Synthesis of hybrids of D-glucose and D-galactose with pyrrolidine-based iminosugars as glycosidase inhibitors

Article abstract of DOI:10.1002/ejoc.200800770

Sugar-iminosugar hybrid molecules made up of D-glucose and D-galactose with pyrrolidine-based iminosugars, viz. 1,4-dideoxy-1,4-imino-L-xylitol and 1,4-dideoxy-1,4-imino-L-lyxitol, are synthesized from glycal epoxides and found to be moderate glycosidase

Full text of DOI:10.1002/ejoc.200800770

FULL PAPER
DOI: 10.1002/ejoc.200800770
Synthesis of Hybrids of
D
-Glucose and
D
-Galactose with Pyrrolidine-Based
Iminosugars as Glycosidase Inhibitors
Venkata Ramana Doddi,[a] Hari Prasad Kokatla,[a] A. P. John Pal,[a] Ranjan K. Basak,[a] and
Yashwant D. Vankar*[a]
Keywords: Glycosidase inhibitors / Iminosugars / Azasugars / Oxidative cyclization
Sugar–iminosugar hybrid molecules made up of
and -galactose with pyrrolidine-based iminosugars, viz. 1,4-
dideoxy-1,4-imino- -xylitol and 1,4-dideoxy-1,4-imino-
D
-glucose
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
D
L
L-
lyxitol, are synthesized from glycal epoxides and found to be
moderate glycosidase inhibitors.
Introduction
Naturally occurring iminosugars (also known as aza-
sugars) or their synthetic analogues are classified as glyco-
mimetics due to their structural resemblance to sugars and
many of them act as good glycosidase inhibitors.[1] These
inhibitors have found applications as antineoplastic,[2] anti-
diabetic[3] and antiviral agents.[4] Among these, polyhy-
droxylated piperidine and pyrrolidine alkaloids and their
synthetic analogues are more important.[5,6] MDL 73945 (1)
(Figure 1), a disaccharide mimetic possessing piperidine
based iminosugar and a sugar entity within the molecule, is
known to show promising antidiabetic activity.[7] Pyrroli-
dine-derived iminosugars are also known[5] to exhibit
powerful glycosidase inhibition activity though the stereo-
chemical similarity between these iminosugars and the ap-
propriate hexoses or enzyme-bound intermediates derived
from it is not apparent. 1,4-Dideoxy-1,4-imino--arabinitol
2 is a potent α-glucosidase inhibitor[8] and 1,4-dideoxy-1,4-
imino--lyxitol 3 is an α-galactosidase inhibitor.[9]
Recently, design and synthesis of hybrid molecules have
gained importance as they could be useful in improving or
altering the properties of pharmaceutically important mole-
cules.[10] As part of our ongoing programme towards the
design and synthesis and biological evaluation of imino-
sugars[11a,11b] including hybrid sugars[11c–11f] as glycosidase
inhibitors, in this paper we wish to report the synthesis and
biological evaluation of the hybrid molecules 6–9 derived
Figure 1. Piperidine- and pyrrolidine-based iminosugars.
through domain integration of pyrrolidine-based imi-
nosugars: 1,4-dideoxy-1,4-imino--xylitol 4,[12] 1,4-dideoxy-
1,4-imino--lyxitol 5,[13] and sugar entities.
Results and Discussions
Thus, the synthesis emanated from 1,2-anhydro-3,4,6-tri-
O-benzyl-α--glucopyranose 11 which can be easily ob-
tained from tri-O-benzylglucal (10), by reaction with in situ
generated DMDO from a known procedure developed by
Dondoni et al.[14] (Scheme 1). A regiospecific and stereo-
specific ring opening of oxirane 11 with vinylmagnesium
bromide[15] in THF at –78 °C gave an alcohol 12 as a single
diastereomer and it was protected as its p-methoxybenzyl
ether (–O-PMB) 13 by treating with p-methoxybenzyl chlo-
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
Fax: +91-512-259-0007
E-mail: vankar@iitk.ac.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 5731–5739
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V. R. Doddi, H. P. Kokatla, A. P. J. Pal, R. K. Basak, Y. D. Vankar
FULL PAPER
Scheme 1.
ride and NaH as a base. Dihydroxylation of olefin 13 with group, at ambient temperature gave a polar product which,
OsO4 and NMO furnished a mixture of the corresponding without further purification, was subjected to mesylation to
diastereomeric diols 14 in 3:2 ratio as an inseparable mix- obtain mesylate 18. Presence of two singlet peaks at δ =
ture. However, protection of the primary hydroxyl group 2.90 and 2.85 ppm for –OMs group and absence of OMe at
with a trityl group permitted the separation of the dia- δ = 3.74 ppm as well as decrement of protons in the aro-
1
stereomeric secondary alcohols 15 and 16 by SiO2 column matic region of the H NMR spectrum of compound 18
chromatography. The stereochemical outcome of this dihy- confirmed its structure. This served as an evidence for the
droxylation follows Kishi’s empirical rule.[16] These second- deprotection of trityl group with TrBF4 under dilute condi-
ary alcohols 15 and 16 were converted uneventfully to the tions.[18] Treatment of the dimesylate derivative 18 with neat
cyclized compounds 23 and 24, respectively, by oxidative benzylamine at 110 °C gave the pyrrolidine derivative 19 by
ring closure using DDQ[17] (see Scheme 2). The nOe corre- sequential intermolecular and intramolecular nucleophilic
lations at this stage, served to confirm the configuration at substitutions. The 1H NMR spectrum showed the complete
C-7 in compounds 15 and 16 and the equatorial nature of disappearance of mesylate peaks and increment in the phe-
the p-methoxyphenyl group in the two acetals 23 and 24 as nylic protons which confirmed the formation of pyrrolidine
well.
system 19. This was further confirmed from its mass spec-
Protection of the secondary hydroxyl group in 15 with trum which showed HRMS [M + H]+ peak at 656.3376
benzyl group gave the differentially protected compound (calculated 656.3371).[19] Pyrrolidine derivative 19 on treat-
17. We aimed at the deprotection of both O-PMB ether and ment with 20% Pd(OH)2/C in methanol at 5 atm H2 gave
trityl group in a single step using trifluoroacetic acid as the hybrid molecule 6 in 96% yield. Bicyclic pyrrolidine 6
both the groups are acid labile, however, the reaction represents a hybrid of -glucose and pyrrolidine azasugar 4
yielded a complex mixture of products. Treatment of 17 as shown in Scheme 1. Likewise, the bicyclic pyrrolidine 7
with TrBF4 in CH2Cl2,[18] a recently developed methodol- was synthesized from the compound 16 using the same syn-
ogy from our group for the deprotection of anomeric –OMe thetic sequence and reaction conditions as shown in
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Synthesis of Hybrids of -Glucose and -Galactose
firm both the configuration at C-7 in compounds 32 and
33, as well as the equatorial nature of the p-methoxyphenyl
group in the two acetals 25 and 26. Dimesylate derivatives
35 and 38 were subjected to cyclization with neat benzyl-
amine at 125 °C, a temperature comparatively higher than
that required for glucal series, gave the pyrrolidine deriva-
tives 36 and 39 by intermolecular followed by intramolecu-
lar nucleophilic substitution reactions. Further, cyclization
of dimesylates 35 and 38 via consecutive nucleophilic sub-
stitution reactions was comparatively slow due to the de-
veloping 1,3-diaxial interaction in the galactal ring when it
underwent intramolecular nucleophilic substitution reac-
tion.
Enzyme inhibition activity of these hybrid molecules has
been studied with only three glycosidases.[20] Thus, the 1,4-
dideoxy-1,4-imino--xylitol 4 inhibits almond emulsion β-
glucosidase at a concentration of 7.3 m.[12a] Interestingly,
in our studies with the same glucosidase, no inhibition was
shown for hybrid molecules 6 and 8 of -glucose and -
galactose with 1,4-dideoxy-1,4-imino--xylitol 4 even at
5 m concentrations. However, 6 showed inhibition of α-
galactosidase (coffee beans) at low concentration (0.88 m)
and moderate inhibition of β-galactosidase (bovine) at c =
2.56 m. The hybrid 8 of -galactose with 1,4-dideoxy-1,4-
imino--xylitol 4 showed moderate inhibition of α-gluco-
sidase (yeast) at 4.8 m concentration and also β-galactos-
Scheme 2. Diagnostic nOe correlations for compounds 23, 24, 25
and 26.
Scheme 3. Bicyclic pyrrolidine 7 represents a hybrid of - idase (bovine) at c = 1.8 m. Likewise, the hybrid 7 of -
glucose and pyrrolidine azasugar 5 (Scheme 3). glucose with 1,4-dideoxy-1,4-imino--lyxitol 5 showed only
Compounds 8 (Scheme 1) and 9 (Scheme 3) synthesized moderate inhibition of α-galactosidase (coffee beans) at c =
from 3,4,6-tri-O-benzyl--galactal 27 are hybrids of -ga- 1.24 m. Hybrid molecule 9 showed inhibition against α-
lactose with pyrrolidine-based iminosugars: 1,4-dideoxy- galactosidase (coffee beans), and β-galactosidase (bovine)
1,4-imino--xylitol 4 and 1,4-dideoxy-1,4-imino--lyxitol 5, at 1.0 m and 2.56 m, respectively (see Table 1). These
respectively. The synthetic pathway follows the same se- studies indicate that the hybrid molecules 6, 7, 8 and 9 are
quence as used for the synthesis of hybrids 6 and 7 from indeed moderate inhibitors of glycosidases. Interestingly,
3,4,6-tri-O-benzyl--glucal 10. The nOe correlations of hybrids 6, 7 and 9 specifically inhibit galactosidases only.
compounds 25 and 26 indicated in Scheme 2 served to con- Hybrid 8 only inhibits α-glucosidase along with β-galactos-
Scheme 3.
Eur. J. Org. Chem. 2008, 5731–5739
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V. R. Doddi, H. P. Kokatla, A. P. J. Pal, R. K. Basak, Y. D. Vankar
FULL PAPER
trityl chloride (1.1 mmol), Et3N (2 mmol). The reaction mixture
was stirred for 8 h and then the usual work-up with water and
CH2Cl2 gave a crude product which was purified by flash
chromatography to give the pure tritylated compounds.
idase. Clearly, there is a change in terms of specificity as
well as the inhibition constant values as a result of the com-
bination of the structural features as aimed in the present
studies. This further suggests that structural variations of
these hybrid molecules could promote better and specific
glycosidase inhibition. We are currently investigating this
possibility and will report our results in due course.
General Procedure (D). One-Pot Deprotection of p-Methoxybenzyl
Ether and Trityl Ether Followed by Dimesylation of Diol: To a solu-
tion of the protected compound (1 mmol) in dry CH2Cl2 (20 mL)
was added trityl tetrafluoroborate (1 mmol) under nitrogen atmo-
sphere. The reaction mixture was stirred at room temperature for
20–30 min. After completion of the reaction (TLC monitoring), the
reaction mixture was quenched with excess of sodium hydrogen
carbonate. The organic phase was washed with water, dried with
anhydrous Na2SO4, and concentrated under reduced pressure to
obtain a crude diol. To the stirred solution of a crude diol in
CH2Cl2 (8 mL) at 0 °C was added Et3N (3 mmol), followed by
MsCl (2.1 mmol) and catalytic amount of DMAP. After 2 h, 5 mL
of aqueous solution of NaHCO3 was added and the organic layer
was washed with water (2ϫ5 mL), followed by brine (5 mL). The
organic layer was dried with MgSO4 and concentrated in vacuo.
Purification was done by silica gel column chromatography to give
the dimesylates.
Table 1. IC50 (m) values for compounds 6, 7, 8 and 9.[a]
Enzyme
6
7
8
9
α-Glucosidase (yeast)
β-Glucosidase (almonds)
n.i.
n.i.
n.i.
n.i.
4.8 m n.i.
n.i.
n.i.
α-Galactosidase (coffee beans) 0.8 m 1.24 m n.i.
1.0 m
β-Galactosidase (bovine)
α-Mannosidase (Jack beans)
2.5 m n.i.
n.i. n.i.
1.8 m 2.5 m
n.i. n.i.
[a] Inhibition studies were carried out at millimolar concentration,
optimal pH of the enzymes, and 37 °C; no inhibition (n.i.) at 5 m
concentration of the inhibitor.
Conclusion
General Procedure (E). Cyclization of Dimesylates with Benzyl-
amine: The dimesylate (0.5 mmol) was dissolved in benzylamine
(5 mL) and stirred for 18 h at 110–125 °C. To the reaction mixture,
10 mL of 1  HCl was added and extracted with CH2Cl2
(3ϫ10 mL). The organic layer was washed with saturated aqueous
NaHCO3 (15 mL) and brine (10 mL), dried with MgSO4, concen-
trated in vacuo and the crude produt purified by silica gel column
chromatography.
In summary, we have synthesized four new hybrids of -
glucose and -galactose with pyrrolidine-based imino
sugars: 1,4-dideoxy-1,4-imino--xylitol and 1,4-dideoxy-
1,4-imino--lyxitol and evaluated against a variety of en-
zymes that puts them shown them into a class of glycos-
idase inhibitors. Although the enzyme inhibition activity is
moderate, it may be possible to improve the same by appro-
priately changing the structural features of these molecules.
Work in this direction is being pursued. To the best of our
knowledge a one pot deprotection of –O-PMB ether and
trityl ether with TrBF4, as observed by us in the present
study, is not known in the literature.
General Procedure (F). Deprotection of Benzyl Groups: The cyclized
product (0.3 mmol) was dissolved in 5 mL of MeOH and 20%
Pd(OH)2/C (300 mg) was added to it. The reaction mixture was
stirred under 5 atm H2 pressure for 30–35 h at room temperature.
The catalyst was filtered off through Celite, and concentrated in
vacuo to obtain hybrid molecules.
General Procedure (G). Oxidative Cylization with DDQ: A solution
of alcohol (0.2 mmol) in CH2Cl2/water (9:1, 5 mL) was treated with
DDQ (0.2 mmol) at room temperature and stirred for 10–15 min.
The reaction mixture was diluted with CH2Cl2 and washed with a
saturated solution of NaHCO3, water and brine. The organic layer
was dried with Na2SO4, concentrated and purified by column
chromatography to give the cyclized product.
Experimental Section
General Procedure (A). Benzylation of Alcohols: 60% suspension of
NaH in paraffin oil (4.347 mmol) was added in small portions to
a stirred solution of an alcohol (2.173 mmol) in DMF (10 mL) at
0 °C. After 30 min benzyl chloride or p-methoxybenzyl chloride
(2.607 mmol) was added dropwise at 0 °C and the reaction mixture
stirred for 4 h at room temperature. Excess of NaH was quenched
by pouring the reaction mixture in ice and then extracted with di-
ethyl ether (30 mL) followed by washing with water (3ϫ10 mL).
The orgnic layer was dried with MgSO4 and concentrated in vacuo
and the crude product purified by column chromatography to get
benzylated products.
(2R,3R,4R,5S,6S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(4-
methoxybenzyloxy)-6-vinyltetrahydro-2H-pyran (13): Alcohol 12
(2 g, 4.34 mmol) was benzylated with PMBCl using the general
procedure (A) to give 13 (2.1 g, 93%) as colorless oil. Rf = 0.6
(hexane/EtOAc, 9:1). [α]2D8 = +65.2 (c = 1.0, CH2Cl2). IR (CH2Cl2):
ν
˜
max = 3063, 3030, 2917, 1612, 1248, 1073, 753, 697 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.22 (m, 15 H), 7.11 (d, J = 7.3 Hz,
2 H), 6.84 (d, J = 7.3 Hz, 2 H), 6.14 (ddd, J = 17.6, 11.0, 5.1 Hz,
1 H), 5.47 (dd, J = 17.6, 1.7 Hz, 1 H), 5.42 (dd, J = 11.0, 1.7 Hz,
1 H), 4.92 (d, J = 12.3 Hz, 1 H), 4.80 (d, J = 10.7 Hz, 1 H), 4.77
(d, J = 10.7 Hz, 1 H), 4.62–4.53 (m, 3 H), 4.48 (d, J = 12.0 Hz, 1
H), 4.44 (d, J = 12.0 Hz, 1 H), 3.79 (s, 3 H), 3.78–3.59 (m, 7 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 138.8, 138.2, 138.0, 131.9,
130.2, 129.4, 128.3–127.5 (m), 119.7, 113.7, 82.7, 79.6, 78.2, 75.4,
75.0, 74.0, 73.4, 72.5, 71.9, 69.0, 55.2 ppm. ESMS: m/z 603 [M +
Na]+. C37H40O6 (580.28): calcd. C 76.53, H 6.94, O 16.53; found
C 76.51, H 6.92.
General Procedure (B). Dihydroxylation Using OsO4-NMO: To a
stirred solution of olefin (1 mmol) in acetone/water/tert-butyl
alcohol (1:1: 0.4, 5 mL) at room temperature, were added
NMO·H2O (1.3 mmol) and OsO4 (0.004 equiv.). The reaction mix-
ture was stirred for 24–48 h (monitored by TLC) and it was treated
with Na2S2O5 (1.3 mmol). The reaction mixture was stirred for fur-
ther 1 h and extracted with EtOAc (2ϫ50 mL). The organic layer
was washed with 1  HCl, water and finally with brine, dried with
MgSO4 and concentrated in vacuo. Purification was done by silica
gel column chromatography to give diols.
General Procedure (C). Tritylation of Primary Alcohols: To a solu-
tion of mixture of diols (1 mmol) in CH2Cl2 (5 mL) were added
1-[(2S,3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-(4-
methoxybenzyloxy)tetrahydro-2H-pyran-2-yl]ethane-1,2-diol (14):
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Synthesis of Hybrids of -Glucose and -Galactose
Olefin 13 (580 mg) was dihydroxylated using the general procedure
(B) to give diastereomeric mixture (3:2) 14 (546 mg) as a colorless
thick liquid in 89 % yield. Rf = 0.4 (hexane/EtOAc, 3:2). IR
1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.46 (d, J = 11.4 Hz, 1 H), 4.44
(d, J = 11.4 Hz, 1 H), 4.40 (d, J = 11.7 Hz, 1 H), 4.38 (d, J =
12.0 Hz, 1 H), 4.29 (d, J = 12.0 Hz, 1 H), 4.11 (dd, J = 8.8, 3.4 Hz,
1 H), 4.02 (m, 1 H), 3.91 (t, J = 5.1 Hz, 1 H), 3.85–3.81 (m, 2 H),
3.74 (s, 3 H), 3.65 (m, 1 H), 3.54 (d, J = 2.9 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.0, 144.1, 138.8, 138.4, 168.3,
130.4–126.8 (m), 113.6, 86.7, 78.1, 78.0, 75.9, 75.8, 73.7, 73.2, 72.9,
72.4, 71.9, 70.9, 69.2, 64.3, 55.2 ppm. ESMS: m/z 969 [M + Na]+.
C63H62O8 (946.45): calcd. C 79.89, H 6.60, O 13.51; found C 79.90,
H 6.54.
(CH Cl ): νmax = 3401, 3063, 2924, 1605, 1453, 1090, 736, 692 cm–1.
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 7.33–7.13 (m, 17 H, both iso-
mers), 6.84 (d, J = 8.8 Hz, 2 H, major), 6.83 (d, J = 8.8 Hz, 2 H,
minor), 4.86–4.65 (m, 4 H, both isomers), 4.18–4.16 (m, 2 H, both
isomers), 3.92–3.81 (m, 2 H, both isomers), 3.88 (s, 3 H, both iso-
mers), 3.88–3.65 (m, 3 H, both isomers), 3.62–3.50 (m, 2 H, both
isomers), 2.45 (br. s, 1 H, both isomers) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.7, 138.3, 138.0, 129.9–127.7 (m), 114.1, 113.9,
81.4, 78.9, 78.7, 77.4, 77.5, 74.7, 74.8, 74.4, 74.0, 73.8, 73.4, 72.3,
72.4, 70.1, 69.4, 69.0, 64.3, 64.4, 55.2 ppm. ESMS: m/z 637 [M +
Na]+. C37H42O8 (614.28): calcd. C 72.29, H 6.89, O 20.82; found
C 72.20, H 6.87.
(R)-2-(Benzyloxy)-2-[(2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-
(benzyloxymethyl)-3-(methylsulfonyloxy)tetrahydro-2H-pyran-2-yl]-
ethyl Methanesulfonate (18): Compound 17 (946 mg) was converted
to give dimesylate 18 (462 mg, 62%, two steps) as a colorless oil
using the general procedure (D). Rf = 0.5 (hexane/EtOAc, 7:3).
Diol 14 (614 mg) was tritylated using the general procedure (C) to [α]2D8 = +6.2 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 3063, 3030,
˜
max
give 15 (441 mg) and 16 (295 mg) in a ratio (3:2) (86%).
2
2
2
2
1
2924, 1603, 1496, 1093, 1028, 741, 698 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.42 (d, J = 7.0 Hz, 2 H), 7.36–7.19 (m, 18 H), 5.01
(br. s, 1 H), 4.91 (d, J = 10.2 Hz, 1 H), 4.69–4.61 (m, 3 H), 4.54–
4.45 (m, 5 H), 4.39 (dd, J = 11.0, 3.4 Hz, 1 H), 4.16 (d, J = 3.68 Hz,
1 H), 4.12 (dd, J = 6.8, 3.4 Hz, 1 H), 4.08 (d, J = 7.0 Hz, 1 H),
3.94 (br. d, J = 9.0 Hz, 1 H), 3.76 (dd, J = 10.0, 6.3 Hz, 1 H), 3.64
(dd, J = 10.2, 5.8 Hz, 1 H), 3.55 (dd, J = 6.8, 3.4 Hz, 1 H), 2.90 (s,
3 H), 2.85 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.9,
137.5, 137.3, 137.1, 128.7–127.8 (m), 75.0, 74.6, 74.1, 73.4, 73.3,
72.9, 72.7, 72.6, 72.3, 67.8, 67.1, 39.2, 37.3 ppm. ESMS: m/z 763
[M + Na]+. C38H44O11S2 (740.23): calcd. C 61.60, H 5.99, O 23.75,
S 8.66; found C 61.51, H 6.00.
(R)-1-[(2S,3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-
(4-methoxybenzyloxy)tetrahydro-2H-pyran-2-yl]-2-(trityloxy)-
ethanol (15): (441 mg, 51%) White solid. Rf = 0.5 (hexane/EtOAc,
4:1). [α]2D8 = +32.0 (c = 0.8, CH Cl ). IR (CH Cl ): ν
= 2924,
˜
max
2
2
2
2
2855, 1611, 1513, 1492, 1249, 1087, 742, 700 cm–1 1H NMR
.
(500 MHz, CDCl3): δ = 7.46–7.13 (m, 32 H), 6.82 (d, J = 6.8 Hz,
2 H), 4.79 (d, J = 11.5 Hz, 1 H), 4.72 (d, J = 11.2 Hz, 1 H), 4.71
(d, J = 10.9 Hz, 1 H), 4.65 (d, J = 11.2 Hz, 1 H), 4.56 (d, J =
11.2 Hz, 1 H), 4.47 (d, J = 12.3 Hz, 1 H), 4.44 (d, J = 10.9 Hz, 1
H), 4.34 (d, J = 12.3 Hz, 1 H), 4.32–4.31 (m, 1 H), 3.95 (dd, J =
8.9, 4.9 Hz, 1 H), 3.91–3.84 (m, 2 H), 3.79 (s, 3 H), 3.64 (dd, J =
8.9, 7.5 Hz, 1 H), 3.49–3.43 (m, 2 H), 3.31 (dd, J = 9.8, 3.2 Hz, 1
(3R,3aR,5R,6S,7R,7aS)-1-Benzyl-3,6,7-tris(benzyloxy)-5-(benzyl-
H), 3.27–3.20 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = oxymethyl)octahydropyrano[3,2-b]pyrrole (19): Dimesylate 18
159.5, 144.1, 138.4, 138.2, 137.7, 130.0–127.0 (m), 114.0, 86.6, 81.5,
(370 mg) was subjected to cylization using the general procedure
79.0, 74.8, 74.4, 73.9, 73.5, 71.9, 69.7, 68.3, 65.1, 55.3, 29.8 ppm. (E) to give 19 (248 mg, 76%) as a thick liquid. Rf = 0.4 (hexane/
ESMS: m/z 879 [M + Na]+. C56H56O8 (856.40): calcd. C 78.48, H
6.59, O 14.93; found C 78.32, H 6.60.
EtOAc, 7:3). [α]2D8 = –19.5 (c = 1.0, CH Cl ). IR (CH Cl ): ν
=
˜
2
2
2
2
max
3062, 2923, 1602, 1495, 1096, 1027, 735, 697 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.31–7.21 (m, 25 H), 5.04 (d, J = 2.9 Hz,
1 H), 4.78 (d, J = 11.4 Hz, 1 H), 4.67–4.52 (m, 6 H), 4.40 (d, J =
11.7 Hz, 1 H), 4.21–4.20 (m, 1 H), 4.15–4.16 (m, 1 H), 3.97 (dd, J
= 7.8, 4.6 Hz, 1 H), 3.86 (dd, J = 7.0, 5.3 Hz, 1 H), 3.81 (dd, J =
10.7, 5.3 Hz, 1 H), 3.77–3.71 (m, 4 H), 2.91 (dd, J = 8.0, 12.4 Hz,
1 H), 2.84 (dd, J = 12.4, 4.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.2, 128.4–127.5 (m), 126.8, 97.3, 78.1, 74.5, 74.2,
73.4, 73.1, 71.2, 71.1, 70.5, 68.4, 53.5, 51.9, 29.6 ppm. HRMS
calcd. for C43H46NO5 [M+ H]+ 656.3371, found 656.3373.
(S)-1-[(2S,3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-
(4-methoxybenzyloxy)tetrahydro-2H-pyran-2-yl]-2-(trityloxy)-
ethanol (16): (295 mg, 35%) White solid. Rf = 0.49 (hexane/EtOAc,
4:1). [α]2D8 = +76.0 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 2924,
˜
max
2
2
2
2
2855, 1611, 1513, 1492, 1249, 1087, 742, 700 cm–1 1H NMR
.
(500 MHz, CDCl3): δ = 7.42–7.10 (m, 32 H), 6.76 (d, J = 8.3 Hz,
2 H), 4.83 (d, J = 11.2 Hz, 1 H), 4.72 (d, J = 10.9 Hz, 1 H), 4.71
(d, J = 10.9 Hz, 1 H), 4.52 (d, J = 11.5 Hz, 1 H), 4.50 (d, J =
11.5 Hz, 1 H), 4.43 (d, J = 11.2 Hz, 1 H), 4.38 (d, J = 12.6 Hz, 1
H), 4.34 (d, J = 12.6 Hz, 1 H), 4.21–4.20 (m, 1 H), 4.13 (dd, J = (3R,3aR,5R,6S,7R,7aS)-5-(Hydroxymethyl)octahydropyrano[3,2-b]-
8.1, 8.0 Hz, 1 H), 4.00 (br. d, J = 8.9 Hz, 1 H), 3.80–3.76 (m, 1 H),
3.76 (s, 3 H), 3.69 (dd, J = 8.1, 6.3 Hz, 1 H), 3.56–3.51 (m, 2 H),
3.45 (br. d, J = 10.1 Hz, 1 H), 3.36 (dd, J = 9.2, 3.5 Hz, 1 H), 3.27
(dd, J = 9.2, 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
159.3, 143.9, 138.8, 138.4, 138.1, 130.1–127.0 (m), 113.8, 86.8, 82.2,
pyrrole-3,6,7-triol (6): Compound 19 (196 mg) was subjected to
global deprotection using the general procedure (F) to give 6
(60 mg, 98%) as a thick liquid. Rf = 0.3 (MeOH/EtOAc, 1:4). [α]
= –13.4 (c = 1.0, H2O). 1H NMR (400 MHz, D2O): δ = 3.75–
28
D
3.59 (m, 2 H), 4.78 (d, J = 11.4 Hz, 1 H), 3.18–2.92 (m, 5 H) ppm.
78.7, 74.9, 74.5, 74.3, 73.3, 72.9, 70.6, 68.8, 64.9, 55.3, 29.8 ppm. 13C NMR (100 MHz, CDCl3): δ = 80.8, 77.2, 73.1, 69.2, 62.5, 50.8,
ESMS: m/z 879 [M + Na]+. C56H56O8 (856.40): calcd. C 78.48, H
6.59, O 14.93; found C 78.52, H 6.52.
44.5, 35.5 ppm. ESMS: m/z 206 [M + H]+. C8H15NO5 (205.10):
calcd. C 46.82, H 7.37, N 6.83, O 38.98; found C 46.84, H 7.39, N
6.84.
(2R,3R,4S,5R,6S)-3,4-Bis(benzyloxy)-6-[(R)-1-(benzyloxy)-2-(trityl-
oxy)ethyl]-2-(benzyloxymethyl)-5-(4-methoxybenzyloxy)tetrahydro- (2R,3R,4S,5R,6S)-3,4-Bis(benzyloxy)-6-[(S)-1-(benzyloxy)-2-(trityl-
2H-pyran (17): Alcohol 15 (856 mg) was benzylated with BnCl
using the general procedure (A) to give 17 (890 mg, 91%) as color-
less oil. Rf = 0.6 (hexane/EtOAc, 9:1). [α]2D8 = –10.6 (c = 1.0,
oxy)ethyl]-2-(benzyloxymethyl)-5-(4-methoxybenzyloxy)tetrahydro-
2H-pyran (20): Alcohol 16 (856 mg) was benzylated with BnCl
using the general procedure (A) to give 20 (879 mg, 93%) as white
solid. Rf = 0.55 (hexane/EtOAc, 9:1). [α]2D8 = +16.9 (c = 0.8,
CH Cl ). IR (CH Cl ): ν = 3061, 2924, 2855, 1611, 1513, 1493,
˜
max
2
2
2
2
1451, 1092, 1029, 736, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ
CH Cl ). IR (CH Cl ): ν
= 2924, 2854, 1612, 1513, 1450, 1248,
˜
2
2
2
2
max
= 7.47–7.44 (m, 6 H), 7.29–7.18 (m, 29 H), 7.10 (d, J = 8.5 Hz, 2 1072, 742, 700 cm–1. H NMR (400 MHz, CDCl3): δ = 7.43–7.40
H), 6.71 (d, J = 8.5 Hz, 2 H), 4.78 (d, J = 11.4 Hz, 1 H), 4.60 (d, (m, 6 H), 7.26–7.19 (m, 29 H), 7.11 (d, J = 7.8 Hz, 2 H), 6.84 (d,
J = 11.4 Hz, 1 H), 4.58 (d, J = 12.4 Hz, 1 H), 4.55 (d, J = 12.4 Hz, J = 7.8 Hz, 2 H), 4.75 (d, J = 10.7 Hz, 1 H), 4.70 (d, J = 11.0 Hz,
1
Eur. J. Org. Chem. 2008, 5731–5739
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5735

V. R. Doddi, H. P. Kokatla, A. P. J. Pal, R. K. Basak, Y. D. Vankar
FULL PAPER
1 H), 4.64–4.46 (m, 6 H), 4.41–4.36 (m, 2 H), 4.27 (dd, J = 8.5, H), 4.63–4.53 (m, 4 H), 4.51 (d, J = 11.9 Hz, 1 H), 4.44 (d, J =
8.7 Hz, 1 H), 4.11 (dd, J = 6.8, 3.2 Hz, 1 H), 4.05 (br. d, J = 9.5 Hz, 11.9 Hz, 1 H), 4.04–3.99 (m, 2 H), 3.95 (dd, J = 2.7, 2.4 Hz, 1 H),
1 H), 3.95–3.94 (m, 1 H), 3.79–3.75 (m, 1 H), 3.78 (s, 3 H), 3.58
(d, J = 8.5 Hz, 1 H), 3.53 (dd, J = 8.8, 6.8 Hz, 1 H), 3.50–3.43 (m,
3.79 (s, 3 H), 3.68–3.65 (m, 1 H), 3.61 (dd, J = 8.8, 2.7 Hz, 1 H),
3.55 (dd, J = 10.0, 3.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
1 H), 3.36 (br. d, J = 6.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2, 138.7, 138.6, 138.2, 132.7, 130.6, 129.4, 128.3–
CDCl3): δ = 144.1, 138.9, 138.6, 130.7, 129.3–126.9 (m), 113.8,
87.2, 82.0, 79.5, 79.4, 78.2, 74.8, 74.6, 73.8, 73.7, 73.3, 73.2, 69.2,
55.2 ppm. ESMS: m/z 969 [M + Na]+. C63H62O8 (946.45): calcd.
C 79.89, H 6.60, O 13.51; found C 79.93, H 6.54.
127.3 (m), 118.0, 113.7, 78.8, 76.5, 75.0, 73.9, 73.3, 73.2, 72.9, 71.9,
68.4, 55.2 ppm. ESMS: m/z 603 [M + Na]+. C37H40O6 (580.28):
calcd. C 76.53, H 6.94, O 16.53; found C 76.52, H 6.96.
1-[(2S,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-(4-
methoxybenzyloxy)tetrahydro-2H-pyran-2-yl]ethane-1,2-diol (31):
Olefin 30 (580 mg) was dihydroxylated using the general procedure
(E) to give 31 (497 g, 81 %) as a colorless thick liqid. Dia-
stereomeric mixture (3:2). Rf = 0.4 (hexane/EtOAc, 3:2). IR
(S)-2-(Benzyloxy)-2-[(2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-
(benzyloxymethyl)-3-(methylsulfonyloxy)tetrahydro-2H-pyran-2-yl]-
ethyl Methanesulfonate (21): Compound 20 (946 mg) was converted
to give dimesylate 21 (495 mg, 67%, two steps) as a colorless oil
using the general procedure (D). Rf = 0.5 (hexane/EtOAc, 7:3).
(CH Cl ): νmax = 3401, 3063, 2924, 1605, 1453, 1090, 736, 692 cm–1.
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 7.34–7.24 (m, 15 H, both iso-
mers), 7.15 (d, J = 8.2 Hz, 2 H, major), 7.09 (d, J = 8.5 Hz, 2 H,
minor), 6.88 (d, J = 8.5 Hz, 2 H, minor), 7.09 (d, J = 8.2 Hz, 2 H,
major), 4.67–4.44 (m, 8 H, both isomers), 4.21–4.19 (m, 2 H, both
isomers), 3.97–3.96 (m, 1 H, both isomers), 3.87–3.76 (m, 5 H,
both isomers), 3.77 (s, 3 H, both isomers), 3.66–3.63 (m, 1 H, both
isomers), 3.58–3.54 (m, 1 H, both isomers) ppm. 13C NMR
(100 MHz, CDCl3) major: δ = 159.5, 138.2, 138.1, 137.9, 129.8–
127.6 (m), 113.9, 74.9, 74.5, 73.7, 73.1, 73.0, 72.1, 69.5, 69.1, 66.3,
64.7, 55.2 ppm. ESMS: m/z 637 [M + Na]+. C37H42O8 (614.28):
calcd. C 72.29, H 6.89, O 20.82; found C 72.20, H 6.86.
[α]2D8 = +54.8 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 3063, 3030,
˜
max
2
2
2
2
1
2924, 1603, 1496, 1093, 1028, 741, 698 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.40–7.12 (m, 20 H), 4.81 (d, J = 11.2 Hz, 1 H), 4.71
(d, J = 11.2 Hz, 1 H), 4.67 (d, J = 11.7 Hz, 1 H), 4.66 (d, J =
10.7 Hz, 1 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.56 (d, J = 11.9 Hz, 1
H), 4.48 (d, J = 10.5 Hz, 1 H), 4.46 (d, J = 11.9 Hz, 1 H), 4.45 (d,
J = 10.9 Hz, 1 H), 4.40 (dd, J = 4.1, 5.8 Hz, 1 H), 4.36 (dd, J =
10.5, 4.4 Hz, 1 H), 4.33 (dd, J = 6.5, 2.2 Hz, 1 H), 4.31 (dd, J =
7.3, 4.1 Hz, 1 H), 4.23–4.15 (m, 1 H), 3.69 (dd, J = 10.7, 2.2 Hz, 1
H), 3.71–3.55 (m, 3 H), 2.90 (s, 3 H), 2.80 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.8, 137.7, 137.1, 128.5–127.2 (m), 80.2,
78.9, 78.4, 75.3, 75.1, 74.9, 74.6, 74.3, 73.5, 67.8, 66.9, 37.5, 37.0
ppm. ESMS: m/z 763 [M + Na]+. C38H44O11S2 (740.23): calcd. C
61.60, H 5.99, O 23.75, S 8.66; found C 61.66, H 6.12.
Diols 31 (614 mg) was tritylated using the general procedure (C) to
give 32 (440 mg, 51%) and 33 (296 mg, 35%).
(R)-1-[(2S,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-3-
(4-methoxybenzyloxy)tetrahydro-2H-pyran-2-yl]-2-(trityloxy)-
ethanol (32): (440 mg, 51%) White solid. Rf = 0.5 (hexane/EtOAc,
(3S,3aR,5R,6S,7R,7aS)-1-Benzyl-3,6,7-tris(benzyloxy)-5-(benzyl-
oxymethyl)octahydropyrano[3,2-b]pyrrole (22): Dimesylate 21
(370 mg) was subjected to cylization using the general procedure
(E) to give 22 (154 mg, 79%) as colorless oil. Rf = 0.4 (hexane/
9:1). [α]2D8 = +38.5 (c = 0.8, CH Cl ). IR (CH Cl ): ν
= 2924,
˜
max
2
2
2
2
2855, 1610, 1513, 1492, 1248, 1091, 1032, 741, 700 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.42–7.24 (m, 32 H), 7.13 (d, J = 8.5 Hz,
2 H), 4.63 (d, J = 12.2 Hz, 1 H), 4.57–4.16 (m, 4 H), 4.38 (d, J =
12.2 Hz, 1 H), 4.32 (d, J = 11.9 Hz, 1 H), 4.19 (d, J = 4.8 Hz, 1
H), 4.11 (dd, J = 7.0, 6.6 Hz, 1 H), 3.97 (br. d, J = 2.9 Hz, 1 H),
3.89–3.79 (m, 3 H), 3.79 (s, 3 H), 3.70 (br. d, J = 2.9 Hz, 1 H), 3.67
(d, J = 7.0 Hz, 1 H), 3.35 (dd, J = 6.6, 3.6 Hz, 1 H), 3.25 (dd, J =
6.6, 3.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.9,
130.1–126.8 (m), 113.9, 86.7, 75.1, 74.7, 73.5, 72.8, 72.2, 71.8, 69.3,
68.7, 66.2, 65.4, 64.7, 55.2 ppm. ESMS: m/z 879 [M + Na]+.
C56H56O8 (856.40): calcd. C 78.48, H 6.59, O 14.93; found C 78.51,
H 6.57.
EtOAc, 7:3). [α]2D8 = –28.6 (c = 1.0, CH Cl ). IR (CH Cl ): ν
=
˜
max
2
2
2
2
1
2922, 2853, 1594, 1493, 1094, 736, 697 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.31–7.25 (m, 25 H), 5.05 (d, J = 2.7 Hz, 1 H), 4.82
(d, J = 11.2 Hz, 1 H), 4.67 (d, J = 11.2 Hz, 1 H), 4.65–4.51 (m, 7
H), 4.41 (d, J = 11.7 Hz, 1 H), 4.24 (dd, J = 5.8, 2.6 Hz, 1 H),
4.02–3.96 (m, 1 H), 3.92–3.75 (m, 4 H), 2.92 (dd, J = 12.4, 8.0 Hz,
1 H), 2.84 (dd, J = 12.4, 3.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 139.9, 138.2, 128.3–127.6 (m), 126.9, 97.7, 77.8, 76.0,
74.4, 73.5, 73.4, 71.1, 70.4, 68.3, 53.4, 51.9, 29.6 ppm. HRMS
calcd. for C43H46NO5 [M + H]+ 656.3371, found 656.3376.
(3S,3aR,5R,6S,7R,7aS)-5-(Hydroxymethyl)octahydropyrano-
[3,2-b]pyrrole-3,6,7-triol (7): Compound 22 (196 mg) was subjected
to global deprotection using the general procedure (F) to give 7
(60 mg, 99 %) as a thick liquid. Rf = 0.3 (MeOH/EtOAc, 1:4).
(S)-1-[(2S,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
3-(4-methoxybenzyloxy)tetrahydro-2H-pyran-2-yl]-2-(trityloxy)etha-
nol (33): (296 mg, 35%) Colorless oil. Rf = 0.49 (hexane/EtOAc,
1
[α]2D8 = –15.9 (c = 1.0, H2O). H NMR (400 MHz, D2O): δ = 3.78–
9:1). [α]2D8 = +97.6 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 3060,
˜
max
2
2
2
2
3030, 2925, 7611, 1513, 1248, 1091, 1030, 736, 699 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.45–7.15 (m, 30 H), 6.93 (d, J = 8.5 Hz,
2 H), 6.75 (d, J = 8.5 Hz, 2 H), 4.59–4.48 (m, 6 H), 4.16 (br. s, 1
H), 4.16–3.95 (m, 6 H), 3.77 (s, 3 H), 3.74 (dd, J = 5.1, 2.9 Hz, 1
H), 3.70 (dd, J = 11.2, 3.4 Hz, 1 H), 3.05 (br. s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.3, 144.0, 138.6, 138.4, 129.9–
126.9 (m), 113.8, 86.5, 74.7, 73.7, 73.2, 72.9, 72.6, 72.2, 71.0, 69.4,
66.5, 64.2, 55.2 ppm. ESMS: m/z 879 [M + Na]+. C56H56O8
(856.40): calcd. C 78.48, H 6.59, O 14.93; found C 78.47, H 6.60.
3.70 (m, 2 H), 3.58–3.54 (m, 2 H), 3.45 (dd, J = 11.5, 7.5 Hz, 1 H),
3.19–3.17 (m, 2 H), 3.11 (dd, J = 9.5, 9.0 Hz, 1 H), 3.00–2.97 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 80.8, 77.2, 73.1, 69.2,
62.5, 50.8, 44.5, 35.5 ppm. ESMS: m/z 206 [M + H]+. C8H15NO5
(205.10): calcd. C 46.82, H 7.37, N 6.83, O 38.98; found C 46.85,
H 7.38, N 6.82.
(2R,3S,4R,5S,6S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(4-
methoxybenzyloxy)-6-vinyltetrahydro-2H-pyran (30): Alcohol 29
(2 g) was benzylated with PMBCl using the general procedure (A)
to give 30 (2.37 g, 94%) as colorless oil. Rf = 0.55 (hexane/EtOAc,
(2R,3S,4S,5R,6S)-3,4-Bis(benzyloxy)-6-[(R)-1-(benzyloxy)-2-(trityl-
oxy)ethyl]-2-(benzyloxymethyl)-5-(4-methoxybenzyloxy)tetrahydro-
9:1). [α]2D8 = +66.3 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 2923,
˜
max
2
2
2
2
1612, 1513, 1094, 1028, 735 cm–1. H NMR (400 MHz, CDCl3): δ 2H-pyran (34): Alcohol 32 (856 mg) was benzylated with BnCl
1
= 7.35–7.25 (m, 17 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.03 (ddd, J =
15.4, 10.7, 4.4 Hz, 1 H), 5.40 (dt, J = 15.4, 1.9 Hz, 1 H), 5.31 (ddd,
J = 10.7, 1.9, 1.7 Hz, 1 H), 4.84 (d, J = 11.4 Hz, 1 H), 4.69 (s, 2
using the general procedure (A) to give 34 (860 mg, 91%) as a white
solid. Rf = 0.6 (hexane/EtOAc, 9:1). [α]2D8 = +55.2 (c = 1.0, CH2Cl2).
IR (CH Cl ): νmax = 3060, 3029, 2924, 2855, 1609, 1512, 1073, 738,
˜
2
2
5736
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5731–5739

Synthesis of Hybrids of -Glucose and -Galactose
1
699, 633 cm–1. H NMR (400 MHz, CDCl3): δ = 7.48–7.13 (m, 35
4.26 (m, 2 H), 4.09–4.10 (m, 1 H), 3.94 (br. d, J = 4.8 Hz, 1 H),
3.87–3.83 (m, 2 H), 3.60 (dd, J = 6.1, 5.4 Hz, 1 H), 3.46 (dd, J =
H), 7.01 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.5 Hz, 2 H), 4.78 (d, J
= 11.4 Hz, 2 H), 4.69 (d, J = 5.6 Hz, 1 H), 4.60 (d, J = 11.9 Hz, 1 9.6, 5.4 Hz, 1 H), 3.16 (dd, J = 9.6, 2.8 Hz, 1 H) ppm. 13C NMR
H), 4.50 (d, J = 12.9 Hz, 1 H), 4.43 (d, J = 10.0 Hz, 1 H), 4.40 (d,
(100 MHz, CDCl3): δ = 159.2, 144.3, 144.1, 139.2, 139.0, 138.8,
J = 11.9 Hz, 1 H), 4.35 (d, J = 11.9 Hz, 1 H), 4.27–4.25 (m, 1 H), 138.6, 130.7–126.7 (m), 113.7, 86.6, 80.1, 76.3, 74.6, 74.4, 73.9,
4.24 (d, J = 11.2 Hz, 1 H), 4.19 (d, J = 11.9 Hz, 1 H), 4.12 (d, J = 73.1, 73.0, 72.9, 72.6, 69.0, 63.3, 55.2 ppm. ESMS: m/z 969 [M +
11.9 Hz, 1 H), 4.09 (d, J = 9.2 Hz, 1 H), 4.00–3.95 (m, 2 H), 3.90
(dd, J = 8.3, 5.4 Hz, 1 H), 3.82–3.75 (m, 2 H), 3.75 (s, 3 H), 3.72
(br. s, 1 H), 3.63 (br. d, J = 10.0 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.3, 144.3, 138.9, 138.7, 138.6, 138.4,
130.4, 129.4–126.7 (m), 113.7, 86.5, 75.2, 74.9, 73.8, 73.4, 73.0,
72.7, 72.2, 71.4, 67.2, 66.4, 65.4, 64.0, 55.2 ppm. ESMS: m/z 969
[M + Na]+. C63H62O8 (946.44): calcd. C 79.89, H 6.60, O 13.51;
found C 79.92, H 6.58.
Na]+. C63H62O8 (946.44): calcd. C 79.89, H 6.60, O 13.51; found
C 79.96, H 6.61.
(S)-2-(Benzyloxy)-2-[(2S,3R,4S,5S,6R)-4,5-bis(benzyloxy)-6-
(benzyloxymethyl)-3-(methylsulfonyloxy)tetrahydro-2H-pyran-2-
yl]ethyl Methanesulfonate (38): Compound 37 (946 mg) was con-
verted to give dimesylate 38 (510 mg, 69%, two steps) as a colorless
oil using the general procedure (D). Rf = 0.5 (hexane/EtOAc, 7:3).
[α]2D8 = +27.8 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 3030, 2924,
˜
max
2
2
2
2
(R)-2-(Benzyloxy)-2-[(2S,3R,4S,5S,6R)-4,5-bis(benzyloxy)-6- 2854, 1595, 1453, 1174, 1097, 1050, 964, 739, 689 cm–1. H NMR
1
(benzyloxymethyl)-3-(methylsulfonyloxy)tetrahydro-2H-pyran-2-
yl]ethyl Methanesulfonate (35): Compound 34 (946 mg) was con-
verted to give dimesylate 35 (466 mg, 63%, two steps) as a colorless
oil using the general procedure (D). Rf = 0.5 (hexane/EtOAc, 7:3).
(400 MHz, CDCl3): δ = 7.34–7.18 (m, 20 H), 5.05 (dd, J = 8.7,
7.3 Hz, 1 H), 4.80 (d, J = 11.4 Hz, 1 H), 4.75 (d, J = 10.7 Hz, 1
H), 4.54 (d, J = 10.7 Hz, 1 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.49 (d,
J = 11.7 Hz, 1 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.38–4.34 (m, 6 H),
4.25 (dd, J = 9.2, 2.6 Hz, 1 H), 4.15 (t, J = 6.1 Hz, 1 H), 3.56 (dd,
J = 9.0, 7.3 Hz, 1 H), 3.36 (dd, J = 9.2, 5.1 Hz, 1 H), 2.93 (s, 3 H),
2.91 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0, 137.6,
[α]2D8 = +14.28 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 2924, 2855,
˜
max
2
2
2
2
1599, 1495, 1455, 1176, 1093, 998, 740, 699, 525 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.24 (m, 20 H), 4.98 (d, J = 4.1 Hz,
1 H), 4.97–4.48 (m, 9 H), 4.33–4.31 (m, 1 H), 4.28 (dd, J = 11.0, 137.2, 128.5–127.6 (m), 78.0, 77.3, 75.0, 74.4, 73.9, 73.5, 72.5, 69.0,
3.6 Hz, 1 H), 4.12–4.07 (m, 3 H), 3.93 (dd, J = 6.0, 2.9 Hz, 1 H), 68.3, 37.6, 37.0 ppm. ESMS: m/z 763 [M + Na]+. C38H44O11S2
3.78–3.73 (m, 2 H), 2.82 (s, 3 H), 2.79 (s, 3 H) ppm. ESMS: m/z
763 [M + Na]+. C38H44O11S2 (740.23): calcd. C 61.60, H 5.99, O
23.75, S 8.66; found C 61.51, H 6.02.
(740.23): calcd. C 61.60, H 5.99, O 23.75, S 8.66; found C 61.68,
H 6.02.
(3S,3aR,5R,6R,7R,7aS)-1-Benzyl-3,6,7-tris(benzyloxy)-5-(benzyl-
oxymethyl)octahydropyrano[3,2-b]pyrrole (39): Dimesylate 38
(370 mg) was subjected to cylization using the general procedure
(E) to give 39 (248 mg, 76%) as colorless oil. Rf = 0.4 (hexane/
(3R,3aR,5R,6R,7R,7aS)-1-Benzyl-3,6,7-tris(benzyloxy)-5-(benzyl-
oxymethyl)octahydropyrano[3,2-b]pyrrole (36): Dimesylate 35
(370 mg) was subjected to cylization using the general procedure
(E) to give 36 (248 mg, 76%) as colorless oil. Rf = 0.4 (hexane/
EtOAc, 7:3). [α]2D8 = +26.3 (c = 1.0, CH Cl ). IR (CH Cl ): ν
=
˜
max
2
2
2
2
EtOAc, 7:3). [α]2D8 = –12.83 (c = 1.0, CH Cl ). IR (CH Cl ): ν
2922, 2853, 1597, 1492, 1093, 1024, 734, 699 cm–1 1H NMR
.
˜
2
2
2
2
max
= 2923, 2853, 1668, 1602, 1495, 1094, 1027, 753, 697 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.21 (m, 25 H), 4.97 (br. s, 1
H), 4.89 (d, J = 11.4 Hz, 1 H), 4.65–4.58 (m, 3 H), 4.49 (m, 7 H),
(400 MHz, CDCl3): δ = 7.34–7.15 (m, 25 H), 4.98 (br. s, 1 H), 4.88
(d, J = 11.4 Hz, 1 H), 4.65–4.37 (m, 8 H), 4.23 (br. s, 1 H), 4.12
(m, 1 H), 3.99 (br. s, 1 H), 3.93 (dd, J = 6.3, 6.6 Hz, 1 H), 3.71–
4.43 (d, J = 12.4 Hz, 1 H), 4.34 (d, J = 11.7 Hz, 1 H), 4.23–4.20 3.69 (m, 2 H), 3.66–3.61 (m, 2 H), 2.79 (d, J = 6.6 Hz, 2 H) ppm.
(m, 2 H), 3.99–3.98 (m, 1 H), 3.91–3.90 (m, 1 H), 3.77–3.75 (m, 2 13C NMR (100 MHz, CDCl3): δ = 151.8, 138.5, 138.4, 138.2, 138.0,
H), 3.72 (s, 2 H), 2.91 (dd, J = 12.2, 8.0 Hz, 1 H), 2.78 (dd, J = 128.3–126.7 (m), 99.0, 78.7, 75.5, 73.5, 73.4, 72.0, 70.9, 70.6, 67.9,
12.2, 4.1 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.8,
140.0, 138.5, 138.2, 137.9, 128.3–126.8 (m), 98.2, 77.8, 75.7, 73.4,
73.2, 71.4, 70.9, 70.7, 68.0, 53.4, 51.6, 29.6 ppm. HRMS calcd. for
C43H46NO5 [M+ H]+ 656.3371, found 656.3379.
53.1, 50.9, 29.6 ppm. HRMS calcd. for C43H46NO5 [M+ H]+
656.3371, found 656.3379.
(3S,3aR,5R,6R,7R,7aS)-5-(Hydroxymethyl)octahydropyrano[3,2-b]-
pyrrole-3,6,7-triol (9): Compound 39 (196 mg) was subjected to
global deprotection using the general procedure (F) to give 9
(59 mg, 98 %) as a thick liquid. Rf = 0.3 (MeOH/EtOAc, 1:4).
(3R,3aR,5R,6R,7R,7aS)-5-(Hydroxymethyl)octahydropyrano[3,2-b]-
pyrrole-3,6,7-triol (8): Compound 36 (196 mg) was subjected to
global deprotection using the general procedure (F) to give 8
(59 mg, 98 %) as a thick liquid. Rf = 0.3 (MeOH/EtOAc, 1:4).
1
[α]2D8 = –16.3 (c = 0.8, H2O). H NMR (400 MHz, D2O): δ = 3.85–
3.81 (m, 1 H), 3.73–3.70 (m, 2 H), 3.64 (br. s, 1 H), 3.61–3.52 (m,
2 H), 3.39–3.35 (m, 1 H), 3.29 (dd, J = 12.5, 3.0 Hz, 1 H), 3.15–
3.05 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 78.9, 77.1,
1
[α]2D8 = –10.2 (c = 0.8, H2O). H NMR (400 MHz, D2O): δ = 3.75–
3.74 (m, 2 H), 3.67–3.64 (m, 2 H), 3.61 (dd, J = 8.5, 3.0 Hz, 1 H),
3.55 (dd, J = 11.5, 3.0 Hz, 1 H), 3.41 (m, 2 H), 2.97–2.88 (m, 2 H) 68.6, 67.4, 67.2, 61.9, 53.9, 29.3 ppm. ESMS: m/z 206 [M + H]+.
ppm. 13C NMR (100 MHz, CDCl3): δ = 78.6, 76.7, 70.3, 68.7, 67.5,
61.9, 42.1, 29.0 ppm. ESMS: m/z 206 [M + H]+. C8H15NO5
(205.10): calcd. C 46.82, H 7.37, N 6.83, O 38.98; found C 46.83,
H 7.39, N 6.84.
C8H15NO5 (205.10): calcd. C 46.82, H 7.37, N 6.83, O 38.98; found
C 46.85, H 7.38, N 6.82.
(2S,4R,4aS,6R,7R,8S,8aR)-7,8-Bis(benzyloxy)-6-(benzyloxy-
methyl)-2-(4-methoxy-phenyl)-4-(trityloxymethyl)hexahydro-pyrano-
[3,2-d][1,3]dioxine (23): Alcohol 15 (100 mg) was subjected to oxi-
(2R,3S,4S,5R,6S)-3,4-Bis(benzyloxy)-6-[(S)-1-(benzyloxy)-2-(trit-
yloxy)ethyl]-2-(benzyloxymethyl)-5-(4-methoxybenzyloxy)tetra- dative cyclization using the general procedure (G) to give 23
hydro-2H-pyran (37): Alcohol 33 (856 mg) was benzylated with
BnCl using the general procedure (A) to give 37 (860 mg, 91%) as
colorless oil. Rf = 0.55 (hexane/EtOAc, 9:1). [α]2D8 = +106.9 (c =
(80 mg, 80%) as colorless oil. Rf = 0.55 (hexane/EtOAc, 9:1). [α]2D8
= +36.5 (c = 1.0, CH Cl ). IR (CH Cl ): ν
= 2920, 1597, 1099,
˜
2
1
2
2
2
max
1023, 736, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.48–7.14
1.2, CH Cl ). IR (CH Cl ): ν = 3060, 2925, 2855, 1611, 1091, (m, 32 H, Ar-H), 6.89 (d, J = 8.7 Hz, 2 H, Ar-H), 5.95 (s, 1 H, 9-
˜
max
2
2
2
2
1
753, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.46–7.16 (m, 35
H), 7.02 (d, J = 8.2 Hz, 2 H), 6.78 (d, J = 8.2 Hz, 2 H), 4.69–4.58 H, -OCH2Ph), 4.62 (d, J = 11.4 Hz, 1 H, -OCH2Ph), 4.53 (d, J =
(m, 4 H), 4.53–4.44 (m, 6 H), 4.33 (dd, J = 4.8, 2.5 Hz, 1 H), 4.28– 12.2 Hz, 1 H, -OCH2Ph), 4.49 (d, J = 11.9 Hz, 1 H, -OCH2Ph),
H), 4.74 (d, J = 11.2 Hz, 1 H, -OCH2Ph), 4.69 (d, J = 11.4 Hz, 1
Eur. J. Org. Chem. 2008, 5731–5739
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5737

V. R. Doddi, H. P. Kokatla, A. P. J. Pal, R. K. Basak, Y. D. Vankar
FULL PAPER
4.39 (d, J = 11.9 Hz, 1 H, -OCH2Ph), 4.28 (dd, J = 9.2, 11.1 Hz, 1
H, 2-H), 4.20 (br. d, J = 5.6 Hz, 1 H, 7-H), 4.03 (dd, J = 5.4,
4.12–4.06 (m, 2 H, 5-H, 2-H), 4.03–4.02 (m, 1 H, 7-H), 3.97 (dd, J
= 8.0, 11.7 Hz, 1 H, 3-H), 3.90 (dd, J = 3.2, 2.9 Hz, 1 H, 8-H),
2.9 Hz, 1 H, 5-H), 3.92 (dd, J = 9.2, 2.9 Hz, 1 H, 1-H), 3.89 (dd, 3.83–3.78 (m, 2 H, 8-H, 1-H), 3.80 (s, 3 H, -OCH3), 3.55 (dd, J =
J = 7.0, 11.1 Hz, 1 H, 3-H), 3.83 (dd, J = 7.0, 5.4 Hz, 1 H, 4-H),
3.81 (s, 3 H, -OCH3), 3.66–3.59 (m, 2 H, 6-H, 6Ј-H), 3.46–3.38 (m,
2 H, 8-H, 8Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.9,
143.6, 138.3, 138.2, 138.1, 131.0, 128.7–126.9 (m), 113.5, 96.2, 81.4,
75.6, 74.6, 73.4, 73.3, 72.4, 69.6, 66.9, 63.5, 55.2, 29.6 ppm. ESMS:
m/z 877 [M + Na]+. C56H54O8 (854.38): calcd. C 78.66, H 6.37, O
14.97; found C 78.63, H 6.39.
9.5, 6.8 Hz, 1 H, 6-H), 3.26 (dd, J = 9.5, 5.3 Hz, 1 H, 6Ј-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 160.0, 144.0, 138.6, 138.4, 138.3,
130.4, 128.8–126.8 (m), 113.5, 110.5, 86.6, 78.1, 75.8, 75.3, 74.0,
73.4, 73.0, 71.9, 66.0, 63.3, 61.1, 55.3 ppm. ESMS: m/z 877 [M +
Na]+. C56H54O8 (854.38): calcd. C 78.66, H 6.37, O 14.97; found
C 78.67, H 6.36.
Supporting Information (see also the footnote on the first page of
this article): Copies of spectra for all new compounds viz. 6, 7, 8,
9, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 30, 31, 32,
33, 34, 35, 36, 37, 38, 39.
(2S,4S,4aS,6R,7R,8S,8aR)-7,8-Bis(benzyloxy)-6-(benzyloxymethyl)-
2-(4-methoxyphenyl)-4-(trityloxymethyl)hexahydro-pyrano[3,2-d]-
[1,3]dioxine (24): Alcohol 16 (100 mg) was subjected to oxidative
cyclization using the general procedure (G) to give 24 (85 mg, 85%)
as a white solid. Rf = 0.53 (hexane/EtOAc, 9:1). [α]2D8 = +15.3 (c =
Acknowledgments
1.0, CH Cl ). IR (CH Cl ): ν = 2912, 1595, 1093, 1021, 739,
˜
max
2
2
2
2
701 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.47–7.14 (m, 32 H,
Ar-H), 6.86 (d, J = 8.7 Hz, 2 H, Ar-H), 5.56 (s, 1 H, 9-H), 4.73 (d,
J = 11.9 Hz, 1 H, -OCH2Ph), 4.69 (d, J = 11.9 Hz, 1 H, -OCH2Ph),
4.67 (d, J = 11.7 Hz, 1 H, -OCH2Ph), 4.49 (d, J = 11.4 Hz, 1 H,
-OCH2Ph), 4.35 (d, J = 11.4 Hz, 1 H, -OCH2Ph), 4.24 (d, J =
11.7 Hz, 1 H, -OCH2Ph), 4.12 (dd, J = 11.4, 8.8 Hz, 1 H, 2-H),
4.05–4.04 (m, 2 H, 5-H, 7-H), 3.93–3.82 (m, 3 H, 4-H, 3-H, 1-H),
3.79 (s, 3 H, -OCH3), 3.64 (dd, J = 10.4, 3.4 Hz, 1 H, 6-H), 3.58
(dd, J = 10.4, 3.2 Hz, 1 H, 6-H), 3.51 (dd, J = 9.7, 6.6 Hz, 1 H, 8-
H), 3.34 (dd, J = 9.7, 5.3 Hz, 1 H, 8Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.0, 138.4, 138.2, 128.0–126.8 (m), 113.5,
100.2, 86.6, 77.8, 74.4, 73.3, 72.1, 69.9, 29.6 ppm. ESMS: m/z 877
[M + Na]+. C56H54O8 (854.38): calcd. C 78.66, H 6.37, O 14.97;
found C 78.69, H 6.38.
We thank the Department of Science and Technology, New Delhi,
for financial support to one of us (Y. D. V.) in the form of a
Ramanna Fellowship (Grant No. SR/S1/RFOC-04/2006). V. R. D.,
H. P. K., and R. K. B. thank the Council of Scientific and Indus-
trial Research, New Delhi and A. P. J. P thanks the University
Grants Commission, New Delhi for senior research fellowships.
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˜
max
2
2
2
2
698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.44–7.18 (m, 32 H,
Ar-H), 6.89 (d, J = 8.3 Hz, 2 H, Ar-H), 5.84 (s, 1 H, 9-H), 4.65 (d,
J = 11.9 Hz, 1 H, -OCH2Ph), 4.63 (d, J = 11.7 Hz, 1 H, -OCH2Ph),
4.58 (d, J = 11.7 Hz, 1 H, -OCH2Ph), 4.57 (d, J = 11.0 Hz, 1 H,
-OCH2Ph), 4.56 (d, J = 11.0 Hz, 1 H, -OCH2Ph), 4.49 (d, J =
11.9 Hz, 1 H, -OCH2Ph), 4.42–4.39 (m, 1 H, 5-H), 4.26–4.23 (m, 2
H, 2-H, 7-H), 4.11 (dd, J = 5.8, 2.7 Hz, 1 H, 4-H), 4.00 (dd, J =
11.7, 8.5 Hz, 1 H, 6-H), 3.85 (dd, J = 6.6, 3.4 Hz, 1 H, 3-H), 3.80
(s, 3 H, -OCH3), 3.82–3.75 (m, 2 H, 6-H, 1-H), 3.47–3.42 (m, 2 H,
8-H, 8Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 143.6,
138.5, 130.9, 128.7–127.1 (m), 113.5, 96.4, 87.2, 75.8, 75.3, 74.0,
73.9, 73.1, 72.1, 66.0, 63.1, 62.9, 55.3 ppm. ESMS: m/z 877 [M +
Na]+. C56H54O8 (854.38): calcd. C 78.66, H 6.37, O 14.97; found
C 78.68, H 6.33.
(2S,4S,4aS,6R,7S,8S,8aR)-7,8-Bis(benzyloxy)-6-(benzyloxymethyl)-
2-(4-methoxyphenyl)-4-(trityloxymethyl)hexahydro-pyrano[3,2-d]-
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˜
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2
2
2
2
697 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.48–7.07 (m, 32 H,
Ar-H), 6.88 (d, J = 8.8 Hz, 2 H, Ar-H), 5.54 (s, 1 H, 9-H), 4.96 (d,
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-OCH2Ph), 4.41 (dd, J = 8.0, 5.8 Hz, 1 H, 4-H), 4.35 (d, J =
11.9 Hz, 1 H, -OCH2Ph), 4.28 (d, J = 11.9 Hz, 1 H, -OCH2Ph),
5738
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5731–5739

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Received: August 5, 2008
Published Online: October 22, 2008
Eur. J. Org. Chem. 2008, 5731–5739
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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