Synthesis of 3-(glycosyloxymethyl)isocoumarins and (S)-3- (glycosyloxymethyl)-3,4-dihydroisocoumarins by coupling of propargyl glycosides with 2-iodobenzoic acid mediated by palladium complex and zinc chloride

Article abstract of DOI:10.1055/s-2006-942504

Palladium-catalyzed coupling of propargyl glycosides with o-iodobenzoic acid leads to the selective syntheses of hitherto unknown, novel isocoumarin glycosides in 43-55% yields. We have observed that reduction of the keto acids to the corresponding alcoho

Full text of DOI:10.1055/s-2006-942504

2944
PAPER
Synthesis of 3-(Glycosyloxymethyl)isocoumarins and (S)-3-(Glycosyloxy-
methyl)-3,4-dihydroisocoumarins by Coupling of Propargyl Glycosides with
2-Iodobenzoic Acid Mediated by Palladium Complex and Zinc Chloride
S
ynthesisof 3-(G
l
a
ycosyloxym
r
ethyl)is
iocoumarins Babu Mereyala,* Gopal Pathuri
Organic Chemistry Division II, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27193382; E-mail: mereyalahb@rediffmail.com
Received 13 January 2006; revised 3 May 2006
the mild reaction conditions typically required to build
Abstract: Palladium-catalyzed coupling of propargyl glycosides
with o-iodobenzoic acid leads to the selective syntheses of hitherto
unknown, novel isocoumarin glycosides in 43–55% yields. We
have observed that reduction of the keto acids to the corresponding
isocoumarin glycoside frame-work bearing labile O-gly-
cosidic linkage and protecting groups, we considered pal-
ladium-catalyzed cross-coupling methodologies that have
alcohols was highly stereospecific due to the neighboring glycosyl become increasingly important for carbon–carbon bond
formation in organic synthesis.12 Of these, palladium-
phosphine complex and zinc chloride system, as reported
substitution and leads to the formation of (S)-3-(glycosyloxymeth-
yl)-3,4-dihydroisocoumarins in 21–37% overall yield.
Key words: palladium-catalyzed coupling, propargyl glycosides,
2-iodobenzoic acid, isocoumarin glycosides, (S)-3-(glycosyloxy-
methyl)-3,4-dihydroisocoumarins, antifungal
by Cheng and co-workers for coupling of 2-iodobenzoic
acid and methyl 2-iodobenzoate with internal alkynes to
prepare selectively isocoumarins rather than phthalides,
was selected.13
As a starting point for this study, the propargyl glycoside
derivatives 1a–e required for the coupling reaction were
synthesized by literature-described methods and fully
characterized.14 Compound 1a was prepared by reaction
of b-D-glucose pentaacetate with propargyl alcohol/
BF3·OEt2 and compounds 1b–e by O-alkylation of the
appropriate sugar alcohols with propargyl bromide/
NaH.14b
Isocoumarins and 3,4-dihydroisocoumarins are naturally
occurring lactones that display a wide range of biological
activities,1,2 such as antibacterial,3 anti-inflammatory,4 an-
tiulcer,5 antifungal (plant pathogenic fungi),6 sweetening7
and anti-trail pheromonal effects.1,2,8 Notable among them
are 3-hydroxymethylisocoumarin antibiotic cytogenin,5,9
several 3-alkylisocoumarin derivatives,6b and 3-hydroxy-
lated amino acid side-chain substituted dihydroisocou-
marin derivative AI-77-B,10 3-aminoalkyldihydro-
isocoumarin viz., amicoumacins and 3-aryldihydroiso-
coumarin viz., phyllodulcin.2a,11 Recently, the 3-aryl and
-alkyl side-chain was shown to be a prerequisite for high
antifungal activity against rice blast fungus pyricularia
grisea.6 As a part of our ongoing investigation, and con-
sidering the wealth of bioactivities found in isocoumarin
derivatives, we decided to examine the synthesis and an-
tifungal properties of hitherto-unknown isocoumarin and
3,4-dihydroisocoumarin glycoside scaffolds. Because of
14a
With the required propargyl glycosides in hand, the cou-
pling reaction of propargyl glucoside derivative 1a with 2-
iodobenzoic acid (2) was studied. Thus, reaction of 1a and
2 in presence of Pd(PPh3)4 (5% mol), ZnCl2 (1 mol equiv)
and Et3N (5 mol equiv) in DMF at 100 °C under nitrogen
for eight hours gave 3-glucopyranosyloxymethylisocou-
marin 3a (Table 1) in moderate yield (55%) (Scheme 1).13
The isocoumarin glycoside derivative 3a was character-
ized from 1H NMR spectrum by the appearance of H-4 at
d = 6.50 as a singlet and the anomeric proton H-1¢ at 4.44
Table 1 Isocoumarin Derivatives 3 Prepared
27
Entry
Propargyl glycoside
Product
3a
Yield (%)
Mp (°C)
114–115
syrup
[a]D
1
2
3
4
5
1a
1b
1c
1d
1e
55
45
44
43
45
–18.9 (c = 0.5, MeOH)
–30.3 (c = 0.1, CH2Cl2)
+51.2 (c = 0.05, CH2Cl2)
–28.0 (c = 0.1, CH2Cl2)
–55.8 (c = 1.0, CH2Cl2)
3b
3c
93–94
3d
136–138
134–136
3e
SYNTHESIS 2006, No. 17, pp 2944–2950
x
x.
x
x
.
2
0
0
6
Advanced online publication: 27.07.2006
DOI: 10.1055/s-2006-942504; Art ID: Z01506SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-(Glycosyloxymethyl)isocoumarins
2945
I
X
ii
i
X
H
CH2
+
O
43–55%
63–83%
CO2H
O
1a–e
2
3a–e
H
H
X
iii
X
iv
X
O
OH
O
78–83%
CO2H
CO2H
O
4b–e
5b–e
(S)-6b–e
O
O
O
O
O
O
O
OAc
OAc
H
X =
O
O
O
H
O
AcO
O
O
O
OAc
a
b
c
O
O
O
O
O
O
O
O
H
O
O
O
O
d
e
Scheme 1 Reagents and conditions: (i) Pd(Ph3P)4 (5 mol%), ZnCl2 (1 equiv), Et3N (5 equiv), DMF, 100 °C, 8 h; (ii) aq 5% KOH, EtOH,
reflux, 4 h; (iii) NaBH4, aq 1% NaOH, r.t., 2 h; (iv) Ac2O, reflux, 2 h
as a doublet (J1¢,2¢ = 9.1 Hz), and 13C NMR spectrum by rivative 1c with 2 under the same reaction conditions
the appearance of C-1 at d = 162.2, C-3 at 121.1, C-4 at afforded the corresponding 3-mannofuranosyloxymethyl-
105.1, C-1¢ at 100.5. Interestingly, the sensitive ester pro- isocoumarin derivative 3c in 44% yield (Table 1). Once
tecting groups of the sugar were tolerant of the reaction again similar yields were obtained due to the presence of
conditions.
labile isopropylidene protecting groups present on the
sugar. In an analogous manner, coupling of propargyl glu-
cofuranose derivative 1d with 2 gave the corresponding 3-
glucofuranosyloxymethylisocoumarin derivative 3d in
43% yield, and 1e with 2 gave 3-fructopyranosyloxy-
methylisocoumarin derivative 3e in 45% yield (Table 1).
The lower yields are reflective of sensitive cyclohexyl-
idene protecting groups of the sugar. The spectroscopic
features of isocoumarin glycosyl derivatives 3c, 3d and 3e
were analogous to products 3a and 3b and fully supported
the assigned structures. The reaction conditions were tol-
erant of ester, isopropylidene and cyclohexylidene pro-
tecting groups present on the propargyl glycoside
derivatives 1a–e.
After finding a suitable method for the synthesis of iso-
coumarin glycoside derivative 3a, we have explored the
applicability of this methodology for general synthesis of
several other isocoumarin glycosides. Thus, reaction of
propargyl galactoside derivative 1b with 2-iodobenzoic
acid (2) under the same conditions for eight hours afford-
ed 3-galactosyloxymethylisocoumarin 3b (Table 1) in
moderate yield (45%) (Scheme 1).13 The sensitive isopro-
pylidene protecting groups were tolerant of the reaction
conditions. The isocoumarin galactoside derivative 3b
was characterized from 1H NMR spectrum by the appear-
ance of H-4 at d = 6.63 as a singlet and the anomeric pro-
ton H-1¢ at 5.51 as a doublet (J1¢,2¢ = 3.8 Hz), and 13C NMR
spectrum by the appearance of C-1 at d = 162.2, C-3 at Next, we turned our attention to transform isocoumarin
122.7, C-4 at 103.9, C-1¢ at 96.3, and also from IR spec- glucosides 3a–e to the corresponding 3-glycosyloxymeth-
trum by the appearance of carbonyl absorption at 1731 yl-3,4-dihydroisocoumarin glycoside derivatives 6a–e by
cm–1 characteristic of isocoumarin.
a sequence of alkaline hydrolysis, reduction and cycliza-
tion reactions. Thus, reaction of 3a–e in aqueous 5% po-
tassium hydroxide in ethanol at reflux temperature for
four hours gave the corresponding lactone ring-opened
keto acids 4b–e, respectively, in good yields (63–83%).
The scope of the reaction was further extended for cou-
pling of propargyl glycoside derivatives 1c, 1d and 1e
with 2. Thus, coupling of propargyl mannofuranoside de-
Synthesis 2006, No. 17, 2944–2950 © Thieme Stuttgart · New York

2946
H. B. Mereyala, G. Pathuri
PAPER
Compound 4a could not be isolated under these reaction protecting groups. This approach in principle is applicable
conditions probably due to hydrolysis of alkali labile ester to the synthesis of other chiral 3,4-dihydroisocoumarins.
groups of the sugar. The keto acid 4b was characterized We have examined antifungal activity of all the new com-
from 1H NMR spectrum by the appearance of H-1¢ at d = pounds against five pathogens, however none showed ap-
5.48 (J1¢,2¢ = 3.7 Hz) as a doublet, methylene protons adja- preciable activity.
cent to carbonyl group at 3.69 (1 H) and 3.55 (1 H) as AB-
type doublets (Jgem = 12.0 Hz), benzyl protons (2 H) at
3.20 (1 H) and 3.17 (1 H) as AB-type doublets
point apparatus and are uncorrected. IR spectra were recorded on a
Melting points were determined by using Fisher John’s melting
(Jgem = 14.0 Hz) and by the appearance of carbonyl ab-
sorptions at 1725 and 1693 cm–1 in the IR spectrum. The
keto acids 4c, 4d and 4e were fully characterized analo-
gous to 4b.
Thermo Nicolet Nexus 670 FT-IR spectrometer. FAB Mass Spectra
were recorded on an AUTO SPEC-M (Manchester, UK) mass spec-
trometer. 1H NMR spectra in CDCl3 were recorded at 300 MHz on
a Bruker Avance and at 400 MHz on a Unity FT-NMR spectrometer
with TMS as an internal standard (chemical shifts in d, ppm). 13C
NMR spectra in CDCl3 were recorded exclusively at 300 MHz on a
The critical reduction step of keto acids 4b–e was carried
out with sodium borohydride in aqueous 1% NaOH at Bruker Avance FT-NMR spectrometer. Optical rotations were mea-
sured with a JASCO DIP-370 instrument. All CD spectra were re-
room temperature for twohours to afford the correspond-
ing alcohols 5b–e in good yields (69–85%).6a The hy-
corded on JASCO 810 spectrophotometer on methanolic solutions
of products. For column chromatography, silica gel 60–120 mesh
droxy acids 5b–e could not be characterized by NMR
analysis due to rapid cyclization to the corresponding di-
was used. For TLC, silica gel 60 F254 (Merck) was used.
hydroisocoumarin glycosides 6b–e during work-up. The
1,2:5,6-Di-O-cyclohexylidene-3-O-(prop-2-ynyl)-a-D-gluco-
hydroxy acids 5b–e were alternatively cyclized by heating
to reflux in Ac2O for two hours to isolate the correspond-
ing 3-glycosyloxymethyl-3,4-dihydroisocoumarins 6b–e
in good yields (78–82%). The dihydroisocoumarin deriv-
atives 6b–e were found to be nearly single isomers by 1H
NMR spectra and were purified by column chromatogra-
phy. The 3,4-dihydroisocoumarin glycoside derivative 6b
furanoside (1d)
To a solution of 1,2:5,6-di-O-cyclohexylidene-a-D-glucofuranose
(5.0 g, 14.7 mmol) in DMF (10 mL) at 5 °C was added NaH (0.9 g,
37.5 mmol) and the mixture was stirred for 15 min. The mixture was
cooled to 0 °C and propargyl bromide (1.75 g, 14.7 mmol) was add-
ed dropwise. The mixture was brought to r.t. and stirred for 2 h. The
reaction was quenched by the addition of MeOH (0.5 mL), diluted
with H2O (100 mL) and extracted with Et2O (2 × 50 mL). The com-
bined organic phases were washed with H2O (2 × 50 mL), dried
(Na2SO4) and evaporated on a rotary evaporator to obtain 1d; yield:
4.2 g (76%); colorless syrup; [a]D27 +2.0 (c = 0.5, CH2Cl2).
1
was characterized from H NMR spectrum from the ap-
pearance of H-1¢ at d = 5.45 (d, J1¢, 2¢ = 3.5 Hz), H-3 as a
multiplet at 4.70–4.60, H-4 at 3.20–2.95 as a multiplet,
and 13C NMR spectrum from the appearance of C-1 at d =
164.9, C-1¢ at 96.3, and from the lactone carbonyl absorp-
tion at 1724 cm–1 in the IR spectrum. The 3, 4-dihydroiso-
IR (film): 2118 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.81 (d, J1,2 = 3.9 Hz, 1 H, H-1),
4.52 (d, J = 3.9 Hz, 1 H, H-2), 4.27 (d, J = 1.2 Hz, 2 H, OCH2), 4.21
coumarin glycosides 6c–e were characterized in a similar (m, 1 H, H-4), 4.15–3.90 (m, 4 H, H-3,5,6,6¢), 2.42 (t, J = 1.2 Hz, 1
way from the 1H NMR spectra.
H, C≡CH), 1.75–1.30 (m, 20 H, cyclohexylidene).
ESI MS: m/z = 401 [M + Na]+, 379 [M + H]+.
The absolute configuration of the dihydroisocoumarin
Anal. Calcd for C21H30O6: C, 66.64; H, 7.98. Found: C, 66.82; H,
7.89.
glycosides 6b–e was determined as S at C-3 by analysis of
their CD spectra15a and by direct comparison with related
compounds of known stereochemistry, such as (S)-3-(hy-
droxymethyl)-5,7-dimethoxydihydroisocoumarin.15b The
compounds 6b–e showed the CD bands at 296–286, 288–
277, 244–237, 227–222 and 205–204 nm, with negative
sign. The selectivity observed for stereospecific reduction
of keto acids could be attributed to the neighboring gly-
cosyl substitution and thus, this methodology has advan-
tages over the existing methods.
1,2:4,5-Di-O-cyclohexylidene-3-O-(prop-2-ynyl)-a-D-fructo-
pyranoside (1e)
To a solution of 1,2:4,5-di-O-cyclohexylidene-a-D-fructopyranose
(5.1 g, 15.0 mmol) in DMF (12 mL) at 5 °C was added NaH (0.9 g,
37.5 mmol) and the mixture was stirred for 15 min. The mixture was
cooled to 0 °C and propargyl bromide (1.75 g, 14.7 mmol) was add-
ed dropwise. The mixture was brought to r.t. and stirred for 2 h. The
reaction was quenched by addition of MeOH (0.6 mL), diluted with
H2O (100 mL) and extracted with Et2O (2 × 50 mL). The combined
organic phases were washed with H2O (2 × 50 mL), dried (Na2SO4)
and evaporated on a rotary evaporator to obtain 1e; yield: 4.1 g
(72%); colorless syrup; [a]D27 –38.5 (c = 1.00, CHCl3).
In summary, a general synthesis of novel isocoumarin
glycosides 3a–e and (S)-3-glycosyloxymethyl-3,4-dihy-
droisocoumarins 6b–e in moderate yields (21–37%) has
been achieved by palladium/ZnCl2 mediated coupling of
various terminal acetylene glycosides with 2-iodobenzoic
acid (2). It was established that the reaction conditions are
IR (film): 2357 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.41 (d, J = 1.2 Hz, 2 H, OCH2),
4.30–4.15 (m, 3 H, H-4,5,6), 4.08 (d, J1,1¢ = 13.1 Hz, 1 H, H-1), 3.96
selective to afford isocoumarins; they are also mild, and (d, J = 13.1 Hz, 1 H, H-1¢), 3.84 (d, J6,6¢ = 8.7 Hz, 1 H, H-6¢), 3.66
(d, J3,4 = 7.3 Hz, 1 H, H-3), 2.37 (t, J = 1.2 Hz, 1 H, C≡CH), 1.80–
1.25 (m, 20 H, cyclohexylidene).
tolerant of sensitive isopropylidene, cyclohexylidene and
acetate protecting groups of the glycosides. Isocoumarin
glycosides 3a–e, upon alkaline hydrolysis, stereospecific
ESI MS: m/z = 401 [M + Na]+, 379 [M + H]+.
reduction, and cyclization, give the corresponding (S)-3-
glycosyloxymethyl-3,4-dihydroisocoumarins 6b–e in
good yields, except the glycoside 6a which bears acetate
Anal. Calcd for C21H30O6: C, 66.64; H, 7.98. Found: C, 66.83; H,
7.82.
Synthesis 2006, No. 17, 2944–2950 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(Glycosyloxymethyl)isocoumarins
IR (KBr): 1732 cm–1.
2947
3-[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxymeth-
yl)]isocoumarin (3a)
1H NMR (400 MHz, CDCl3): d = 8.25 (d, J7,8 = 7.5 Hz, 1 H, H-8),
7.70 (t, J7,8 = J6,7 = 7.5 Hz, 1 H, H-7), 7.50 (t, J6,7 = J5,6 = 7.5 Hz, 1
H, H-6), 7.40 (d, J = 7.5 Hz, 1 H, H-5), 6.44 (s, 1 H, H-4), 5.08 (d,
To a solution of 2-iodobenzoic acid (2; 3.7 g, 15.0 mmol) in DMF
(5 mL) was added prop-2-ynyl (2,3,4,6-tetra-O-acetyl)-b-D-glu-
copyranoside (1a; 7.68 g, 18.0 mmol), Et3N (7.59 g, 75.0 mmol),
Pd(PPh3)4 (0.87 g, 0.75 mmol), and ZnCl2 (2.04 g, 15.0 mmol) un-
der N2 and heated to 100 °C for 8 h. The mixture was column chro-
matographed [SiO2, EtOAc–hexane (1:9)] to isolate 3a; yield: 4.2 g
J1¢,2¢ = 3.1 Hz, 1 H, H-1¢), 4.79 (dd, J2¢,3¢ = 3.3 Hz, 1 H, H-2¢), 4.66
(dd, J3¢,4¢ = 5.5 Hz, 1 H, H-3¢), 4.51 (m, 1 H, H-4¢), 4.30 (AB-type
doublet, Jgem = 10.3 Hz, 1 H, OCH2), 4.10–3.95 (m, 3 H, H-
5¢,6¢,6¢¢), 1.46, 1.38, 1.34, 1.30 [4 s, 12 H, 2 × (CH3)2CO2].
27
(55%); colorless solid; mp 114–115 °C; [a]D –18.2 (c = 0.5,
MeOH).
13C NMR (50 MHz, CDCl3): d = 162.0 (C-1), 152.7 (C-8a), 136.5
(C-4a), 134.8, 129.7, 128.5, 125.6 (arom), 120.8 (C-3), 112.8, 109.2
(2 × Me2CO2), 106.0 (C-1¢), 104.6 (C-4), 85.0, 80.8, 79.4, 73.0,
67.6, 65.1 (C-2¢,3¢,4¢,5¢,6¢, CH2O), 26.8, 25.8, 25.1, 24.5 [2 ×
(CH3)2CO2].
IR (KBr): 1760, 1720 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.25 (d, J7,8 = 7.7 Hz, 1 H, H-8),
7.65 (dd, J6,7 = 7.6 Hz, 1 H, H-7), 7.50 (dd, J5,6 = 7.7 Hz, 1 H, H-6),
7.38 (d, J = 7.7 Hz, 1 H, H-5), 6.50 (s, 1 H, H-4), 5.25–5.05 (m, 3
H, H-2¢,3¢,4¢), 4.68–4.60 (m, 1 H, H-6¢), 4.44 (d, J1¢,2¢ = 9.1 Hz, 1 H,
H-1¢), 4.35–4.25 (m, 1 H, H-6¢¢), 4.15–4.05 (m, 2 H, CH2O), 3.78–
3.70 (m, 1 H, H-5), 2.10, 2.04, 2.00, 1.96 (4 s, 12 H, OCOCH3).
FAB MS: m/z = 419 [M + H]+.
Anal. Calcd for C22H26O8: C, 62.84; H, 6.71. Found: C, 62.95; H,
6.79.
13C NMR (50 MHz, CDCl3): d = 170.9, 170.4, 169.7 × 2 (4 ×
OCOCH3), 162.2 (C-1), 152.5 (C-8a), 136.8 (C-4a), 135.3, 130.1,
128.7, 126.2 (arom), 121.1 (C-3), 105.1 (C-4), 100.5 (C-1¢), 73.0,
72.4, 71.6, 68.7, 67.4 (C-2¢,3¢,4¢,5¢,6¢), 62.2 (CH2O), 20.9 × 2,
20.8 × 2 (4 × CH3).
3-[3-(1,2:5,6-Di-O-cyclohexylidene-a-D-glucofuranosyloxy-
methyl)]isocoumarin (3d)
To a solution of 2-iodobenzoic acid (2; 4.0 g, 16.1 mmol) in DMF
(16 mL) was added 1,2:5,6-di-O-cyclohexylidene-3-O-(prop-2-
ynyl)-a-D-glucofuranoside (1d; 6.1 g, 16.1 mmol), Et3N (8.09 g, 80
mmol), Pd(PPh3)4 (0.93 g, 0.8 mmol), and ZnCl2 (2.18 g, 16.0
mmol) under N2 and heated to 100 °C for 8 h. Progress of the reac-
tion was monitored by TLC. After work-up, the residue obtained
was column chromatographed [SiO2, EtOAc–hexane (1:9)] to iso-
FAB MS: m/z = 507 [M + H]+.
Anal. Calcd for C24H26O12: C, 56.92; H, 5.20. Found: C, 57.12; H,
5.11.
27
late 3d; yield: 3.47 g (43%); white solid; mp 136–138 °C; [a]D
–28.0 (c = 0.1, CH2Cl2).
3-[6-(1,2:3,4-Di-O-isopropylidene-a-D-galactopyranosyloxy-
methyl)]isocoumarin (3b)
To a solution of 2-iodobenzoic acid (2; 4.0 g, 16.1 mmol) in DMF
(16 mL) was added 1,2:3,4-di-O-isopropylidene-6-O-(prop-2-yn-
yl)-a-D-galactopyranoside (1b; 4.8 g, 16.1 mmol), Et3N (8.0 g, 80
mmol), Pd(PPh3)4 (0.96 g, 0.8 mmol), and ZnCl2 (2.18 g, 16 mmol)
under N2 and heated to 100 °C for 8 h. The mixture was chromato-
graphed [SiO2, EtOAc–hexane (1:3)] to isolate 3b; yield: 3.06 g
(45%); colorless syrup; [a]D27 –30.3 (c = 0.1, CH2Cl2).
IR (KBr): 1728 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J7,8 = 7.7 Hz, 1 H, H-8),
7.72 (t, J7,8 = J6,7 = 7.7 Hz, 1 H, H-7), 7.52 (t, J6,7 = J5,6 = 7.7 Hz, 1
H, H-6), 7.40 (d, J = 7.7 Hz, 1 H, H-5), 6.62 (s, 1 H, H-4), 5.84 (d,
J1¢,2¢ = 3.7 Hz, 1 H, H-1¢), 4.60 (d, J = 3.7 Hz, 1 H, H-2¢), 4.52, 4.45
(AB-type doublet, Jgem = 10.1 Hz, 2 H, OCH2), 4.35–4.30 (m, 1 H,
H-3¢), 4.15–4.00 (m, 4 H, H-4¢,5¢,6¢,6¢¢), 1.73–1.35 (m, 20 H, cyclo-
hexylidene).
IR (film): 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.27 (d, J7,8 = 7.5 Hz, 1 H, H-8),
7.67 (dd, J6,7 = 7.7 Hz, 1 H, H-7), 7.47 (dd, J5,6 = 7.6 Hz, 1 H, H-6),
7.38 (d, J = 7.6 Hz, 1 H, H-5), 6.63 (s, 1 H, H-4), 5.51 (d, J1¢,2¢ = 3.8
Hz, 1 H, H-1¢), 4.61 (dd, J3,4 = 3.4 Hz, J2,3 = 8.5 Hz, 1 H, H-3¢),
4.43, 4.35 (AB-type doublet, Jgem = 10.5 Hz, 2 H, OCH2), 4.30–4.20
(m, 2 H, H-2¢,4¢), 3.97 (m, 1 H, H-5¢), 3.85–3.60 (m, 2 H, H-6¢,6¢¢),
1.52, 1.41, 1.32, 1.21 [4 s, 12 H, 2 × (CH3)2CO2].
13C NMR (50 MHz, CDCl3): d = 161.9 (C-1), 152.9 (C-8a), 136.6
(C-4a), 134.7, 129.6, 128.3, 125.5 (arom), 120.7 (C-3), 112.6, 109.7
(2 × CO2), 105.9 (C-1¢), 103.4 (C-4), 82.3 × 2, 81.2, 71.8, 68.3, 67.2
(C-2¢,3¢,4¢,5¢,6¢, CH2O), 35.6, 34.7, 25.0, 23.4 (cyclohexylidene).
FAB MS: m/z = 498 [M + H]+.
Anal. Calcd for C28H33O8: C, 67.59; H, 6.68. Found: C, 67.72; H,
6.73.
13C NMR (50 MHz, CDCl3): d = 162.2 (C-1), 153.6 (C-8a), 136.8
(C-4a), 134.7, 129.6, 128.1, 125.6 (arom), 122.7 (C-3), 109.3, 108.6
(2 × Me2CO2), 103.9 (C-4), 96.3 (C-1¢), 71.1, 70.7, 70.5, 69.9, 69.3,
66.9 (C-2¢,3¢,4¢,5¢,6¢ and CH2O), 26.0, 25.9, 24.9, 24.4 [2 ×
(CH3)2CO2].
3-[3-(1,2:4,5-Di-O-cyclohexylidene-a-D-fructopyranosyloxy-
methyl)]isocoumarin (3e)
To a solution of 2-iodobenzoic acid (2; 3.0 g, 12.0 mmol) in DMF
(12 mL) was added 1,2:4,5-di-O-cyclohexylidene-3-O-(prop-2-yn-
yl)-a-D-fructopyranoside (1e; 4.5 g, 12.0 mmol), Et3N (6.00 g, 60.0
mmol), Pd(PPh3)4 (0.70 g, 0.6 mmol), and ZnCl2 (1.60 g, 12 mmol)
under N2 and heated to 100 °C for 8 h. Progress of the reaction was
monitored by TLC. After completion of the reaction, the mixture
was worked up and the residue obtained was column chromato-
graphed [SiO2, neat hexane] to isolate 3e; yield: 2.70 g (45%); col-
orless solid; mp 134–136 °C; [a]D27 –55.8 (c = 1.0, CH2Cl2).
FAB MS: m/z = 419 [M + H]+.
Anal. Calcd for C22H26O8: C, 63.14; H, 6.26. Found: C, 63.28; H,
6.17.
3-(2,3:5,6-Di-O-isopropylidene-b-D-mannofuranosyloxymeth-
yl)isocoumarin (3c)
To a solution of 2-iodobenzoic acid (2; 4.0 g, 16.0 mmol) in DMF
(16 mL) was added prop-2-ynyl 2,3:5,6-di-O-isopropylidene-b-D-
mannofuranoside (1c; 4.77 g, 16.0 mmol), Et3N (8.09 g, 80.0
mmol), Pd(PPh3)4 (0.93 g, 0.8 mmol), and ZnCl2 (2.18 g, 16.0
mmol) under N2 and heated to 100 °C for 8 h. The progress of the
reaction was monitored by TLC. After completion of the reaction,
the mixture was chromatographed [SiO2, EtOAc–hexane (1:19)] to
IR (KBr): 1737 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24 (d, J7,8 = 7.7 Hz, 1 H, H-8),
7.65 (dd, J6,7 = 7.6 Hz, 1 H, H-7), 7.47 (dd, J5,6 = 7.8 Hz, 1 H, H-6),
7.35 (d, J = 7.8 Hz, 1 H, H-5), 6.52 (s, 1 H, H-4), 4.78, 4.50 (AB-
type doublet, Jgem = 13.6 Hz, 2 H, OCH2), 4.35 (dd, J3¢,4¢ = 7.2 Hz,
J
4¢,5¢ = 4.8 Hz, 1 H, H-4¢), 4.20–4.05 (m, 2 H, H-5¢,6¢), 4.12 (d,
1¢,1¢¢ = 12.5 Hz, 1 H, H-1¢, merged), 3.96 (d, J6¢,6¢¢ = 7.95 Hz, 1 H, H-
27
isolate 3c; yield: 2.96 g (44%); colorless solid; mp 93–94 °C; [a]D
+51.2 (c = 0.5, CH2Cl2).
J
Synthesis 2006, No. 17, 2944–2950 © Thieme Stuttgart · New York

2948
H. B. Mereyala, G. Pathuri
PAPER
1¢¢), 3.91 (d, J6¢,6¢¢ = 7.95 Hz, 1 H, H-6¢¢), 3.47 (d, J = 7.2 Hz, 1 H,
H-3¢), 1.80–1.20 (m, 20 H, cyclohexylidene).
Anal. Calcd for C22H28O9: C, 60.54; H, 6.47. Found: C, 60.73; H,
6.55.
13C NMR (50 MHz, CDCl3): d = 162.1 (C-1), 152.1 (C-8a), 136.7
(C-4a), 134.8, 129.7, 128.2, 125.6 (arom), 121.0 (C-3), 112.9, 109.9
(2 × CO2), 104.7 (C-4), 103.7 (C-2¢), 77.6, 77.0, 73.5, 71.5, 68.8,
60.4 (C-1¢,3¢,4¢,5¢,6¢, CH2O), 38.0, 36.5, 35.4, 24.9, 23.8, 23.6 (cy-
clohexylidene).
2[3-(1,2:5,6-Di-O-cyclohexylidene-a-D-glucofuranosyl)-2-oxo-
propyl]benzoic Acid (4d)
To a solution of 3d (3.08 g, 6.2 mmol) in EtOH (132 mL) was add-
ed 5% aq KOH (220 mL) and the mixture was refluxed for 4 h.
Progress of the reaction was monitored by TLC. After completion
of reaction, the mixture was cooled to r.t., acidified with 10% aq
HCl (176 mL), and extracted with CH2Cl2 (2 × 30 mL) and EtOAc
(2 × 25 mL). The combined organic phases were washed with H2O
(2 × 50 mL), dried (Na2SO4) and evaporated on a rotary evaporator
to obtain the title compound 4d; yield: 2.64 g (83%); colorless solid;
mp 145–147 °C; [a]D27 –16.0 (c = 0.25, CH2Cl2).
FAB MS: m/z = 521 [M + Na].
Anal. Calcd for C28H33O8: C, 67.18; H, 7.24. Found: C, 67.27; H,
7.16.
2[3-{6-(1,2:3,4-Di-O-isopropylidene-a-D-galactopyranosyl)-2-
oxopropyl)}]benzoic Acid (4b)
IR (film): 3418, 1726, 1695 cm–1.
To a solution of 3b (3.24 g, 7.7 mmol) in EtOH (144 mL) was added
aq 5% KOH (270 mL) and refluxed for 4 h. Progress of the reaction
was monitored by TLC. After completion of the reaction, the mix-
ture was cooled to r.t., acidified with 10% aq HCl (90 mL), and ex-
tracted with CH2Cl2 (2 × 40 mL) and EtOAc (2 × 25 mL). The
combined organic phases were washed with H2O (2 × 20 mL), dried
(Na2SO4) and evaporated on a rotary evaporator to obtain the title
1H NMR (400 MHz, CDCl3): d = 8.05 (d, J5,6 = 7.2 Hz, 1 H, H-6),
7.58 (dd, J4,5 = 7.1 Hz, 1 H, H-5), 7.42 (dd, J3,4 = 7.2 Hz, 1 H, H-4),
7.18 (dd, J = 7.2 Hz, 1 H, H-3), 5.86 (2 d, J1¢,2¢ = 3.8 Hz, 1 H, H-1¢),
4.64–3.50 (m, 8 H, H-2¢,3¢,4¢,5¢,6¢,6¢¢, OCH2CO), 3.20–2.90 (m, 2
H, PhCH2), 1.85–1.30 (m, 20 H, cyclohexylidene).
13C NMR (50 MHz, CDCl3): d = 204.9 (C=O), 164.3 (CO2H),
136.0, 133.8, 130.2, 129.9, 128.5, 127.4 (arom), 112.7, 110.2 (2 ×
CO2), 105.1 (C-1¢), 82.1 × 2, 81.4 × 2, 72.5, 67.3 (C-2¢,3¢,4¢,5¢,6¢,
OCH2CO), 36.4, 36.2, 35.6, 34.3, 24.8, 24.7, 23.7 × 2 (cyclohexyl-
idene, PhCH2CO).
27
compound 4b; yield: 2.82 g (84%); colorless syrup; [a]D –23.4
(c = 0.25, CHCl3).
IR (KBr): 1725, 1693 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.10 (d, J5,6 = 7.1 Hz, 1 H, H-6),
7.51 (dd, J4,5 = 7.2 Hz, 1 H, H-5), 7.40 (dd, J3,4 = 7.1 Hz, 1 H, H-4),
7.18 (d, J = 7.4 Hz, 1 H, H-3), 5.48 (d, J1¢,2¢ = 3.7 Hz, 1 H, H-1¢),
4.59 (m, 1 H, H-3¢), 4.40–3.70 (m, 5 H, H-2¢,4¢,5¢,6¢,6¢¢), 3.69, 3.55
(AB-type doublet, Jgem = 12.0 Hz, 2 H, OCH2CO), 3.20, 3.17 (AB-
type doublet, Jgem = 14.0 Hz, 2 H, C6H5CH2), 1.56, 1.51, 1.48, 1.43
[4 s, 12 H, 2 × (CH3)2CO2].
ESI MS: m/z = 539 [M + Na]+, 517 [M + H]+.
Anal. Calcd for C28H36O9: C, 65.10; H, 7.02. Found: C, 65.32; H,
7.09.
2[3-(1,2:4,5-Di-O-cyclohexylidene-a-D-fructopyranosyl)-2-oxo-
propyl]benzoic Acid (4e)
13C NMR (50 MHz, CDCl3): d = 204.7 (C=O), 165.1 (CO2H),
136.3, 133.6, 130.1, 129.0, 127.3, 127.2 (arom), 109.1, 108.2 (2 ×
Me2CO2), 96.1 (C-1¢), 71.0, 70.7 × 2, 70.5, 70.3, 66.8 (C-
2¢,3¢,4¢,5¢,6¢, OCH2CO), 36.2, 25.9, 25.8, 24.8, 24.3 [PhCH2CO, ×
(CH3)2CO2].
To a solution of 3e (2.30 g, 4.6 mmol) in EtOH (90 mL) was added
5% aq KOH (180 mL), and the mixture was refluxed for 4 h. The
progress of the reaction was monitored by TLC. After completion
of reaction, the mixture was cooled to r.t., acidified with 10% aq
HCl (120 mL), and extracted with CH2Cl2 (2 × 25 mL) and EtOAc
(2 × 25 mL). The combined organic phases were washed with H2O
(2 × 50 mL), dried (Na2SO4) and evaporated on a rotary evaporator
to obtain the title compound 4e; yield: 1.51 g (63%); colorless solid;
mp 140–142 °C, [a]D27 –32.4 (c = 0.25, CHCl3).
ESI MS: m/z = 459 [M + Na]+, 437 [M + H]+.
Anal. Calcd for C22H21O9: C, 60.54; H, 6.47. Found: C, 60.67; H,
6.38.
IR (KBr): 1727, 1695 cm–1.
2[3-{1-(2,3:5,6-Di-O-isopropylidene-b-D-mannofuranosyl)-2-
oxopropyl)}]benzoic Acid (4c)
1H NMR (400 MHz, CDCl3): d = 8.10 (d, J5,6 = 7.4 Hz, 1 H, H-6),
7.51 (dd, J4,5 = 7.2 Hz, 1 H, H-5), 7.42 (dd, J3,4 = 7.4 Hz, 1 H, H-4),
7.18 (d, 1 H, H-3), 4.50–3.50 (m, 9 H, H-1¢,1¢¢, 3¢, 4¢, 5¢,6¢,6¢¢,
OCH2CO), 3.20–2.90 (m, 2 H, PhCH2CO), 1.85–1.30 (m, 20 H, cy-
clohexylidene).
To a solution of 3c (3.24 g, 7.7 mmol) in EtOH (144 mL), was added
aq 5% KOH (270 mL), and the mixture was refluxed for 4 h.
Progress of the reaction was monitored by TLC. After completion
of reaction, the mixture was cooled to r.t., acidified with 10% aq
HCl (90 mL), and extracted with CH2Cl2 (2 × 40 mL) and EtOAc
(2 × 25 mL). The combined organic phases were washed with H2O
(2 × 20 mL), dried (Na2SO4) and evaporated on a rotary evaporator
to obtain the title compound 4c; yield: 2.52 g (75%); colorless syr-
up; [a]D27 +12.0 (c = 0.25, CH2Cl2).
13C NMR (50 MHz, CDCl3): d = 204.7 (C=O), 164.1 (CO2H),
136.3, 133.7, 130.0, 128.3, 127.4 × 2 (arom), 112.6, 110.0 (2 ×
CO2), 103.6 (C-2¢), 76.4, 75.9, 75.6, 73.2, 71.4, 60.6 (C-1¢, 3¢, 4¢, 5¢,
6¢, OCH2CO), 37.7, 35.2, 24.9, 24.8, 23.8, 23.6 (cyclohexylidene,
PhCH2CO).
IR (film): 3416, 1739, 1688 cm–1.
ESI MS: m/z = 539 [M + Na]+, 517 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 8.08 (d, J5,6 = 7.5 Hz, 1 H, H-6),
7.55–7.15 (m, 3 H, H-3,4,5), 5.10–5.04 (2 d, J1¢,2¢ = 3.8 Hz, 1 H, H-
1¢), 4.95–4.25 (m, 5 H, H-2¢,3¢,4¢-OCH2CO), 4.10–3.80 (m, 3 H, H-
5¢,6¢,6¢¢), 3.30–2.95 (m, 2 H, PhCH2CO), 1.45 × 2, 1.34, 1.25 [4 s,
12 H, 2 × (CH3)2CO2].
Anal. Calcd for C28H36O9: C, 65.10; H, 7.02. Found: C, 65.32; H,
7.09.
(S)-3-[6-(1,2:3,4-Di-O-isopropylidene-a-D-galactopyranosyl-
oxymethyl)]-3,4-dihydroisocoumarin (6b)
13C NMR (50 MHz, CDCl3): d = 205.1 (C=O), 165.8 (CO2H),
136.9, 130.6, 130.2, 127.4 × 2 (arom), 112.7, 109.2 (2 × Me2CO2),
106.3 (C-1¢), 84.7, 80.3, 79.2, 73.0, 71.2, 66.4 (C-2¢, 3¢, 4¢, 5¢, 6¢,
OCH2CO), 29.5, 26.6, 25.7, 25.0, 24.3 [PhCH2CO, 2 × (CH3)2CO2].
To a solution of compound 4b (1.3 g, 3.0 mmol) in 1% aq NaOH
(34 mL) was added NaBH4 (0.3 g) at 0 °C. The mixture was stirred
for 2 h at r.t. and acidified with 10% aq HCl (120 mL) and extracted
with EtOAc (2 × 30 mL). The combined organic phases were
washed with H2O (2 × 15 mL), dried (Na2SO4) and evaporated on a
rotary evaporator to obtain 5b (1.05 g, 80) as a syrup. A solution of
ESI MS: m/z = 459 [M + Na]+, 437 [M + H]+.
Synthesis 2006, No. 17, 2944–2950 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(Glycosyloxymethyl)isocoumarins
2949
5b (0.9 g, 2 mmol) in Ac2O (2 mL) was refluxed for 2 h. After com-
pletion of the reaction, the mixture was cooled, H2O (10 mL) was
added, stirred for 15 min, and extracted with CH2Cl2 (2 × 20 mL).
The combined organic phases were washed with H2O, dried
(Na2SO4) and evaporated on a rotary evaporator to obtain the title
compound 6b; yield: 0.7 g (81%); colorless syrup; [a]D27 –46.0 (c =
0.25, CH2Cl2).
and acidified with 10% aq HCl (80 mL) and extracted with EtOAc
(2 × 30 mL). The combined organic phases were washed with H2O
(2 × 20 mL), dried (Na2SO4) and evaporated on a rotary evaporator
to give 5c (0.8 g, 79.6%) as a syrup. A solution of 5d (0.5 g, 1 mmol)
in Ac2O (1 mL) was refluxed for 2 h. After completion of the reac-
tion, the mixture was cooled to r.t., H2O (1 mL) was added, stirred
for 15 min and extracted with CH2Cl2 (2 × 30 mL). The combined
organic phases were washed with H2O (2 × 10 mL), dried (Na2SO4)
and evaporated on a rotary evaporator to obtain the crude compound
(0.82 g). The crude compound 6d was filtered on silica gel column
IR (film): 1724 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J7,8 = 7.7 Hz, 1 H, H-8),
7.50 (dd, J6,7 = 7.8 Hz, 1 H, H-7), 7.37 (dd, J5,6 = 7.7 Hz, 1 H, H-6),
7.23 (d, J = 7.7 Hz, 1 H, H-5), 5.45 (d, J1¢,2¢ = 3.5 Hz, 1 H, H-1¢),
4.65 (m, 1 H, H-3), 4.55 (dd, J3¢,4¢ = 2.8 Hz, J4¢,5¢ = 3.2 Hz, 1 H, H-
4¢), 4.23 (m, 1 H, CH2O), 3.95–3.60 (m, 5 H, H-2¢,3¢,5¢,6¢,6¢¢), 3.20–
2.95 (m, 2 H, H-4), 1.52, 1.41, 1.31, 1.24 [4 s, 12 H, 2 × (CH3)2CO2].
27
to obtain the title compound 6d; yield: 0.4 g (83%); syrup; [a]D
+4.9 (c = 0.75, CHCl3).
IR (film): 1727 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J7,8 = 7.7 Hz, 1 H, H-8),
7.51 (dd, J6,7 = 7.8 Hz, 1 H, H-7), 7.38 (dd, J5,6 = 7.7 Hz, 1 H, H-6),
7.21 (d, 1 H, H-5), 5.81 (d, J1¢,2¢ = 3.2 Hz, 1 H, H-1¢), 4.70–4.65 (m,
1 H, H-3), 4.53 (d, J = 3.2 Hz, 1 H, H-2¢), 4.50–3.80 (m, 6 H, H-
3¢,4¢,5¢,6¢, CH2O), 3.25 (dd, Jgem = 14.2 Hz, J3,4 = 6.8 Hz, 1 H, H-
4), 2.95 (dd, J3,4¢ = 3.0 Hz, 1 H, H-4), 1.70–1.20 (m, 20 H, cyclohex-
ylidene).
13C NMR (50 MHz, CDCl3): d = 164.9 (C-1), 138.9 (C-8a), 133.7,
130.2, 127.5 × 2 (arom), 125.0 (C-4a), 109.3, 108.5 (2 × Me2CO2),
96.3 (C-1¢), 71.1, 70.6 × 2, 70.5 × 2, 67.0 (C-2¢,3¢,4¢,5¢,6¢, C-3,
CH2O), 36.7 (PhCH2) 26.1, 25.9, 24.9, 24.4 [2 × (CH3)2CO2].
CD (MeOH): lmax (∆e) = 277.2 (–0.37), 226.3 (–1.25), 205.0 nm
(–0.53).
13C NMR (50 MHz, CDCl3): d = 165.2 (C-1), 138.8 (C-8a), 133.7,
130.4, 127.7, 127.5 (arom), 124.7 (C-4a), 112.7, 109.7 (2 × CO2),
104.9 (C-1¢), 83.5, 83.3, 82.4, 81.4, 72.0, 71.6, 67.4 (C-2¢,3¢,4¢,5¢,6¢,
CH2O, C-3), 36.5 (PhCH2), 29.9, 29.6, 24.9, 23.9, 23.6 (cyclohexy-
lidene).
FAB MS: m/z = 443 [M + Na]+.
Anal. Calcd for C22H28O8: C, 62.84; H, 6.71. Found: C, 62.89; H,
6.68.
(S)-3-[1-(2,3:5,6-Di-O-isopropylidene-b-D-mannofuranosyl-
oxymethyl)]-3,4-dihydroisocoumarin (6c)
CD (MeOH): lmax (∆e) = 286.4 (–0.46), 243.4 (–0.61), 222.2
(–1.50), 204.0 nm (–5.23).
To a solution of 4c (1.6 g, 3.7 mmol) in 1% aq NaOH (45 mL) was
added NaBH4 (0.4 g) at 0 °C. The mixture was stirred for 2 h at r.t.,
acidified with 10% aq HCl (80 mL) and extracted with EtOAc
(2 × 30 mL). The combined organic phases were washed with H2O
(2 × 20 mL), dried (Na2SO4) and evaporated on a rotary evaporator
to give 5c; yield: 1.0 g (69%); colorless syrup. A solution of 5c (0.8
g, 1.8 mmol) in Ac2O (2 mL) was refluxed for 2 h. After completion
of the reaction, the mixture was cooled to 15 °C, H2O (10 mL) was
added, stirred for 15 min, and extracted with CH2Cl2 (2 × 20 mL).
The combined organic phases were washed with H2O (2 × 10 mL),
dried (Na2SO4) and evaporated on a rotary evaporator to afford a
residue (1.24 g) that was column chromatographed [SiO2, EtOAc–
hexane (1:4)] to isolate the title compound 6c; yield: 0.6 g (78%);
colorless syrup; [a]D27 +23.5 (c = 1.0, CHCl3).
FAB MS: m/z = 523 [M + Na]+.
Anal. Calcd for C28H36O8: C, 67.18; H, 7.24. Found: C, 67.38; H,
7.15.
(S)-3-[(1,2:4,5-Di-O-cyclohexylidene-a-D-fructopyranosyl-
oxymethyl)]-3,4-dihydroisocoumarin (6e)
To a solution of 4e (0.7 g, 1.4 mmol) in 1% aq NaOH (30 mL) was
added NaBH4 (0.15 g) at 0 °C. The mixture was stirred for 2 h at r.t.,
acidified with 10% aq HCl (80 mL) and extracted with EtOAc
(2 × 30 mL). The combined organic phases were washed with H2O
(2 × 20 mL), dried (Na2SO4) and evaporated on a rotary evaporator
to afford 5e (0.6 g, 85%) as a syrup. A solution of 5e (0.5 g, 1 mmol)
in Ac2O (1 mL) was refluxed for 2 h. After completion of the reac-
tion, the mixture was cooled to r.t., H2O (1 mL) was added, stirred
for 15 min and extracted with CH2Cl2 (2 × 30 mL). The combined
organic phases were washed with H2O (2 × 10 mL), dried (Na2SO4)
and evaporated on a rotary evaporator to obtain the title compound
6e; yield: 0.4 g (83%); solid; mp 119–120 °C; [a]D27 –58.0 (c = 0.25,
CH2Cl2).
IR (film): 1726 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.05 (d, J7,8 = 7.4 Hz, 1 H, H-8),
7.54 (dd, J6,7 = 7.6 Hz, 1 H, H-7), 7.40 (dd, J5,6 = 7.7 Hz, 1 H, H-6),
7.20 (d, J = 7.7 Hz, 1 H, H-5), 5.01 (d, J1¢,2¢ = 2.3 Hz, 1 H, H-1¢),
4.78 (m, 1 H, H-2¢), 4.68 (m, 1 H, H-3), 4.56–4.08 (m, 3 H, H-
3¢,4¢,5¢), 4.00–3.80 (m, 3 H, H-6¢, CH2O), 3.72 (m, 1 H, H-6¢¢),
3.10–2.96 (m, 2 H, H-4), 1.45, 1.41, 1.37, 1.32 [4 s, 12 H, 2 ×
(CH3)2CO2].
IR (KBr): 1730 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10 (d, J7,8 = 7.5 Hz, 1 H, H-8),
7.51 (dd, J6,7 = 7.7 Hz, 1 H, H-7), 7.35 (dd, J5,6 = 7.5 Hz, 1 H, H-6),
7.21 (d, J = 7.5 Hz, 1 H, H-5), 4.70–4.55 (m, 1 H, H-3), 4.30–3.60
(m, 8 H, H-1¢,1¢¢,3¢,4¢,5¢,6¢,6¢¢, OCH2CO), 3.45 (dd, Jgem = 13.0 Hz,
J = 10.2 Hz, 1 H, OCH2), 3.10–2.90 (m, 2 H, PhCH2), 1.80–1.10 (m,
20 H, cyclohexylidene).
13C NMR (50 MHz, CDCl3): d = 164.7 (C-1), 138.3 (C-8a), 133.8,
130.3, 127.7, 127.4 (arom), 124.5 (C-4a), 112.8, 109.2 (2 ×
Me2CO2), 106.8 (C-1¢), 84.9, 80.9, 79.4, 76.5, 73.1, 68.2, 66.8 (C-
2¢,3¢,4¢,5¢,6¢, C-3, CH2O), 35.8 (PhCH2), 26.8, 25.9, 25.2, 24.5 [2 ×
(CH3)2CO2].
13C NMR (50 MHz, CDCl3): d = 164.9 (C-1), 138.9 (C-8a), 133.8,
130.2, 127.4 × 2, (arom), 124.8 (C-4a), 112.7, 109.8 (2 × CO2),
103.8 (C-2¢), 76.9, 76.5, 73.4, 72.5, 71.4, 72.1 (C-1¢,3¢,4¢,5¢,6¢,
CH2O, C-3), 38.0 (PhCH2), 36.4, 35.4, 30.1, 24.9, 23.9, 23.7 (cyclo-
hexylidene).
CD (MeOH): lmax (∆e) = 281.3 (–0.60), 237.5 (–1.25), 222.0
(–1.70), 205.2 nm (–3.10).
FAB MS: m/z = 443 [M + Na]+, 421 [M + H]+.
Anal. Calcd for C22H28O8: C, 62.84; H, 6.71. Found: C, 63.04; H,
6.62.
CD (MeOH): lmax (∆e) = 296.2 (–1.90), 244.2 (–1.19), 227.0 nm
(–0.67).
(S)-3-[(1,2:5,6-Di-O-cyclohexylidene-a-D-glucofuranosyloxy-
methyl)]-3,4-dihydroisocoumarin (6d)
FAB MS: m/z = 523 [M + Na]+.
To a solution of 4d (1.0 g, 2 mmol) in 1% aq NaOH (30 mL) was
added NaBH4 (0.2 g) at 0 °C. The mixture was stirred for 2 h at r.t.
Anal. Calcd for C28H36O8: C, 67.18; H, 7.24. Found: C, 67.38; H,
7.15.
Synthesis 2006, No. 17, 2944–2950 © Thieme Stuttgart · New York

2950
H. B. Mereyala, G. Pathuri
PAPER
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Acknowledgment
GP thanks Director, IICT for financial assistance and support of this
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