Discriminative Glycosylation of 3-(Aryloxy)propane-1,2-diols by Choice of a Glycosyl Donor

Article abstract of DOI:10.1055/s-2003-42437

Regioselective glycosylation of rac-guaifenesin (1A) with various glycosyl donors viz., β-D-glucosepentaacetate (2), pyridyl 2,3,4,6-O-tetra-O-benzyl- 1-thio-β-D-galactopyranoside (9), 1-O-acetyl-2,3,5-tri-O-benzoyl-α/ β-D-ribo- (13) and xylofuranoside (17) is reported. Glycosyl donors 2, 13 and 17 bearing ester protecting groups is reported to exhibit high regioselectivity to form the corresponding diastereomeric mixture of 1-O-glycosylated guaifenesin derivatives 3A, 14A and 18A, respectively; formation of diglycosylated derivatives 5A, 15A and 19A is not observed. While no such selectivity is observed when the donor 9 bearing ether protecting groups is used in the coupling reaction with 1A, resulting in the formation of digalactosylated derivatives 10A. That the regioselectivity is not dependent upon substituents present on the aromatic ring is shown by coupling IB with 2 to isolate 1-O-glycosylated derivative 3B; formation of diglycosylated derivative 5B was not observed. Applicability of this finding is shown by preparation of enantiopure guaifenesin [(R)-1 (98% ee) and (S)-1 (98% ee)] by separation of their corresponding diastereomers (R)-3 and (S)-3, respectively.

Full text of DOI:10.1055/s-2003-42437

2378
PAPER
Discriminative Glycosylation of 3-(Aryloxy)propane-1,2-diols by Choice of a
Glycosyl Donor
Discriminative
G
ly
a
cosylation
r
of 3-(A
r
i
yloxy)propan
B
e
-1,2-diols abu Mereyala,*a Sreeman Kumar Mamidyala,a Krishna Prasad Chigurupati,b Sastri R. Srinivasab
a
Speciality, Gas Based Chemicals and Processes Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Fax +91(40)27160921; E-mail: mereyalahb@rediffmail.com
b
Granules India Ltd, Road No.2, Banjara Hills, Hyderabad 500 033, India
Received 21 May 2003; revised 21 July 2003
Abstract: Regioselective glycosylation of rac-guaifenesin (1A)
with various glycosyl donors viz., -D-glucosepentaacetate (2), py-
ridyl 2,3,4,6-O-tetra-O-benzyl-1-thio- -D-galactopyranoside (9), 1-
O-acetyl-2,3,5-tri-O-benzoyl- / -D-ribo- (13) and xylofuranoside
(17) is reported. Glycosyl donors 2, 13 and 17 bearing ester protect-
ing groups is reported to exhibit high regioselectivity to form the
corresponding diastereomeric mixture of 1-O-glycosylated guaifen-
esin derivatives 3A, 14A and 18A, respectively; formation of digly-
cosylated derivatives 5A, 15A and 19A is not observed. While no
such selectivity is observed when the donor 9 bearing ether protect-
ing groups is used in the coupling reaction with 1A, resulting in the
formation of digalactosylated derivatives 10A. That the regioselec-
tivity is not dependent upon substituents present on the aromatic
ring is shown by coupling 1B with 2 to isolate 1-O-glycosylated de-
rivative 3B; formation of diglycosylated derivative 5B was not ob-
served. Applicability of this finding is shown by preparation of
enantiopure guaifenesin [(R)-1 (98% ee) and (S)-1 (98% ee)] by
separation of their corresponding diastereomers (R)-3 and (S)-3, re-
spectively.
Figure 1 Structures of guaifensin, chlorphenesin and mephenesin
The benefits of the study include synthesis of single iso-
mer drugs14 and prodrugs15 by separation of diastereomers
formed due to glycosylation.
Regioselective glycosylation of rac-1A was evaluated by
reacting with two mole equivalents of -D-glucosepen-
15
taacetate (2) in CH2Cl2/BF3·OEt2 at room temperature
(Scheme 1). It resulted in the isolation of monoglycosylat-
ed guaifenesin diastereomers (R)-3 (42%), (S)-3 (44%)
along with the transesterification product 1-O-
acetylguaifenesin derivative rac-4A (8%) after separation
by column chromatography. Formation of the 1,2-di-O-
glycosylated derivatives 5A was not observed even when
the same reaction was performed using a large excess of
the donor 2 (3 mole equiv). Products (R)-3 and (S)-3 were
designated as -glycosides due to C-2 neighboring group
participation of the glycosyl donor 2 and from the appear-
ance of corresponding H-1 at = 4.84 and 4.96, respec-
tively, as doublets with a coupling constant of J = 8.4 Hz
in their 1H NMR spectra. (R)-3 and (S)-3 were character-
ized as monoglycosylated derivatives of 1A from their 1H
NMR spectra by integration of the protons, however, re-
giochemistry in the glycosylation could not be assigned
due to overlap of signals between = 3.60–4.30. In order
to establish the regiochemistry in glycosylation reaction,
(R)-3 and (S)-3 were converted to their corresponding ac-
etates (R)-6 and (S)-6, respectively. (R)-6 and (S)-6 were
characterized by 1H NMR spectra as 1-O-glycosyl deriv-
atives from the appearance of the corresponding H-2 pro-
tons at = 5.10–5.30 respectively shifted downfield due
to acetylation. Rac-4 was characterized as 1-O-
Key words: regioselective glycosylations, 3-(aryloxy)propane-
1,2-diols, glycosyl donors, guaifenesin, resolution
The O-glycosylation method to attach a sugar to other
than sugar molecules1 (aglycons) such as macrolides,2
inositols,3 amino acids4/peptides,5 phenols,6 and others7
has been routinely practiced to synthesize natural prod-
ucts of biological and pharmaceutical importance.8 From
a synthetic standpoint, the efficacy of the O-glycosylation
reaction generally involves achieving high chemical
yield, regioselectivity,9 and stereoselectivity.10 Among
them, high regioselectivity was realized by the selective
protection of the hydroxyl group of the aglycon bearing
more than one hydroxyl group to avoid greater number of
possibilities though it increases the number of unit opera-
tions in a multistep total synthesis. While the practical
stereoselective O-glycosylations (1,2-cis10j and 1,2-trans)
has been very well demonstrated and reviewed,10 there is
a need to study regioselective glycosylations of aglycons.
We report here our studies in this direction on the regiose-
lective glycosylation of 3-(aryloxy)propane-1,2-diols that
are components of pharmaceutically important products
such as guaifenesin (1),11 chlorfenesin,12 and
mephanesin13 (Figure 1).
1
acetylguaifenesin by comparison of H NMR spectrum
with that of an authentic sample. Thus, acetylation of 1A
with Ac2O/pyridine resulted in the isolation of mono- and
1,2-di-O-acetylguaifenesin (rac-4 and rac-7), formation
of 2-O-acetylguaifensin (rac-8) was not observed. In the
1H NMR spectra of rac-4, H-1 appeared at = 4.35 (2 H)
and H-2 of rac-7 appeared at = 5.32 (1 H).
SYNTHESIS 2003, No. 15, pp 2378–2384
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Advanced online publication: 23.10.2003
DOI: 10.1055/s-2003-42437; Art ID: Z06603SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Discriminative Glycosylation of 3-(Aryloxy)propane-1,2-diols
2379
derivative 5B was not observed. Compounds 3B, its cor-
responding acetyl derivative 6B and rac-4B were charac-
terized analogous to (R)-3, (R)-6 and rac-4A by 1H NMR
spectra. Thus, it was evident that substituents on the aro-
matic ring did not play any decisive role in directing
regioselective glycosylations.
In order to evaluate, if the observed regioselectivity is also
common to other glycosyl donors, we chose pyridyl
2,3,4,6-tetra-O-benzyl-1-thio- -D-galactopyranoside
(9)18 as a glycosyl donor and iodomethane activation pro-
cedure that was proven in our laboratory to be mild and
highly stereoselective for performing this experiment.
Thus, coupling of rac-1A and rac-1B separately with one
and two mole equivalents of the donor 9 for 48–72 hours
in dichloromethane and 5% iodomethane at 50 °C result-
ed in the isolation of di-O-galactosylated derivatives 10A
and 10B and the corresponding mono-O-galactosylated
derivatives 11A and 11B respectively. Thus, no regiose-
lectivity was observed in these reactions. Compounds
10A and 10B were characterized as di-O-galactosylated
derivatives from the 1H NMR spectrum by the integration
of the protons. Compounds 11A and 11B were character-
ized as 1-O-galactosylated derivatives by converting them
to the corresponding 2-O-acetyl derivatives 12A and 12B,
respectively and from the appearance of the H-2 proton at
= 5.20–5.30 shifted downfield due to acetylation.
In order to ascertain whether the observed regioselectivity
is related to the glycosyl donor bearing electron-with-
drawing ester group or electron-donating ether protecting
group, glycosylation of rac-1A was carried out with 1-O-
acetyl-2,3,5-tri-O-benzoyl- / -D-ribofuranoside (13)19
(CH2Cl2/BF3·OEt2). It resulted in the isolation of a dia-
stereomeric mixture of 1-O- -D-ribofuranosyl guaifenes-
in derivative rac-14A in good yield (82%); formation of
di-O-ribosylated derivative 15A and trans esterification
products were not observed. Compound 14A was charac-
terized by 1H NMR spectrum, analogous to (R)-3, as its 1-
O-ribofuranosyl derivative by preparation of its corre-
sponding acetylated derivative rac-16A.
Scheme 1
The high regioselectivity observed in these reactions was
surprising while working in the area of glycosylations of
inositols, saccharides (pyrano and furano forms) and 2-
deoxysaccharides for the last two decades. It has been re-
ported that 3-(aryloxy)propane-1,2-diols with a substitu-
ent in the para position show a much higher
enantioselectivity (92–94% ee, S) than the corresponding
derivatives with ortho-substituents (34–88% ee, S) in li-
The generality of high regioselectivty was further con-
firmed by coupling rac-1A with 1-O-acetyl-2,3,5-tri-O-
benzoyl- / -D-xylofuranose (17).20 Reaction of rac-1A
with 17 (CH2Cl2/BF3·OEt2) resulted in the isolation of di-
astereomeric mixture of 1-O-xylofuranosyl guaifenesin
derivative 18A (80%), once again exhibiting high regio-
selectivity. Formation of di-O-xylofuranosyl derivative
19A was not observed. Compound 18A and its acetyl de-
rivative 20A were characterized by 1H NMR spectra anal-
ogous to 12A and 16A.
pase-catalyzed sequential trans esterification route.16
A
similar observation was made in Sharpless asymmetric di-
hydroxylation of aryl allyl ethers, the ortho-substituted
derivatives have been shown to give low enantiopurity
(28–63% ee, S).17
In order to check the regioselectivity versus the role of
substituent, we decided to study the glycosylation of un-
substituted aryloxy derivatives. Thus, regioselective gly-
cosylation of 3-(phenoxy)propane-1,2-diol (rac-1B) with
2 (one, two, and three mole equivalents separately) under
similar reaction conditions was performed to observe
once again high regioselectivity leading to the isolation of
the mono 1-O-glycosylated derivative 3B (82%, dia-
stereomeric mixture) and the monoacetylated derivative
rac-4B (7%) similar to the reactivity observed for rac-1A.
Formation of the corresponding 1,2-di-O-glycosylated
The observed regioselectivity was benefited by the isola-
tion of enantiopure (R)- and (S)-guaifenesin (1). The com-
pounds (R)-3 and (S)-3 were deacetylated in 10%
methanolic ammonia solution to (R)-21 and (S)-21, re-
spectively, in quantitative yield and were individually
subjected to acid-catalyzed hydrolysis in 10% aq H2SO4 at
90 °C for 3 hours to isolate by extraction into ethyl acetate
enantiomerically enriched guaifenesin (S)-1 (93.0% ee)
Synthesis 2003, No. 15, 2378–2384 © Thieme Stuttgart · New York

2380
H. B. Mereyala et al.
PAPER
rac-4A
Yield: 0.24 g (8%).
1H NMR (200 MHz, CDCl3): = 2.10 (s, 3 H, OCOCH3), 3.82 (s, 3
H, OCH3), 3.90–4.10 (m, 2 H, H-1), 4.20 (m, 3 H, H-2, 3), 6.90 (m,
4 H, ArH).
and (R)-1 (91.0% ee), respectively (Figure 2). Further re-
crystallization from hot ethanol improved the enantiopu-
rity to 98.0%ee.17,21
MS (EI, 70 eV): m/z (%) = 240 (1, [M+]).
(R)-3
Yield: 2.85 g (42%); [ ]D24 +6.3 (c = 2.0, CHCl3); mp 82–84 °C.
1H NMR (200 MHz, CDCl3): = 1.90, 1.98, 2.02, 2.10 (4 s, 12 H,
4 × OCOCH3), 3.60–3.80 (m, 3 H, H-1, 6 ), 3.90 (s, 3 H, OCH3)
3.96–4.30 (m, 5 H, H-2, 3, 5 , 6 ), 4.84 (d, 1 H, J1,2 = 8.4 Hz, H-1 ),
4.90–5.22 (m, 3 H, H-2 , 3 , 4 ), 6.90 (m, 4 H, ArH).
MS (FAB): m/z = 529 [M+ + H].
Anal. Calcd for C24H32O13: C, 54.52; H, 6.10. Found: C, 54.39; H,
6.01.
Figure 2 Structures of compounds (S)- and (R)-1, 3, 6, and 21
(S)-3
The compounds 14A and 18A were deacetylated Yield: 2.98 g (44%); [ ]D24 –11.10 (c = 2.0, CHCl3).
1H NMR (200 MHz, CDCl3): = 1.96, 2.00, 2.02, 2.04 (4 s, 12 H,
4 × OCOCH3), 3.60–3.75 (m, 2 H, H-6 , 6 ), 3.85 (s, 3 H, OCH3),
3.96–4.34 (m, 6 H, H-1, 2, 3, 5 ), 4.96 (d, 1 H, J1,2 = 8.3 Hz, H-1 ),
5.00–5.30 (m, 3 H, H-2 , 3 , 4 ), 6.94 (m, 4 H, ArH).
(NaHCO3/MeOH) to obtain diastereomeric mixture of 1-
O- -D-ribofuranosylguaifenesin (22A) and 1-O- -D-xy-
lofuranosylguaifenesin (23A), attempts were not made to
separate the diastereomers.
MS (FAB): m/z = 529 [M+ + H].
In conclusion, high regioselective glycosylation of rac-
guaifenesin (1) was achieved by choice of a glycosyl do-
nor. Glycosyl donor bearing electron-withdrawing (ester)
protecting groups exhibited high regioselectivity. No
regioselectivity was observed when glycosyl donor pos-
sessing benzyl ether protecting group was used. The
stereoselectivty was controlled by use of well-established
Anal. Calcd for C24H32O13: C, 54.52; H, 6.10. Found: C, 54.37; H,
6.02.
3-Phenoxy-1-O-(2,3,4,6-tetra-O-acetyl- -D-glucopyranosyl)pro-
pane-1,2-diol (3B)
A reaction of 2 (6.0 g, 15.4 mmol) in CH2Cl2 (60 mL) with rac-1B
(1.3 g, 7.7 mmol) and BF3·OEt2 (1.17 mL, 9.2 mmol) for 6 h per-
protocols in the coupling reactions. The high regioselec- formed as described for (R)-3 resulted in the isolation of 4B, fol-
lowed by 3B.
tivty observed is not related to the substituent present on
the aromatic group was also demonstrated. The utility of
4B
these results was benefited by preparation of enantiopure
Yield: 0.11 g (7%).
(R)- and (S)-guaifenesin (1) in 98% ee.
1H NMR (200 MHz, CDCl3): = 2.08 (s, 3 H, OCOCH3), 3.98 (d,
2 H, J2,3 = 6.8 Hz, H-3), 4.04–4.30 (m, 3 H, H-1, 2), 6.80–7.00 (m,
3 H, ArH), 7.18–7.32 (m, 2 H, ArH).
1H NMR spectra were recorded using the following instruments: at
200 MHz on a Varian Gemini; at 300 MHz on a Bruker Avance; at
MS (EI, 70 eV): m/z = 210 (1, [M+]).
400 MHz on a Varian Unity, with TMS as an internal standard for
solutions in CDCl3. The J values are reported in Hz. Optical rota-
3B
tions were measured with a Jasco DIP-370 instrument. Organic so-
Yield: 3.16 g (82%).
lutions were dried over anhyd Na2SO4.
1H NMR (300 MHz, CDCl3): = 1.96, 2.02, 2.04, 2.08 (4 s, 12 H,
4 × OCOCH3), 3.60–4.30 (m, 9 H, H-1, 2, 3, OH, 5 , 6 , 6 ), 4.80–
5.20 (m, 4 H, H-1 , 2 , 3 , 4 ), 6.80–6.92 (m, 3 H, ArH), 7.30 (m, 2
H, ArH).
MS (FAB): m/z = 499 [M+ + H].
(2R)-3-(2-Methoxyphenoxy)-1-O-(2,3,4,6-tetra-O-acetyl- -D-
glucopyranosyl)propane-1,2-diol [(R)-3] and (2S)-3-(2-Methoxy-
phenoxy)-1-O-(2,3,4,6-tetra-O-acetyl- -D-glucopyranosyl)pro-
pane-1,2-diol [(S)-3]; Typical Procedure
To a solution of -D-glucosepentaacetate 2 (10 g, 25.6 mmol) in an-
hyd CH2Cl2 (100 mL) was added 1A (2.54 g, 12.8 mmol) and
BF3·OEt2 (1.93 ml, 15.38 mmol) at 0 °C. The reaction mixture was
stirred for 8 h at r.t. Progress of the reaction was monitored by TLC.
After completion of the reaction, anhyd K2CO3 (1.93 g) was added,
stirred for 30 min, filtered, and the residue was washed with CH2Cl2
(150 mL). The filtrate was transferred to a separating funnel,
washed with H2O (2 × 50 mL), brine (50 mL), the organic phase
was separated, dried (Na2SO4), and concentrated to obtain a residue
containing a diastereomeric mixture of (R)-3, (S)-3, and rac-4A.
They were separated by column chromatography (silica gel, 60–120
mesh, eluent: hexane–EtOAc, 4:1) to isolate (2R/S)-1-O-acetyl-3-
(2-methoxyphenoxy)propane-1,2-diol (rac-4A), followed by (R)-3
and (S)-3.
Anal. Cacld for C23H30O12: C, 55.41; H, 6.06. Found: C, 54.81; H,
6.16.
(2R/S)-1-O-Acetyl-3-(2-methoxyphenoxy)propane-1,2-diol
(rac-4A) and (2R/S)-1,2-Di-O-acetyl-3-(2-methoxyphenoxy)pro-
pane-1,2-diol (rac-7A); Typical Procedure
To a solution of rac-1A (1.98 g, 10 mmol) in CH2Cl2 (40 mL) was
added Ac2O (2.5 mL, 25 mmol) and pyridine (2 mL) and the mix-
ture was stirred for 3 h at r.t. The product rac-7A was isolated by
standard work-up procedure and chromatography (silica gel, 60–
120 mesh, eluent: hexane–EtOAc, 4:1) as a syrup, followed by
monoacetyl derivative rac-4A.
Synthesis 2003, No. 15, 2378–2384 © Thieme Stuttgart · New York

PAPER
Discriminative Glycosylation of 3-(Aryloxy)propane-1,2-diols
2381
rac-7A
MS (FAB): m/z = 571 [M+ + H].
Yield: 0.28 g (10%).
1H NMR (200 MHz, CDCl3):
Anal. Calcd for C26H34O14: C, 54.93; H, 5.67. Found: C, 54.77; H,
5.63.
= 2.14, 2.16 (2 s, 6 H,
2 × OCOCH3), 3.82 (s, 3 H, OCH3), 4.16 (m, 2 H, H-3), 4.28 (m, 1
H, H-1), 4.50 (m, 1 H, H-1), 5.36 (m, 1 H, H-2), 6.90 (m, 4 H, ArH).
MS (EI, 70 eV): m/z = 282 [M+].
3-(2-Methoxyphenoxy)-1,2-di-O-(2,3,4,6-tetra-O-benzyl- -D-
galactopyranosyl)propane-1,2-diol (10A) and 3-(2-Methoxy-
phenoxy)-1-O-(2,3,4,6-tetra-O-benzyl- -D-galactopyrano-
syl)propane-1,2-diol (11A); Typical Procedure
A mixture of 9 (1.8 g, 2.99 mmol), rac-1A (0.29 g, 1.49 mmol) and
powdered 4 Å molecular sieves (50 mg) in anhyd CH2Cl2 (50 mL)
containing 5% MeI was heated to 50 °C for 48–72 h. Reaction was
monitored by TLC, when complete it was filtered on a Celite pad,
and the residue was washed with EtOAc (100 mL). The combined
filtrates were concentrated, and the residue was chromatographed
(silica gel, 60–120 mesh, hexane–EtOAc, 9:1) to obtain the title
compound as a syrup followed by 11a.
Anal. Calcd for C14H18O6: C, 59.56; H, 6.42. Found: C, 60.06; H,
6.36.
rac-4A
Yield: 1.85 g (78%).
1-O-Acetyl-3-(phenoxy)propane-1,2-diol (4B) and 1,2-Di-O-
acetyl-3-(phenoxy)propane-1,2-diol (7B)
A reaction of 1B (1.0 g, 5.95 mmol) in CH2Cl2 (20 mL) with Ac2O
(1.2 mL) and pyridine (2.4 mL) was performed as described for 4A
to isolate 7B as a syrup, followed by the monoacetyl derivative 4B.
11a
Yield: 0.58 g (31%); [ ]D +30.00 (c = 1.0, CHCl3).
7B
1H NMR (400 MHz, CDCl3): = 3.38–3.60 (m, 4 H, H-1, 6 , 6 ),
3.50 (s, 3 H, OCH3), 3.60 (s, 3 H, OCH3), 3.80–4.04 (m, 4 H, H-1,
3), 4.18–5.00 (m, 24 H, H-2 , 2 , 3, 3 , 4 , 4 , 5 , 5 , 8 × CH2C6H5),
5.20 (d, 1 H, J1,2 = 2.5 Hz, H-1 ), 5.20 (d, 1 H, J1,2 = 3.10 Hz, H-1 ),
6.80 (m, 4 H, ArH), 7.10–7.40 (m, 40 H, ArH).
Yield: 0.27 g (18%).
1H NMR (200 MHz, CDCl3):
2 × OCOCH3), 4.04 (d, 2 H, J2,3 = 6.7 Hz, H-3, 3 ), 4.12 (dd, 1 H,
1,2 = 6.6 Hz, J1,1 = 12.2 Hz, H-1), 4.20 (dd, 1 H, J1 ,2 = 3.48 Hz, H-
= 2.04, 2.08 (2 s, 6 H,
J
1 ), 5.30 (m, 1 H, H-2), 6.80–7.00 (m, 3 H, ArH), 7.18–7.34 (m, 2
H, ArH).
MS (EI, 70 eV): m/z = 252 (1, [M+]).
Anal. Calcd for C78H82O14: C, 75.34; H, 6.64. Found: C, 75.55; H,
6.35.
11A
Anal. Calcd for C13H16O5: C, 61.89; H, 6.39. Found: C, 62.15; H,
6.51.
Syrup; yield: 0.34 g (55%); [ ]D +27.40 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): = 3.40–3.78 (m, 4 H, H-1, 6 , 6 ),
3.82 (s, 3 H, OCH3), 3.86–5.00 (m, H-2, 3, 2 , 3 , 4 , 5 ,
4 × CH2C6H5), 5.15 (d, 1 H, J1,2 = 2.5 Hz, H-1 ), 6.85 (m, 4 H, ArH),
7.10–7.40 (m, 20 H, ArH).
4B
Yield: 0.89 g (71%).
(2R)-2-O-Acetyl-3-(2-methoxyphenoxy)-1-O-(2,3,4,6-tetra-O-
acetyl- -D-glucopyranosyl)propane-1,2-diol [(R)-6]; Typical
Procedure
Anal. Calcd for C44H48O9: C, 73.31; H, 6.71. Found: C, 72.96; H,
6.46.
To a solution of (R)-3 (0.2 g) in CH2Cl2 (6 mL) was added pyridine
(0.4 mL), Ac2O (0.28 mL), and a catalytic amount of N,N-dimethy-
laminopyridine (2 mg). The reaction mixture was stirred at r.t. for 6
h, diluted with H2O (10 mL), and stirred for 5 min. CH2Cl2 (50 mL)
was added and the organic layer was washed with 5% aq CuSO4
(2 × 35 mL), H2O (50 mL), dried (Na2SO4), and concentrated. The
residue obtained was chromatographed (silica gel; hexane–EtOAc,
9:1) to isolate the title compound as a solid; yield: 0.09 g (92%); mp
109–111 °C; [ ]D24 –6.0 (c = 1.0, CHCl3) .
1H NMR (300 MHz, CDCl3): = 1.90, 1.96, 2.00, 2.02, 2.06, 2.08
(5 s, 15 H, 5 × OCOCH3), 3.70 (m, 1 H, H-6 ), 3.90 (s, 3 H, OCH3),
3.98–4.40 (m, 6 H, H-1, 3, 5 , 6 ), 4.98 (d, 1 H, J1,2 = 8.2 Hz, H-1 ),
5.02–5.16 (m, 4 H, H-2, 2 , 3 , 4 ), 6.90 (m, 4 H, ArH).
2-O-Acetyl-3-(2-methoxyphenoxy)-1-O-(2,3,4,6-tetra-O-benzyl-
-D-galactopyranosyl)propane-1,2-diol (12A)
A reaction of 11A (0.18 g, 0.25 mmol) in CH2Cl2 (4 mL) with Ac2O
(0.15 mL), pyridine (0.30 mL) and a catalytic amount of N,N-di-
methylaminopyridine (3 mg) was performed as described for (R)-6
to isolate the title compound as a syrup; yield: 0.17 g (87%).
1H NMR (300 MHz, CDCl3): = 3.42–3.80 (m, 4 H, H-1, 6 , 6 ),
3.84 (s, 3 H, OCH3), 3.86–5.00 (m, 14 H, H-3, 2 , 3 , 4 , 5 ,
4 × CH2C6H5), 5.20 (d, 1 H, J1,2 = 2.5 Hz, H-1 ), 5.28 (m, 1 H, H-2),
6.88 (m, 4 H, ArH), 7.15–7.40 (m, 20 H, ArH).
Anal. Calcd for C46H50O10: C, 72.42; H, 6.60. Found: C, 72.54; H,
6.76.
MS (FAB): m/z = 571 [M+ + H].
3-Phenoxy-1,2-di-O-(2,3,4,6-tetra-O-benzyl- -D-galactopyra-
nosyl)propane-1,2-diol (10B) and 3-Phenoxy-1-O-(2,3,4,6-tetra-
O-benzyl- -D-galactopyranosyl)propane-1,2-diol (11B)
Anal. Calcd for C26H34O14: C, 54.93; H, 5.67. Found: C, 54.63; H,
5.43.
A reaction of 9 (2.0 g, 3.23 mmol) with rac-1B (0.27 g, 1.66 mmol)
and powdered 4Å molecular sieves (50 mg) in anhyd CH2Cl2 (50
mL) containing 5% MeI for 48–72 h was carried out as described
for 10A to isolate the title compound as a syrup, followed by 11B.
(2S)-2-O-Acetyl-3-(2-methoxyphenoxy)-1-O-(2,3,4,6-tetra-O-
acetyl- -D-glucopyranosyl)propane-1,2-diol [(S)-6]
A reaction of (S)-3 (0.1 g, 0.19 mmol) in CH2Cl2 (2 mL) with pyri-
dine (0.1 mL), Ac2O (0.2 mL), and a catalytic amount of N,N-dim-
ethylaminopyridine (1 mg) was carried out as described for (R)-6 to
isolate the title compound as a syrup; yield: 0.085 g (89%); [ ]D
–3.1 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): = 1.90, 1.98, 2.00, 2.02, 2.04 (5 s,
15 H, 5 × OCOCH3), 3.85 (m, 1 H, H-6 ), 3.92 (s, 3 H, OCH3), 3.98–
4.40 (m, 6 H, H-1, 3, 5 , 6 ), 4.94 (d, 1 H, J1,2 = 8.0 Hz, H-1 ), 5.00–
5.30 (m, 4 H, H-2, 2 , 3 , 4 ), 6.90 (m, 4 H, ArH).
10B
24
Yield: 0.80 g (41%); [ ]D +40.86 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): = 3.34–3.58 (m, 4 H, H-6 , 6 ),
3.78–4.02 (m, 2 H, H-1), 4.20–5.00 (m, 24 H, H-2 , 2 , 3 , 3 , 4 , 4 ,
5 , 5 , 8 × CH2C6H5), 5.10 (d, 1 H, J1,2 = 3.3 Hz, H-1 ), 5.22 (d, 1
H, J1,2 = 3.7 Hz, H-1 ), 6.80–6.90 (m, 3 H, ArH), 7.04–7.40 (m, 42
H, ArH).
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H. B. Mereyala et al.
PAPER
Anal. Calcd for C77H80O13: C, 76.24; H, 6.64. Found: C, 75.86; H,
6.51.
(m, 1 H, H-2 ), 5.80 (m, 1 H, H-3 ), 6.80 (m, 4 H, ArH), 7.20–8.20
(m, 15 H, ArH).
MS (FAB): m/z = 643 [M+ + H].
11B
Anal. Calcd for C36H34O11: C, 67.28; H, 5.33. Found: C, 67.12; H,
5.24.
Yield: 0.25 g (44%); [ ]D +34.53 (c = 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): = 3.40–3.58 (m, 2 H, H-6 , 6 ),
3.72–4.10 (m, 5 H, H-1, 2, 3), 4.34–4.98 (m, 12 H, H-2 , 3 , 4 , 5 ,
4 × CH2C6H5), 5.22 (d, 1 H, J1,2 = 3.7 Hz, H-1 ), 6.70–6.98 (m, 3 H,
ArH), 7.04–7.40 (m, 22 H, ArH).
(2R/S)-2-O-Acetyl-3-(2-methoxyphenoxy)-1-O-(2,3,5-tri-O-benz-
oyl- -D-xylofuranosyl)propane-1,2-diol (20A)
A reaction of 18A (1.5 g, 2.33 mmol) in CH2Cl2 (15 mL) with pyri-
dine (0.38 mL, 4.67 mmol), Ac2O (0.26 mL, 2.8 mmol) and a cata-
lytic amount of N,N-dimethylaminopyridine (5 mg) was performed
as described for (R)-6 to isolate the title compound as a syrup; yield:
1.45 g (91%); [ ]D24 +24.5 (c = 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): = 2.04 (s, 3 H, OCOCH3), 3.70–4.20
(m, 7 H, H-1, 3, OCH3), 4.44–4.80 (m, 3 H, H-4 , 5 , 5 ), 5.20–5.30
(m, 2 H, H-1 , 2), 5.60–5.90 (m, 2 H, H-2 , 3 ), 6.84 (m, 4 H, ArH),
7.20–8.20 (m, 15 H, ArH).
Anal. Calcd for C43H46O8: C, 74.76; H, 18.52. Found: C, 75.81; H,
6.59.
2-O-Acetyl-3-phenoxy-1-O-(2,3,4,6-tetra-O-benzyl- -D-galacto-
pyranosyl)propane-1,2-diol (12B)
A reaction of 11B (0.2 g, 0.29 mmol) in CH2Cl2 (6 mL) with Ac2O
(0.2 mL), pyridine (0.4 mL) and a catalytic amount of N,N-dimeth-
ylaminopyridine (5 mg) was performed as described for (R)-6 to
isolate the title compound as a syrup; yield: 0.19 g (87%).
1H NMR (300 MHz, CDCl3): = 3.44–3.62 (m, 2 H, H-6 , 6 ),
3.72–4.14 (m, 4 H, H-1, 3), 4.32–5.00 (m, 12 H, H-2 , 3 , 4 , 5 ,
4 × CH2C6H5), 5.24 (d, 1 H, J1,2 = 3.5 Hz, H-1 ), 5.28 (m, 1 H, H-2),
6.72–7.00 (m, 3 H, ArH), 7.10–7.40 (m, 22 H, H-ArH).
MS (FAB): m/z = 685 [M+ + H].
Anal. Calcd for C38H36O12: C, 66.66; H, 5.30. Found: C, 66.59; H,
5.19.
(2R)-3-(2-Methoxyphenoxy)-1-O-( -D-glucopyranosyl)pro-
pane-1,2-diol [(R)-21]
Anal. Calcd for C45H48O9: C, 73.75; H, 6.60. Found: C, 72.94; H,
6.41.
To a solution of 3 (2.0 g, 3.8 mmol) in MeOH (20 mL) was added
10% methanolic ammonia (10 mL). The mixture was stirred for 3 h
at r.t.. After completion of the reaction, the solvent was removed to
(2R/S)-3-(2-Methoxyphenoxy)-1-O-(2,3,5-tri-O-benzoyl- -D-ri-
bofuranosyl)propane-1,2-diol (14A)
A reaction of 13 (2.0 g, 3.96 mmol), rac-1A (0.78 g, 3.96 mmol)
with BF3·OEt2 (0.6 mL, 4.76 mmol) in anhyd CH2Cl2 (40 mL) for 4
h as described for (R)-3 resulted in the isolation of the title com-
pound; yield: 2.10 g (82%); [ ]D24 +28.10 (c = 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): = 3.70–4.20 (m, 8 H, H-1, 2, 3,
OCH3), 4.50–4.80 (m, 3 H, H-4 , 5 , 5 ), 5.28 (s, 1 H, H-1 ), 5.60–
5.80 (m, 2 H, H-2 , 3 ), 6.80 (m, 4 H, ArH), 7.20–8.20 (m, 15 H,
ArH).
24
obtain the title compound as a syrup; yield: 1.36 g (99%); [ ]D
–7.13 (c = 1.0, MeOH).
1H NMR (200 MHz, CDCl3): = 3.24–3.80 (m, 7 H, H-1, 3, 5 , 6 ,
6 ), 3.84 (s, 3 H, OCH3), 4.20–4.40 (m, 4 H, H-2, 2 , 3 , 4 ), 4.70 (d,
1 H, J1,2 = 7.0 Hz, H-1 ), 7.04 (m, 4 H, ArH).
MS (FAB): m/z = 377 [M+ + H].
Anal. Calcd for C16H24O9: C, 53.33; H, 6.71. Found: C, 53.21; H,
6.58.
MS (FAB): m/z = 643 [M+ + H].
(2S)-3-(2-Methoxyphenoxy)-1-O-( -D-glucopyranosyl)propane-
1,2-diol [(S)-21]
A reaction of 3 (1.8 g, 3.40 mmol) in MeOH (20 mL) with 10%
methanolic ammonia (10 mL) for 4 h was performed as described
for (R)-21 to obtain the title compound as a syrup; yield: 1.2 g
(97%); [ ]D24 –25.5 (c = 1.0, MeOH).
1H NMR (300 MHz, CDCl3): = 3.20–3.80 (m, 7 H, H-1, 3, 5 , 6 ,
6 ), 3.90 (s, 3 H, OCH3), 4.00–4.30 (m, 4 H, H-2, 2 , 3 , 4 ), 4.50 (d,
1 H, J1,2 = 7.1 Hz, H-1 ), 7.04 (m, 4 H, ArH).
Anal. Calcd for C36H34O11: C, 67.28; H, 5.33. Found: C, 67.19; H,
5.24.4
(2R/S)-2-O-Acetyl-3-(2-methoxyphenoxy)-1-O-(2,3,5-tri-O-
benzoyl- -D-ribofuranosyl)propane-1,2-diol (16A)
A reaction of 14A (1.6 g, 2.49 mL) in CH2Cl2 (16 mL) with pyridine
(0.4 mL, 4.98 mmol), Ac2O (0.28 mL, 2.99 mmol) and a catalytic
amount of N,N-dimethylaminopyridine (5 mg) was carried out as
described for (R)-6 to isolate the title compound as a syrup; yield:
1.58 g (92%); [ ]D24 +22.4 (c = 1.0, CHCl3).
MS (FAB): m/z = 377 [M+ + H].
1H NMR (200 MHz, CDCl3): = 2.06 (s, 3 H, OCOCH3), 3.68–4.20
(m, 7 H, H-1, 3, OCH3), 4.40–4.80 (m, 3 H, H-4 , 5 , 5 ), 5.20–5.30
(m, 2 H, H-1 , 2), 5.60–5.90 (m, 2 H, H-2 , 3 ), 6.80 (m, 4 H, ArH),
7.20–8.20 (m, 15 H, ArH).
Anal. Calcd for C16H24O9: C, 53.33; H, 6.71. Found: C, 53.19; H,
6.59.
(2S)-3-(2-Methoxyphenoxy)propane-1,2-diol [(S)-1]; Typical
Procedure
MS (FAB): m/z = 685 [M+ + H].
To a solution of (R)-21 (1.3 g, 3.45 mmol) in H2O (13 mL) was add-
ed 10% aq H2SO4 (2 mL) at r.t. The reaction mixture was heated to
90 °C for 3 h. After completion of the reaction, the mixture was neu-
tralized with aq Ba(OH)2 solution, filtered through a Celite pad and
washed with H2O (10 mL). The filtrate was transferred to a separat-
ing funnel, extracted with EtOAc (2 × 25 mL), the combined organ-
ic phases were dried (Na2SO4), and evaporated. The residue was
recrystallized twice from EtOH (4 mL) to obtain the title com-
pound; yield: 0.61 g (90%) [98% ee determined by chiral HPLC
Anal. Calcd for C38H36O12: C, 66.66; H, 5.30. Found: C, 66.51; H,
5.19.
(2R/S)-3-(2-Methoxyphenoxy)-1-O-(2,3,5-tri-O-benzoyl- -D-xy-
lofuranosyl)propane-1,2-diol (18A)
A reaction of 17 (2.0 g, 3.96 mmol) in anhyd CH2Cl2 (40 mL), rac-
1A (0.78 g, 3.96 mmol) and BF3·Et2O (0.6 mL, 4.76 mmol) for 5 h
was performed as described for (R)-3 to isolate the title compound
as a syrup; yield: 2.05 g (80%); [ ]D24 +29.5 (c = 1.0, CHCl3).
24
method on a Chiracel OD column); [ ]D +11.1 (c = 1.0, EtOH);
1H NMR (CDCl3, 400 MHz): = 3.70–430 (m, 8 H, H-1, 2, 3,
OCH3), 4.50–4.80 (m, 3 H, H-4 , 5 , 5 ), 5.30 (s, 1 H, H-1 ), 5.70
[Lit.3 [ ]D +8.3 (c = 1.18, MeOH); Lit.13 [ ]D +11.2 (c = 1.0,
24
24
EtOH)].
Synthesis 2003, No. 15, 2378–2384 © Thieme Stuttgart · New York

PAPER
Discriminative Glycosylation of 3-(Aryloxy)propane-1,2-diols
2383
(2R)-3-(2-Methoxyphenoxy)propane-1,2-diol [(R)-1]
(4) (a) Lemieux, R. U.; Hendrike, K. B.; Stick, R. V.; James, K.
J. Am. Chem. Soc. 1975, 97, 4056. (b) Klaus, B.; Troels, S.
J. Chem. Soc., Perkin Trans. 1 1991, 1181. (c)Mereyala,H.
B.; Gurrala, S. R.; Gadikota, R. R. J. Chem. Soc., Perkin
Trans. 1 1997, 3179. (d) Taylor, C. M. Tetrahedron 1998,
54, 11317. (e) Arsequell, G.; Valencia, G. Tetrahedron:
Asymmetry 1999, 10, 3045. (f) Davis, B. G. R. J. Chem.
Soc., Perkin Trans. 1 1999, 3215. (g) Davis, B. G.;
Maughan, M. A. T.; Green, M. P.; Ullman, A.; Jones, J. B.
Tetrahedron: Asymmetry 2000, 11, 245.
Acid-catalyzed hydrolysis of (S)-21 (1.1 g, 2.92 mmol) in H2O (11
mL) and 10% aq H2SO4 (2 mL) for 3 h was carried out as described
for (S)-1 to isolate the title compound; yield: 0.52 g (88%) [98% ee
determined by chiral HPLC method on a Chiracel OD column);
[ ]D –11.0 (c = 1.0, EtOH); [Lit.3 [ ]D –8.3 (c = 1.18, MeOH);
24
Lit.13 [ ]D –1.2 (c = 1.0, EtOH)].
(2R/S)-3-(2-Methoxyphenoxy)-1-O-( -D-ribofuranosyl)pro-
pane-1,2-diol (22A)
A reaction of 14A (1.4 g, 2.04 mmol) in MeOH (14 mL) with 10%
methanolic ammonia (6 mL) at r.t. for 5 h was performed as de-
scribed for (R)-21 to isolate the title compound 22A as a syrup;
yield: 0.53 g (79%); [ ]D24 +11.5 (c = 1.0, MeOH).
1H NMR (200 MHz, D2O): = 3.40–3.82 (m, 3 H, H-1, 2), 3.90 (s,
3 H, OCH3), 4.10–4.40 (m, 7 H, H- 3, 2 , 3 , 4 , 5 , 5 ), 5.00 (s, 1 H,
H-1 ), 7.15 (m, 4 H, ArH).
(5) (a) Lebinean, A.; Galli, J. L.; Lemoine, R. J. Chem. Soc.,
Chem. Commun. 1993, 1419. (b) Veeneman, G. H.; Van der
Marl, G. A.; Van Boom, J. H. Carbohydr. Res. 1993, 241,
153. (c) Peters, S.; Lowary, T. L.; Hindsgaul, D.; Meldal,
M.; Bock, K. J. Chem. Soc., Perkin Trans. 1 1995, 3017.
(6) (a) Smits, E.; Engberts, B. F. N.; Kellogg, R. M.; Van Doren,
H. A. J. Chem. Soc., Perkin Trans. 1 1996, 2873.
(b) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl.
1980, 19, 731.
MS (FAB): m/z = 331 [M+ + H].
(7) (a) Kimura, Y.; Suzuki, M.; Matsumoto, T.; Abe, R.;
Terashima, S. Chem. Lett. 1984, 501. (b) Preus, R.;
Schmidt, R. R. Synthesis 1988, 694. (c) Nicolaou, K. C.;
Shreiner, E. P.; Iwabuchi, Y.; Suzuki, T. Angew. Chem., Int.
Ed. Engl. 1992, 31, 340.
Anal. Calcd for C15H22O8: C, 54.54; H, 6.70. Found: C, 54.41; H,
6.58.
(2R/S)-3-(2-Methoxyphenoxy)-1-O-( -D-xylofuranosyl)pro-
pane-1,2-diol (23A)
(8) (a) Hakomori, S.; Murakami, W. T. Proc. Natl. Acad. Sci.
U.S.A. 1968, 59, 254. (b) Watkins, W. M. In Glycoproteins;
Elsevier: Amsterdam, 1972, 830. (c) Kennedy, J. F.; White,
C. A. Bioactive Carbohydrates in Chemistry, Biochemistry;
Halsted Press: New York, 1983. (d) Tsuji, S.; Arita, M.;
Nagai, Y. J. Biochem. 1983, 94, 303. (e) Sharp, J. K.;
Valent, B.; Albershiem, P. J. Biol. Chem. 1984, 259, 11312.
(f) Nojiri, H.; Takaku, F.; Terui, Y.; Miura, Y.; Saito, M.
Proc. Natl. Acad. Sci. U.S.A. 1986, 59, 254. (g) Takeuchi,
M.; Inoue, N.; Strickland, T. C.; Kubota, M.; Wada, M.;
Shimizu, R.; Hoshi, S.; Kozutzumi, H.; Takahashi, S.;
Kobota, A. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 7819.
(h) Mc Dougall, G. J.; Fry, S. C. Plant Physiol. 1990, 93,
1042. (i) Goelz, S. E.; Hesson, C.; Goff, D.; G riffith, B.;
Tezard, R.; Newman, B.; Chi-Rosso, G.; Lobb, R. Cell 1990,
63, 1349.
(9) (a) Demchenko, A.; Boons, G. J. Tetrahedron Lett. 1997, 38,
1629. (b) Wang, W.; Kong, F. J. Org. Chem. 1998, 63,
5744. (c) Ellervik, U.; Magnusson, G. J. Org. Chem. 1998,
63, 9314. (d) Li, B.; Yu, B.; Hui, Y.; Li, M.; Han, X.; Fung,
K. P. Carbohydr. Res. 2001, 331, 1. (e) Geurtsen, R.;
Boons, G. J. Eur. J. Org. Chem. 2002, 1473. (f) Rencurosi,
A.; Poletti, L.; Russo, G.; Lay, L. Eur. J. Org. Chem. 2003,
1672. (g) Zeng, Y.; Kong, F. Carbohydr. Res. 2003, 338,
843.
(10) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(b) Schmidt, R. R. Adv. Carbohydr. Chem. Biochem. 1995,
50, 21. (c) Collins, P. M.; Ferrier, R. J. Monosaccharides;
Wiley: Chichester, 1995. (d) Boons, G. J. Tetrahedron
1996, 52, 1095. (e) Boons, G. J. Contemp. Org. Synth. 1996,
3, 173. (f) Whitfield, D. M.; Douglas, S. P. Glycoconjugate
J. 1996, 13, 5. (g) Garegg, P. J. Adv. Carbohydr. Chem.
Biochem. 1997, 52, 179. (h) Hanessian, S. Preparative
Carbohydrate Chemistry; Marcel Dekker: New York, 1998.
(i) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137.
(j) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35.
(11) (a) Nelson, W. L.; Wood, C. E. Jr. J. Chem. Soc., Chem.
Commun. 1973, 896. (b) Nelson, W. L.; Wennerstorm, J. E.;
Sankar, S. R. J. Org. Chem. 1977, 42, 1006. (c) Walsh, D.
A.; Lo, Y. S.; Shamblee, D. A.; Welstead, W. J. Jr. J. Med.
Chem. 1990, 33, 2070.
A reaction of 18A (1.2 g, 1.75 mmol) in MeOH (10 mL), 10% meth-
anolic ammonia (5 mL) for 14 h was performed as described for (R)-
21 to obtain the title compound 23A as a syrup; yield: 0.51 g (88%);
[ ]D24 +12.4 (c = 1.0, MeOH).
1H NMR (200 MHz, D2O): = 3.40–3.85 (m, 3 H, H-1, 2), 3.90 (s,
3 H, OCH3), 4.00–4.40 (m, 7 H, H-3, 2 , 3 , 4 , 5 , 5 ), 5.04 (s, 1 H,
H-1 ), 7.10 (m, 4 H, ArH).
MS (FAB): m/z = 331 [M+ + H].
Anal. Cacld for C15H22O8: C, 54.44; H, 6.7. Found: C, 54.32; H,
6.58.
Acknowledgment
MSK thanks Council for Scientific and Industrial Research, New
Delhi for the financial assistance in the form of a Senior Research
Fellowship.
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Synthesis 2003, No. 15, 2378–2384 © Thieme Stuttgart · New York