Toward the synthesis of fine chemicals from lactose: preparation of d-xylo and l-lyxo-aldohexos-5-ulose derivatives

Article abstract of DOI:10.1016/j.carres.2009.01.014

The transformation of (5R)-2,6-di-O-benzyl-5-C-methoxy-β-d-galactopyranosyl-(1→4)-2,3:5,6-di-O-isopropylidene-aldehydo-d-glucose dimethyl acetal (8) into partially protected derivatives of d-xylo- and l-lyxo-aldohexos-5-ulose has been reported, applying a

Full text of DOI:10.1016/j.carres.2009.01.014

Carbohydrate Research 344 (2009) 717–724
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Toward the synthesis of fine chemicals from lactose: preparation of D-xylo
and L-lyxo-aldohexos-5-ulose derivatives q
a
a
b
Giorgio Catelani a, , Felicia D’Andrea , Lorenzo Guazzelli , Venerando Pistarà
*
a Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno, 33 I-56126 Pisa, Italy
b Dipartimento di Scienze Chimiche, Università di Catania, viale A. Doria, 6 I-95125 Catania, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The transformation of (5R)-2,6-di-O-benzyl-5-C-methoxy-b-
D
-galactopyranosyl-(1?4)-2,3:5,6-di-O-iso-
Received 21 November 2008
Received in revised form 13 January 2009
Accepted 14 January 2009
Available online 19 January 2009
propylidene-aldehydo-
-lyxo-aldohexos-5-ulose has been reported, applying appropriate epimerisation methods to its 30-O-
and 40-O-protected alcoholic derivatives.
D-glucose dimethyl acetal (8) into partially protected derivatives of D-xylo- and
L
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Lactose
D-xylo-Aldohexos-5-ulose
L
-lyxo-Aldohexos-5-ulose
1,5-Bis-glycopyranosides
Epimerisation
1. Introduction
ity3 of the two polyacetonides 1 and 2 (Fig. 1), which could be
considered as simple b- -galactopyranosides, due to the complete
protection of the -glucose unit. Aldohexos-5-uloses (3) represent
an interesting, although yet poorly investigated class of dicarbonyl
hexoses,4 that are useful synthetic intermediates for the prepara-
tion of high value-added compounds such as iminosugars5 and
cyclitols, as inositols,6 or polyhydroxycyclopentanes.7
A general approach (Chart 1) to aldohexos-5-uloses (3) was
developed8 using the key reaction, the epoxidation–methanolysis
of hex-4-enopyranosides of type 5, which are in turn obtained from
D
Lactose is the most abundant naturally occurring reducing
disaccharide, which is obtained from whey as a by-product of the
agro-industrial cheese production. Although it has a large world-
wide availability, which is estimated at about 500,000 tons/year,2a
only a low percentage of recovered lactose is utilised mainly in the
food, feed and pharmaceutical fields. The chemical valorisation of
lactose is achieved through simple transformations into commer-
cially available products such as lactobionic acid,2 a component
D
of the preservative solution for transplanting organs, lactitol,2
a
3,4-O-isopropylidene-b-
D-galactopyranosides (6).
suitable component of sugar-free, reduced caloric and low glyce-
mic products and lactulose and galacto-oligosaccharides (GOS),2
largely used in probiotic therapy.
Since lactose is inexpensive and there is a potential environ-
mental risk connected with the uncontrolled dispersion of whey
in freshwater, new synthetic channels need to be investigated in
order to synthesise fine chemicals starting from this renewable
raw material.
In this communication, we present the synthesis of partially
protected derivatives of
D-xylo and L-lyxo-aldohexos-5-uloses
achieved here from the disaccharide 10,50-bis-glycoside 8, analo-
gous to 4, which is in turn easily obtained from lactose,9 following
the same general approach outlined in Chart 1. The influence of the
O
CMe2
Recently, we planned a synthetic strategy to elaborate the non-
reducing unit without modifying the reducing one, as is commonly
done. This useful approach takes advantage of the large availabil-
OR
O
O
acetonation
Ref. 3
O
Me2C
Lactose
O
O
O
CMe2
OH
(MeO)2HC
O
q
1: R = H
2: R = C(OMe)Me2
Part 26 of the series ‘Chemical Valorisation of Milk-derived Carbohydrates’. For
part 25 see Ref. 1.
* Corresponding author. Tel.: +39 0502219700; fax: +39 0502219660.
E-mail address: giocate@farm.unipi.it (G. Catelani).
Figure 1. Polyacetonides directly obtained by acetonation of lactose.
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.01.014

718
G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
OP
OP
OP
O
PO
OP
OMe
PO
O
O
O
Me2C
O
OR
OR
OR
O
PO
CHO
OP
OP
OP
OP
PO
PO
6
3
4
5
P = H or protecting group
Chart 1. General approach to aldohexos-5-uloses from-D-galactopyranosides.
axial C-50-OMe group on the chemo- and stereoselectivity of some
reactions performed on the bis-glycoside unit is also observed and
discussed.
of the axial C-50 methoxyl group sensibly influenced the reaction.
Swern oxidation attempts failed completely, while treatment with
PCC showed a low conversion even after long reaction times. Better
results were obtained with the TPAP–NMO system, employing,
however, an unexpectedly high catalyst molar ratio (40%) with re-
spect to that usually needed (5%).12 NMR analysis of the crude oxi-
dation product showed a mixture of the 40-ulosyl derivative 12 (C-
2. Results and discussion
Preliminary attempts to obtain 1,5-bis-glycopyranosides of the
13
40 C chemical shift: 198.3 ppm) and of its hydrate 13 (C-40 13C
D
-xylo series through epoxidation–methanolysis of a 30-O-pro-
tected derivative of the known disaccharide hex-40-enopyranoside
7,9 following the method which was previously used in monosac-
charide series,8b were abandoned due to the difficulties encoun-
tered in the separation of the complex crude diastereoisomeric
mixture. An alternative way based on the regioselective protection
of 30-OH of the known diol 8,9 followed by stereoselective epimer-
isation at C-40 (Scheme 1), was then considered. The first step was
easily achieved through a stannylidene acetal-mediated alkylation.
The method, which has largely been used to differentiate 1,2-cis-
diols of a sugar,10 has never been reported until now, on a 1,5-
chemical shift: 97.1 ppm). In the crude oxidation mixture, com-
pounds 12 and 13, which were isolated in about 89% yield, were
present in about 4:1 ratio, as determined on the basis of the rela-
tive intensity of the 13C 50-OMe signals. Chromatographic purifica-
tion led again to a mixture of 12 and 13 in the same 4:1 ratio, but
with substantial loss of product, lowering the yield to a modest
56%. The reduction of the crude oxidation mixture with NaBH4 in
MeOH led to 14 and 9 in 64% and 20% isolated yields, respectively,
indirectly confirming the structures of 12 and 13 and the extensive
loss of the uloside during the chromatography on silica gel. In the
case of the hydride reduction, the presence of the axial 50-OMe
group was beneficial for the stereoselectivity, determining the
prevalence, although not complete, of attack on the b-face. This re-
sult is at variance with respect to the hydride reduction of analo-
bis-glycopyranoside. As in the case of b-D
-galactopyranosides,10
the alkylation took place with complete regioselectivity on the
30-OH group, leading in almost quantitative yield to the alcohol 9.
The first C-40 epimerisation strategy was attempted via an SN2
displacement on the triflate 10, which was obtained from 9 in high
isolated yield (88%) by treatment with Tf2O in pyridine. Surpris-
ingly, the treatment of 10 with Bu4NNO2 in toluene led to the for-
mation of enol ether 11, isolated in 70% yield, instead of the desired
inverted bis-glycoside 14. This result is quite unexpected in light of
the high yields reported for nucleophilic substitutions of structur-
ally related 4-O-triflates of galactopyranosides11 and is evidently
due to some interference between the axial 50-OMe group and
the nucleophile approaching the vicinal reacting centre. The com-
plementary strategy based on an oxidation–reduction sequence
of 9 was thus explored. Also in the oxidation of 9, the presence
gous 4-keto-
D
-arabino-hexopyranosides, mainly leading to
D-
galactopyranosides.13 Finally, the target 2,6-di-O-benzyl-
D
-xylo-
aldohexos-5-ulose (15) was obtained from 14 (72% yield) by acid
hydrolysis with CF3COOH in CH3CN–water (50 °C, 12 h) and by
separation from D-glucose by extraction with EtOAc. As previously
reported,8b 15 was present in CD3CN as a 55:45
a,b-1,4-furanose
mixture, as confirmed by NMR analysis.
The preparation of
proach used in the monosaccharide series,8c providing an oxida-
tion–reduction sequence of a 3-OH free 1,5-bis-methyl -arabino-
hexopyranoside, obtained through the completely regioselective
L-lyxo derivatives was based on the same ap-
L
OBn
OBn
MeO
BnO
OR
R'O
OBn
O
O
O
Ref. 9
OGlc
HO
OGlc
OGlc
OBn
BnO
BnO
c
OMe
11
7
8: R = R' = H
9: R = H, R' = Bn
10: R = Tf, R' = Bn
a
b
d
OBn
OBn
OH
OBn
O
OBn
O
O
O
O
e
f
HO
BnO
HO
BnO
OGlc
HO
BnO
OGlc
OGlc
BnO
CHO
OBn
15
OBn
OBn
OBn
OMe
OMe
13
OMe
12
14
Scheme 1. Stereoselective synthesis of 2,3,6-tri-O-benzyl-D-xylo-hexos-5-ulose. Reagents and conditions: (a) Bu2SnO, C6H5CH3, reflux, 12 h, then BnBr, Bu4NBr, reflux, 1.5 h
(94%); (b) Tf2O, 1:1 CH2Cl2-Py, rt, 6 h (88%); (c) Bu4NNO2, C6H5CH3, reflux, 8 h (70%); (d) TPAP, NMO, CH2Cl2, 4 Å, rt, 4 h; (e) NaBH4, MeOH, rt, 1.5 h, (64% from 9); (f) 90% aq
CF3COOH, 4:1 CH3CN-H2O, 50 °C, 12 h (72%).

G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
719
OR
R'O
OAc
OBn
O
OBn
O
OR
OBn
O
OH
OBn
O
b
c
OGlc
OGlc
OGlc
+
OGlc
OBn
OBn
OBn
OBn
OMe
OMe
17
OMe
OR'
18: R = Ac, R' = H
19: R = H, R' = Ac
20: R = R' = Ac
OMe
OH
O
21
8: R = R' = H
a
16: R = OAc, R' = H
d
d
g
e
f
OBn
OBn
OBn
OBn
O
OR
OBn
O
OBn
OBn
O
O
c
b
f
OGlc
OGlc
OGlc
RO
CHO
OBn
OBn
OBn
OMe
OMe
OH
OBn
O
OMe
OH
26: R = H
27: R = Bn
22: R = H
23: R = Bn
24
25
Scheme 2. Synthesis of 2,6-di-O-benzyl- and 2,4,6-tri-O-benzyl-L-lyxo-aldohexos-5-ulose. Reagents and conditions: (a) CH3C(OEt)3, TsOH, C6H5CH3, 45 °C, 25 min, then 80%
aq AcOH, rt, 15 min (quantitative); (b) TPAP, NMO, CH2Cl2, 4 Å, rt, 45 min (17: 98%, 24: 76%); (c) NaBH4, MeOH, rt, 20 min (25: 88%); (d) 1:2 Ac2O-Py, rt, 20 h; (e) NaH, BnBr
(1 equiv), DMF, 0 °C, 25 min (22: 75% + 23: 15%); (f) 90% aq CF3COOH, 4:1 CH3CN-H2O, 50 °C, 4 h (26: 78%, 27: 86%); (g) 0.1 M MeONa-MeOH, rt, 2 h (quantitative).
orthoester-mediated 40-O-acetylation of the diol 8 (Scheme 2). As
expected, the treatment of 8 with CH3C(OEt)3 and TsOH in toluene,
followed by the opening of the ortho-acetate ring with AcOH, affor-
ded the alcohol 16 in almost quantitative yield. The next oxidation
step was achieved again by using the TPAP–NMO system under
milder reaction conditions with respect to those used before (TPAP
5%, 2 h, 98% yield). The reduction of 17 (NaBH4 in MeOH) appeared
not as that simple as that for the analogous 1,5-bis-methyl-
glycopyranoside, for which only the formation of the two 50-OMe
to give the previously reported 2,6-di-O-benzyl-
L-lyxo-aldohexos-
5-ulose (26).8c
The problems encountered in the reduction of 17 could be
avoided simplifying the chromatographic purifications, by chang-
ing the protection of the 40-OH group from the acetate to a base-
stable ethereal one. The direct monobenzylation of 8 was consid-
ered as the method of choice for the 40-regioselective protection
on the basis of the findings from Bernet and Vasella,14 which
underlined, in both sugars and inositols, an enhanced acidity for
axial hydroxy groups having a vicinal anti-alkoxy group. The ben-
zylation with BnBr (1 equiv) and NaH in DMF at 0 °C pleasantly
led to the 40-O-monobenzyl derivative 22, isolated in a satisfactory
75% yield, after an easy chromatographic separation from the 3,4-
di-O-benzyl derivative 23 (Scheme 2). No traces of the product of
30-O-monobenzylation (14) were observed at any stage of the reac-
tion. A specific role of the axial 50-OMe in enhancing the acidity of
40-OH is outlined by comparing the lower regioselectivity in the
L
-lyxo and L
-arabino diastereoisomers in a 5:1 ratio was reported.8c
In fact, the reduction of the uloside 17 led to a complex product
mixture constituted (TLC, 1:1 EtOAc–hexane) of at least four com-
ponents displaying two well-differentiated ranges of Rf values on
silica gel. The flash chromatography permitted only a partial sepa-
ration of the two faster moving components (Rf 0.39 and 0.34,
respectively), surprisingly identified (NMR) as the two isomeric L-
lyxo monoacetates 18 and 19, accounting for a combined 52% yield.
The structure of the above compounds was further confirmed
through conventional acetylation leading, in both cases, to the
same diacetate 20. Two other fractions containing the lower mov-
ing components (Rf 0.23 and 0.20) were collected, one constituted
monobenzylation of methyl 2,6-di-O-benzyl-b-D-galactopyrano-
side, where 3-OH and 4-OH alkylation products were obtained in
a 1:2 ratio.15 The alcohol 22 was then submitted to an oxidation
reaction with TPAP–NMO, and the desired 30-ulosyl derivative 24
was obtained in 76% yield. The reduction of 24 with NaBH4 in
MeOH afforded 25 in a completely stereoselective way, owing to
the negative 1,3-syn diaxial interaction between the 50-OMe group
by the pure L-lyxo diol 21 (13% yield) and the other by a mixture
(about 1:1, combined yield 26%) of 18 and one other, yet unidenti-
fied, diastereoisomeric diol. While the presence of the 40-O-acetyl
18 could be simply explained by a lower base-promoted O-deacety-
lation rate with respect to the monosaccharide analogue,8c it is dif-
ficult to imagine the formation of the 30-O-acetyl 19 directly from
18 through an acetyl shift taking place, after the reduction, from
the axial 40-OH group to the axial anti 30-OH one. A better hypothesis
as to why 19 is formed would be due to an acyl shift on an enolic
intermediate such as 28, where the 30-OH group and the 40-OAc
one are co-planar (Scheme 3). The enolisation of 17 could explain
both the migration of the acetyl group and the loss of stereochemical
purity either at C-40 and C-30, which also gives rise to the isolation in
low amount of an unidentified diastereoisomeric diol.
and the hydride attacking from the
a-face. 2,4,6-Tri-O-benzyl-L-
lyxo-aldohexos-5-ulose (27) was obtained after removal of the ace-
tal groups by acid hydrolysis (CF3COOH and CH3CN–water), and its
NMR data were identical to those of the sample which was previ-
ously reported,6b pointing to a complex tautomeric mixture, whose
structure was indirectly confirmed by its transformation into the
expected inosose.6b
In conclusion, with this work an understanding of the potenti-
ality of lactose as a renewable starting material for the synthesis
of fine chemicals has been increased via the preparation of aldoh-
exos-5-ulose derivatives in the D-xylo and L-lyxo series. The crucial
The O-deacetylation of 20 (MeONa–MeOH) afforded quantita-
tively 21, raising its overall yield to an acceptable 65%. Diol 21
was finally subjected to acid hydrolysis (CF3COOH–CH3CN–water)
role of the axial anomeric 50-OMe group of the 10,50-bis-glycosides
has also been pinpointed in both the synthetic routes. In the first
one, which leads to the D-xylo derivative 15, it decreases the reac-
tivity in the C-40 oxidation, and in addition, completely turns the
reactivity of the axial 40-O-trifluoromethansulfonate from substitu-
tion to elimination. Moreover, for steric reasons, the outcome of
the 40-uloside reduction diastereoselection is changed from a
near-complete galacto to a predominant gluco configuration. In
Unexpectedly, this second diastereoisomeric diol did not correspond to the L-
arabino derivative 8. Owing to the difficulties to obtain
a pure sample of this
compound, present in the crude reaction mixture in low yield (about 13%), we
abandoned any effort to further elucidate its structure, a point that was outside the
scope of the present work.
the second synthetic pathway, leading to the L-lyxo-hexos-5-ulose

720
G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
OBn
OBn
OBn
OBn
OGlc
OGlc
OGlc
AcO
O
O
O
OGlc
O
O
OMe
OMe
OMe
O
AcO
HO
OMe
+
AcO
O
AcO
OBn
OBn
OBn
OBn
17
28
29
30
Scheme 3. Base-promoted isomerisation of the uloside 17.
27, the presence of the axial C-50 methoxyl group allows the regio-
selective alkylation of 40-OH group and the completely stereoselec-
tive reduction of the intermediate 30-uloside.
3.3. (5R)-2,3,6-Tri-O-benzyl-4-O-trifluoromethansulfonyl-5-C-
methoxy- -arabino-hexopyranosyl-(1?4)-2,3:5,6-di-O-
isopropylidene-aldehydo- -glucose dimethyl acetal (10)
a
-L
D
To a solution of 9 (213 mg, 0.277 mmol) in dry 1:1 Py–CH2Cl2
(3 mL) cooled to –14 °C was added dropwise Tf2O (55 L,
3. Experimental
l
0.333 mmol) dissolved in dry CH2Cl2 (10 mL). The mixture was
warmed to room temperature and stirred until the starting mate-
rial disappeared (6 h, TLC, 6:4 hexane–EtOAc). Satd aq NaHCO3
(8 mL) was added, and the mixture was partitioned between water
and CH2Cl2. The aq phase was extracted with CH2Cl2 (3 ꢀ 25 mL),
the organic extracts were collected, dried (MgSO4) and concen-
trated under diminished pressure. The residue (264 mg) was sub-
jected to flash chromatography (3:1 hexane–EtOAc) to give 10
3.1. General methods
General methods are those reported in Ref. 16. Compound 8 was
prepared according to the described procedure.9
3.2. (5R)-2,3,6-Tri-O-benzyl-5-C-methoxy-a-L-arabino-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
glucose dimethyl acetal (9)
(0.221 g, 88% yield) as a colourless syrup; [a]D +15.7 (c 1.2, CHCl3);
Rf 0.29 (7:3 hexane–EtOAc); 1H NMR (250 MHz, CD3CN): see Table
1 and d 7.59–7.27 (m, 15H, Ar–H), 4.83, 4.59 (AB system, 2H, JA,B
11.3 Hz, CH2Ph), 4.79, 4.67 (AB system, 2H, JA,B 11.4 Hz, CH2Ph),
4.63, 4.49 (AB system, 2H, JA,B 11.5 Hz, CH2Ph), 4.36 (m, 2H, H-1,
H-2), 4.24 (bq, 1H, H-5), 4.08 (dd, 1H, J5,6b 5.7 Hz, J6a,6b 8.6 Hz, H-
6b), 4.03 (m, 1H, J3,4 1.7 Hz, H-3), 3.88 (dd, 1H, J4,5 5.9 Hz, H-4),
3.87 (dd, 1H, J5,6a 5.4 Hz, H-6a), 3.32 (s, 6H, 2 ꢀ OMe-1), 3.22 (s,
3H, OMe-50), 1.36, 1.35, 1.33, 1.26 (4s, each 3H, 2 ꢀ CMe2); 13C
NMR (62.9 MHz, CD3CN): see Table 2 and d 139.2, 138.6, 138.4
(3 ꢀ Ar–C), 129.3–128.5 (Ar–CH), 110.3, 109.2 (2 ꢀ CMe2), 100.3
(C-10), 75.9, 73.8, 73.7 (3 ꢀ CH2Ph), 56.5, 53.6 (2 ꢀ OMe-1), 49.3
(OMe-50), 27.4, 26.9, 26.7, 25.3 (2 ꢀ CMe2). Anal. Calcd for
C42H53F3O14S: C, 57.92; H, 6.13; F, 6.54; S, 3.68. Found: C, 57.94;
H, 6.14; F, 6.56; S, 3.69.
A solution of 89 (3.94 g, 5.80 mmol) in toluene (90 mL) was treated
with Bu2SnO (1.86 g, 7.44 mmol), heated to reflux and subjected to
azeotropic removal of water with a Dean–Stark apparatus. The
reaction mixture was stirred at reflux (12 h), and then treated with
Bu4NBr (944 mg, 2.90 mmol) and BnBr (0.94 mL, 7.88 mmol) and
further stirred until the starting material disappeared (1.5 h, TLC,
7:3 hexane–EtOAc). The solvent was removed under diminished
pressure, and the residue (9.02 g) was subjected to flash chromatog-
raphy (first hexane 400 mL, then 7:3 hexane–EtOAc) to give 9 (4.20 g,
94% yield) as a colourless syrup; [a]D +4.0 (c 1.2, CHCl3); Rf 0.29 (7:3
hexane–EtOAc); 1H NMR (600 MHz, CDCl3): see Table 1 and d 7.35–
7.26 (m, 15H, Ar–H), 4.84, 4.68 (AB system, 2H, JA,B 11.1 Hz, CH2Ph),
4.72, 4.47 (AB system, 2H, JA,B 12.3 Hz, CH2Ph), 4.68 (s, 2H, CH2Ph),
4.49 (dd, 1H, J1,2 6.5 Hz, J2,3 7.7 Hz, H-2), 4.31 (d, 1H, H-1), 4.26 (bq,
1H, H-5), 4.14 (dd, 1H, J5,6b 5.5 Hz, J6a,6b 8.9 Hz, H-6b), 4.02 (dd, 1H,
J3,4 1.0 Hz, H-3), 3.88 (m, 1H, H-6a), 3.86 (dd, 1H, J4,5 5.8 Hz, H-4),
3.4. (5R)-2,3,6-Tri-O-benzyl-4-deoxy-5-C-methoxy-b-
hex-3-enopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-
aldehydo- -glucose dimethyl acetal (11)
D-glycero-
0
3.27, 3.26, 3.23 (3s, each 3H, 3 ꢀ OMe), 2.48 (d, 1H, J4 ,OH 1.9 Hz,
OH-40), 1.40, 1.38, 1.37, 1.36 (4s, each 3H, 2 ꢀ CMe2); 13C NMR
(50 MHz, CDCl3): see Table 2 and d 138.6, 138.0, 137.7 (3 ꢀ Ar–C),
128.4–127.4 (Ar–CH), 109.9, 108.5 (2 ꢀ CMe2), 75.2, 73.5, 72.5
(3 ꢀ CH2Ph), 55.7, 52.5 (2 ꢀ OMe-1), 47.9 (OMe-50), 27.3, 26.9, 26.5,
25.3 (2 ꢀ CMe2). Anal. Calcd for C42H56O13: C, 65.61; H, 7.34. Found:
C, 65.70; H, 7.39.
D
A solution of 10 (102 mg, 0.113 mmol) in dry toluene (5 mL)
was treated with Bu4NNO2 (147 mg, 0.51 mmol) at room tempera-
ture and warmed to reflux under stirring. After 8 h, when the start-
ing material disappeared (TLC, 3:2 hexane–EtOAc), the mixture
Table 1
1H NMR parameters (d, ppm; J, Hz) of the nonreducing unit of 9–11, 14, 16–20 and 22–25
H-10
H-20
H-30
H-40
H-60a
H-60b
J6 a,6 b
0
J1 ,2
0
0
J2 ,3
0
0
J3 ,4
0
0
0
Compound
Solvent
9
10
11
14
16
17
18
19
20
22
23
24
25
CDCl3
CD3CN
CD3CN
CD3CN
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CD3CN
CDCl3
4.86
4.92
5.15
4.86
4.93
5.04
5.24
5.31
5.31
4.86
4.82
4.91
5.17
3.61
3.51
3.91
3.38
3.42
4.04
3.45
3.63
3.42
3.52
3.82
4.31
3.51
3.89
4.02
—
3.60
3.97
—
3.45
5.24
5.21
4.00
3.82
—
4.11
5.33
5.06
3.79
5.41
5.09
5.10
3.42
5.08
3.87
4.05
3.74
3.73
3.59
3.70
3.65
3.72
3.42
3.57
3.33
3.52
3.42
3.53
3.57
3.61
3.55
3.50
3.38
3.31
3.58
3.25
3.34
3.27
3.46
3.24
3.45
3.41
3.55
3.42
7.9
7.9
6.2
8.0
7.9
7.3
8.2
8.2
8.3
7.9
7.6
7.5
8.4
9.4
9.8
—
9.1
10.0
—
3.3
3.6
3.4
9.9
n.d.
—
3.7
2.4
—
9.1
3.4
—
n.d.
3.3
3.0
3.4
n.d.
—
10.4
11.0
10.2
10.1
10.8
10.6
10.3
10.6
10.5
10.3
10.1
10.6
10.2
3.99
3.4
3.2

G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
721
C-60
Table 2
Selected 13C NMR signals (d, ppm) of the disaccharide derivatives 9–11, 14 and 16–25a
Compound
Solvent
C-1
C-2
C-3
C-4
C-5
C-6
C-10
C-20
C-30
C-40
C-50
9
10
11
14
16
17
18
19
20
21
22
23
24
25
CDCl3
CD3CN
CD3CN
CD3CN
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CD3CN
CDCl3
105.5
106.4
106.6
106.9
105.5
106.1
106.2
105.6
105.8
105.9
105.4
105.2
106.5
106.4
74.4
75.7
76.0
76.2
74.5*
75.0*
75.5
74.8*
74.8
74.7
74.3
74.0
75.8
74.9
77.8
76.6
78.8
78.4
77.8*
77.6
77.7
78.0
77.9*
77.8
77.8
77.6
78.4
77.9
75.0
76.5
76.5
76.9
76.4
75.1*
75.2
74.7*
75.1
75.4
74.6
74.8
77.4
75.2
77.2
77.7
77.9
77.8
77.6*
76.9
77.3
77.7
77.8*
77.5
77.3
76.9
77.7
76.3
65.5
66.1
66.2
66.2
64.8
65.3
65.4
65.3
65.2
65.4
65.2
65.4
66.2
65.7
98.9
100.3
99.6
99.7
98.4
100.0
96.4
96.2
95.9
96.1
99.1
99.1
100.9
97.3
78.8
79.2
76.5
82.8*
74.3*
80.2
74.3
73.8*
73.1
74.7
79.6
79.4
82.0
78.5*
78.6
78.3
67.2
82.7
99.4
74.1
68.8*
74.9*
69.2*
68.4
68.4*
69.6
77.5
75.1
82.0
78.3*
100.3
99.8
99.5
99.9
99.5
64.7
65.3
70.3
74.4
64.1
64.2
64.9
66.2
65.2
65.9
64.7
64.5
64.9
66.2
155.3
82.0*
69.6*
197.2
69.3*
71.6
99.9
101.6
101.4
100.5
102.3
100.8
100.6
101.6
103.5
68.5*
71.6
70.7
79.2
202.3
70.1
a
Assignments (*) may be interchanged.
was cooled to room temperature and concentrated under dimin-
ished pressure. The residue (160 mg) was subjected to flash chro-
matography (4:1 hexane–EtOAc) to give 11 (60 mg, 70% yield) as
of signals for both components: d 129.4–127.5 (Ar–CH), 27.8–25.4
(CMe2).
a colourless syrup; [
a
]
ꢁ24.0 (c 1.36, CHCl3); Rf 0.29 (7:3 hex-
3.6. (5R)-2,3,6-Tri-O-benzyl-5-C-methoxy-b-D-xylo-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
glucose dimethyl acetal (14)
D
ane–EtOAc); 1H NMR (250 MHz, CD3CN): see Table 1 and d 7.43–
7.25 (m, 15H, Ar–H), 4.90, 4.84 (AB system, 2H, JA,B 11.9 Hz, CH2Ph),
4.74 (s, 2H, CH2Ph), 4.55, 4.49 (AB system, 2H, JA,B 12.0 Hz, CH2Ph),
4.37 (d, 1H, J1,2 5.5 Hz, H-1), 4.34 (dd, 1H, J2,3 6.4 Hz, H-2), 4.23 (m,
1H, H-5), 4.12 (dd, 1H, J5,6b 1.3 Hz, J6a,6b 8.5 Hz, H-6b), 4.06 (dd,1H,
J3,4 1.6 Hz, H-3), 4.03 (dd, 1H, J5,6a 6.1 Hz, H-6a), 3.88 (dd, 1H, J4,5
5.3 Hz, H-4), 3.34, 3.30, 3.25 (3s, each 3H, 2 ꢀ OMe-1, OMe-50),
1.33, 1.32, 1.30, 1.26 (4s, each 3H, 2 ꢀ CMe2); 13C NMR
A solution of a mixture of crude 12 and 13 (912 mg) in dry
MeOH (50 mL) was cooled at 0 °C and treated with NaBH4
(180 mg, 4.77 mmol). The reaction mixture was gently warmed
to room temperature and left stirring until the TLC analysis (7:3
hexane–EtOAc) showed the complete disappearance of the starting
material (1.5 h). Water (15 mL) was added, the solution was stirred
for 30 min, and then concentrated under diminished pressure. The
residue was partitioned between water (40 mL) and CH2Cl2
(80 mL). The aq phase was extracted with CH2Cl2 (3 ꢀ 80 mL),
and the organic extracts were collected, dried (MgSO4) and concen-
trated under diminished pressure. The residue (869 mg) was sub-
jected to flash chromatography over silica gel (7:3 hexane–
EtOAc) to give 14 (583 mg, 64% yield) and 9 (187 mg, 20% yield).
(62.9 MHz, CD3CN): see Table
2 and d 139.5, 139.4, 137.8
(3 ꢀ Ar–C), 129.4–128.6 (Ar–CH), 110.5, 109.1 (2 ꢀ CMe2), 74.8,
74.1, 73.0 (3 ꢀ CH2Ph), 56.6, 53.5 (2 ꢀ OMe-1), 50.0 (OMe-50),
27.5, 27.1, 26.8, 25.4 (2 ꢀ CMe2). Anal. Calcd for C41H52O11: C,
68.31; H, 7.27. Found: C, 68.35; H, 7.29.
3.5. (5R)-2,3,6-Tri-O-benzyl-5-C-methoxy-a-L-threo-hex-4-
ulopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
glucose dimethyl acetal (12)
Compound 14: colourless syrup; [
a
]
ꢁ15.9 (c 1.0, CHCl3); Rf
D
0.12 (7:3 hexane–EtOAc); 1H NMR (200 MHz, CD3CN): see Table
1 and d 7.39–7.26 (m, 15H, Ar–H), 4.84, 4.66 (AB system, 2H, JA,B
11.4 Hz, CH2Ph), 4.81, 4.75 (AB system, 2H, JA,B 11.3 Hz, CH2Ph),
4.62, 4.48 (AB system, 2H, JA,B 11.8 Hz, CH2Ph), 4.48 (dd, 1H, J1,2
6.3 Hz, J2,3 7.4 Hz, H-2), 4.33 (d, 1H, H-1), 4.21 (m, 1H, H-5), 4.09
(dd, 1H, J5,6b 5.7 Hz, J6a,6b 8.5 Hz, H-6b), 4.08 (dd, 1H, J3,4 1.6 Hz,
H-3), 3.87 (dd, 1H, J5,6a 6.2 Hz, H-6a), 3.85 (bd, 1H, H-4), 3.36,
3.32, 3.30 (3s, each 3H, 2 ꢀ OMe-1, OMe-50), 1.36, 1.35, 1.34, 1.26
(4s, each 3H, 2 ꢀ CMe2); 13C NMR (50 MHz, CD3CN): see Table 2
and d 140.2, 139.7, 139.2 (3 ꢀ Ar–C), 129.3–128.2 (Ar–CH), 110.4,
109.2 (2 ꢀ CMe2), 75.7, 75.5, 74.3 (3 ꢀ CH2Ph), 56.6, 54.3
(2 ꢀ OMe-1), 49.0 (OMe-50), 27.5, 27.1, 27.0, 25.5 (2 ꢀ CMe2). Anal.
Calcd for C42H56O13: C, 65.61; H, 7.34. Found: C, 65.73; H, 7.38.
Compound 9: colourless syrup; NMR parameters were identical
to those of the sample prepared above.
A solution of 9 (493 mg, 0.641 mmol) in dry CH2Cl2 (12 mL) and
pre-dried 4-methylmorpholine-N-oxide (NMO) (123 mg, 1.05 mmol)
containing 4 Å powdered molecular sieves (120 mg) was stirred un-
der an argon atmosphere for 30 min at room temperature. Tetra-
propylammonium perruthenate (TPAP) (90 mg, 40%) was added,
and the resulting green mixture was stirred for further 4 h at room
temperature. The reaction mixture was filtered through alternate
pads of Celite and silica gel and extensively washed with CH2Cl2
and then with EtOAc. The combined organic phases were concen-
trated under diminished pressure to give a syrup (439 mg) consti-
tuted (13C NMR, CDCl3) by a mixture of 12 and 13 in a ratio of
about 4:1 as estimated on the basis of the relative 50-OMe NMR sig-
nal intensities. Flash chromatographic purification of the crude res-
idue, eluting with 6:4 hexane–EtOAc, gave a 4:1 mixture of 12 and
13 (276 mg combined yield about 56%) as a colourless syrup; [a]
D
+9.3 (c 1.1, CHCl3); Rf 0.92 (9:1 CH2Cl2–Me2CO); selected 13C NMR
(50 MHz, CD3CN) signals: major component 12: d 198.3 (C-40),
139.7, 137.4, 137.3 (3 ꢀ Ar–C), 110.4, 109.2 (2 ꢀ CMe2), 106.6 (C-
1), 99.4 (C-50), 99.1 (C-10), 84.7, 82.3 (C-20, C-30), 78.4, 77.9 (C-3,
C-5), 76.7, 75.9 (C-4, C-2), 75.7, 75.7, 74.1 (3 ꢀ CH2Ph), 67.2, 66.0
(C-6, C-60), 56.6, 53.9 (2 ꢀ OMe-1), 50.2 (OMe-50); minor component
13: d 139.8, 138.9, 138.2 (3 ꢀ Ar–C), 110.3, 109.2 (2 ꢀ CMe2), 106.4
(C-1), 99.4 (C-50), 99.4 (C-10), 97.1 (C-40), 82.5, 81.5 (C-20, C-30), 81.4,
78.4 (C-3, C-5), 77.6, 77.5 (C-4, C-2), 76.4, 75.7, 74.1 (3 ꢀ CH2Ph),
70.3, 66.0 (C-6, C-60), 56.4, 53.6 (2 ꢀ OMe-1), 48.8 (OMe-50). Cluster
3.7. 2,3,6-Tri-O-benzyl-D-xylo-hexos-5-ulose (15)
A solution of 14 (276 mg, 0.359 mmol) in 4:1 (v/v) CH3CN–
water (7 mL) was treated with 90% aq CF3COOH (1.4 mL) and
warmed to 50 °C with stirring until TLC analysis (EtOAc) showed
the complete disappearance of the starting material (12 h). The
mixture was concentrated under diminished pressure and repeat-
edly co-evaporated with toluene (4 ꢀ 20 mL) under diminished
pressure. The crude residue was partitioned between brine
(20 mL) and EtOAc (30 mL), and the aq phase was extracted with

722
G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
EtOAc (3 ꢀ 30 mL). The organic phases were collected, dried
(MgSO4) and concentrated under diminished pressure to give a res-
idue (125 mg) that was directly filtered onto silica gel, eluting with
3:7 hexane–EtOAc, to give pure 15 (122 mg, 72% yield) as a colour-
less syrup. NMR data were in full agreement with those reported.8b
13C NMR (50 MHz, CDCl3): see Table 2 and d 168.5 (MeCO), 137.1,
136.8 (2 ꢀ Ar–C), 129.7–127.8 (Ar–CH), 109.9, 108.6 (2 ꢀ CMe2),
73.2, 72.9 (2 ꢀ CH2Ph), 56.2, 53.6 (2 ꢀ OMe-1), 48.7 (OMe-
50),27.2, 26.5, 26.3, 25.3 (2 ꢀ CMe2), 20.3 (MeCO).
3.9.2. Reduction of 17
3.8. (5R)-4-O-Acetyl-2,6-di-O-benzyl-5-C-methoxy-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
glucose dimethyl acetal (16)
a
-
L
-arabino-
A solution of crude 17 (352 mg, 0.489 mmol) in dry MeOH
(10 mL) was cooled to 0 °C and treated, under an argon atmo-
sphere, with NaBH4 (138 mg, 3.65 mmol). The reaction mixture
was gently warmed to room temperature and left under stirring
until TLC analysis (1:1 hexane–EtOAc) showed the complete disap-
pearance of the starting material (30 min). Water (15 mL) was
added and the solution was stirred for 4 h, and then concentrated
under diminished pressure. The residue was partitioned between
water (20 mL) and CH2Cl2 (40 mL). The aq phase was extracted
with CH2Cl2 (5 ꢀ 25 mL), and the organic extracts were collected,
dried (MgSO4) and concentrated under diminished pressure. The
residue (307 mg) was subjected to flash chromatography (first
11:9 hexane–EtOAc, then 2:3 hexane–EtOAc), collecting four main
fractions. The first two fractions were constituted by the monoac-
etates 18 (65 mg) and 19 (120 mg), each in mixture with about 10%
of the other, accounting for an overall 52% yield. The third fraction
contained pure diol 21 (43 mg, 13% yield), and the fourth one con-
tained a 1:1 mixture of 21 and another yet unidentified diastereo-
isomeric diol (86 mg, each about 13% yield).
To a solution of 89 (341 mg, 0.502 mmol) in dry toluene (10 mL)
warmed to 45 °C, CH3C(OEt)3 (1.1 mL, 6.02 mmol) and TsOH
(9.5 mg, 0.05 mmol) were added. The solution was stirred for 2 h
at 45 °C until TLC analysis (1:1 hexane–EtOAc) showed the complete
disappearance of the starting material (Rf 0.38) with the formation a
faster moving product (Rf 0.60). The mixture was allowed to attain
room temperature, treated with Et3N (0.1 mL) and further stirred
for 10 min. The solution was concentrated under diminished pres-
sure, and the residue (228 mg) was treated with 80% aq AcOH
(3.0 mL) and stirred at room temperature until the product at Rf
0.60 was completely reacted (TLC, 1:1 hexane–EtOAc, 15 min). The
mixture was diluted with CH2Cl2 (20 mL) and carefully neutralised
with 40% aq NaOH (4 mL). The reaction mixture was diluted with
water (7 mL), and the aq phase was extracted with CH2Cl2
(3 ꢀ 20 mL). The combined organic layers were dried (MgSO4), fil-
tered and concentrated under diminished pressure. The residue
(356 mg) was constituted exclusively (NMR) of 16 (quant yield).
An analytical sample of 16 was obtained through flash chromatogra-
phy eluting with 3:2 hexane–EtOAc. Pure 16 (308 mg, 85% yield) was
3.9.2.1. (5R)-4-O-Acetyl-2,6-di-O-benzyl-5-C-methoxy-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-
glucose dimethyl acetal (18).
Rf 0.39 (1:1 hexane–EtOAc); 1H
a-L-xylo-
D-
a white foam; [
a
]
ꢁ24.2 (c 0.95, CHCl3); Rf 0.51 (1:1 hexane–
NMR (200 MHz, CDCl3): see Table 1 and d 7.34–7.18 (m, 10H, Ar–
H), 4.71, 4.59 (AB system, 2H, JA,B 12.0 Hz, CH2Ph), 4.56, 4.49 (AB
system, 2H, JA,B 12.0 Hz, CH2Ph), 4.42 (dd, 1H, J1,2 6.4 Hz, J2,3
7.0 Hz, H-2), 4.32 (d, 1H, H-1), 4.25 (m, 2H, H-5, H-6a), 4.05–3.90
(m, 3H, H-3, H-4, H-6b), 3.32, 3.30. 3.29 (3s, each 3H, 2 ꢀ OMe-1,
D
EtOAc); 1H NMR (200 MHz, CDCl3): see Table 1 and d 7.35–7.26
(m, 10H, Ar–H), 4.92, 4.59 (AB system, 2H, JA,B 11.3 Hz, CH2Ph),
4.49 (dd, 1H, J1,2 6.7 Hz, J2,3 7.0 Hz, H-2), 4.46 (s, 2H, CH2Ph), 4.32
(d, 1H, H-1), 4.30–3.95 (m, 5H, H-3, H-4, H-5, H-6a, H-6b), 3.34,
3.33 (2s, each 3H, 2 ꢀ OMe-1), 3.27 (s, 3H, OMe-50), 2.22 (bs, 1H,
OH-30), 1.96 (s, 3H, MeCO), 1.45, 1.32 (2s, each 3H, CMe2), 1.41 (s,
6H, CMe2); 13C NMR (50 MHz, CDCl3): d see Table 2 and 169.5
(MeCO), 137.8, 136.9 (2 ꢀ Ar–C), 129.4–127.4 (Ar–CH), 109.6,
108.1 (2 ꢀ CMe2), 74.3, 73.1 (2 ꢀ CH2Ph), 55.6, 52.9 (2 ꢀ OMe-1),
47.8 (OMe-50), 26.8, 26.1, 26.0, 24.7 (2 ꢀ CMe2), 20.4 (MeCO). Anal.
Calcd for C37H52O14: C, 61.65; H, 7.27. Found: C, 61.59; H, 7.23.
OMe-50), 2.69 (d, 1H, J4 ,OH 5.3 Hz, OH-40), 2.02 (s, 3H, MeCO),
0
1.41, 1.32 (2s, each 3H, CMe2); 1.40 (s, 6H, CMe2); 13C NMR
(50 MHz, CDCl3): see Table 2 and d 170.5 (MeCO), 138.2, 137.4
(2 ꢀ Ar–C), 128.5–126.9 (Ar–CH), 110.0, 108.4 (2 ꢀ CMe2), 73.4,
72.6 (2 ꢀ CH2Ph), 55.8, 52.8 (2 ꢀ OMe-1), 48.1 (OMe-50), 27.3,
26.6, 26.3, 25.4 (2 ꢀ CMe2), 20.9 (MeCO). Anal. Calcd for
C37H52O14: C, 61.65; H, 7.27. Found: C, 61.58; H, 7.25.
3.9. Oxidation–reduction of (5R)-4-O-Acetyl-2,6-di-O-benzyl-5-
3.9.2.2. (5R)-3-O-Acetyl-2,6-di-O-benzyl-5-C-methoxy-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-
glucose dimethyl acetal (19).
Rf 0.34 (1:1 hexane–EtOAc); 1H
a-L-xylo-
C-methoxy-
a-
L-arabino-hexopyranosyl-(1?4)-2,3:5,6-di-O-
D-
isopropylidene-aldehydo-D-glucose dimethyl acetal (16)
NMR (200 MHz, CDCl3): see Table 1 and d 7.33–7.26 (m, 10H, Ar–H),
4.81, 4.63 (AB system, 2H, JA,B 12.1 Hz, CH2Ph), 4.47, 4.40 (AB system,
2H, JA,B 11.7 Hz, CH2Ph), 4.47 (dd, 1H, J1,2 6.4 Hz, J2,3 7.6 Hz, H-2),
4.28–3.94 (m, 3H, H-5, H-6a, H-6b), 4.32 (d, 1H, H-1), 4.06 (dd, 1H,
J3,4 1.2 Hz, H-3), 3.92 (dd, 1H, J4,5 5.0 Hz, H-4), 3.37, 3.36, 3.35 (3s,
3.9.1. Oxidation of 16
A suspension of 16 (356 mg, 0.494 mmol) in dry CH2Cl2 (6 mL)
and pre-dried 4-methylmorpholine-N-oxide (NMO) (98 mg,
0.841 mmol) containing 4 Å powdered molecular sieves (250 mg)
was stirred under an argon atmosphere for 30 min at room tem-
perature. Tetrapropylammonium perruthenate (TPAP) (35 mg,
20%) was added, and the resulting green mixture was stirred until
TLC analysis (13:7 hexane–EtOAc) revealed the disappearance of
the starting material (45 min, Rf 0.25). The reaction mixture was
filtered through alternate paths of Celite and silica gel and exten-
sively washed first with CH2Cl2 and then with EtOAc. The com-
bined organic phases were concentrated under diminished
pressure to give a syrup (352 mg) constituted exclusively (NMR)
by the uloside 17; Rf 0.17 (13:7 hexane–EtOAc); 1H NMR
(200 MHz, CDCl3): see Table 1 and d 7.30–7.22 (m, 10H, Ar–H),
4.80, 4.65 (AB system, 2H, JA,B 11.9 Hz, CH2Ph), 4.52, 4.43 (AB sys-
tem, 2H, JA,B 12.4 Hz, CH2Ph), 4.46 (dd, 1H, J1,2 6.6 Hz, J2,3 7.1 Hz,
H-2), 4.32 (d, 1H, H-1), 4.25 (m, 1H, H-5), 4.17–3.85 (m, 4H, H-3,
H-4, H-6a, H-6b), 3.36 (s, 6H, 2 ꢀ OMe-1), 3.29 (s, 3H, OMe-50),
1.86 (s, 3H, MeCO), 1.41, 1.38, 1.35, 1.31 (4s, each 3H, 2 ꢀ CMe2);
each 3H, 2 ꢀ OMe-1, OMe-50), 3.14 (d, 1H, J3 ,OH 8.0 Hz, OH-30),
0
1.78 (s, 3H, MeCO), 1.43 (s, 6H, CMe2); 1.42, 1.32 (2s, each 3H,
CMe2); 13C NMR (50 MHz, CDCl3): see Table 2 and d 168.5 (MeCO),
137.9, 137.3 (2 ꢀ Ar–C), 128.3–127.6 (Ar–CH), 109.9, 108.5
(2 ꢀ CMe2), 73.3, 72.5 (2 ꢀ CH2Ph), 56.1, 53.7 (2 ꢀ OMe-1), 48.4
(OMe-50), 27.2, 26.5, 26.4, 25.3 (2 ꢀ CMe2), 20.5 (MeCO). Anal. Calcd
for C37H52O14: C, 61.65; H, 7.27. Found: C, 61.60; H, 7.22.
3.9.2.3. (5R)-2,6-Di-O-benzyl-5-C-methoxy-
osyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-
dimethyl acetal (21). White foam; [
D ꢁ27.2 (c 0.99, CHCl3);
Rf 0.32 (2:3 hexane–EtOAc); 1H NMR (250 MHz, CDCl3): d 7.31–
a-
L
-xylo-hexopyran-
D-glucose
a]
7.22 (m, 10H, Ar–H), 5.18 (d, 1H, J1 ,2 7.8 Hz, H-10), 4.81, 4.65 (AB
system, 2H, JA,B 12.2 Hz, CH2Ph), 4.57, 4.50 (AB system, 2H, JA,B
12.3 Hz, CH2Ph), 4.47 (dd, 1H, J1,2 6.7 Hz, J2,3 7.1 Hz, H-2), 4.31 (d,
1H, H-1), 4.30–4.17 (m, 2H, H-5, H-6b), 4.05–3.98 (m, 5H, H-30,
0
0

G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
723
H-40, H-3, H-4, H-6a), 3.60–3.50 (m, 3H, H-20, H-60a, H-60b), 3.31 (s,
plete disappearance of the starting material (5 h). The mixture
was concentrated under diminished pressure and repeatedly co-
evaporated with toluene (5 ꢀ 20 mL). The residue was partitioned
between brine (20 mL) and EtOAc (40 mL), and the aq phase was
extracted with EtOAc (3 ꢀ 40 mL). The organic phases were col-
lected, dried (MgSO4) and concentrated under diminished pressure
to give a residue (96 mg) that was directly subjected to a flash
chromatographic purification, eluting with 1:3 hexane–EtOAc, to
give pure 26 (75 mg, 78% yield) as colourless syrup. NMR data were
in agreement with those reported.8b
9H, 2 ꢀ OMe-1, OMe-50), 3.13 (d, 1H, J3 ,OH 7.5 Hz, OH-30), 2.60 (d,
0
1H, J4 ,OH 5.2 Hz, OH-40), 1.41 (s, 9H, CMe2); 1.32 (s, 3H, CMe2);
0
13C NMR (62.9 MHz, CDCl3): see Table 2 and d 138.1, 137.2
(2 ꢀ Ar–C), 128.5–127.5 (Ar–CH), 109.9, 108.5 (2 ꢀ CMe2), 73.3,
72.6 (2 ꢀ CH2Ph), 56.0, 53.1 (2 ꢀ OMe-1), 48.4 (OMe-50), 27.2,
26.6, 26.5, 25.3 (2 ꢀ CMe2). Anal. Calcd for C35H50O13: C, 61.93; H,
7.42. Found: C, 61.90; H, 7.39.
3.9.2.4. Unidentified diol.
Selected 13C NMR (50 MHz, CDCl3)
data for the unidentified diastereoisomeric diol isolated in mixture
with 21: d 106.0 (C-1), 98.6 (C-50), 98.2 (C-10), 81.2 (C-20), 77.8,
77.6, 77.3 (C-3, C-4, C-5), 75.5, 74.8, 71.6 (C-2, C-30, C-40), 73.7,
73.74 (2 ꢀ CH2Ph), 69.9 (C-60), 65.2 (C-6), 56.0, 53.6 (2 ꢀ OMe-1),
48.5 (OMe-50).
3.13. (5R)-2,4,6-Tri-O-benzyl-5-C-methoxy-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-
glucose dimethyl acetal (22) and (5R)-2,3,4,6-tetra-O-benzyl-5-
C-methoxy- -arabino-hexopyranosyl-(1?4)-2,3:5,6-di-O-
isopropylidene-aldehydo- -glucose dimethyl acetal (23)
a-L-arabino-
D
-
a-L
D
3.10. (5R)-3,4-Di-O-acetyl-2,6-di-O-benzyl-5-C-methoxy-
a-L-
lyxo-hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-
aldehydo-D-glucose dimethyl acetal (20)
A suspension of pre-washed (hexane) 60% NaH in mineral oil
(1.29 g, 53.7 mmol) in dry DMF (25.0 mL) was cooled to 0 °C and
treated, under an argon atmosphere, with a solution of 8 (3.62 g,
5.34 mmol) in dry DMF (100 mL). The mixture was warmed to room
temperature and stirred for 30 min, cooled again to 0 °C and treated
with BnBr (0.63 mL, 5.34 mmol) and further stirred until the starting
material was consumed (25 min, TLC, 7:3 hexane–EtOAc). MeOH
(12 mL) and water (100 mL) were slowly added, and the reaction
mixture was extracted with Et2O (4 ꢀ 50 mL). The combined ex-
tracts were collected, dried (MgSO4) and concentrated under dimin-
ished pressure. The residue (4.68 g) was subjected to flash
chromatography (first hexane 600 mL, then 4:1 hexane–EtOAc) to
give 22 (3.09 g, 75% yield) and 23 (684 mg, 15% yield).
Compound 21 (40 mg, 0.059 mmol) was acetylated with a 1:2
mixture of Ac2O and pyridine (3 mL) and stirred at room tempera-
ture. After 20 h, the reaction mixture was repeatedly co-evapo-
rated with toluene (4 ꢀ 10 mL) at diminished pressure. Flash
chromatographic purification (13:7 hexane–EtOAc) of the residue
(52 mg) gave 20 (44 mg, 97% yield) as a syrup; [
a]
D
ꢁ46.9 (c 0.9,
CHCl3); Rf 0.38 (3:2 hexane–EtOAc); 1H NMR (200 MHz, CDCl3):
see Table 1 and d 7.35–7.23 (m, 10H, Ar–H), 4.68, 4.58 (AB system,
2H, JA,B 11.9 Hz, CH2Ph), 4.43, 4.40 (s, 2H, CH2Ph), 4.46 (dd, 1H, J1,2
6.5 Hz, J2,3 7.3 Hz, H-2), 4.33 (d, 1H, H-1), 4.26 (m, 1H, H-5), 4.03
(dd, 1H, J3,4 1.3 Hz, H-3), 4.16 (dd, 1H, J5,6b 6.2 Hz, J6a,6b 8.5 Hz, H-
6b), 3.98 (m, 2H, H-4, H-6a), 3.34, 3.33, 3.32 (3s, each 3H,
2 ꢀ OMe-1, OMe-50), 2.00, 1.85 (2s, each 3H, 2 ꢀ MeCO), 1.41 (s,
6H, CMe2); 1.40, 1.32 (2s, each 3H, CMe2); 13C NMR (50 MHz,
CDCl3): see Table 2 and d 169.5, 168.1 (2 ꢀ MeCO), 137.8, 137.3
(2 ꢀ Ar–C), 128.4–127.5 (Ar–CH), 110.1, 108.4 (2 ꢀ CMe2), 73.4,
72.6 (2 ꢀ CH2Ph), 55.8, 53.4 (2 ꢀ OMe-1), 48.1 (OMe-50), 27.2,
26.6, 26.2, 25.4 (2 ꢀ CMe2), 20.8, 20.6 (2 ꢀ MeCO). Anal. Calcd for
C39H54O15: C, 61.41; H, 7.14. Found: C, 61.38; H, 7.12.
Compound 22: colourless syrup; [a] +16.8 (c 1.07, CHCl3); Rf
D
0.24 (7:3 hexane–EtOAc); 1H NMR (600 MHz, CDCl3): see Table 1
and d 7.36–7.22 (m, 15H, Ar–H), 4.76, 4.60 (AB system, 2H, JA,B
11.6 Hz, CH2Ph), 4.62, 4.58 (AB system, 2H, JA,B 11.3 Hz, CH2Ph),
4.58, 4.34 (AB system, 2H, JA,B 12.1 Hz, CH2Ph), 4.49 (dd, 1H, J1,2
6.5 Hz, J2,3 7.6 Hz, H-2), 4.31 (d, 1H, H-1), 4.27 (bq, 1H, H-5), 4.16
(dd, 1H, J5,6b 5.6 Hz, J6a,6b 8.7 Hz, H-6b), 4.00 (m, 1H, H-4), 3.95
(dd, 1H, J5,6a 6.2 Hz, H-6a), 3.92 (dd, 1H, J3,4 0.8 Hz, H-3), 3.27,
3.25, 3.22 (3s, each 3H, 2 ꢀ OMe-1, OMe-50), 1.43, 1.41, 1.38, 1.31
(4s, each 3H, 2 ꢀ CMe2); 13C NMR (50 MHz, CDCl3): see Table 2
and d 138.6, 138.3, 137.2 (3 ꢀ Ar–C), 128.3–127.2 (Ar–CH), 109.8,
108.4 (2 ꢀ CMe2), 74.9, 74.5, 73.2 (3 ꢀ CH2Ph), 55.6, 52.3
(2 ꢀ OMe-1), 47.9 (OMe-50), 27.2, 26.5, 26.4, 25.0 (2 ꢀ CMe2). Anal.
Calcd for C42H56O13: C, 65.61; H, 7.34. Found: C, 65.73; H, 7.44.
The acetylation of the fractions containing either 19 (115 mg,
0.160 mmol) or 18 (65 mg, 0.090 mmol) as reported above gave,
after chromatographic purification (13:7 hexane–EtOAc), 21
(183 mg, 96% yield) having NMR parameters identical to those of
the sample prepared above.
Compound 23: colourless syrup; [a] +17.6 (c 1.2, CHCl3); Rf
D
3.11. (5R)-2,6-Di-O-benzyl-5-C-methoxy-
hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
glucose dimethyl acetal (21)
a
-
L
-lyxo-
0.38 (7:3 hexane–EtOAc); 1H NMR (200 MHz, CDCl3): see Table 1
and d 7.33–7.23 (m, 20H, Ar–H), 4.95, 4.57 (AB system, 2H, JA,B
11.5 Hz, CH2Ph), 4.83, 4.73 (AB system, 2H, JA,B 10.7 Hz, CH2Ph),
4.70 (s, 2H,CH2Ph), 4.56, 4.28 (AB system, 2H, JA,B 12.1 Hz, CH2Ph),
4.54 (dd, 1H, J1,2 6.7 Hz, J2,3 9.7 Hz, H-2), 4.31 (d, 1H, H-1), 4.18 (m,
1H, H-5), 4.05 (m, 2H, H-4, H-6b), 3.98 (dd, 1H, J3,4 2.9 Hz, H-3),
3.87 (dd, 1H, J5,6a 5.8 Hz, J6a,6b 8.9 Hz, H-6a), 3.25, 3.22, 3.21 (3s,
each 3H, 2 ꢀ OMe-1, OMe-50), 1.42, 1.41, 1.37, 1.30 (4s, each 3H,
2 ꢀ CMe2); 13C NMR (50 MHz, CDCl3): see Table 2 and d 138.7,
138.5, 138.4, 137.2 (4 ꢀ Ar–C), 128.1–127.1 (Ar–CH), 109.6, 108.3
(2 ꢀ CMe2), 74.8, 74.5, 73.1, 72.6 (4 ꢀ CH2Ph), 55.4, 52.0
(2 ꢀ OMe-1), 47.8 (OMe-50), 27.2, 26.6, 26.1, 25.1 (2 ꢀ CMe2). Anal.
Calcd for C49H62O13: C, 68.51; H, 7.27. Found: C, 68.63; H, 7.34.
To a solution of 20 (183 mg, 0.240 mmol) in dry MeOH (5 mL)
was added 0.1 M methanolic solution of MeONa (0.2 mL) at room
temperature. The reaction mixture was stirred until TLC analysis
(3:2 hexane–EtOAc) showed the complete disappearance of the
starting material (2 h) and the formation of a lower moving prod-
uct. The solution was neutralised with resin acid (Amberlyst 15),
and the suspension was filtered and concentrated to give a foam
residue constituted by pure (NMR) 21 (162.5 mg, quantitative
yield), identical to the sample obtained above. The combined over-
all yield of 21, which was obtained by adding the sample that was
directly isolated in the oxidation–reduction of 16, was 65%.
3.14. (5R)-2,4,6-Tri-O-benzyl-5-C-methoxy-a-L-threo-hex-3-
ulopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
3.12. 2,6-Di-O-benzyl-
L
-lyxo-hexos-5-ulose (26)
glucose dimethyl acetal (24)
A solution of 21 (185 mg, 0.272 mmol) in 4:1 (v/v) CH3CN–
water (6 mL) was treated with 90% aq CF3COOH (1.2 mL), warmed
to 50 °C and stirred until TLC analysis (EtOAc) showed the com-
A suspension of 22 (1.03 g, 1.34 mmol) in dry CH2Cl2 (27 mL),
pre-dried 4-methylmorpholine-N-oxide (NMO) (275 mg, 2.34 mmol)
and 4 Å powdered molecular sieves (400 mg) was stirred under an

724
G. Catelani et al. / Carbohydrate Research 344 (2009) 717–724
argon atmosphere for 30 min at room temperature. Tetrapropylam-
monium perruthenate (TPAP) (47 mg, 10%) was added, and the
resulting green mixture was stirred for 4 h at room temperature un-
til the TLC (9:1 CH2Cl2–Me2CO) showed the complete disappearance
of the starting material. The reaction mixture was filtered through
alternate paths of Celite and silica gel, and extensively washed with
CH2Cl2 and EtOAc. The solution and washings were combined and
concentrated under diminished pressure to give almost pure 24
(NMR). A sample of the residue was subjected to flash chromatogra-
phy (7:3 hexane–EtOAc) to give 24 (76% yield) as a colourless syrup;
3.16. 2,4,6-Tri-O-benzyl-L-lyxo-hexos-5-ulose (27)
A solution of 25 (456 mg, 0.594 mmol) in 4:1 (v/v) CH3CN–
water (11 mL) was treated with 90% aq CF3COOH (2.3 mL) and
warmed to 50 °C with stirring until TLC analysis (EtOAc) showed
the complete disappearance of the starting material (4 h). The mix-
ture was concentrated under diminished pressure and repeatedly
co-evaporated with toluene (5 ꢀ 20 mL). The residue was parti-
tioned between brine (20 mL) and EtOAc (40 mL), and the aq phase
was extracted with EtOAc (3 ꢀ 40 mL). The organic phases were
collected, dried (MgSO4) and concentrated under diminished pres-
sure to give a residue (285 mg) that was directly subjected to a
flash chromatographic purification, eluting with 4:6 hexane–
EtOAc, to give 27 (228 mg, 86% yield) as a colourless syrup. NMR
data were in agreement with those of the sample previously pre-
pared by us.6b
[a
]
D
ꢁ37.4 (c 1.16, CHCl3); Rf 0.73 (9:1 CH2Cl2–Me2CO); 1H NMR
(200 MHz, CD3CN): see Table 1 and d 7.38–7.13 (m, 15H, Ar–H),
4.70, 4.64 (AB system, 2H, JA,B 12.5 Hz, CH2Ph), 4.53, 4.47 (AB system,
2H, JA,B 12.4 Hz, CH2Ph), 4.40–4.32 (m, 4H, H-1, H-2, CH2Ph), 4.21 (m,
1H, H-5), 4.07 (dd, 1H, J5,6b 6.0 Hz, J6a,6b 8.5 Hz, H-6b), 4.03 (dd, 1H,
J2,3 6.9 Hz, J3,4 1.1 Hz, H-3), 3.93 (dd, 1H, J5,6a 6.3 Hz, H-6a), 3.87
(dd, 1H, J4,5 5.5 Hz, H-4), 3.31, 3.25, 3.23 (3s, each 3H, 2 ꢀ OMe-1,
OMe-50), 1.34, 1.33, 1.32, 1.27 (4s, each 3H, 2 ꢀ CMe2); 13C NMR
(50 MHz, CD3CN): see Table 2 and d 138.8, 138.6, 137.8 (3 ꢀ Ar–C),
129.3–128.8 (Ar–CH), 110.4, 109.2 (2 ꢀ CMe2), 74.0, 73.9, 73.0
(3 ꢀ CH2Ph), 56.5, 53.8 (2 ꢀ OMe-1), 49.1 (OMe-50), 27.4, 26.9,
26.8, 25.5 (2 ꢀ CMe2). Anal. Calcd for C42H54O13: C, 65.78; H, 7.10.
Found: C, 65.88; H, 7.38.
Acknowledgement
This research was partly supported by Ministero dell’Università
e della Ricerca (MIUR, Rome, Italy) in the frame of the COFIN
national project.
References
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hexopyranosyl-(1?4)-2,3:5,6-di-O-isopropylidene-aldehydo-D-
glucose dimethyl acetal (25)
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a]
D
+2.20 (c 0.7, CHCl3); Rf 0.38 (9:1
CH2Cl2–Me2CO); 1H NMR (200 MHz, CDCl3): see Table 1 and d
7.38–7.05 (m, 15H, Ar–H), 4.81, 4.63 (AB system, 2H, JA,B
12.2 Hz, CH2Ph), 4.58, 4.36 (AB system, 2 H, JA,B 12.1 Hz, CH2Ph),
4.48 (dd, 1 H, J1,2 6.7 Hz, J2,3 7.6 Hz, H-2), 4.47, 4.39 (AB system,
2H, JA,B 11.4 Hz, CH2Ph), 4.31 (d, 1H, H-1), 4.24 (m, 1H, H-5),
4.03 (dd, 1H, J3,4 1.0 Hz, H-3), 4.00 (m, 2H, H-6a, H-6b), 3.88
(dd, 1H, J4,5 5.2 Hz, H-4), 3.28, 3.25, 3.15 (3s, each 3H, 2 ꢀ OMe-
1, OMe-50), 1.44, 1.43, 1.42, 1.33 (4s, each 3H, 2 ꢀ CMe2); 13C
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