provided cycloheptene de- NMR and 13C NMR spectra and elemental analysis. Final-
rivative 18 (Scheme 2). The seven-membered carbacycle ly, hydrogenation of 19 over 10% palladium on carbon in
18 is characterized by two peaks at d 129.5 and 130.8 methanol gave the polyhydroxylated seven-membered
7
BnO
7'
1
OBn
6
BnO
BnO
a)
c)
8
3
OR OR
OBn
BnO
16 R = H
18
b)
17 R = Bn
d)
OH
OH
HO
HO
BnO
BnO
e)
OH
OH
OH
OBn
HO
BnO
3
19
Scheme 2 Reagents and conditions: (a) Ph3P=CH2, THF–Et2O, –78 °C to r.t., 12 h, 77%; (b) NaH, BnBr, DMF, 0 °C to r.t., 6 h, 72%; (c)
[Ru(=CHPh)Cl2(PCy3)2] (5 mol%), CH2Cl2, r.t., 20 h, 87%; (d) OsO4, NMO, THF–H2O (1:1), r.t., 5 h, 91%; (e) H2, 10% Pd/C, MeOH, 4 h, 92%.
Synthesis 2007, No. 4, 523–528 © Thieme Stuttgart · New York

PAPER
Synthesis of L-ido-Configured Six- and Seven-Membered Carba-Sugars
525
13C NMR (50 MHz, CDCl3): d = 25.8, 26.4, 33.0, 39.4, 61.2, 74.5,
1
carba-sugar 3 (Scheme 2). The H NMR and 13C NMR
spectra and elemental analysis supported the assigned
structure 3.
82.7, 84.7, 103.6, 110.8, 116.7, 135.3.
MS (EI): m/z = 229 [M+ – 15].
Anal. Calcd for C12H20O5: C, 59.0; H, 8.25. Found: C, 58.81; H,
8.49.
To conclude, a simple approach for the synthesis of six-
and seven-membered carbacycles was found from the eas-
ily available D-glucurono-6,3-lactone derived building
block 4 through simple synthetic operations and ring-
closing olefin metathesis as the key step. Experiments are
in progress towards the synthesis of methylated antifactor
Xa pentasaccharide analogues containing carba-L-iduron-
ic acid.
5-C-Allyl-3,5-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-
L-idofuranose (7)
Compound 6 (8.0 g, 32.8 mmol) in DMF (20 mL) was added to a
stirred suspension of 60% NaH dispersion in oil (3.27 g, 82.0 mmol)
in DMF (30 mL) at 0 °C. The resulting soln was stirred at r.t. for 30
min, and then BnBr (8.7 mL, 72.1 mmol) and TBAI (0.1 g, 0.27
mmol) were added. After 2 h, the reaction was quenched with ice-
cold H2O and the mixture was extracted with EtOAc (3 × 50 mL).
The combined organic layer was washed with H2O (2 × 100 mL),
dried (Na2SO4), and concentrated. Purification of the residue by col-
umn chromatography (silica gel, EtOAc–light PE, 1:9) gave 7.
Air- and/or moisture-sensitive reactions were carried out in anhyd
solvents under an atmosphere of argon in oven-dried glassware. All
anhyd solvents were distilled prior to use: THF and Et2O from Na–
benzophenone, CH2Cl2 from CaH2, and MeOH from Mg cake.
Commercial reagents were used without further purification. Col-
umn chromatography was carried out on Spectrochem silica gel
(60–120 mesh). Optical rotations were determined on a Jasco DIP-
Yield: 12.23 g (88%); [a]D25 –43.5 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.34 (s, 3 H), 1.52 (s, 3 H), 2.15–
2.37 (m, 2 H), 2.44–2.56 (m, 1 H), 3.27 (dd, J = 4.2, 9.3 Hz, 1 H),
3.36 (dd, J = 4.4, 9.3 Hz, 1 H), 3.80 (d, J = 2.9 Hz, 1 H), 4.11 (dd,
J = 2.9, 9.3 Hz, 1 H), 4.28 (d, J = 11.7 Hz, 1 H), 4.32 (d, J = 12.2
Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 4.57 (d, J = 3.9 Hz, 1 H), 4.58
(d, J = 11.7 Hz, 1 H), 5.01 (dd, J = 2.4, 9.8 Hz, 1 H), 5.05 (dd,
J = 1.5, 17.1 Hz, 1 H), 5.71–5.85 (m, 1 H), 5.90 (d, J = 3.9 Hz, 1 H),
7.22–7.37 (m, 10 H).
1
370 digital polarimeter. H and 13C NMR spectroscopy measure-
ments were carried out on Bruker AC 200 MHz or Bruker DRX 500
MHz spectrometers, and TMS was used as internal standard. Mass
spectroscopy (EI, 70 eV, direct inlet system) was carried out on a
Finnigan MAT-1020 spectrometer. Elemental analysis data were
obtained on a Thermo Finnigan Flash EA 1112 Series CHNS Anal-
yser.
13C NMR (50 MHz, CDCl3): d = 26.1, 26.6, 32.7, 37.1, 68.7, 71.2,
72.8, 80.5, 81.6, 81.8, 104.1, 110.8, 116.3, 127.2, 128.0, 136.2,
137.4, 138.3.
5-C-Allyl-5-deoxy-1,2-O-isopropylidene-b-L-idofuranurono-
6,3-lactone (5)
Anal. Calcd for C26H32O5: C, 73.56; H, 7.60. Found: C, 73.33; H,
7.85.
A soln of 4 (9.0 g, 38.4 mmol), AllSnBu3 (12.9 mL, 42.2 mmol),
and AIBN (25 mg) in benzene (75 mL) under argon was heated un-
der reflux for 10 h and then concentrated. A sat. soln of KF in Et2O
was introduced, and the mixture was stirred vigorously for 4 h. The
Et2O layer was separated, dried (Na2SO4), and concentrated. Purifi-
cation of the residue by column chromatography (silica gel,
EtOAc–light PE, 1:9) gave 5 as a colorless oil.
5-C-Allyl-3,5-di-O-benzyl-5-deoxy-a/b-L-idofuranose (8)
A mixture of 7 (3.0 g, 7.1 mmol) and 6 M HCl (10 mL) in THF–H2O
(5:1, 30 mL) was heated at 70 °C for 3 h. The mixture was neutral-
ized by the addition of solid NaHCO3, filtered, and concentrated.
The residue was partitioned between EtOAc and H2O, and the or-
ganic layer was separated, washed with H2O (3 × 50 mL), dried
(Na2SO4), and concentrated. Purification of the residue by column
chromatography (silica gel, EtOAc–light PE, 1:3) gave 8 as a thick
oil.
Yield: 8.47 g (92%); [a]D25 +70.9 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.34 (s, 3 H), 1.50 (s, 3 H), 2.32
(dt, J = 8.0, 14.0 Hz, 1 H), 2.49 (dt, J = 6.0, 14.0 Hz, 1 H), 2.81 (dd,
J = 6.0, 8.0 Hz, 1 H), 4.71 (d, J = 3.4 Hz, 1 H), 4.75 (d, J = 3.4 Hz,
1 H), 4.81 (d, J = 4.0 Hz, 1 H), 5.18 (d, J = 10.7 Hz, 1 H), 5.22 (d,
J = 16.6 Hz, 1 H), 5.69–5.90 (m, 1 H), 5.94 (d, J = 4.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 25.9, 26.0, 31.6, 46.4, 81.7, 82.0,
83.7, 105.4, 111.8, 118.0, 132.8, 175.7.
Yield: 2.0 g (74%).
1H NMR (200 MHz, CDCl3): d = 2.11–2.32 (m, 2 H), 2.41–2.51 (m,
1 H), 3.29–3.41 (m, 2 H), 3.48–3.56 (m, 2 H), 3.77–3.84 (m, 1 H),
4.12–4.61 (m, 6 H), 4.97–5.47 (m, 3 H), 5.70–5.92 (m, 1 H), 7.19–
7.30 (m, 10 H).
MS (EI): m/z = 225 [M+ – 15].
13C NMR (50 MHz, CDCl3): d = 32.6, 32.8, 37.6, 38.4, 68.8, 69.0,
71.3, 71.8, 72.9, 74.5, 76.4, 77.3, 79.1, 82.1, 82.2, 83.6, 95.6, 102.7,
116.3, 116.4, 127.4, 127.5, 127.6, 128.0, 128.1, 128.3, 136.3, 136.5,
136.9, 137.6, 138.2.
Anal. Calcd for C12H16O5: C, 59.99; H, 6.71. Found: C, 59.92; H,
6.75.
5-C-Allyl-5-deoxy-1,2-O-isopropylidene-b-L-idofuranose (6)
A suspension of LAH (1.26 g, 33.3 mmol) and 5 (8.0 g, 33.3 mmol)
in THF (50 mL) was stirred at r.t. for 1 h. The excess LAH was
quenched with a sat. soln of Na2SO4, the mixture was filtered, and
the residue was thoroughly washed with EtOAc. The filtrate was
concentrated and the residue was purified by column chromatogra-
phy (silica gel, EtOAc–light PE, 1:1); this gave 6 as a thick oil.
Anal. Calcd for C23H28O5: C, 71.85; H, 7.34. Found: C, 71.67; H,
7.65.
Oct-7-en-4-ols 9 and 10
To a soln of 8 (2.0 g, 5.2 mmol) in THF–H2O (3:1, 20 mL) at 0 °C
was added NaBH4 (0.2 g, 5.2 mmol) in portions. After 10 min, the
solvent was removed and 1 M HCl (2 mL) was added; the mixture
was extracted with EtOAc (3 × 30 mL), dried (Na2SO4), and con-
centrated. The residue was stirred with CH2Cl2 (10 mL), 2,2-
dimethoxypropane (1.7 mL), and PTSA (30 mg). After 1 h, the mix-
ture was neutralized with Et3N and concentrated. The residue was
partitioned between EtOAc and H2O, the organic layer was dried
(Na2SO4) and concentrated, and the residue was purified by column
Yield: 7.32 g (90%); [a]D25 -17.7 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.31 (s, 3 H), 1.48 (s, 3 H), 1.95–
2.18 (m, 2 H), 2.41–2.50 (m, 1 H), 3.20 (br s, 1 H), 3.49 (dd, J = 2.0,
10.5 Hz, 1 H), 3.78 (dd, J = 2.0, 10.5 Hz, 1 H), 3.91 (dd, J = 2.0, 8.8
Hz, 1 H), 4.14–4.24 (m, 1 H), 4.15 (d, J = 2.0 Hz, 1 H), 4.52 (d,
J = 3.6 Hz, 1 H), 5.05 (br d, J = 10.2 Hz, 1 H), 5.07 (br d, J = 17.2
Hz, 1 H), 5.68–5.84 (m, 1 H), 5.88 (d, J = 3.6 Hz, 1 H).
Synthesis 2007, No. 4, 523–528 © Thieme Stuttgart · New York

526
C. V. Ramana et al.
PAPER
chromatography (silica gel, EtOAc–light PE, 1:4); this gave 9 and
10 as colorless oils.
filtered, and concentrated. The residue was partitioned between
EtOAc and H2O, and the organic layer was dried (Na2SO4) and con-
centrated. The crude diol was dissolved in CH2Cl2 (5 mL), and then
Et3N (0.6 mL, 4.5 mmol) and MsCl (0.3 mL, 3.7 mmol) were added.
After 30 min, the mixture was partitioned between EtOAc and H2O,
and the organic layer was dried (Na2SO4) and concentrated. A mix-
ture of the dimesylate (0.86 g) and NaI (1.2 g, 8.1 mmol) in MEK
(10 mL) was heated under reflux for 6 h. The solvent was removed,
the residue was partitioned between EtOAc and H2O, and the organ-
ic layer was dried (Na2SO4) and concentrated. Purification of the
residue by column chromatography (silica gel, EtOAc–light PE,
1:19) afforded 12 as a clear oil.
(2S,3S,4R,5S)-3-(Benzyloxy)-5-[(benzyloxy)methyl]-1,2-O-iso-
propylideneoct-7-en-4-ol (9)
Yield: 1.44 g (65%); [a]D25 –21.3 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.37 (s, 3 H), 1.44 (s, 3 H), 1.79–
1.88 (m, 1 H), 2.08–2.18 (m, 1 H), 2.36–2.45 (m, 1 H), 3.24 (dd,
J = 3.9, 9.6 Hz, 1 H), 3.33 (dd, J = 5.1, 9.6 Hz, 1 H), 3.39–3.45 (m,
1 H), 3.52 (dd, J = 1.4, 7.3 Hz, 1 H), 3.63 (t, J = 8.0 Hz, 1 H), 4.03
(dd, J = 6.6, 8.0 Hz, 1 H), 4.31–4.46 (m, 3 H), 4.58 (d, J = 11.7 Hz,
1 H), 4.88 (d, J = 11.2 Hz, 1 H), 4.97–5.02 (m, 2 H), 5.67–5.80 (m,
1 H), 7.24–7.34 (m, 10 H).
Yield: 0.51 g (61%, 3 steps); [a]D25 +12.1 (c 1.0, CHCl3).
13C NMR (50 MHz, CDCl3): d = 25.6, 26.7, 32.2, 42.0, 66.2, 69.9,
72.5, 73.3, 73.6, 78.2, 79.5, 109.3, 116.3, 127.6–128.3, 137.1,
138.3, 138.6.
1H NMR (200 MHz, CDCl3): d = 2.01–2.18 (m, 2 H), 2.25–2.38 (m,
1 H), 3.38–3.52 (m, 2 H), 3.87 (dd, J = 2.4, 6.8 Hz, 1 H), 4.08 (t,
J = 7.3 Hz, 1 H), 4.37 (d, J = 12.2 Hz, 1 H), 4.42 (d, J = 11.2 Hz, 1
H), 4.47 (d, J = 12.2 Hz, 1 H), 4.58 (d, J = 11.2 Hz, 1 H), 4.67 (d,
J = 11.7 Hz, 1 H), 4.93–5.07 (m, 3 H), 5.35 (dd, J = 2.3, 7.7 Hz, 1
H), 5.38 (dd, J = 2.3, 10.7 Hz, 1 H), 5.68–5.97 (m, 2 H), 7.34–7.40
(m, 15 H).
MS (EI): m/z = 426 [M+].
Anal. Calcd for C26H34O5: C, 73.21; H, 8.03. Found: C, 72.95; H,
8.18.
13C NMR (50 MHz, CDCl3): d = 30.6, 40.0, 70.0, 70.5, 72.9, 74.9,
80.8, 83.4, 115.5, 118.8, 127.2, 127.6, 128.2, 135.7, 137.4, 138.5,
139.3.
(2S,3S,4R,5S)-3-(Benzyloxy)-5-[(benzyloxy)methyl]-2,4-O-iso-
propylideneoct-7-en-1-ol (10)
Yield: 0.32 g (14%); [a]D25 –20.7 (c 1.0, CHCl3).
MS (EI): m/z = 351 [M+ – Bn].
1H NMR (500 MHz, CDCl3): d = 1.42 (s, 3 H), 1.44 (s, 3 H), 2.04–
2.09 (m, 1 H), 2.13–2.19 (m, 1 H), 2.43–2.50 (m, 1 H), 3.28–3.29
(m, 1 H), 3.30 (dd, J = 4.0, 9.5 Hz, 1 H), 3.34 (dd, J = 4.0, 9.5 Hz,
1 H), 3.55 (dd, J = 4.9, 11.1 Hz, 1 H), 3.73 (dd, J = 7.2, 11.1 Hz, 1
H), 3.80 (dd, J = 1.2, 9.1 Hz, 1 H), 3.89 (ddd, J = 1.2, 4.9, 7.2 Hz, 1
H), 4.35 (d, J = 12.1 Hz, 1 H), 4.45 (d, J = 12.1 Hz, 1 H), 4.50 (d,
J = 11.9 Hz, 1 H), 4.57 (d, J = 11.9 Hz, 1 H), 4.95–5.02 (m, 2 H),
5.69–5.78 (m, 1 H), 7.22–7.35 (m, 10 H).
Anal. Calcd for C30H34O3: C, 81.41; H, 7.74. Found: C, 81.65; H,
7.78.
(3R,4R,5S)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]cyclohex-
ene (13)
Compound 12 (0.2 g, 0.45 mmol) was dissolved in anhyd CH2Cl2
(20 mL) and the soln was degassed with argon.
[Ru(=CHPh)Cl2(PCy3)2] (18 mg, 5 mol%) was added and the mix-
ture was stirred at r.t. for 6 h. The solvent was removed and the res-
idue was purified by column chromatography (silica gel, EtOAc–
light PE, 3:97); this gave 13 as a colorless syrup.
13C NMR (125 MHz, CDCl3): d = 18.8, 29.4, 31.3, 38.6, 62.1, 67.7,
70.5, 72.3, 72.8, 73.1, 73.8, 98.7, 116.1, 127.2, 127.5, 127.6, 127.9,
128.0, 136.6, 138.0, 138.2.
Anal. Calcd for C26H34O5: C, 73.21; H, 8.03. Found: C, 73.15; H,
8.10.
Yield: 0.17 g (91%); [a]D25 –77.3 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 2.08–2.16 (m, 2 H), 2.44 (dquin,
J = 2.3, 6.8 Hz, 1 H), 3.51 (dd, J = 6.8, 9.1 Hz, 1 H), 3.66 (dd,
J = 7.6, 9.1 Hz, 1 H), 3.89–3.96 (m, 2 H), 4.54 (s, 2 H), 4.56 (d,
J = 12.2 Hz, 1 H), 4.59 (d, J = 11.9 Hz, 1 H), 4.64 (d, J = 11.9 Hz,
1 H), 4.67 (d, J = 12.2 Hz, 1 H), 5.79–5.87 (m, 1 H), 6.02 (dt,
J = 3.4, 9.7 Hz, 1 H), 7.32–7.40 (m, 15 H).
13C NMR (125 MHz, CDCl3): d = 25.1, 34.4, 70.6, 71.1, 71.9, 72.4,
72.8, 75.5, 124.4, 127.3, 127.4, 127.5, 127.6, 128.1, 130.6, 138.6,
138.7.
(2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]-1,2-O-
isopropylideneoct-7-ene (11)
The benzylation of 9 (1.3 g, 3.1 mmol) was performed as described
in the preparation of 7 above; used were NaH (0.14 g, 3.7 mmol),
TBAI (0.1 g, 0.27 mmol), and BnBr (0.4 mL, 3.4 mmol) in DMF (10
mL); this gave 11 after purification by column chromatography (sil-
ica gel, EtOAc–light PE, 1:19) as a thick syrup.
Yield: 1.11 g (70%); [a]D25 –7.3 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.37 (s, 3 H), 1.45 (s, 3 H), 2.25
(m, 3 H), 3.37 (dd, J = 4.6, 9.6 Hz, 1 H), 3.49 (dd, J = 5.3, 9.6 Hz,
1 H), 3.54 (t, J = 5.3 Hz, 1 H), 3.66 (t, J = 8.0 Hz, 1 H), 3.73 (t,
J = 4.6 Hz, 1 H), 3.85 (dd, J = 6.5, 8.0 Hz, 1 H), 4.26–4.36 (m, 2 H),
4.43 (d, J = 11.7 Hz, 1 H), 4.55 (s, 2 H), 4.66 (d, J = 11.7 Hz, 1 H),
4.78 (d, J = 11.7 Hz, 1 H), 4.99 (br d, J = 10.2 Hz, 1 H), 5.04 (br d,
J = 17.1 Hz, 1 H), 5.67–5.87 (m, 1 H), 7.22–7.40 (m, 15 H).
13C NMR (50 MHz, CDCl3): d = 25.6, 26.5, 31.7, 39.7, 66.0, 69.8,
72.8, 73.0, 73.8, 76.8, 78.6, 79.7, 108.9, 116.0, 127.3, 128.1, 137.2,
138.6.
MS (EI): m/z = 323 [M+ – Bn].
Anal. Calcd for C28H30O3: C, 81.13; H, 7.29. Found: C, 81.34; H,
7.50.
(1S,2R,3S,4R,5S)-1,2-Bis(acetoxy)-3,4-bis(benzyloxy)-5-[(ben-
zyloxy)methyl]cyclohexane (15)
A soln of K2CO3 (99 mg, 0.72 mmol), K3Fe(CN)6 (0.23 g, 0.72
mmol), and 0.04 M OsO4 in toluene (0.24 mL, 9.6 mmol) in t-
BuOH–H2O (1:1, 8 mL) was added to 13 (0.1 g, 0.24 mmol). After
12 h, the mixture was quenched with Na2SO3 and extracted with
EtOAc, and the organic phase was dried (Na2SO4) and concentrat-
ed. The crude diol 14 was treated with Ac2O (0.06 mL, 0.63 mmol)
and Et3N (0.11 mL, 0.83 mmol) in CH2Cl2 (5 mL). The reaction
mixture was partitioned between CH2Cl2 and H2O. The organic lay-
er was separated, dried (Na2SO4), and concentrated. The residue
was purified by column chromatography (silica gel, EtOAc–light
PE, 3:17); this gave 15 as a colorless oil.
MS (EI): m/z = 517 [M+ + 1].
Anal. Calcd for C33H40O5: C, 76.71; H, 7.80. Found: C, 76.94; H,
7.80.
(3R,4R,5S)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]octa-1,7-
diene (12)
A soln of 11 (1.0 g, 1.9 mmol) and 0.8% H2SO4 (2 mL) in MeOH
(10 mL) was stirred at r.t. for 5 h, neutralized with solid NaHCO3,
Yield: 83 mg (65%); [a]D25 –5.9 (c 1.1, CHCl3).
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Synthesis of L-ido-Configured Six- and Seven-Membered Carba-Sugars
527
1H NMR (200 MHz, acetone-d6): d = 1.68 (dt, J = 3.9, 12.2 Hz, 1
H), 1.97 (s, 3 H), 2.02 (s, 3 H), 2.09–2.14 (m, 1 H), 2.40–2.55 (m, 1
H), 3.50 (dd, J = 6.8, 8.8 Hz, 1 H), 3.68 (dd, J = 7.9, 8.8 Hz, 1 H),
3.80 (t, J = 3.4 Hz, 1 H), 4.06 (t, J = 3.9 Hz, 1 H), 4.44 (d, J = 11.7
Hz, 1 H), 4.51 (s, 2 H), 4.57 (d, J = 11.2 Hz, 1 H), 4.64 (d, J = 15.1
Hz, 1 H), 4.73 (d, J = 11.7 Hz, 1 H), 5.17 (dt, J = 3.9, 11.2 Hz, 1 H),
5.29 (t, J = 3.4 Hz, 1 H), 7.23–7.39 (m, 15 H).
13C NMR (50 MHz, CDCl3): d = 20.8, 21.0, 24.2, 36.3, 69.3, 69.9,
70.5, 72.0, 72.8, 73.0, 73.6, 75.3, 127.5, 127.8, 128.2, 128.3, 137.8,
138.4, 170.1, 170.6.
1H NMR (200 MHz, CDCl3): d = 2.07–2.34 (m, 3 H), 3.39 (dd,
J = 4.6, 9.0 Hz, 1 H), 3.49 (dd, J = 7.6, 9.0 Hz, 1 H), 3.72 (dd,
J = 4.1, 7.0 Hz, 1 H), 4.01 (dd, J = 4.1, 7.5 Hz, 1 H), 4.10 (dd,
J = 2.9, 7.0 Hz, 1 H), 4.38 (br d, J = 12.2 Hz, 2 H), 4.47 (d, J = 11.7
Hz, 1 H), 4.58 (d, J = 11.7 Hz, 1 H), 4.66 (d, J = 11.7 Hz, 1 H), 4.74
(s, 2 H), 4.79 (d, J = 11.2 Hz, 1 H), 4.97 (br d, J = 10.2 Hz, 1 H),
5.02 (br d, J = 17.6 Hz, 1 H), 5.32 (br d, J = 16.6 Hz, 1 H), 5.33 (br
d, J = 10.3 Hz, 1 H), 5.60–5.80 (m, 1 H), 5.89–6.07 (m, 1 H), 7.29–
7.33 (m, 20 H).
13C NMR (50 MHz, CDCl3): d = 31.3, 39.6, 70.4, 70.6, 72.9, 74.2,
74.8, 78.9, 80.7, 83.0, 115.8, 118.5, 127.5, 128.2, 135.8, 137.6,
138.2, 138.7, 139.4.
Anal. Calcd for C32H36O7: C, 72.16; H, 6.81. Found: C, 71.94; H,
6.86.
MS (EI): m/z = 562 [M+].
(1S,2S,3S,4R,5S)-5-(Hydroxymethyl)cyclohexane-1,2,3,4-tetrol
(2)
A soln of crude 14 (50 mg, 0.11 mmol) in MeOH (5 mL) was hy-
drogenated in the presence of 10% Pd/C (10 mg) at r.t. After 4 h, the
mixture was filtered through a pad of Celite, and concentrated.
Yield: 18 mg (91%); [a]D25 +5.8 (c 1.5, MeOH) {Lit.10 [a]D25 +7.0
(c 1.5, MeOH)}.
1H NMR (500 MHz, D2O): d = 1.68 (dt, J = 4.4, 13.5 Hz, 1 H), 1.75
(dt, J = 9.2, 13.5 Hz, 1 H), 2.08–2.18 (m, 1 H), 3.68 (dd, J = 6.4,
10.7 Hz, 1 H), 3.76 (dd, J = 6.6, 10.7 Hz, 1 H), 3.77 (t, J = 4.2 Hz,
1 H), 3.83 (t, J = 4.2 Hz, 1 H), 3.99 (t, J = 4.4 Hz, 2 H).
Anal. Calcd for C38H42O4: C, 81.10; H, 7.52. Found: C, 81.40; H,
7.35.
(3S,4R,5R,6S)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl]cy-
cloheptene (18)
Compound 17 (0.4 g, 0.7 mmol) was dissolved in anhyd CH2Cl2
(30 mL) and the soln was degassed with argon.
[Ru(=CHPh)Cl2(PCy3)2] (29 mg, 5 mol%) was added and the mix-
ture was stirred at r.t. for 20 h. The solvent was removed and the res-
idue was purified by column chromatography (silica gel, EtOAc–
light PE, 1:49); this gave 18 as a colorless oil.
Yield: 0.33 g (87%); [a]D25 +11.2 (c 1.0, CHCl3).
13C NMR (50 MHz, D2O–acetone-d6): d = 26.4, 38.5, 62.8, 68.2,
71.0, 71.5, 73.4.
1H NMR (500 MHz, CDCl3): d = 2.06–2.10 (m, 1 H), 2.30–2.37 (m,
1 H), 2.39–2.45 (m, 1 H), 3.41 (dd, J = 6.7, 8.8 Hz, 1 H), 3.55 (dd,
J = 7.7, 8.8 Hz, 1 H), 3.84 (dd, J = 4.8, 9.5 Hz, 1 H), 4.0 (dd, J = 2.3,
4.8 Hz, 1 H), 4.41 (dt, J = 1.7, 9.5 Hz, 1 H), 4.47 (d, J = 11.9 Hz, 1
H), 4.50 (d, J = 11.9 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 4.73 (d,
J = 11.1 Hz, 1 H), 4.76 (s, 2 H), 4.80 (d, J = 11.6 Hz, 1 H), 4.98 (d,
J = 11.1 Hz, 1 H), 5.71–5.78 (m, 2 H), 7.29–7.39 (m, 20 H).
13C NMR (125 MHz, CDCl3): d = 27.2, 38.4, 71.7, 72.9, 73.1, 74.3,
78.8, 81.5, 86.0, 127.3, 128.3, 129.5, 130.8, 138.4, 138.7, 138.9,
139.0.
Anal. Calcd for C7H14O5: C, 47.18; H, 7.92. Found: C, 47.44; H,
7.66.
(3S,4R,5R,6S)-4-(Benzyloxy)-6-[(benzyloxy)methyl]nona-1,8-
diene-3,5-diol (16)
Ph3P=CH2 {prepared from [PPh3Me]I (2.1 g, 5.17 mmol) and 1.6 M
n-BuLi (0.33 mL, 0.53 mmol)} was added dropwise to a soln of 8
(1.0 g, 2.6 mmol) in anhyd THF (10 mL) at –78 °C. After the mix-
ture had stirred at r.t. for 12 h, it was quenched by the addition of a
sat. aq soln of NH4Cl. The two layers were separated, and the organ-
ic layer was dried (Na2SO4) and concentrated. Purification of the
residue by column chromatography (silica gel, EtOAc–light PE,
1:4) furnished 16 as a colorless oil.
MS (EI): m/z = 443 [M+ – Bn].
Anal. Calcd for C36H38O4: C, 80.87; H, 7.16. Found: C, 80.99; H,
7.27.
Yield: 0.76 g (77%); [a]D25 –16.1 (c 1.0, CHCl3).
(1R,2R,3S,4S,5R,6S)-3,4,5-Tris(benzyloxy)-6-[(benzyl-
oxy)methyl]cycloheptane-1,2-diol (19)
1H NMR (200 MHz, CDCl3): d = 1.83–1.99 (m, 1 H), 2.17 (dt,
J = 8.2, 14.2 Hz, 1 H), 2.34–2.47 (m, 1 H), 2.68 (br s, 2 H), 3.45 (d,
J = 4.9 Hz, 2 H), 3.59 (t, J = 4.1 Hz, 1 H), 3.81 (br t, J = 4.7 Hz, 1
H), 4.31 (br t, J = 4.6 Hz, 1 H), 4.45 (br s, 2 H), 4.65 (d, J = 11.3 Hz,
1 H), 4.76 (d, J = 11.3 Hz, 1 H), 5.03 (br d, J = 10.0, 1 H), 5.07 (br
d, J = 17.3 Hz, 1 H), 5.25 (br dt, J = 1.4, 10.4 Hz, 1 H), 5.40 (br dt,
J = 1.4, 17.3 Hz, 1 H), 5.69–6.02 (m, 2 H), 7.25–7.40 (m, 10 H).
13C NMR (50 MHz, CDCl3): d = 31.5, 41.7, 70.6, 73.0, 73.2, 73.7,
81.9, 116.0, 116.3, 127.6, 128.0, 128.4, 137.1, 138.2, 138.4.
MS (EI): m/z = 382 [M+], 291 [M+ – Bn].
To a soln of 18 (30 mg, 56.17 mmol) in THF–H2O (1:1, 2 mL) was
added a 50 wt% soln of NMO in H2O (0.04 mL, 0.17 mmol) and a
0.04 M soln of OsO4 in toluene (0.06 mL, 2.24 mmol). After 5 h at
r.t., the mixture was diluted with EtOAc (10 mL), washed with H2O
(2 × 5 mL) and sat. Na2SO3 (1 × 5 mL), dried (Na2SO4), and con-
centrated. The crude product thus obtained was purified by column
chromatography (silica gel, EtOAc–light PE, 1:4); this gave 19 as a
clear liquid.
Yield: 29 mg (91%); [a]D25 –47.9 (c 2.7, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.42–1.47 (m, 1 H), 1.80–1.87 (m,
1 H), 2.29–2.35 (m, 1 H), 2.44 (br s, 1 H), 3.09 (s, 1 H), 3.20–3.27
(m, 2 H), 3.74 (dd, J = 2.2, 6.7 Hz, 1 H), 3.78 (dd, J = 1.4, 9.6 Hz,
1 H), 3.88–3.90 (m, 1 H), 3.92 (dd, J = 6.7, 9.6 Hz, 1 H), 4.03 (dd,
J = 1.4, 5.5 Hz, 1 H), 4.24 (d, J = 11.5 Hz, 1 H), 4.26, 4.40 (2d,
J = 11.9 Hz, 2 H), 4.51, 4.52 (2d, J = 11.5 Hz, 2 H), 4.54, 4.57 (2d,
J = 11.9 Hz, 2 H), 4.82 (d, J = 11.5 Hz, 1 H), 7.14–7.26 (m, 20 H).
13C NMR (50 MHz, CDCl3): d = 28.0, 32.4, 69.6, 71.4, 72.1, 72.2,
72.4, 72.5, 75.3, 75.7, 80.3, 83.3, 127.4–128.6, 137.9, 138.0, 138.3,
138.5.
Anal. Calcd for C24H30O4: C, 75.36; H, 7.91. Found: C, 75.11; H,
8.18.
(3S,4R,5R,6S)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)meth-
yl]nona-1,8-diene (17)
The benzylation of 16 (0.51 g, 1.3 mmol) was performed as de-
scribed in the preparation of 7 above; used were NaH (0.13 g, 3.3
mmol), TBAI (0.1 g, 0.27 mmol), and BnBr (0.3 mL, 2.9 mmol) in
DMF (10 mL); this gave 17 after purification by column chroma-
tography (silica gel, EtOAc–light PE, 1:19).
Yield: 0.54 g (72%); [a]D25 +27.8 (c 1.0, CHCl3).
Anal. Calcd for C36H40O6: C, 76.03; H, 7.09. Found: C, 76.17; H,
7.22.
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528
C. V. Ramana et al.
PAPER
P.; Herault, J.-P.; Herbert, J.-M.; Petitou, M.; Sinaÿ, P.
(1R,2R,3S,4S,5R,6S)-6-(Hydroxymethyl)cycloheptane-
1,2,3,4,5-pentol (3)
Chem. Eur. J. 2001, 7, 4821.
Compound 3 was obtained by the hydrogenation of 19 (20 mg, 35.2
mmol) with 10% Pd/C in MeOH (2 mL), by the same method as that
described above for the synthesis of 2 .
Yield: 6.7 mg (92%); [a]D25 –96.3 (c 0.7, MeOH).
1H NMR (200 MHz, D2O): d = 1.60–1.94 (m, 2 H), 2.07–2.27 (m, 1
H), 3.51–3.90 (m, 5 H), 4.01–4.09 (m, 1 H), 4.16–4.25 (m, 1 H).
(4) (a) Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455.
(b) Ogawa, S.; Ara, M.; Kondoh, T.; Saitoh, M.; Masuda, R.;
Toyokuni, T.; Suami, T. Bull. Chem. Soc. Jpn. 1980, 53,
1121. (c) Ogawa, S.; Tsukiboshi, Y.; Iwasawa, Y.; Suami, T.
Carbohydr. Res. 1985, 136, 77. (d) Blattner, R.; Ferrier, R.
J. J. Chem. Soc., Chem. Commun. 1987, 1008. (e) Paulsen,
H.; von Deyn, W. Liebigs Ann. Chem. 1987, 125.
(f) Barton, D. H. R.; Géro, S. D.; Cléophax, J.; Machado, A.
S.; Quiclet-Sire, B. J. Chem. Soc., Chem. Commun. 1988,
1184. (g) Marco-Contelles, J.; Pozuelo, C.; Jimeno, M. L.;
Martinez, L.; Martinez-Grau, A. J. Org. Chem. 1992, 57,
2625. (h) Dalko, P. I.; Sinaÿ, P. Angew. Chem. Int. Ed. 1999,
38, 773. (i) Sollogoub, M.; Pearce, A. J.; Hérault, A.; Sinaÿ,
P. Tetrahedron: Asymmetry 2000, 11, 283. (j)Trotter, N. S.;
Larsen, D. S.; Stoodley, R. J.; Brooker, S. Tetrahedron Lett.
2000, 41, 8957.
13C NMR (50 MHz, D2O–acetone-d6): d = 27.6, 34.5, 64.4, 69.7,
71.8, 73.4, 74.5, 78.4.
Anal. Calcd for C8H16O6: C, 46.15; H, 7.75. Found: C, 45.87; H,
7.58.
Acknowledgment
S.R.C. is grateful to CSIR (New Delhi) for the award of a research
fellowship.
(5) Gurjar, M. K.; Chaudhuri, S. R. Tetrahedron Lett. 2002, 43,
2435.
(6) Parolis, H. Carbohydr. Res. 1983, 114, 21.
(7) (a) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013.
(b) Yet, L. Chem. Rev. 2000, 100, 2963. For a latest
comprehensive review on the utilization of RCM in
carbohydrate chemistry, see: (c) Roy, R.; Das, S. K. Chem.
Commun. 2000, 519.
(8) (a) Manna, S.; Jacques, Y. P.; Falck, J. R. Tetrahedron Lett.
1986, 27, 2679. (b) Gurjar, M. K.; Patil, V. J.; Pawar, S. M.
Carbohydr. Res. 1987, 165, 313.
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Synthesis 2007, No. 4, 523–528 © Thieme Stuttgart · New York