Synthesis of enantiomerically pure enones (2-benzyloxypyran-3-ones)derived from pentoses

Article abstract of DOI:10.1016/j.carres.2019.05.005

The useful synthons sugar enones (2-benzyloxypyran-3-ones)derived from pentoses have been prepared starting from 2-acetoxyglycals or benzyl pentopyranosides. The glycals were glycosylated with benzyl alcohol in the presence of a Lewis acid (SnCl₄

Full text of DOI:10.1016/j.carres.2019.05.005

Accepted Manuscript
Synthesis of enantiomerically pure enones (2-benzyloxypyran-3-ones) derived from
pentoses
Lucas Dada, Verónica E. Manzano, Oscar Varela
PII:
S0008-6215(19)30224-1
https://doi.org/10.1016/j.carres.2019.05.005
CAR 7712
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 11 April 2019
Revised Date: 2 May 2019
Accepted Date: 15 May 2019
Please cite this article as: L. Dada, Veró.E. Manzano, O. Varela, Synthesis of enantiomerically pure
enones (2-benzyloxypyran-3-ones) derived from pentoses, Carbohydrate Research (2019), doi: https://
doi.org/10.1016/j.carres.2019.05.005.
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Synthesis of enantiomerically pure enones (2-benzyloxypyran-3-ones)
derived from pentoses
Lucas Dada,a,b Verónica E. Manzano,a,b Oscar Varelaa,b,*
aUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales, Departamento de
Química Orgánica. Ciudad Universitaria, Pabellón 2, C1428EHA, Buenos Aires, Argentina
bConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-UBA, Centro de
Investigación en Hidratos de Carbono (CIHIDECAR).
*Corresponding Author. E mail: varela@qo.fcen.uba.ar
Highlights
•
•
•
•
Efficient synthesis of enantiomerically enriched or pure enones from pentoses.
Glycosylation of 2-acetoxyglycals with BnOH/InCl3 gave enones with ee > 78%.
Enantiomerically pure enones were synthesized from benzyl pentopyranosides.
Reactions involving substituted benzyl groups gave lower yields than those unsubstituted.

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Abstract
The useful synthons sugar enones (2-benzyloxypyran-3-ones) derived from pentoses have
been prepared starting from 2-acetoxyglycals or benzyl pentopyranosides. The glycals were
glycosylated with benzyl alcohol in the presence of a Lewis acid (SnCl4 or InCl3) to give
enantioenriched enones (ee = 80-90%). Under catalysis with InCl3, benzyl 2-
enopyranosides gave also the enones (ee = 87%). On the other hand, enantiomerically pure
enones were synthesized via an improved straightforward and high yielding sequence (70%
overall) from benzyl pentopyranosides. However, the yields of both, the glycosylation of
glycals as well as some specific reactions of the sequence from glycosides, were lowered
when a p-nitro substituent was introduced into the benzyl group. These routes became
impractical in the case of p-acetamidobenzyl derivatives, because of the large extent of
decomposition. Therefore, alternative sequences have been developed for the synthesis of
2-(p-acetamidobenzyloxy)pyran-3-ones.
Keywords:
Pentopyranoside
Sugar enone
3-Enopyranose
2-Benzyloxy pyranone
Glycal rearrangement

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Introduction
Common carbohydrates and derivatives are widely used as chiral precursors in
enantiospecific synthesis. Particularly, sugar enones, which combine the versatile
unsaturated carbonyl motif in addition with the intrinsic chirality of the carbohydrate, are
useful synthons for the synthesis of a wide variety of natural and unnatural compounds [1-
4]. The most popular sugar enone is levoglucosenone (1,6-anhydro-3,4-dideoxy-β-D-
glycero-hex-3-enopyranos-2-ulose), which is considered to be a promising platform for
both fine and commodity chemical industries [5] and even for the development of new
therapeutics [6]. The varied applications of this chiral template for the synthesis of
enantiomerically pure compounds, as well as its reactivity and chemical transformations to
provide key intermediates, chiral auxiliaries, catalysts, and organocatalysts useful in
asymmetric synthesis have been profusely reviewed [5, 7-10].
Levoglucosenone is usually obtained as one of the products of pyrolysis of cellulose [7-10],
in contrast to these rather drastic reaction conditions we have described mild and efficient
procedures (see below) for the preparation of analogous sugar enones (alkyl 3-
enopyranosid-2-uloses or 2-alkoxypyran-3-ones). These compounds proved to be useful
precursors in the synthesis of a varied type of molecules. Thus, they have been employed as
dienophiles in Diels-Alder cycloadditions with butadienes and cyclic dienes [11-15], or
dipolarophiles in 1,3-dipolar cycloadditions with azomethine ylides [16-18]. The enones
also behave as Michael acceptors of thiols or 1-thioaldoses in the respective synthesis of 3-
deoxy-4-thio-glycosides [19-22] or thiodisaccharides [23-27]. Furthermore, sugar 3,4-
epoxides, prepared by epoxidation of pyranones, underwent nucleophilic substitution by 1-
thioaldoses to give (1→3)- and (1→4)-linked thiodisaccharides [28]. Analogous opening of

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thiiranes derived from enones led to branched thiooligosaccharides and disulfides [29].
Naturally occurring amino deoxy sugars, constituents of antibiotics, have been synthesized
starting from pyranones [30,31].
One of the most useful methods to prepared sugar-derived 2-alkoxypyran-3-ones is the
Lewis acid-promoted glycosylation of 2-acetoxyglycal derivatives obtained from common
pentoses [11] or hexoses [32,33]. This procedure applied to glycals derived from hexoses
led to enantiomerically pure enones, while glycals derived from pentoses gave pyranones
having enantiomeric excesses (ee) in the range 80-90% [11]. To prepare enantiomerically
pure enones derived from pentopyranoses, we have developed a multistep sequence from
common glycosides [34], or employed chiral alcohols for the glycosylation. Thus, the use
of 2(R) or 2(S)-octanol led to practically enantiomerically pure enones (ee > 97%), after a
rather difficult separation of the diastereoisomers by column chromatography [11]. When
(−)-menthol was employed as chiral alcohol, the analogous pryranones were crystalline
products, that were readily purified by recrystallization to obtain the enantiomerically pure
product [16-18]. However, we have demonstrated that the stereocenters in the aglycon
affected the stereochemical course of the reactions performed on the α,β-unsaturated
carbonyl system [16-18]. Furthermore, the benzyloxy substituent at the anomeric center of
the pentopyranoside unit of (1→4) thiodisaccharides inhibitors, obtained from 2-benzyloxy
pyranones, play an important role in the interaction with the catalytic site of the enzyme
[35]. Particularly, saturation transfer difference (STD) and transferred-NOESY experiments
showed major transfer to the aromatic benzyl protons. We expected that the introduction in
the benzyl aromatic ring of substituents with different electronic properties and able to
participate in hydrogen bonding could affect the interaction with the enzyme, and hence the

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inhibitory activity. To explore this hypothesis we needed, as precursor of the
thiodisaccharides, pyran-3-ones carrying benzyloxy rings with substituents of diverse
nature. Therefore, we have explored and we report here the approaches developed for the
preparation of such enantiomerically pure 2-benzyloxypyranones.
Results and discussion
The Lewis acid-promoted glycosylation of 2-acetoxylglycal derivatives of pyranoses
proved to be a straightforward and high yielding procedure for the synthesis of sugar
enones (alkyl 3-enopyranosid-2-uloses) [11,32,33]. During such glycosylation the Lewis
acid promotes a double allylic (Ferrier) rearrangement to afford the pyran-3-one. The
alcohol nucleophile is diastereoselectively introduced, as the axial orientation is preferred
because of the anomeric effect. Thus, glycals from hexopyranoses gave the α-anomer of the
enone as practically the only product. In contrast, the stereochemistry of the C-4 substituent
in glycals of pentopyranoses induces the approach of the alcohol from the opposite face,
and with assistance of the anomeric effect affords the corresponding α or β anomers [11].
When common alcohols (no chiral ones) are employed, the glycosylation leads to
enantioenriched enones as the only stereocenter in the product is that generated during the
reaction (C-1). For example, the reaction of D-xylal 1 with benzyl alcohol, promoted by
SnCl4 led to the enone 2S having an enantiomeric excess (ee) of approximately 86%
(Scheme 1) [11]. Now, we have explore this reaction using InCl3 as an alternative to the
hygroscopic and moisture sensitive SnCl4. In view of the different properties of these two
Lewis acids and their capacity to promote the conversion of glycals into enones, in the

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present work we have focused on them. An advantage of using InCl3 over SnCl4 was that
the concentration of the indium catalyst could be lowered to 20 mole% and the enone was
obtained in an excellent yield (91%), and the ee (78%) was slightly lower compared with
that of SnCl4. The ee were estimated as optical purities, according to the ratio between the
optical rotation of the product and that of the pure enone 2S [34] ([α]D = +248.4). Further
lowering in the indium catalyst to 5 mole% led to a similar ee (80%), but the reaction
required a longer time (as happened with the use of catalytic SnCl4) and some degradation
of the product took place, leading to a lower yield of the reaction (83%).
Scheme 1. Lewis acid-promoted glycosylation and rearrangement of 2-acetoxyglycals.
In order to obtain enantiomerically pure enones the double allylic rearrangement
was conducted in two steps. This is, the intermediate enopyranosides 3α and 3β, formed by
Ferrier rearrangement upon glycosylation of 1, were isolated and the major isomer (3β) was
converted into the enone 2S, via a second allylic rearrangement promoted by a Lewis acid.

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As N-iodosuccinimide (NIS) is a convenient reagent for the conversion of 2-acetoxyglycals
into enopyranosides [36], the glycosylation of 1 with benzyl alcohol was conducted using
catalytic NIS (20 mole%) to successfully produce the enopyranosides 3α,β. This
diastereomeric mixture was separated by column chromatography. The anomeric
configuration of each product was stablished by conversion of the major isomer (3β) into
1
the known enone (see below) and also on the basis of the H NMR spectra. Interestingly,
the coupling constant pattern for 3β showed a high preference of this compound for the 5HO
conformation as deduced from the values for the vinylic (3J3,4 = 6.9 Hz) and allylic (4J1,3
~
0 Hz) coupling constants in agreement with the magnitude estimated from dihedral angle
(Ɵ) formed between those protons (Garbisch equation [37]). In addition, such a
conformation is also supported by the W-coupling between H-3 and H-5eq (4J3,5eq = 1.1 Hz)
and the small values for the J4,5ax (2.8 Hz) and J4,5eq (0.9 Hz).
5
The HO conformation of 3β is stabilized by the anomeric and allylic effects [38-
40], as both the anomeric benzyloxy and the allylic acetate are axially disposed. In contrast,
the isomer 3α cannot satisfied both stereoelectronic effects, and hence its conformation
5
O
may be described as an equilibrium HO ⇌ H5 since J3,4, J4,5 and J4,5’ showed values
5
characteristic of the HO form (J1,3 = 0.6, J1,5 = 0.7 and J3,5’ = 0.5 Hz), while the small J3,4
O
(2.8 Hz) and large J4,5’ (8.0 Hz) magnitudes are indicative of the presence of the H5
5
conformer. In addition, the long-range homoallylic coupling constant J1,4 = 1.2 Hz,
observed only for 3α is in agreement with the cis axial-equatorial disposition of H-1 and H-
4 in both conformers [41], while in 3β these protons are unfavorably disposed (trans-
diequatorial) and the homoallylic coupling is not detected.
As next step, the enopyranoside 3β was converted into the pyranone 2S upon
treatment with benzyl alcohol and InCl3 (20 mole%). In contrast to our expectations,

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compound 2S showed an optical rotation that was in absolute value ([α]D = −216) smaller
than that of the enantiomerically pure enone. This result indicated that 3β underwent partial
isomerization of the anomeric center, under the acidic conditions employed for the
rearrangement, to give an ee ≈ 87%. To confirm that the product obtained was
enantioenriched, NMR experiments were performed using a chiral lanthanide shift reagent
for racemic resolution. Thus, addition of increasing amounts of europium (III) tris[3-
heptafluoropropylhydroxymethylene-(+)-camphorate] showed gradual splitting of some
signal (See Supporting Information). In particular, the anomeric proton signal, which
appeared in a clean region of the spectrum, split into two broad singlets. From the integral
of these signals (er = 93:7) the enantiomeric composition was estimated as ee ≈ 86%, in
agreement with the value determined from the optical rotation.
In view of the difficulties encountered to prepare the enantiomerically pure enone
from the glycal 1, we turned back to the enantioespecific synthesis of 2S or 2R from benzyl
pentopyranosides that we have already described [34]. Following, the original synthetic
scheme, an improvement was now achieved by modifying the reagents and reaction
conditions employed in some steps (Scheme 2). Thus, the starting benzyl β-D-
arabinopyranoside (4) was treated with 1,1’-thiocarbonylimidazole followed by acetylation
to give the 2-O-acetyl-3,4-thionocarbonate derivative 5 in 97% yield. The increment in the
yield compared with the previous synthesis (75%) was reached by using higher temperature
(100 °C against 80 °C) and shorter time (4 h against 40 h) in the formation of the
thionocarbonate. In addition, a slight excess of the reagent (1.3 equiv) was added at the
beginning of the reaction and no successive additions were required, that led to a larger
amount (2.7 equiv) of the reagent in the reported synthesis.

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Scheme 2. Enantiospecific synthesis of 2(S)-benzyloxy-2H-pyran-3(6H)-one (2S).
For the Corey-Winter olefination of the thionocarbonate 5 the originally employed
trimethyl phosphite, which needed distillation prior to use, was replaced by triethyl
phosphite that was used as commercially provided. The yield in both cases was similar (~
90%) using the same reaction temperature but a shorter time for triethyl phosphite (2.5 h
instead of 10 h). Furthermore, it was confirmed that the acetylation step prior to the
olefination is needed, as although the alcohol derivative 8 was also obtained in good yield
(92%), it partially decomposed during the elimination to afford 7 in 43% yield.
The oxidation of the hydroxyl group of 8 was conducted with 2-iodoxybenzoic acid
(IBX), thus avoiding the use of the chromium (VI) oxidizing agent PDC previously
employed. The expected enone 2S was obtained after a rapid purification by column
chromatography in a yield (85%) somewhat higher than in the PDC oxidation (80%). The
optical rotation value of 8 ([α]D −248.3) was coincident with that determined for the
enantiomerically pure enone [34] ([α]D −248.4).
As next step, we have employed the optimized sequence described above to prepare
enone analogues of 2S with a substituent on the benzyl aromatic ring. As explained in the

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introduction section, the resulting enone will be employed as starting material in the
synthesis of thiodisaccharides, in order to study how such a substitution modifies the
interaction with the E. coli β-galactosidase. In first instance, we explore the preparation of
the enantiomerically pure enone 16S having an electron withdrawing (nitro) group on the
benzyl substituent (Scheme 3).
Scheme 3. Synthesis of 2(S)-(4-nitrobenzyloxy)-2H-pyran-3(6H)-one (16S).
The sequence involves treatment of tetra-O-acetyl-α,β-L-arabinopyranose (9) with
30% HBr in AcOH to produce the glycosyl bromide 10 [42], which was employed crude
for the next step. The glycosylation of 10 with 4-nitrobenzyl alcohol in the presence of
InCl3 [43], led after purification by column chromatography the α-L-arabinopyranoside
derivative 11. The 1H NMR spectrum of 11 was in agreement with that previously reported
[44]. The anomeric configuration was confirmed based on the coupling constant values for
J1,2 (7.6 Hz), J2,3 (9.3 Hz) and small ones for J3,4, J4,5ax and J4,5eq (3.5, 3.6 and 1.9 Hz

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respectively). Removal of the acetyl groups of 11 with NaOMe/MeOH gave the crystalline,
unprotected glycoside 12. Compound 12 possesses the convenient cis equatorial-axial
orientation of OH-3 and OH-4 for the formation of the thionocarbonate ring, which was
obtained upon treatment with 1,1’-thiocarbonyldiimidazole to give 13 after acetylation.
This compound was sensitive to the temperature employed for the elimination with triethyl
phosphite. At 150 °C high decomposition was observed, so the temperature was lowered to
115 °C. After 3.5 h of heating about 50% of conversion of 13 into the enopyranoside 14
was observed, and then the decomposition increased rapidly. Therefore, the mixture was
concentrated and fractioned by column chromatography to give enopyranoside 14 and
remaining starting 13 was also recovered. A second elimination process applied to the
remaining 13 afforded some additional 14 (58% overall yield). The 2-O-acetyl group of
enopyranoside 14 was quantitatively hydrolyzed with NaOMe/MeOH to the corresponding
HO function, which was oxidized with IBX in acetonitrile (80 °C, 3.5 h). The target enone
16S was thus obtained, although in an overall yield ( 32% from 12) smaller than that of the
preparation from 4 (70% overall).
Alternatively, the enone 16S was prepared by the InCl3-promoted glycosylation of
glycal 1 with p-nitrobenzyl alcohol. The target molecule 16S was obtained in 75% yield,
but the optical rotation ([α]D = −136.8) smaller in absolute value to that of 16S obtained
from 12, indicated partial isomerization of the stereocenter (ee ≈ 82%).
In order to obtain the enone 16R, enantiomer of 16S, the elimination/oxidation route
was applied to 4-nitrobenzyl 2,3,4-tri-O-acetyl-α-D-arabinopyranoside (17) (Scheme 4).
Compound 17 was prepared from the enantiomer of 9 as previously described, and it was

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O-deacetylated to give 18. The 4-nitrobenzyl glycoside 18 was converted into the
thionocarbonate 19, which via the enopyranoside 21 led to 16R (27% overall yield).
Scheme 4. Enantiospecific synthesis of 2(R)-(4-nitrobenzyloxy)-2H-pyran-3(6H)-one (16R).
As described above, the introduction of a nitro substituent on the benzyl group led
to a lower yield in the formation of the thionocarbonate 13 from the 4-nitrobenzyl glycoside
12, with respect to that of and 5 from the benzyl glycoside 4. The yield was even more
severely lowered in the Corey-Winter olefination of thionocarbonate 13 (4-nitrobenzyl) to
the enopyranoside 14 compared with the analogous reaction of 5 (benzyl) to 6. Therefore,
the substituent of the benzyl group plays a relevant role in these two reactions. In order to
obtain the 2(S)-(4-acetamidobenzyloxy)-2H-pyran-3(6H)-one (27S) through a similar route,
the 4-acetamidobenzyl α-L-arabinopyranoside (23) was required. The attempted preparation
of 23 from 9, according to the route applied for the synthesis of glycoside 12, was
unsuccessful when p-acetamidobenzyl alcohol was employed. However, 23 was
satisfactorily prepared via 22, by catalytic hydrogenation of the nitro group of 11 followed
by acetylation (Scheme 5). Treatment of 22 with 1:4:5 Et3N:MeOH:H2O resulted in the
removal of the O-protecting groups to afford 23. The next step of the sequence, the
formation of the thionocarbonate 24, was unsuccessful and led to decomposition under the

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varied reaction conditions assayed. Again, the replacement of the benzyl group (in 5) by 4-
acetamidobenzyl (in 23) led to an unexpected instability of the compounds involved in the
thionocarbonation reaction. To overcome this difficulty, an alternative route was designed
starting from the enopyranoside 14. Thus, the nitro group of 14 was successfully reduced
under mild conditions with NaBH4/charcoal [45] to give, upon acetylation, the 4-
acetamidobenzyl glycoside 25. Removal of the O-acetyl group, followed by IBX-oxidation
of the resulting OH group in 26 led to the target enantiomerically pure 2-(4-
acetamidobenzyloxy)-pyranone 27S (59% overall yield from 14).
AcO
AcO
S
O
1) Im2CS, C5H5N
RO
RO
1) H2,10% Pd/C,
EtOAc, rt, 5 h
O
100 °C, 6.5 h
O
O
OpNBn
OpNAcBn
OpNAcBn
O
x
2) Ac2O, C5H5N,
rt, 2 h
OAc
OR
2) Ac2O, rt, 3 h
OAc
24
1:4:5
Et3N:MeOH:H2O
rt, 5 h
11
22 R = Ac (75%)
23 R = H (98%)
H C
pNAcBn =
NHAc
2
OpNAcBn
OpNBn
OpNAcBn
1) NaBH4/C, THF-H2O
60 ºC, 5 h
pNHAcBnOH,
SnCl4,CH2Cl2
AcO
IBX, MeCN,
O
O
O
O
80 °C, 3.5 h
(83%, ee = 100%)
2) Ac2O, C5H5N,
rt, 2 h
18 °C, 1 h
(22%, ee = 80%)
O
OAc
AcO
OAc
OR
1
27S
14
25 R = Ac (73%)
1:4:5 Et3N:MeOH:H2O
rt, 2 h
(80%,
IBX, MeCN,
80 °C, 3.5 h ee = 83%)
26 R = H (98%)
OpNBn
OpNAcBn
OpNBn 1) NaBH4,CeCl3,
1) NaBH4/C,THF-H2O
RO
O
AcO
O
MeOH, 18 ºC, 3 h
60 ºC, 5 h
O
2) Ac2O, C5H5N,
rt, 2 h
2) Ac2O, C5H5N,
rt, 2 h
O
28 (70%)
16S
(ee = 82%)
29 R = Ac (70%)
30 R = H (97%)
1:4:5 Et3N:MeOH:H2O
rt, 2 h
Scheme 5. Synthesis of 2(S)-(4- acetamidobenzyloxy)-2H-pyran-3(6H)-one (27S).
The enone 27S (having an ee = 80%) was alternatively prepared by the SnCl4-
promoted glycosylation of 2-acetoxyglycal 1 with p-acetamidobenzyl alcohol, but the yield
obtained was low (22%). This reaction failed when the catalyst employed was InCl3. As the

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first step in the catalytic process is the coordination of the metal (Lewis acid) with the
allylic acetoxy group [4,11], which leads to the allylic rearrangement, probably the
acetamido group (a stronger Lewis base) could compete with the acetoxy group for
chelation of the metal, diminishing the effective concentration of the catalyst. In this
context, In(III), a softer acid than Sn(IV), is expected to exhibit lower reactivity against
hard basic centers. These considerations are in agreement with the fact that the analogous
reaction with benzyl or p-nitrobenzyl alcohols took place with good yields. The enone 16S
(ee = 82%), which is the product of the last mentioned reaction, was employed as starting
material for the synthesis of 27S. Thus, the carbonyl function of 16S was reduced with
NaBH4 in the presence of CeCl3 to give, after acetylation, the enol ester 28. The nitro
substituent of the benzyl group of 28 was reduced with NaBH4/charcoal to afford the
corresponding amine, which was acetylated to give 29. The O-acetyl group of 29 was
hydrolyzed under smooth basic conditions (1:4:5 Et3N:MeOH:H2O) to produce the allylic
alcohol 30, which was oxidized with IBX to the target pyranone 27S (26% overall yield
from 16S). From the optical rotation value of 27S ([α]D = −137.1) was estimated the ee
(83%), which was in agreement with that of the starting enone 16S.
In conclusion, we succeeded in the preparation of the target enones derived from
pentoses, which have a benzyloxy group or a benzyloxy derivative attached to the anomeric
center. The substituent of the benzyloxy group affect the stability of the compounds, and
hence the yield of most of the reactions. Thus, the Lewis acid-promoted glycosylation of 2-
acetoxyglycals derived from pentoses took place satisfactorily for benzyl or p-nitrobenzyl
alcohols, but failed for the p-acetamidobenzyl alcohol. The pyranones obtained by these

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procedures were enantioenriched products, with one of the enantiomers strongly prevailing
over the other (high enantiomeric excesses).
A straightforward and high yielding route for the enantioselective synthesis of this
type of enones was optimized. Thus, starting from benzyl arabinopyranoside, the
corresponding 2-benzyloxy-pyran-3-one was obtained in 70% overall yield and in
enantiomerically pure form. However, the nitro substitution on the benzyloxy group of the
starting glycoside resulted in a lower yield of two steps of such route: the formation of a
thionocarbonate, which involved OH-3 and OH-4 of the pentopyranoside, and the
following olefination to the corresponding enopyranoside. The thionocarbonation led only
to decomposition in the case of the 4-acetamidobenzyl glycoside. This result, prompted the
development of alternative sequences to the enantiomerically pure or enantioenriched 2-(4-
acetamidobenzyloxy)pyran-3-one, starting respectively from a 4-nitrobenzyl enopyranoside
or enone compounds, that have been prepared as part of previous synthesis within the
present work.
3. Experimental section
3.1. General experimental procedures
NMR spectra were recorded (25 °C) at 500 MHz (1H) or 125.7 MHz (13C).
Chemical shifts (δ, in ppm) are referred to internal standard (Me4Si in CDCl3 (δ 0.0) for 1H
13
and CDCl3 (δ 77.0) for C) or to a residual solvent peak. Data multiplicities are indicated
as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad); coupling
1
13
constants (J) given in Hertz (Hz). Assignments of H and C NMR spectra were assisted
1
1
by 2D H-COSY or NOESY, and 2D H-13C HSQC or HMBC experiments. The NMR

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spectra for compounds 2S [11], and 4 to 8 [34] were in good agreement with those
previously published. High-resolution mass spectra (HRMS) were obtained using the
electrospray ionization (ESI) technique and Q-TOF detection. Analytical thin-layer
chromatography (TLC) was carried out on silica gel 60 F254 aluminum-supported plates
(layer thickness 0.2 mm). The spots were visualized by exposure to UV light and by
charring with 5% v/v sulfuric acid in EtOH, containing 0.5% p-anisaldehyde. Column
chromatography was carried out with silica gel 60 (230–400 mesh) and using a stepwise
solvent polarity gradient correlated with TLC mobility, unless otherwise stated. Optical
rotations were measured at the sodium D line at room temperature in a 1 dm cell, in the
solvent indicated. Unless otherwise noted, all commercially available compounds were
used as obtained from suppliers without further purification.
3.2. Synthesis of enantioenriched 2(S)-Benzyloxy-2H-pyran-3(6H)-one 2S from 2-
acetoxyglycal 1
3.2.1. Catalysis with InCl3
To a solution of 1 [11] (1.00 g, 3.87 mmol) and benzyl alcohol (0.45 mL, 4.33
mmol) in dry CH2Cl2 (30 mL) was added InCl3 (42 mg, 0.19 mmol). The solution was
stirred overnight (12 h) at rt. When TLC (CH2Cl2/EtOAc 30:1) showed formation of a less
polar product (Rf 0.83) and complete disappearance of the starting glycal (Rf 0.28). The
organic solution was diluted with CH2Cl2 (30 mL) and washed with sat aq NaHCO3, water
and brine. After drying (MgSO4), solvent evaporation afforded a residue that was purified
by column chromatography (hexane/EtOAc, 9:1) to afford 2S (0,66 g, 83%); and [α]D
−198.0 (c 1.13, CHCl3); ee = 80%.
3.2.2. Via the enopyranoside 3β

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3.2.2.1. Benzyl 2,4-di-O-acetyl-3-deoxy-β-
anomer 3α
D-glycero-pent-2-enopyranoside 3β and its α-
A solution of benzyl alcohol (0.24 mL, 2.3 mmol) and NIS (90 mg, 0.39 mmol) in
dry CH2Cl2 (2.0 mL) was stirred at room temperature. When the pale-yellow solution
turned to a light red color, the mixture was cooled to −18 °C and 2,3,4-tri-O-acetyl-1,5-
anhydro-
D
-threo-pent-1-enitol (2-acetoxy-3,4-di-O-acetyl- -xylal 1, 500 mg, 1.92 mmol)
D
was added. The temperature was kept for 1 h and then the solution was allowed to reach
room temperature and it was stirred for 30 min. At this point TLC (CH2Cl2/EtOAc 20:1)
revealed the conversion of the starting 1 (Rf 0.40) into two main products (Rf 0.69 and
0.62), which were separated by column chromatography (19:1→9:1 hexane/EtOAc). The
first compound that eluted from the column was identified as 3α (180 mg, 31%); [α]D +69.2
(c 1.09, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.40–7.29 (m, 5H, OBn), 5.79 (dt, 1H, J1,3
≈ J3,5’ = 0.6, J3,4 = 2.8 Hz, H-3), 5.50 (dddd, 1H, J1,4 = 1.2, J3,4 = 2.8, J4,5 = 5.6, J4,5’ = 8.0
Hz, H-4), 5.14 (m, 1H, J1,3≈ J1,5 ≈ 0.6, J1,4 = 1.2 Hz, H-1), 4.84, 4.62 (2 d, 2H, J = 12.0 Hz,
OCH2Ar), 3.95 (ddd, 1H, J1,5 = 0.7, J4,5 = 5.6, J5,5’ = 11.2 Hz, H-5), 3.90 (ddd, 1H, J3,5’
=
0.5, J4,5’ = 8.0, J5,5’ = 11.2 Hz, H-5’), 2,14, 2.09 (2 s, 3H each, CH3CO); 13C NMR (CDCl3,
125.7 MHz) δ 170.4, 168.2 (CH3CO), 147.4 (C-2), 137.3, 128.4, 127.9, 127.8 (C-aromatic),
115.3 (C-3), 92.9 (C-1), 70.3 (OCH2Ar), 65.5 (C-4), 60.2 (C-5), 20.9, 20.8 (CH3CO).
HRMS (ESI) m/z [M+Na]+ calcd for C16H18NaO6 329.0996, found 329.1004; [M+K]+ calcd
for C16H18KO6 345.0735, found 345.0727.
From further fractions from the column compound was isolated 3β (160 mg, 51%);
1
[α]D +52.7 (c 0.53, CHCl3); ee = 100%; H NMR (CDCl3, 500 MHz) δ 7.40–7.29 (m, 5H,
OBn), 5.90 (dd, 1H, J3,4 = 6.9, J3,5eq = 1.1 Hz, H-3), 5.18 (ddd, 1H, J3,4 = 6.9, J4,5ax = 2.8,

ACCEPTED MANUSCRIPT
J4,5eq = 0.9 Hz, H-4), 5.09 (s, 1H, H-1), 4.78, 4.59 (2 d, 2H, J = 12.2 Hz, OCH2Ar), 4.19
(dd, 1H, J4,5ax = 2.8, J5ax,5eq = 13.0 Hz, H-5ax), 3.84 (dt, 1H, J3,5eq ≈ J4,5eq = 1.0, J5ax,5eq
=
13.0 Hz, H-5eq), 2,12, 2.08 (2 s, 3H each, CH3CO); 13C NMR (CDCl3, 125.7 MHz) δ
170.6, 167.9 (CH3CO), 149.2 (C-2), 137.3, 128.4, 128.0, 127.9 (C-aromatic), 111.7 (C-3),
92.0 (C-1), 70.1 (OCH2Ar), 64.9 (C-4), 61.2 (C-5), 21.0, 20.9 (CH3CO). Anal. Calcd for
C16H18O6: C, 62.74%; H, 5.92%. Found: C, 62.79%; H, 5.97%. HRMS (ESI) m/z [M+Na]+
calcd for C16H18NaO6 329.0996, found 329.0997; [M+K]+ calcd for C16H18KO6 345.0735,
found 345.0722.
3.2.2.2. Conversion of the β-enopyranoside 3β into 2(S)-benzyloxy-2H-pyran-3(6H)-one
2S.
A solution of 3β (155 mg, 0.51 mmol) and benzyl alcohol (0.1 mL, 1.0 mmol) in
anhydrous CH2Cl2 (1 mL) was stirred at room temperature and InCl3 (24 mg, 0.10 mmol)
was added. The reaction was kept for 2 h, when monitoring by TLC (CH2Cl2/EtOAc 20:1)
revealed complete conversion of the starting material (Rf 0.69) into a less polar product (Rf
0.72). The mixture was diluted with CH2Cl2 and extracted with 10% aq NaHCO3 and brine.
The organic extract was dried (MgSO4), filtered and concentrated. Purification by column
chromatography as above led to enone 2S (85 mg, 82%); [α]D −216 (c 1.40, CHCl3); ee =
88% (from optical purity).
3.2.2.3. Enantiomeric resolution of 2(S)-benzyloxy-2H-pyran-3(6H)-one 2S.
The enantiomeric excess (ee) for enone 2S obtained from the enopyranoside 3β, as
described in item 3.2.2.2, was determined by 1H NMR using europium tris[3-
(heptafluoropropylhydroxymethylene)-(+)-camphorate] as a chiral resolving reagent. To a
solution of 2S (0.05 mmol) in carbon tetrachloride containing 1% benzene-d6 (0.6 mL) was

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added increasing amounts of the europium reagent. When 0.3 molar equiv were added, the
1H NMR spectrum showed a splitting of the H-1 signal into two broad singlets
(enantiomeric shift difference ∆∆δ = 0.12). From the integral of these signals (2S:2R
0.93:0.07), the enantiomeric composition (ee ≈ 86%) was established for 2S.
3.3. Synthesis of enantiomerically pure 2(S)-Benzyloxy-2H-pyran-3(6H)-one 2S from
benzyl glycoside 4
3.3.1. Benzyl 2-O-acetyl-
β-D-arabinopyranoside 3,4-thionocarbonate 5
Benzyl β- -arabinopyranoside 4 (719 mg, 3.00 mmol) was dissolved in pyridine
D
(6.8 mL) in a thick-wall tube, and 1,1′-thiocarbonyldiimidazole (719 mg, 4.03 mmol) was
added. The tube was sealed and heated to 100 °C for 4 h under an inert Ar atmosphere.
TLC analysis (hexane/EtOAc 1:1) showed complete conversion of 4 (Rf 0) into 7 (Rf 0.79).
The mixture was left to reach temperature and acetic anhydride (2.8 mL) was added. After
stirring for 1 h, the solution was diluted with MeOH and concentrated. The residue was
purified by column chromatography (hexane/EtOAc 9:1→8:2) to afford 5 (938 mg, 97%);
[α]D −235.1 (c 0.8, CHCl3, lit. [34] [α]D −234.7).
3.3.2. Benzyl 2-O-acetyl-3,4-dideoxy-α-L-glycero-pent-3-enopyranoside 6
The thionocarbonate 5 (516 mg, 1.59 mmol) was dissolved in commercial triethyl
phosphite (3.8 mL). The tube was sealed under N2 atmosphere and heated at 150 °C for 2.5
h when TLC (hexane/EtOAc 2:1) showed complete conversion into a single spot of Rf 0.64.
Triethyl phosphite was distilled under vacuum and the resulting syrup was subjected to
column chromatography (hexane/EtOAc 2:1) to afford the enopyranoside 6 (348 mg, 88%);
[α]D −128.9 (c 0.9, CHCl3, lit. [34] [α]D −131.4).

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3.3.3. Benzyl
β
-D
-arabinopyranoside 3,4-thionocarbonate 7
Compound 7 was synthetized under the conditions described for 5. The glycoside 4
(419 mg, 1.74 mmol) was allowed to react with 1,1′-thiocarbonyldiimidazole in pyridine at
100 °C for 4 h. The solvent was distilled under vacuum with toluene and the residue was
purified by column chromatography (hexane/EtOAc 9:1→8:2) to afford 7 (455 mg, 92%);
[α]D −170.9 (c 0.70, CHCl3, lit. [34] [α]D +172.1 for the enantiomer).
3.3.4. Benzyl 3,4-dideoxy-α-L-glycero-pent-3-enopyranoside 8
3.3.4.1. Starting from the enopyranoside 6
The 2-O-acetyl derivative 6 (348 mg, 1.40 mmol) was treated with NaOMe/MeOH
0.1 M, 15 mL) at room temperature for 1.5 h. TLC (hexane/EtOAc 2:1) showed complete
conversion into a lower moving compound (Rf 0.49). The reaction mixture was diluted with
MeOH and neutralized with Dowex 50W (H+) resin, filtered and concentrated up to
dryness, to afford 8 (280 mg, 97%); [α]D −131.9 (c 1.1, CHCl3, lit. [34] [α]D −132.3).
3.3.4.2. Starting from thionocarbonate 7
Compound 7 (419 mg, 1.48 mmol) was heated in a sealed tube under N2 atmosphere
with commercial triethyl phosphite (4 mL) at 150 °C for 7 h. TLC (hexane/EtOAc 2:1)
showed complete consumption of 7 (Rf 0.37) and formation of a higher moving compound
(Rf 0.49) as main product. The same work-up as above and purification by column
chromatography (hexane/EtOAc 9:1→8:2) afforded 8 (133 mg, 43%); [α]D −131.5 (c 0.9,
CHCl3, lit. [34] [α]D −132.3).
3.3.5. Oxidation of enopyranoside 8 to 2(S)-benzyloxy-2H-pyran-3(6H)-one 2S.

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To a solution of 8 (120 mg, 0.58 mmol) in anhydrous MeCN (3.5 mL) was added 2-
iodoxybenzoic acid (IBX, 354 mg, 1.26 mmol) and stirred at 80 °C for 2.5 h. The reaction
mixture was diluted with CH2Cl2 and filtered through a celite bed. Concentration of the
filtrate and further purification by column chromatography (hexane/EtOAc, 9:1) led to 2S
(101 mg, 85%); [α]D −248.3 (c 1.03, CHCl3, lit. [34] [α]D −248.4).
3.4. Synthesis of enantiomerically pure 2(S)-(4-Nitrobenzyloxy)-2H-pyran-3(6H)-one 16S
from 4-nitrobenzyl glycoside 12
3.4.1. 4-Nitrobenzyl 2,3,4-tri-O-acetyl-α-L-arabinopyranoside 11
Per-O-acetyl-α,β- -arabinopyranose 9 (700 mg, 2.20 mmol) was stirred in the dark
L
with a solution of 30% HBr in glacial acetic acid (2.2 mL) at 0 °C for 1 h and then at room
temperature for 5 h, when monitoring by TLC (hexane/EtOAc 1:1) showed complete
conversion of the starting material (Rf 0.64) into a less polar product (Rf 0.79). The reaction
mixture was diluted with CH2Cl2 and extracted twice with cold sat aq NaHCO3. The
organic extract was dried, filtered and concentrated in vacuo at 20 °C in a dark brown
round-bottom flask, to avoid exposure to light. The crude glycosyl bromide 10 [42] was
dissolved in dry CH2Cl2 (20 mL) and 4-nitrobenzyl alcohol (370 mg, 2.42 mmol) and
recently dried 4Å molecular sieves (500 mg) were added. The mixture was stirred for 10
min at 0 °C and upon addition of InCl3 (240 mg, 1.08 mmol) the stirring was continued at
room temperature overnight (14 h). Monitoring by TLC (hexane/EtOAc 1:1) showed a
main spot (Rf 0.60) and disappearance of the starting bromide. The reaction was diluted
with CH2Cl2 and filtered through a celite bed. Purification by column chromatography
(hexane/EtOAc 4:1→3:2) led to 11 (516 mg, 57%) as a pale-yellow syrup; [α]D −19.0 (c
0.8, CHCl3, lit. [44] [α]D −11); 1H NMR (CDCl3, 500 MHz) δ 8.21, 7.48 (d, 2H, J = 8.8 Hz,

ACCEPTED MANUSCRIPT
H-aromatic), 5.30 (dd, 1H, J1,2 = 6.6, J2,3 = 9.3 Hz, H-2), 5.29 (m, 1H, overlapped with H-2,
H-4), 5.08 (dd, 1H, J2,3 = 9.3, J3,4 = 3.5 Hz, H-3), 4.99, 4.70 (2d, 2H, J = 13.3 Hz, -
OCH2Ar), 4.55 (d, 1H, J1,2 = 6.6 Hz, H-1), 4.06 (dd, 1H, J4,5ax = 3.6, J5ax,5eq = 13.0 Hz, H-
5ax), 3.66 (dd, 1H, J4,5eq = 1.9, J5ax,5eq = 12.9 Hz, H-5eq); 2.14, 2.07, 2.03 (s, 3H each,
CH3CO-); 13C NMR (CDCl3, 125.7 MHz) δ 170.4, 170.2, 169.6 (CH3CO), 147.6, 144.8,
127.6, 123.8 (C-aromatic), 100.2 (C-1), 70.0 (C-3), 69.2 (C-4,OCH2Ar), 67.5 (C-2), 63.2
(C-5), 21.1, 20.9, 20.8 (CH3CO). HRMS (ESI) m/z [M+Na]+ calcd for C18H21NNaO10
434.1058, found 434.1077.
3.4.2. 4-Nitrobenzyl α-L-arabinopyranoside 12
Glycoside 11 (339 mg, 0.82 mmol) was treated with 0.4 M NaOMe/MeOH (12 mL)
at 0 °C for 3 h. The reaction mixture was diluted with MeOH, neutralized with Dowex-H+
resin and filtered. Solvent evaporation and recrystallization from EtOH afforded 12 (210
1
mg, 91%) as white solid product; mp 88-89 °C; [α]D −17.1 (c 0.9, MeOH); H NMR
(pyridine-d5 with D2O, 500 MHz) δ 8.09, 7.64 (d, 2H, J = 8.3 Hz, H-aromatic), 5.15, 4.90
(2d, 2H, J = 13.6 Hz, OCH2Ar), 4.81 (d, 1H, J1,2 = 8.3 Hz, H-1), 4.56 (t, 1H, J1,2 = J2,3 = 8.3
Hz, H-2), 4.37 (m, 2H, H-4, H-5eq), 4.22 (dd, 1H, J2,3 = 8.8, J3,4 = 3.2 Hz, H-3), 3.81 (dd,
13
1H, J4,5ax = 2.4, J5ax,5eq = 12.9 Hz, H-5ax); C NMR (pyridine-d5 with D2O, 125.7 MHz) δ
136.2, 128.7, 124.2, 124.0 (C-aromatic), 105.1 (C-1), 74.9 (C-3), 72.8 (C-2), 69.8
(OCH2Ar), 69.7 (C-4), 67.6 (C-5). HRMS (ESI) m/z; [M+Na]+ calcd for C12H15NNaO7
308.0741, found 308.0749.
3.4.3. 4-Nitrobenzyl 2-O-acetyl-α-L-arabinopyranoside 3,4-thionocarbonate 13
A solution of glycoside 12 (150 mg, 0.52 mmol) and 1,1’-thiocarbonyldiimidazole
(120 mg, 0.67 mmol) in pyridine (1.2 mL) was stirred at 100 °C for 6.5 h. Monitoring by

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TLC (hexane/EtOAc 1:1.5) showed a faster moving spot (Rf 0.28). Acetic anhydride (1
mL) was added to the mixture and the stirring was continued at room temperature for 3 h,
when analysis by TLC (hexane/EtOAc 1:1.5) revealed a main spot (Rf 0.50). The mixture
was diluted with methanol and concentrated. The residue was purified by column
chromatography (hexane/EtOAc 4:1→3:2) to afford 13 (138 mg, 71%) as main product;
[α]D −151.5 (c 0.7, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.20, 7.50 (d, 2H, J = 8.6 Hz, H-
aromatic), 5.18 (t, 1H, J1,2 ≈ J2,3 ≈ 3.8 Hz, H-2), 5.06 (dt, 1H, J4,5 ≈ J4,5’ ≈ 4.1, J3,4 = 8.2 Hz,
H-4), 4.96 (dd, 1H, J3,4 = 8.1, J3,4 = 3.8 Hz, H-3), 4.92, 4.68 (2d, 2H, J = 13.4 Hz, -
OCH2Ar), 4.81 (d, 1H, J1,2 = 3.6 Hz, H-1), 4.19 (dd, 1H, J5,5’ = 13.5, J4,5 = 4.2 Hz, H-5),
3.98 (dd, 1H, J5,5’ = 13.5, J4,5’ = 4.0 Hz, H-5); 13C NMR (CDCl3, 125.7 MHz) δ 190.1
(C=S), 169.0 (CH3CO-), 147.7, 144.0, 128.0, 123.8 (C-aromatic), 97.3 (C-1), 77.8 (C-3),
76.2 (C-2), 69.0 (OCH2Ar), 68.0 (C-2), 60.0 (C-5), 20.8 (CH3CO-). HRMS (ESI) m/z
[M+Na]+ calcd for C15H15NNaO8S 392.0411, found 392.0424.
3.4.4. 4-Nitrobenzyl 2-O-acetyl-3,4-dideoxy-β-D-glycero-pent-3-enopyranoside 14
The thionocarbonate 13 (130 mg, 0.35 mmol) was dissolved in triethyl phosphite (3
mL) and heated in a sealed tube under N2. After stirring at 115 °C for 3.5 h, TLC
(hexane/EtOAc 1:1) showed the formation of a main product (Rf 0.67) and some stating
material (Rf 0.22) remaining. Column chromatography (hexane/EtOAc 4:1→3:2) led to 14
(46 mg, 45%) and then the remaining 13 (36 mg, 0.10 mmol) was recovered. The unreacted
13 was treated with triethyl phosphite as described above. Column chromatography
1
afforded some additional 14 (14 mg, 58% overall yield); [α]D −243.1 (c 0.4, CHCl3); H
NMR (CDCl3, 500 MHz) δ 8.22, 7.52 (d, 2H, J = 8.6 Hz, H-aromatic), 6.11 (dt, 1H, J3,4
=
10.5, J4,5 ≈ J4,5’ ≈ 2.6 Hz, H-4), 5.88 (ddd, 1H, J2,3 = 4.2, J4,5 = 10.5, J3,5’ = 2.3 Hz, H-3),

ACCEPTED MANUSCRIPT
5.08 (br d, 1H, J2,3 = 4.2 Hz, H-2), 4.91 (d, 1H, J1,2 < 1.0 Hz, H-1), 4.90, 4.73 (2d, 2H, J =
13.4 Hz, OCH2Ar), 4.21 (t, 2H, H-5, H-5’), 2.10 (s, 3H, CH3CO-); 13C NMR (CDCl3,
125.7 MHz) δ 170.5 (CH3CO-), 147.7, 145.1, 127.9, 123.9 (C-aromatic), 131.3 (C-4), 120.3
(C-3), 97.4 (C-1), 68.6 (OCH2Ar), 65.9 (C-2), 59.9 (C-5), 21.2 (CH3CO-). HRMS (ESI)
m/z [M+Na]+ calcd for C14H15NNaO6 316.0792, found 316.0798.
3.4.5. 4-Nitrobenzyl 3,4-dideoxy-β-D-glycero-pent-3-enopyranoside 15
Compound 14 (112 mg, 0.38 mmol) was treated with NaOMe/MeOH (0.2 M, 6 mL)
at 0 °C for 1 h. TLC (hexane/EtOAc 1:1.5) showed complete conversion of 14 (Rf 0.74)
into a lower moving compound (Rf 0.44). The reaction mixture was diluted with MeOH and
neutralized with Dowex 50W (H+) resin, filtered and concentrated up to dryness, to afford
15 (91 mg, 95%); [α]D −184.0 (c 0.6, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.21, 7.52 (d,
2H, J = 8.5 Hz, H-aromatic), 5.95 (dt, 1H, J3,4 = 10.4, J4,5 ≈ J4,5’ ≈ 2.1 Hz, H-4), 5.91 (ddd,
1H, J2,3 = 2.0, J3,4 = 10.4, J3,5’ = 3.7 Hz, H-3), 4.92, 4.72 (2d, 2H, J = 13.3 Hz, -OCH2Ar),
4.81 (d, 1H, J1,2 = 2.7 Hz, H-1), 4.22 (ddd, 1H, J4,5 = 2.0, J3,5 = 3.7, J5,5’ = 17.0 Hz, H-5),
4.15 (dq, 1H, J3,5’ ≈ J4,5’ ≈ 2.1 Hz, H-5’), 3.97 (m, 1H, H-2), 1.93 (d, 1H, J2,OH = 8.3 Hz,
13
OH); C NMR (CDCl3, 125.7 MHz) δ 147.6, 145.2, 128.0, 123.8 (C-aromatic), 129.0 (C-
4), 124.6 (C-3), 100.53 (C-1), 68.9 (OCH2Ar), 64.9 (C-2), 61.1 (C-5). HRMS (ESI) m/z
[M+Na]+ calcd for C12H13NNaO5 274.0686, found 274.0679.
3.4.6. 2(S)-(4-Nitrobenzyloxy)-2H-pyran-3(6H)-one 16S
To a solution of 15 (90 mg, 0.36 mmol) in dry MeCN (3 mL) was added IBX (235
mg, 0.84 mmol) and stirred at 80 °C for 3.5 h. The reaction mixture was diluted with
CH2Cl2 and filtered through a celite bed. Concentration of the filtrate and further
purification by column chromatography (hexane/EtOAc 4:1) led to 16S (72 mg, 80%).

ACCEPTED MANUSCRIPT
[α]D −166.6 (c 0.7, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.21, 7.52 (d, 2H, J = 8.0 Hz, H-
aromatic), 7.09 (dt, 1H, J4,3 = 10.6, J5,6 = 1.8, J5,6’ = 1.8 Hz, H-5), 6.17 (dddd, 1H, J2,4 < 1.0,
J3,4 = 10.6, J4,6 = 2.5, J4,6’ = 1.8 Hz, H-4), 4.93 (br d, 1H, J2,3 < 1.0 Hz, H-2), 4.93, 4.81 (2d,
2H, J = 13.2 Hz, OCH2Ar), 4.54 (ddd, 1H, J4,6 = 2.4, J5,6 = 2.1, J6,6’ = 19.1 Hz, H-6), 4.33
(ddd, 1H, J4,6’ = 1.9, J5,6’ = 3.9, J6,6’ = 19.2 Hz, H-6’); 13C NMR (CDCl3, 125.7 MHz) δ
188.1 (C-3), 148.1 (C-5), 147.7, 144.4, 128.0, 123.9 (C-aromatic), 124.9 (C-4), 97.5 (C-2),
69.4 (OCH2Ar), 60.0 (C-6). HRMS (ESI) m/z [M+Na]+ calcd for C14H15NNaO6 272.0529,
found 272.0519.
3.5. Synthesis of enantioenriched 2(S)-(4-nitrobenzyloxy)-2H-pyran-3(6H)-one 16S starting
from 2-acetoxyglycal 1
To a solution of compound 1 (502 mg, 1.94 mmol) and 4-nitrobenzyl alcohol (300
mg, 1.96 mmol) in anhydrous CH2Cl2 (10 mL) was added InCl3 (22 mg, 0.10 mmol), and
the solution was stirred overnight (16 h) at rt. Analysis by TLC (CH2Cl2/EtOAc 30:1)
showed formation of a less polar product (Rf 0.76) and complete disappearance of the
starting glycal (Rf 0.28). The reaction mixture was diluted with CH2Cl2 (20 mL) and
washed with sat aq NaHCO3, water and brine. After drying (MgSO4), solvent evaporation
afforded a residue that was purified by column chromatography (hexane/EtOAc, 9:1→4:1)
to afford 16S (364 mg, 75%); and [α]D −136.8 (c 0.8, CHCl3). The optical rotation indicated
an ee 82%.
3.6. Synthesis of enantiomerically pure 2(R)-(4-Nitrobenzyloxy)-2H-pyran-3(6H)-one 16R
from 4-nitrobenzyl glycoside 18

ACCEPTED MANUSCRIPT
The NMR spectra of compounds 17-21 and 16R were in good agreement with those of the
respective enantiomers of section 3.4.
3.6.1. 4-Nitrobenzyl 2,3,4-tri-O-acetyl-α-
D-arabinopyranoside 17
The procedure for the glycosylation of 9 applied to per-O-acetyl-α,β-
D
-
arabinopyranose (480 mg, 1.50 mmol) afforded 17 (328 mg, 53%); [α]D +21.3 (c 1.1,
CHCl3).
3.6.2. 4-Nitrobenzyl α-
Deacetylation of 17 (280 mg, 0.68 mmol) gave 18 (178 mg, 92%); Mp 89 °C;
[α]D +17.3 (c 0.9, MeOH).
3.6.3. 4-Nitrobenzyl 2-O-acetyl-α-
D-arabinopyranoside 18
D-arabinopyranoside 3,4-thionocarbonate 19
The synthesis of 13 from 12 was applied to 18 (130 mg, 0.45 mmol) to afford 19
(108 mg, 65%); [α]D +153.1 (c 0.5, CHCl3).
3.6.4. 4-Nitrobenzyl 2-O-acetyl-3,4-dideoxy-β-L-glycero-pent-3-enopyranoside 20
Heating compound 19 (98 mg, 0.26 mmol) under the conditions stated for 13 led to
20 (42 mg, 55% overall yield); [α]D +247.3 (c 0.5, CHCl3).
3.6.5. 4-Nitrobenzyl 3,4-dideoxy-β-L-glycero-pent-3-enopyranoside 21
Removal of the O-acetyl group from 20 (40 mg, 0.14 mmol) afforded 21 (33 mg,
93%); [α]D +180.3 (c 0.7, CHCl3).
3.6.6. 2(R)-(4-Nitrobenzyloxy)-2H-pyran-3(6H)-one 16R

ACCEPTED MANUSCRIPT
Oxidation of 21 (32 mg, 0.13 mmol) with IBX, as described for 16S, gave 16R (27
mg, 82%); [α]D +165.8 (c 0.8, CHCl3).
3.7. Synthesis of enantiomerically pure 2(S)-(4-acetamidobenzyloxy)-2H-pyran-3(6H)-one
27S from glycoside 11
3.7.1. 4-Acetamidobenzyl 2,3,4-tri-O-acetyl-α-L-arabinopyranoside 22
The glycoside 11 (424 mg, 1.03 mmol) was dissolved in EtOAc (20 mL) and treated
with H2 in the presence of 10% Pd/C (63 mg) at rt for 5 h. Monitoring by TLC
(hexane/EtOAc 1:1.5) showed conversion of 11 (Rf 0.60) into a lower moving spot (Rf
0.43). The reaction mixture was diluted with CH2Cl2, filtered through a celite bed and
concentrated. The crude product was acetylated with acetic anhydride (0.9 mL) in pyridine
(1,5 mL) at rt for 2 h, when TLC (EtOAc) showed a main product of Rf 0.62. The solution
was diluted with MeOH and concentrated. The residue was purified by column
chromatography (hexane/EtOAc 3:2→2:3) to afford 22 (327 mg, 75%); [α]D −25.0 (c 0.7,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.50, 7.22 (d, 2H, J = 8.1 Hz, H-aromatic), 7.43 (br
s, 1H, NH), 5.31 (m, 1H, overlapped with H-2, H-4), 5.21(dd, 1H, J1,2 = 6.8, J2,3 = 9.3 Hz,
H-2), 5.01 (dd, 1H, J2,3 = 9.2, J3,4 = 3.5 Hz, H-3), 4.85, 4.55 (2d, 2H, J = 12.2 Hz, -
OCH2Ar), 4.47 (d, 1H, J1,2 = 6.8 Hz, H-1), 4.05 (dd, 1H, J4,5a = 3.5, J5a,5b = 13.0 Hz, H-5a),
3.62 (dd, 1H, J4,5b = 1.6, J5a,5b = 13.0 Hz, H-5eq); 2.16, 2.12, 2.02, 2.00 (s, 3H each,
CH3CO-); 13C NMR (CDCl3, 125.7 MHz) δ 170.5, 170.3, 169.6, 168.5 (CH3CO), 137.8,
132.9, 128.6, 119.9 (C-aromatic), 99.5 (C-1), 70.2 (C-3), 70.1 (OCH2Ar), 69.3 (C-2), 67.7
(C-4), 63.1 (C-5), 24.7, 21.0, 20.9, 20.8 (CH3CO). HRMS (ESI) m/z [M+Na]+ calcd for
C20H25NNaO9 446.1422, found 446.1420.

ACCEPTED MANUSCRIPT
3.7.2. 4-Acetamidobenzyl α-L-arabinopyranoside 23
Glycoside 22 (300 mg, 0.71 mmol) was treated with 1:4:5 Et3N:MeOH:H2O (2.5
mL) and stirred at rt for 5 h, when TLC (EtOAc) showed complete conversion of 22 (Rf
0.62) into a main spot (Rf 0). Reaction mixture was concentrated to dryness to afford 23
1
(207 mg, 98%); [α]D −18.3 (c 1.0, MeOH); H NMR (pyridine-d5, 500 MHz) δ 7.98, 7.53
(d, 2H, J = 8.5 Hz, H-aromatic), 5.11, 4.79 (2d, 2H, J = 11.7 Hz, OCH2Ar), 4.81 (d, 1H, J1,2
= 7.0 Hz, H-1), 4.50 (t, 1H, J1,2 = 7.1, J2,3 = 8.7 Hz, H-2), 4.36 (m, 2H, H-4, H-5eq), 4.19
(dd, 1H, J2,3 = 8.7, J3,4 = 3.0 Hz, H-3), 3.78 (dd, 1H, J4,5ax = 2.7, J5ax,5eq = 13.3 Hz, H-5ax);
13C NMR (pyridine-d5, 125.7 MHz) δ 169.3 (CH3CO), 140.4, 134.1 129.6, 120.3 (C-
aromatic), 104.7 (C-1), 75.0 (C-3), 72.9 (C-2), 69.8 (OCH2Ar), 69.9 (C-4), 67.4 (C-5), 24.7
(CH3CO). HRMS (ESI) m/z [M+Na]+ calcd for C20H25NNaO9 446.1422, found 446.1420.
3.7.3. 4-Acetamidobenzyl 2-O-acetyl-α-L-arabinopyranoside 3,4-thionocarbonate 24
All the attempts to prepare 24 from glycoside 23 at temperatures ranging from 50 to
100 °C were unsuccessful, as highly polar decomposition products were formed in all
cases.
3.8. Synthesis of enantiomerically pure 2(S)-(4-acetamidobenzyloxy)-2H-pyran-3(6H)-one
27S from enopyranoside 14
3.8.1. 4-Acetamidobenzyl 2-O-acetyl-3,4-dideoxy-β-D-glycero-pent-3-enopyranoside 25
To a solution of 14 (135 mg, 0.46 mmol) in a mixture of THF (6 mL) and H2O (3
mL), was added activated charcoal (160 mg) and NaBH4 (104 mg, 2.7 mmol). After 3 hours
of stirring at 60 °C an additional amount of NaBH4 (153 mg, 4.0 mmol) was added and the
stirring was maintained for 2 h. TLC (hexane/EtOAc 1:1) showed complete conversion of