Ferrier rearrangement and 2-deoxy sugar synthesis from d-glycals mediated by layered α-zirconium sulfophenylphosphonate-methanphosphonate as heterogeneous catalyst

Article abstract of DOI:10.1007/s10562-012-0932-z

Layered α-zirconium sulfophenylphosphonate-methanphosphonate is a solid acid catalyst that catalyzes Ferrier rearrangement from d-glycals and alcoholic nucleophiles under mild reaction conditions in short time and good yields. Notably, the combination of α-zirconium sulfophenylphosphonate- methanphosphonate and lithium bromide change the regioselectivity of this process affording 2-deoxy sugars in good yields. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-012-0932-z

Catal Lett (2013) 143:169–175
DOI 10.1007/s10562-012-0932-z
Ferrier Rearrangement and 2-Deoxy Sugar Synthesis
from D-Glycals Mediated by Layered a-Zirconium
Sulfophenylphosphonate-Methanphosphonate
as Heterogeneous Catalyst
•
Ornelio Rosati Massimo Curini Federica Messina
•
•
•
Maria Carla Marcotullio Giancarlo Cravotto
Received: 3 September 2012 / Accepted: 16 October 2012 / Published online: 6 November 2012
Ó Springer Science+Business Media New York 2012
Abstract Layered a-zirconium sulfophenylphosphonate-
methanphosphonate is a solid acid catalyst that catalyzes
Ferrier rearrangement from D-glycals and alcoholic nucle-
ophiles under mild reaction conditions in short time and
good yields. Notably, the combination of a-zirconium
sulfophenylphosphonate-methanphosphonate and lithium
bromide change the regioselectivity of this process
affording 2-deoxy sugars in good yields.
catalysis, we decided to investigate the use of layered
zirconium sulfophenylphosphonate as acidic heterogeneous
catalyst in sugar chemistry.
Starting from a common precursor such as a glycal
derivative, acidic catalysts represent the most frequent
choice as promoters in Ferrier rearrangement processes [7–
12] and less frequently in the synthesis of 2-deoxy sugars
[13–16].
The synthesis of 2-deoxy sugars under acidic conditions
is usually affected by the presence of Ferrier rearranged
byproducts. To solve the problem related to the regiose-
lectivity, however, several methodologies have been
reported in the literature [17–21].
Keywords Heterogeneous catalysis ꢀ Ferrier
rearrangement ꢀ 2-Deoxy sugars ꢀ O-glycosides
1 Introduction
The continuous interest in new selective methodologies
to afford Ferrier’s rearranged derivatives and 2-deoxy
sugars is due to the great importance of these compounds
as strategic synthetic intermediates [22–27] in the prepa-
ration of complex carbohydrates and different natural
compounds, or well-known structural components of sev-
eral biologically active compounds [16, 21, 28–40].
Sabesan and Coll. in 1991 [16] reported an interesting
procedure for the synthesis of 2-deoxy sugars performed by
the use of AG 50W-X8 cation exchange resin as solid acidic
catalyst in the presence of lithium bromide as co-catalyst with
high yields. In this process the most plausible mechanism
elucidation about the regioselectivity toward Ferrier rear-
ranged derivatives or 2-deoxy sugars could be based upon the
necessity of generating a ‘‘nonhydrated’’ proton source that
would preferentially protonate the C-2 carbon of the starting
glycal to give the deoxy glycoside. Such a nonhydrated pro-
ton would have lesser tendency to protonate the C-3 acetoxy
oxygen that normally leads to the rearranged products.
In this procedure LiBr can be considered, indeed, a co-
catalyst being able to generate, in situ, traces of HBr as a
source of ‘‘nonhydrated’’ protons.
There is a growing interest in surface-mediated solid-phase
reactions due to their ease to set-up, mild reaction conditions,
short reaction times, selectivity, increased yield, higher purity
of compounds and lower cost when compared with their
homogeneouscounterparts [1].Wehaverecentlyreportedthat
layered zirconium sulfophenylphosphonate-methanpho-
sphonate [a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8 = a-ZrP–
SO3H: FW = 392.24] [2, 3] is an excellent heterogeneous
catalyst in liquid phase organic synthesis [4–6].
In continuation of our ongoing effort to develop new
synthetic applications in the field of heterogeneous
O. Rosati (&) ꢀ M. Curini ꢀ F. Messina ꢀ M. C. Marcotullio
`
Dipartimento di Chimica e Tecnologia del Farmaco, Universita
degli Studi di Perugia, via del Liceo 1, 06123 Perugia, Italy
e-mail: ornros@unipg.it
G. Cravotto
Dipartimento di Scienza e Tecnologia del Farmaco, Universita
`
degli Studi di Torino, Via P. Giuria 9, 10125 Torino (TO), Italy
123

170
O. Rosati et al.
The limitation of this procedure is due to the high water
time, that regioselectivity is also dependent on the structure
of the starting material.
content in commercial AG 50W-X8 cation exchange resin
(*80 % w/w); thus a previous dehydration by dry aceto-
nitrile treatment is required for the resin to be used as solid
acid catalyst.
The different behaviour of the two glycals is probably
due to spatial disposition of the acetoxy groups, indeed the
presence of substituent groups on both faces of the 3,4,6
tri-O-acetyl glucal could promote the C-3 acetoxy group
elimination with consequent Ferrier adduct formation. On
the other hand 3,4,6-tri-O-acetyl-galactal has less tendency
to produce this kind of elimination. Thus, if 2-deoxy sugars
are the final targets, 3,4,6-tri-O-acetyl-galactal should be
the first choice starting material.
It is important to note that AG 50W-X8 cation exchange
resin is not able to catalyze the addition of alcohols to the
double bond in the absence of LiBr as co-catalyst, and even
rearranged products did not form to significant extent.
a-ZrP–SO3H is a solid acid catalyst that shares the same
–SO3H moiety as AG 50W-X8 cation exchange resin and,
moreover, has the advantage that it does not need to be
dehydrated, because its water content is very low (about
5 %) and it is normally combined as crystallization water.
For these reasons we thought to use a-ZrP–SO3H as a
possible source of ‘‘nonhydrated’’ proton to catalyze the
formation of 2-deoxy sugars.
Since a-ZrP–SO3H shows a poor regioselectivity
towards 2-deoxysugars, LiBr was added as co-catalyst to
generate nonhydrated protons, as proposed by Sabesan [16]
(Scheme 1). Moreover, acetonitrile was chosen to carry out
reaction of alcohols with 3,4,6-tri-O-acetylglucal and
3,4,6-tri-O-acetylgalactal, due to the good solubility of the
LiBr in this solvent. It is important to highlight that the
amount of LiBr used in our process was halved, from three
equivalents used by Sabesan and Coll. [16] to 1.5 equiva-
lent, without any loss of catalytic activity. Also the alcohol
equivalents were reduced from 2.0 to 1.3.
Preliminary experiments to test regioselective capability
of a-ZrP–SO3H were performed by adding methanol to a
solution of 3,4,6-tri-O-acetylglucal and a-ZrP–SO3H
(6 mol%) in dichloromethane, using different methanol/
glucal molar ratios. Under these reaction conditions only
the Ferrier rearranged compound was obtained without
formation of 2-deoxy sugars. This means that a-ZrP–SO3H
is not capable to furnish the ‘‘nonhydrated’’ protons nec-
essary for the formation of 2-deoxy sugar, but it can still
catalyze the Ferrier rearrangement process.
The strategic combination of two catalysts to promote
regioselectivity toward 2-deoxy sugar was also reported by
Yadav (CeCl3ꢀ7H2O–NaI) [18].
As reported in Table 2, the reactions carried out in the
presence of LiBr afforded 2-deoxy sugars with good yields
in short time. It is important to note that the reaction of
3,4,6-tri-O-acetyl-glucal is still affected by the presence of
Ferrier rearrangement products, while 3,4,6-tri-O-acetyl-
2 Results and Discussion
galactal showed
2-deoxy sugars.
a complete regioselectivity toward
In order to evaluate the general applicability of this process
a range of different alcohols as nucleophiles and 3,4,6 tri-
O-acetylglucal and 3,4,6-tri-O-acetyl-galactal as starting
glycals were used under optimized reaction conditions
(Scheme 1).
A lower reactivity of phenolic nucleophile (entry 6)
compared with the alcoholic ones was observed in both
glycals. The different reactivity can be exploited to obtain a
specific regioselectivity when both alcoholic and phenolic
moieties are present in the same compound such as 4-(2-
hydroxyethyl)phenol.
As expected, 3,4,6 tri-O-acetylglucal afforded Ferrier
adducts with good yields and short reaction time (Table 1).
Surprisingly the reactions carried out with 3,4,6-tri-O-
acetyl-galactal afforded also 2-deoxy sugars.
The reaction of 4-(2-hydroxyethyl)phenol and 3,4,6-tri-
O-acetyl glucal (Scheme 2) could possibly lead to the
formation of four isomers. Actually, the purification of the
crude reaction mixture by column chromatography on
These results show a substantial inability of a-ZrP–
SO3H to generate ‘‘nonhydrated’’ proton and, at the same
AcO
R
AcO
AcO
R
α
-ZrP-SO3H/LiBr
α-ZrP-SO3H
CH2Cl2, NuH, 40° C
O
O
O
CH3CN, NuH, 40° C
Nu
R
Nu
- AcOH
AcO
AcO
R = AcO
R = AcO
3,4,6-tri-O-acetyl-glucal
3,4,6-tri-O-acetyl-galactal
Scheme 1 Preparation of Ferrier rearrangement and 2-deoxy sugar derivatives
123

Ferrier Rearrangement and 2-Deoxy Sugar Synthesis
171
Table 1 Reaction of 3,4,6-tri-O-acetyl-glycal with nucleophiles (2.0 eq.), at 40 °C, in CH2Cl2, catalyzed by a-
Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8
No. Nucleophile
3,4,6-Tri-O-acetylglucal
3,4,6-Tri-O-acetylgalactal
Time (h) Ferrier’s adduct yield (a) (%) Time (h) Ferrier’s adduct yield (b) (%) 2-Deoxysugar yield (c) (%)
1
2
3
4
a
Cyclohexylmethanol
2
73 (9:1)a
2
5
5
2
44
25 (1:1)a
32 (3:2)a
45 (1:1)a [16]
10 (1:1)a
Cyclohexanol
Allyl alcohol
Benzyl alcohol
5
90 (4:1)a [38]
83 (4:1)a [41]
87 (2:1)a [41]
23
3.5
2
36 [41]
48 [41]
a/b Molar ratio of Ferrier’s adducts and 2-deoxysugars were measured by GC–MS analysis
Table 2 Reaction of 3,4,6-tri-O-acetyl-glycal with different nucleophiles
No.
Nucleophile
3,4,6-Tri-O-acetyl glucal
3,4,6-Tri-O-acetyl galactal
Time (h)
2-Deoxysugar yield
(a) (%)
Ferrier’s adduct yield
(b) (%)
Time
(h)
2-Deoxysugar yield
(c) (%)
1
2
3
4
5
6
7
Methanol
2
2
2
2
2
4
2
65 (10:1)a [16]
84 (11:1)a
89 (7:1)a [16]
77 (9:1)a [16]
87 (8:1)a
6
2
2
2
2
3
4
2
87 (5:1)a [16]
78 (7:1)a
95 (6:1)a [16]
96 (11:1)a [16]
76 (5:1)a
Cyclohexyl methanol
Allyl alcohol
11
8 [41]
10
Pent-4-en-1-ol
Benzyl alcohol
6 [41]
–
4-Tert-butylphenol
4-(2-Hydroxyethyl)phenol
46 (9:1)a
74 (9:1)a
23 (4:1)a
71 (5:1)a
8
The reaction was carried out at 40 °C, in CH3CN, in the presence of a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8/LiBr
a
a/b Molar ratio of 2-deoxy sugars were measured by GC–MS analysis
silica gel afforded only two final products: a 2-deoxyglucal
with 74 % yield and a Ferrier adduct with 8 % yield, both
as alcoholic glycosides.
The 1H-NMR spectrum of compound 1 shows the
alcoholic methylene signal of 4-(2-hydroxyethyl)phenol
side chain as a doublet of triplets that can be explained with
the proximity of CH2O protons to the anomeric chiral
centre. Also NOESY experiment highlights a consistent
coupling between the H-1 at 5.26 ppm and the CH2O
As expected the reaction of 4-(2-hydroxyethyl)phenol
and 3,4,6-tri-O-acetyl galactal gave only the alcoholic
glycoside derivative of 2-deoxygalactal.
6
Scheme 2 Possible isomers
from reaction of 4-(2-
hydroxyethyl)phenol and 3,4,6-
tri-O-acetyl glucal
Ac O
AcO
Ac O
5
3
O
O
4
O
AcO
O
1
2
AcO
OH
OH
OH
OH
1
2
Ac O
AcO
Ac O
AcO
O
O
O
O
AcO
4
3
123

172
BnO
R
O. Rosati et al.
BnO
R
3 Experimental
O
O
α
-ZrP-SO3H/LiBr
Nu
3.1 General
CH3CN, NuH, 40° C
All chemicals were purchased from the major chemical
suppliers as highest purity grade and used without any
further purification. Column chromatography was per-
formed with Merck silica gel 60 (70–230 mesh ASTM),
using dichloromethane/ethyl acetate or dichloromethane/
methanol mixture. 1H NMR were recorded in CDCl3 with a
Brucker Avance DPX 400 spectrometer at a frequency of
400.13 MHz. GC–MS analysis were obtained with HP-
6890 gas chromatograph (dimethyl silicone column,
12.5 m) equipped with an HP-5973 mass-selective detector
at an ionizing voltage of 70 eV
BnO
BnO
R = BnO
R = BnO
3,4,6-tri-O-benzyl-glucal
3,4,6-tri-O-benzyl-galactal
Scheme 3 Preparation of 2-deoxy sugars from 3,4,6-tri-O-benzyl
glycals
Table 3 Reaction of 3,4,6-tri-O-benzyl-glycals with nucleophiles
No. Nucleophile
Tri-O-benzyl-
glucal (a)
Tri-O-benzy-
galactal (b)
3.2 General Experimental Procedure
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
3.2.1 Procedure 1 (Synthesis of Ferrier Rearrangement
Compounds)
1
2
3
Cyclohexylmethanol
5
97 [42]
77 [43]
92 [44]
2
88
Allyl alcohol
0.25
2
1.5
18
85 [43]
50 [43]
Benzyl alcohol
To a solution of glycal (1 mmol) and alcohol (2.0 mmol) in
dichloromethane (1 ml/mmol of glycal) at room tempera-
ture, under magnetic stirring and nitrogen atmosphere, a-
Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8 (6 mol %) was added
and the temperature was raised to 40 °C.
The reaction mixture was monitored by TLC and GC–
MS and after appropriate time was filtered on buchner
funnel and washed with dichloromethane.
The reaction was carried out at 40 °C, in CH3CN, in the presence of
a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8/LiBr
protons at 3.62 and 3.76 ppm, respectively. Among the
synthesized 2-deoxy glucals, compound 1 presents a par-
ticular shielding effect on H-5 proton with a chemical shift
at 3.47 ppm (about 0.5 ppm less than normal). This
shielding could be explained by an anisotropic effect of the
aromatic ring on H-5, probably due to the stabilization of
the conformation of 1 by intermolecular hydrogen bonds
between the phenolic hydroxyl group and the oxygen of
acetoxy group on C-6.
The organic solution was dried over Na2SO4 and con-
centrated under vacuum. Column chromatography of the
crude product over silica gel was required to separate the
reaction products.
3.2.2 Procedure 2 (Synthesis of 2-Deoxysugar)
Thus, we can conclude that the reaction is highly
selective in favour of 2-deoxyglucal that derives from the
nucleophilic attack of alcoholic OH.
To a solution of glycal (1 mmol) and alcohol (1.3 mmol) in
acetonitrile (1 ml/mmol of glycal) at room temperature, under
magnetic stirring and nitrogen atmosphere, anhydrous lithium
bromide (1.5 mmol) and a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8
(6 mol%)wereaddedandthetemperaturewasraisedto40 °C.
The reaction mixture was monitored by TLC and GC–
MS and after appropriate time was filtered on buchner
funnel and washed with dichloromethane.
To verify the role of the acidic catalyst in the catalytic
system, the reaction of 3,4,6-tri-O-acetylglucal and cyclo-
hexyl methanol was repeated with LiBr in the absence of
a-ZrP–SO3H. Under this reaction condition lower yield of
2-deoxy sugars (57 %) and longer reaction time (24 h)
were obtained confirming the necessity of the simultaneous
presence of LiBr and a-ZrP–SO3H (LiBr providing regi-
oselectivity and a-ZrP–SO3H reaction rate). In order to
verify the influence of the leaving group, tri-O-benzyl
glucal and galactal were used as starting materials
(Scheme 3). Benzyloxy group is less likely to act as a
leaving group than acetoxy. As a result the formation of
Ferrier rearrangement compounds was completely pre-
vented and 2-deoxy sugars were the exclusive reaction
products (Table 3).
The organic solution was washed with water, dried over
Na2SO4 and concentrated under vacuum. Column chro-
matography of the crude product over silica gel was
required to separate the reaction products.
3.3 Characterization Data
All the compounds have been identified by NMR and GC–
MS and comparison with literature data.
123

Ferrier Rearrangement and 2-Deoxy Sugar Synthesis
173
Cyclohexylmethyl 4,6-di-O-acetyl-2,3-dideoxy-a/b-D-ery-
thro-es-2-enopyranoside (Table 1, entry 1a—procedure 1),
purification: SiO2 column chromatoghraphy, eluent:
Cyclohexyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-threo-es-2-
enopyranoside (Table 1, entry 2b—procedure 1), purifi-
cation: SiO2 column chromatoghraphy, eluent: CH2Cl2/
1
1
Petroleum ether/Et2O 9:1, yellow oil H-NMR (400 MHz,
EtOAc 9:1, oil. H-NMR (400 MHz, CDCl3) d 6.15 (dd,
CDCl3) d (a anomer) 5.90 (bd, J = 11.3 Hz, 1H, H-3),
5.85 (ddd, J = 1.6, 2.3, 10.2 Hz, 1H, H-2), 5.31 (m, 1H,
H-4), 5.02 (bs, 1H, H-1), 4.26 (dd, J = 5.3, 12.1 Hz, 1H,
H-6a), 4.20 (dd, J = 2.4, 12.1 Hz, 1H, H-6b), 4.12 (ddd,
J = 2.4, 5.3, 9.6 Hz, 1H, H-5), 3.60 (dd, J = 7.0, 9.3 Hz,
1H, O–HCH), 3.34 (dd, J = 6.1, 9.3 Hz, 1H, O-HCH),
2.12 (s, 3H, CH3), 2.10 (s, 3H, CH3), 1.85–1.56 (m, 6H,
cyclohexyl), 1.25 (m, 3H, cyclohexyl), 0.96 (m, 2H,
cyclohexyl). GC–MS: m/z 325 [M?], 253, 213, 182, 153.
1H-NMR (400 MHz, CDCl3) d (b anomer) 5.97 (m, 2H,
H-2, H-3), 5.20 (m, 1H, H-4), 5.10 (m, 1H, H-1), 4.26 (m,
2H, H-6a,b), 4.04 (dd, J = 5.9, 10.7 Hz, 1H, H-5), 3.68 (dd,
J = 6.6, 9.0 Hz, 1H, O–HCH), 3.29 (dd, J = 6.7, 9.3 Hz,
1H, O–HCH), 2.12 (s, 3H, CH3), 2.11 (s, 3H, CH3),
1.82–1.55 (m, 6H, cyclohexyl), 1.23 (m, 3H, cyclohexyl),
0.94 (m, 2H, cyclohexyl).
J = 5.0, 10.1 Hz, 1H, H-3), 6.05 (ddd, J = 0.7, 2.9,
10.1 Hz, 1H, H-2), 5.25 (d, J = 2.7 Hz, 1H, H-1), 5.06
(ddd, J = 0.5, 2.4, 5.0 Hz, 1H, H-4), 4.46 (m, 1H, H-5),
4.26 (d, J = 6.3 Hz, 2H, H-6a,b), 3.68 (m, 1H, O–CH), 2.12
(s, 3H, CH3), 2.11 (s, 3H, CH3), 2.02–1.75 (m, 4H,
cyclohexyl), 1.47–1.23 (m, 6H, cyclohexyl). GC–MS: m/
z [M?], 311, 239,213, 168, 153, 111.
Cyclohexyl-2-deoxy-3,4,6-tri-O-acetyl-a-D-galactopyran-
oside (Table 1, entry 2c—procedure 1), purification: SiO2
column chromatoghraphy, eluent: CH2Cl2/EtOAc 9:1, oil.
1H-NMR(400 MHz, CDCl3) d5.42(d, J = 2.7 Hz, 1H, H-4),
5.34 (ddd, J = 5.1, 3.6, 2.7 Hz, 1H, H-3), 5.21 (d,
J = 3.0 Hz, 1H, H-1), 4.25 (m, 1H, H-5), 4.13 (m, 2H,
H-6a,b), 3.77 (m, 1H, O–CH), 2.17 (s, 3H, CH3), 2.10 (m, 1H,
H-2eq), 2.08 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.88 (m, H-2ax),
1.84–1.69 (m, 4H, cyclohexyl), 1.45–1.23 (m, 6H, cyclo-
hexyl). GC–MS: m/z 371 [M?], 289, 273, 252, 214, 171, 111,
99.
Cyclohexylmethyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-threo-
es-2-enopyranoside (Table 1, entry 1b—procedure 1),
purification: SiO2, column chromatoghraphy, eluent:
CH2Cl2, oil. 1H-NMR (400 MHz, CDCl3) d 6.14 (dd,
J = 4.7, 10.0 Hz, 1H, H-3), 6.06 (dd, J = 2.5, 10.0 Hz,
1H, H-2), 5.05 (m, 2H, H-1, H-4), 4.42–4.22 (m, 3H, H-5,
H-6a,b), 3.62 (dd, J = 6.9, 9.3 Hz, 1H, O–HCH), 3.33 (dd,
J = 6.1, 9.3 Hz, 1H, O–HCH), 2.11 (s, 6H, 2xCH3),
1.91–1.55 (m, 6H, cyclohexyl), 1.41–1.13 (m, 3H, cyclo-
hexyl), 1.09–0.85 (m, 2H, cyclohexyl). GC–MS: m/z 325
[M?], 213, 182, 153, 111.
Cyclohexylmethyl-2-deoxy-3,4,6-tri-O-acetyl-a/b-D-gluco-
pyranoside (Table 2, entry 2a—procedure 2), purification:
SiO2 column chromatoghraphy, eluent: CH2Cl2/EtOAc 19:1,
1
oil. H-NMR (400 MHz, CDCl3) d (a anomer) 5.32 (ddd,
J = 5.4, 9.5, 11.6 Hz, 1H, H-3), 4.98(t, J = 9.7 Hz,1H,H-4),
4.91 (bd, J = 3.1 Hz, 1H, H-1), 4.29 (dd, J = 4.7, 12.2 Hz,
1H, H-6a), 4.06 (dd, J = 2.2, 12.2 Hz, 1H, H-6b), 3.94 (ddd,
J = 2.2, 4.6, 10.1 Hz, 1H, H-5), 3.42 (dd, J = 6.9, 9.4 Hz,
1H, O–HCH), 3.18 (dd, J = 6.1, 9.4 Hz, 1H, O–HCH), 2.22
(ddd, J = 1.0, 5.3, 12.8 Hz, 1H, H-2eq), 2.09 (s, 3H, CH3),
2.04 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.81 (ddd, J = 3.6, 11.7,
12.7 Hz, 1H, H-2ax), 1.81–1.62 (m, 4H, cyclohexyl), 1.58 (m,
1H, cyclohexyl), 1.33–1.10 (m, 4H, cyclohexyl) 1.0–0.83 (m,
2H, cyclohexyl). GC–MS: m/z 385 [M?], 267, 253, 224, 213,
185, 153.
1H-NMR (400 MHz, CDCl3) d (b anomer) 5.05–4.97
(m, 2H, H-3, H-4), 4.53 (dd, J = 1.9, 9.6 Hz, 1H, H-1),
4.29 (dd, J = 4.6,12.1 Hz, 1H, H-6a), 4.11 (dd, J = 2.5,
12.1 Hz, 1H, H-6b), 3.69 (dd, J = 6.2, 9.4, 1H, O–HCH),
3.59 (ddd, J = 2.4, 4.7, 9.3 Hz, 1H, H-5), 3.24 (dd,
J = 7.0, 9.4 Hz, 1H, O–HCH), 2.32 (m, 1H, H-2eq), 2.08
(s, 3H, CH3), 2.03 (s, 3H, CH3), 2.02 (s, 3H, CH3),
1.81–1.62 (m, 4H, cyclohexyl, H-2ax), 1.58 (m, 1H,
cyclohexyl), 1.33–1.10 (m, 4H, cyclohexyl) 1.0–0.83 (m,
2H, cyclohexyl).
Cyclohexylmethyl-2-deoxy-3,4,6-tri-O-acetyl-a/b-D-
galactopyranoside (Table 1, entry 1c; Table 2, entry 2c—
procedure 1/2) purification: SiO2 column chromatoghra-
1
phy, eluent: CH2Cl2/EtOAc 8:2, oil. H-NMR (400 MHz,
CDCl3) d (a anomer) 5.35 (d, J = 2.8 Hz, 1H, H-4), 5.30
(ddd, J = 3.6, 5.1, 2.8 Hz, 1H, H-3), 4.99 (d, J = 2.9 Hz,
1H, H-1), 4.11 (m, 3H, H-5, H-6a,b), 3.45 (dd, J = 6.9,
9.3 Hz, 1H, O–HCH), 3.21 (dd, J = 6.1, 9.3 Hz, 1H, O–
HCH), 2.15 (s, 3H, CH3), 2.10 (dd, J = 3.6, 12.6 Hz, 1H,
H-2eq), 2.07 (s, 3H, CH3), 2.00 (s, 3H, CH3), 1.88 (dd,
J = 5.1, 12.6 Hz, 1H, H-2ax), 1.73 (m, 5H, cyclohexyl),
1.58 (m, 1H, cyclohexyl), 1.24 (m, 3H, cyclohexyl), 0.96
(m, 2H, cyclohexyl). GC–MS: m/z 385 [M?], 327, 289,
213, 185, 153, 111, 97.
1H-NMR (400 MHz, CDCl3) d (b anomer) 5.27 (d,
J = 2.7 Hz, 1H, H-4), 5.00 (dd, J = 2.7, 5.9 Hz, 1H, H-3),
4.54 (dd, J = 3.3, 8.7 Hz, 1H, H-1), 4.24–4.08 (m, 3H,
H-5, H-6a,b), 3.75 (dd, J = 6.3, 9.6 Hz, 1H, O–HCH), 3.27
(dd, J = 7.2, 9.5 Hz, 1H, O–HCH), 2.15 (s, 3H, CH3), 2.10
(m, 1H, H-2eq), 2.07 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.99
(m, 1H, H-2ax), 1.74 (m, 5H, cyclohexyl), 1.62 (m, 1H,
–CH), 1.22 (m, 3H, cyclohexyl), 0.95 (m, 2H, cyclohexyl).
40-Pentenyl-4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-es-
2-enopyranoside (Table 2, entry 4b—procedure 2) purifi-
cation: SiO2 column chromatography, eluent: CH2Cl2/
1
EtOAc 19:1. H-NMR (400 MHz, CDCl3) d 5.87 (m, 3H,
H-2,H-3,H-40), 5.35 (d, J = 9.6 Hz, 1H, H-4), 5.13–4.98
(m, 3H, H-1, H50), 4.28 (dd, J = 5.5, 12.1 Hz, 1H, H-6),
123

174
O. Rosati et al.
4.21 (dd, J = 2.4, 12.1 Hz, 1H, H-6), 4.14 (ddd, J = 2.4,
5.5, 9.6 Hz, 1H, H-5), 3.84 (dt, J = 6.7, 9.8 Hz, 1H, H-10),
3.55 (dt, J = 6.7, 9.8 Hz, 1H, H-10), 2.17 (m, 2H, H-30),
2.15 (s, 3H, CH3), 2.12 (s, 3H, CH3), 1.74 (m, 2H, H-20).
GC–MS: m/z 298 [M?], 239, 225, 213,154, 111, 86.
Benzyl-2-deoxy-3,4,6-tri-O-acetyl-a/b-D-glucopyranoside
(Table 2, entry 5a—procedure 2) purification: SiO2 column
chromatoghraphy, eluent: Petroleum ether/Et2O 1:1, oil. 1H-
NMR (400 MHz, CDCl3) d(a anomer)7.4 (m, 5H, PhH), 5.38
(ddd, J = 5.4, 9.8, 11.4 Hz, 1H, H-3), 5.06 (m, 1H, H-1), 5.02
(t, J = 9.7 Hz, 1H, H-4), 4.68 (d, J = 12.0 Hz, 1H, HCH–
Ph), 4.52 (d, J = 12.0 Hz, 1H, HCH–Ph), 4.32 (dd, J = 5.3,
10.0 Hz, 1H, H-6a), 4.02 (m, 2H, H-5, H-6b), 2.29 (dd,
J = 5.4, 13.0 Hz, 1H, H-2 eq), 2.10 (s, 3H, CH3), 2.04 (s, 3H,
CH3), 2.01 (s, 3H, CH3), 1.86 (m, 1H, H-2ax). GC–MS: m/
z 379 [M?], 289, 273, 183, 153, 111, 91.
1H-NMR (400 MHz, CDCl3) d (b anomer) 7.4 (m, 5H,
PhH), 5.02–4.98 (m, 3H, H-1, H-3, H-4), 4.90 (d,
J = 12.0 Hz, 1H, HCH–Ph), 4.63 (d, J = 12.0 Hz, 1H,
HCH–Ph), 4.32 (m, 1H, H-6a), 4.16 (dd, J = 2.0, 12.0 Hz,
1H, H-6b), 3.61 (m, 1H, H-5), 2.35 (m, H-2eq), 2.10 (s, 3H,
CH3), 2.04 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.85–1.80 (m,
H-2ax).
(s, 3H, CH3), 2.04 (s, 3H, CH3), 2.07–2.01 (m, 1H, H-2ax),
1.47 (s, 9H, tBu).
40-(Tert-buthyl)phenil-2-deoxy-3,4,6-tri-O-acetyl-a/b-D-
galactopiranoside (Table 2, entry 6c—procedure 2), puri-
fication: SiO2 column chromatoghraphy, eluent: CH2Cl2/
Hexane 9:1, oil. 1H-NMR (400 MHz, CDCl3) d (a anomer)
7.33 (d, J = 9.0 Hz, 2H, PhH), 7.01 (d, J = 9.0 Hz, 2H,
PhH), 5.74 (d, J = 2.8 Hz, 1H, H-1), 5.53 (ddd, J = 3.1,
5.1, 12.4 Hz, 1H, H-3), 5.42 (d, J = 2.9 Hz, 1H, H-4), 4.29
(t, J = 6.7 Hz, 1H, H-5), 4.12 (dd, J = 6.1, 11.2 Hz, 1H,
H-6a,), 4.08 (dd, J = 7.1, 11.2 Hz, 1H, H-6b), 2.27 (m, 1H,
H-2eq), 2.18 (s, 3H, CH3), 2.12 (m, 1H, H-2ax), 2.05 (s, 3H,
CH3), 1.94 (s, 3H, CH3), 1.32 (s, 9H, tBu). GC–MS: m/
z 422 [M?], 362, 273, 213, 150, 135, 111.
1H-NMR (400 MHz, CDCl3) d (b anomer) 7.31 (d,
J = 9.0 Hz, 2H, PhH), 6.97 (d, J = 9.0 Hz, 2H, PhH),
5.34 (d, J = 2.9 Hz, 1H, H-4), 5.17 (dd, J = 2.6, 9.6 Hz,
1H, H-1), 5.11 (ddd, J = 3.12, 5.0, 12.2 Hz, 1H, H-3), 4.25
(dd, J = 7.0, 11.2 Hz, 1H, H-6a), 4.18 (dd, J = 6.2,
11.2 Hz, 1H, H-6b), 3.96 (bt, J = 6.3 Hz, 1H, H-5),
2.29–2.16 (m, 2H, H-2eq,ax), 2.12 (s, 3H, CH3), 2.07 (s, 3H,
CH3), 2.04 (s, 3H, CH3), 1.32 (s, 9H, tBu).
40-Hydroxyphenetyl-2-deoxy-3,4,6-tri-O-acetyl-a-D-gluco-
pyranoside(Table 2,entry7a—procedure 2)purification: SiO2
column chromatoghraphy, eluent: CH2Cl2/EtOAc 2:1, oil. 1H-
NMR (400 MHz, CDCl3)d(aanomer) 7.6 (d, J = 9.2 Hz, 2H,
PhH), 7.2 (d, J = 9.2 Hz, 2H, PhH), 5.27 (ddd, J = 5.3, 9.4,
11.6 Hz, 1H, H-3), 4.94 (d, J = 9.8 Hz, 1H, H-4), 4.91 (bd,
J = 2.8 Hz, 1H, H-1), 4.15 (dd, J = 4.3, 12.3 Hz, 1H, H-6a),
3.92 (dd, J = 2.3, 12.3 Hz, H-6b), 3.74 (m, 1H, O–HCH), 3.62
(m, 1H, O–HCH), 3.47 (ddd, J = 2.3, 4.2, 10.1 Hz, 1H, H-5),
2.81 (t, J = 6.7 Hz, 2H, CH2Ph), 2.23 (ddd, J = 1.1, 5.3,
12.9 Hz, 1H, H-2eq), 2.08, (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.02
(s, 3H, CH3), 1.78 (ddd, J = 3.6, 11.7, 12.8 Hz, 1H, H-2ax).
GC–MS: m/z 410 [M?], 273, 213, 120.
40-Hydroxyphenetyl-2-deoxy-3,4,6-tri-O-acetyl-a-D-galac-
topyranoside (Table 2, entry 7c—procedure 2), purification:
SiO2 column chromatoghraphy, eluent CH2Cl2/EtOAc 9:1, oil.
1H-NMR (400 MHz, CDCl3) d 7.10 (d, J = 9.0 Hz, 2H, PhH),
6.79 (d, J = 9.0 Hz, 2H, Ph–H a,b), 5.26 (m, 2H, H-3, H-4),
4.99 (d, J = 2.6 Hz, 1H, H-1), 4.00 (d, J = 6.8 Hz, 2H,
H-6a,b), 3.77 (m, 1H, O–HCH), 3.70 (bt, J = 6.6 Hz, 1H, H-5),
3.63 (m, 1H, O–HCH), 2.82 (t, J = 7.6 Hz, 2H, PhCH2 b), 2.09
(m, H-2eq), 2.13 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.01 (s, 3H,
CH3), 1.86 (m, H-2ax).
Benzyl-2-deoxy-3,4,6-tri-O-acetyl-a-D-galactopirano-
side (Table 1, entry 4c; Table 2, entry 5c—procedure 2)
purification: SiO2 column chromatography, eluent:
1
CH2Cl2/EtOAc 9:1. H-NMR (400 MHz, CDCl3) d 7.36
(m, 5H, PhH), 5.37 (d, J = 2.6 Hz, 1H, H-4), 5.33 (m, 1H,
H-3), 5.12 (d, J = 3.0 Hz, 1H, H-1), 4.71 (d, J = 11.8 Hz,
1H, HCH–Ph), 4.52 (d, J = 11.8 Hz, 1H, HCH–Ph), 4.22
(m, 1H, H-5), 4.11 (m, 2H, H-6), 2.15 (s, 3H, CH3), 2.10 (m,
1H, H-2eq), 2.07 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.93 (m,
1H, H-2ax). GC–MS: m/z 379 [M?], 320, 289, 273,
213,153.
40-(Tert-buthyl)phenyl-2-deoxy-3,4,6-tri-O-acetyl-a/b-D-
glucopyranoside (Table 2, entry 6a—procedure 2), purifi-
cation: SiO2 column chromatoghraphy, eluent: Hexane/
EtOAc 3:1, oil. 1H-NMR (400 MHz, CDCl3) d (a anomer)
7.65 (d, J = 9.1 Hz, 2H, PhH), 7.10 (d, J = 9.1 Hz, 2H,
PhH), 5.67 (d, J = 2.28 Hz, 1H, H-1), 5.55 (ddd, J = 5.4,
9.5, 11.6 Hz, 1H, H-3), 5.11 (t, J = 9.8 Hz, 1H, H-4), 4.31
(dd, J = 4.5, 12.2 Hz, 1H, H-6a), 4.09 (ddd, J = 2.0, 4.5,
10.2 Hz, 1H, H-5), 4.02 (dd, J = 2.1, 12.2 Hz, 1H, H-6b),
2.47 (ddd, J = 0.8, 5.3, 13.0 Hz, 1H, H-2eq), 2. 80 (s, 3H,
CH3), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.01 (ddd,
J = 3.6, 11.8, 13.0 Hz, 1H, H-2ax), 1.47 (s, 9H, tBu). GC–
MS: m/z 422 [M?], 289, 213, 153.
Cyclohexylmethyl-2-deoxy-3,4,6-tri-O-benzyl-a-D-galacto-
pyranoside (Table 3, entry 1b—procedure 2) purification:
SiO2, column chromatoghrapy, eluent: Petroleum ether/
EtOAc 8:2, yellow oil. 1H-NMR (400 MHz, CDCl3) d 7.33
(m, 15H, PhH), 4.95 (m, 2H, H-1, HCH–Ph), 4.64 (m, 3H,
Benzylic), 4.54 (d, J = 11.7 Hz, 1H, O–HCH–Ph), 4.45 (d,
J = 11.7 Hz, 1H, O–HCH–Ph), 3.94 (m, 3H, H-3, H-4,
H-5), 3.61 (m, 2H, H-6a,b), 3.43 (dd, J = 7.2, 9.5 Hz, 1H,
1H-NMR (400 MHz, CDCl3) d (b anomer) 7.55 (d,
J = 9.0 Hz, 2H, PhH), 6.95 (d, J = 9.0 Hz, 2H, PhH),
5.18 (dd, J = 2.2, 9.6 Hz, 1H, H-1), 5.41–5.50 (m, 2H,
H-3, H-4), 4.30 (m, 1H, H-6a), 4.16 (dd, J = 2.5, 12.1 Hz,
H-6b), 3.76 (ddd, J = 2.5, 9.2, 5.5 Hz, 1H, H-5), 2.52 (dd,
J = 2.0, 4.8, 12.4 Hz, 1H, H-2eq), 2.06 (s, 3H, CH3), 2.05
123

Ferrier Rearrangement and 2-Deoxy Sugar Synthesis
175
9. Ferrier RJ (2001) Top Curr Chem 215:153
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J = 4.5, 12.6 Hz, 1H, H-2ax), 1.83–1.52 (m, 6H, cyclo-
hexyl), 1.24 (m, 3H, cyclohexyl), 0.93 (m, 2H, cyclohexyl).
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In this paper we reported the use of a-Zr(CH3PO3)1.2
(O3PC6H4SO3H)0.8 as acidic catalyst for the synthesis of
Ferrier rearrangement compounds and its combination with
LiBr for the regioselective synthesis of 2-deoxysugars
starting from glycals. The regioselectivity of this process is
also affected by the different structure of the starting gly-
cals (3,4,6-tri-O-acetyl-glucal and 3,4,6-tri-O-acetyl-
galactal). Optimizations of 2-deoxy sugars synthesis med-
iated by a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8/LiBr catalytic
system, such as LiBr and nucleophile equivalents reduc-
tion, were achieved. The use of benzylated glycals as
starting material for a complete regioselective synthesis of
2-deoxysugars has been proposed. Thus the optimized mild
reaction conditions, the recoverable and the recyclable
nature of the catalyst that can be reused without loss of
activity, make these processes simple and of general
applicability with negligible chemical waste.
Acknowledgments Financial support from MIUR, National Project
‘‘Approccio ecocompatibile all’intensificazione di processo nella
sintesi organica’’ is gratefully acknowledged.
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Asymmetry 10:2119
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J Carbohydr Chem 18:609
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