Glycal-mediated syntheses of enantiomerically pure 3-azido-2,3-dideoxy- hexopyranosides and 3-amino-2,3-dideoxy-hexopyranolactones

Article abstract of DOI:10.1016/j.tetasy.2004.10.024

Methodology for the conversion of two commercially available glycals, d-galactal and d-glucal, into 3-azido-2,3-dideoxy-hexopyranosides and 3-amino-2,3-dideoxy-hexopyranolactones is reported. Using this strategy, templates suitable in combinatorial chemis

Full text of DOI:10.1016/j.tetasy.2004.10.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3769–3773
Glycal-mediated syntheses of enantiomerically pure
3-azido-2,3-dideoxy-hexopyranosides and 3-amino-2,3-
dideoxy-hexopyranolactones
Antonella Squarcia, Simona Marroni, Giovanni Piancatelli* and Pietro Passacantilli
`
Dipartimento di Chimica and Istituto di Chimica Biomolecolare del CNR, Sezione di Roma, Universita ‘La Sapienza’,
Piazzale Aldo Moro 5, 00185 Roma, Italy
Received 10 September 2004; accepted 21 October 2004
Abstract—Methodology for the conversion of two commercially available glycals, D-galactal and D-glucal, into 3-azido-2,3-dideoxy-
hexopyranosides and 3-amino-2,3-dideoxy-hexopyranolactones is reported. Using this strategy, templates suitable in combinatorial
chemistry for the construction of a number of interesting biologically active molecules have been prepared. Key features of this strat-
egy include the development of an efficient and original reaction sequence for the differential protection of the oxygen functiona-
lities, the regio- and stereoselective introduction of the azido group, and the chemoselective oxidation of the acetal group.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2,3-dideoxy-methyl-hexopyranosides 5a and 5b and
their conversion into 3-amino-d-lactones 7a and 7b.
3-Azido-2,3-dideoxy carbohydrate derivatives are
important precursors of bio-active compounds, suchas
glycosidic antibiotics,1 antitumoural agents2 and nucleo-
sides against HIV.3 A common method for synthesis of
these sugars is based on the use of acyclic intermediates,
with a significant advantage of this strategy being that
the need for protective groups is minimized.3,4 However,
the majority of the syntheses of these sugars have been
achieved from other carbohydrates, even though re-
moval and manipulation of functionality from the start-
ing carbohydrates were necessary and the reaction
sequences rather long.1a Within this context, the use of
glycals as synthons is appealing thanks to the lower den-
sity of functionalities.
2. Results and discussion
We needed a mild and efficient protocol for the prepara-
tion of carbohydrate intermediates, such as 3 and 4,
equipped at the 3-position with a free hydroxyl group,
suitable for the introduction of an azide function
(Scheme 1). Kirsching et al. described the shortest route
to 3-O-unprotected D-galactal 2a by an oxidation–
reduction sequence on the perbenzylated derivative
mediated by iodine(III) reagents [PhI(OH)OTs]:6 fol-
lowing a modified procedure in the oxidation step, we
obtained compound 2a in good yield (53%).7 As this
strategy on the D-arabino configuration leads to a C3
epimeric mixture,7 a direct regioselective protection–
deprotection sequence of the hydroxylic groups on D-
glucal scaffold 1b was required.
Furthermore, the investigation is limited to the trans-
formation of the glycals into a,b-unsaturated aldehydes,
which are then employed as Michael acceptors in the
conjugate addition of hydrazoic acid: as reported, such
methods lead to a C1 and C3 isomeric mixture of com-
pounds which need to be separated by chromatography.5
The best results have been achieved using TBDPSCl for
the primary alcohol in excellent yield and BzCl for the
allylic position, both highly selective and easy to
remove. As previous attempts to introduce a benzylic
group on C4 were unsuccessful due to steric effects
(using benzylic bromide withpotassium hydride or silver
oxide as bases), we employed 2-methoxyethoxy-methyl-
chloride with good results. Finally, treatment with
Herein we report the use of D-galactal 1a and D-glucal
1b in the synthesis of stereochemically pure 3-azido-
*
Corresponding author. Tel.: +39 06 49913861; fax: +39 06 490631;
e-mail: giovanni.piancatelli@uniroma1.it
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.024

3770
A. Squarcia et al. / Tetrahedron: Asymmetry 15 (2004) 3769–3773
O
OCH3
O
O
O
OCH3
PO
HO
PO
PO
a
d
b
R1
R2
R1
R2
R1
R2
R1
R2
N3
OH
OH
OR
1a: R1=OH, R2=H
1b: R1=H, R2=OH
3a (R=H) 70% (α anomer only)
2a 53%
2b 47%
5a 67%
5b 65%
3b (R=H) 70% (anomeric mixture)
c
a: P=Bn, R1=OBn, R2=H
b: P=TBDPS, R1=H, R2=OMEM
4a (R=Ms) 88% (α anomer only)
4b (R=Ms) 92% (anomeric mixture)
Scheme 1. Synthesis of 5a and b. Reagents and conditions: (a) (i) 1.1equiv TBDPSCl, 2.5equiv imidazole, DMF, T = 0ꢁC to rt, 1h, (ii) 1equiv BzCl,
pyr., T = ꢀ40ꢁC to rt, 1h, 67% for two steps, (iii) 4equiv MEMCl, 2.7equiv DIPEA, CH2Cl2, rt, overnight, (iv) 5equiv MeONa, MeOH, rt, 3h, 70%
for two steps; (b) 1.5equiv MeOH, PPh3ÆHBr cat., CH2Cl2, rt, 45min; (c) 5equiv MsCl, 5equiv pyr., CH2Cl2, T = 0ꢁC to rt, 24h; (d) 3equiv Bu4NCl,
3.5equiv NaN3, toluene, reflux, 24h.
CH3ONa led to the 3-O-unprotected D-arabino-configu-
rated glycal 2b. So far this procedure is the simplest and
the highest yielding method to this scaffold.
BF3ÆO(C2H5)2, cleavage of the MEM group in 6b
occurred (Scheme 2).11
On the protected glycals we investigated the stereoselec-
tive introduction of a masked amino functionality at C3.
We reckoned that a Mitsunobu-type reaction8 would be
the transformation for this purpose, but Kirsching et al.
obtained 3-azide-L-fucal witha yield far from satisfac-
tory (only 15%).6 Furthermore, efforts to convert the
allylic hydroxy group into a better leaving group, such
as mesylate or triflate, to employ in a substitution with
NaN3, failed.
3. Conclusion
In conclusion, an efficient synthesis of enantiomerically
pure 3-azido-2,3-dideoxy-hexopyranosides, useful pre-
cursors of bioactive compounds, has been accomplished
starting from D-galactal and D-glucal. Furthermore, this
short sequence provides an access to 3-amino-2,3-dide-
oxy-hexopyranolactones, intermediates of biologically
interesting hydroxy amino acids and b-lactams.
To circumvent these problems, glycals 2a and 2b were
first converted into 2-deoxy-methylpyranosides 3a and
3b by the addition of MeOH catalyzed by triphenyl-
phosphine hydrobromide (TPHB),9 leading to the pre-
dominant formation of an a-anomer in good yields.
4. Experimental
4.1. General
Subsequent treatment withMsCl in CH Cl2 and SN2
1H NMR (200MHz) and 13C NMR (50.3MHz) spectra
were recorded on a Varian Gemini 200 spectrometer
withCDCl as the solvent and as the internal standard.
2
substitution withsodium azide gave successfully teh
stereochemically pure azides 5a and 5b: interestingly,
the thermodynamically more stable a-anomer was
selected under the azidation conditions.
3
IR spectra were recorded on a Shimadzu IR-470 infra-
red spectrophotometer. HRMS spectra were recorded
witha Micromass Q-TOF micro mass spectrometer
(Waters). Optical rotations were measured using a
sodium D line on a DIP 370 Jasco digital polarimeter.
Yields are given for isolated products after column chro-
matography showing a single spot on TLC and no
The stereochemistry of 5a and 5b was established on the
basis of H NMR data: only one weak coupling of H-1
1
proton withaxially oriented H-2 ( J1,2ax 4.4Hz) is diag-
nostic of the a-anomeric centre; J2ax,3 4.4Hz is charac-
teristic for equatorially oriented H-3 proton in D-xylo
5a and D-ribo 5b configurations.5
1
detectable impurities in H NMR spectrum. All reac-
tions were performed under an inert atmosphere of
argon in flame-dried glassware. All solvents and
commercially available reagents were used without puri-
fication unless otherwise noted. All reactions were moni-
tored by thin-layer chromatography (TLC) carried out
on Merck F-254 silica glass plates visualized withUV/
light and heat-gun treatment with a 2M H2SO4 solution.
Column chromatography was performed with Merck
silica gel 60 (230–400 mesh). Compound 2a was pre-
pared according to the literature.7
As a further synthetic application, 5a and 5b were con-
verted into 3-amino-d-lactones 7a and 7b, chiral syn-
thons of hydroxy amino acids10 and b-lactams:1b
Under the oxidation conditions with mCPBA and
O
O
O
O
PO
PO
a
b
R1
R2
5a, 5b
R1
R2
70%
NHBoc
N3
4.2. 1,5-Anhydro-6-O-(tert-butyldiphenylsilyl)-2-deoxy-4-
O-(2-methoxyethoxymetyl)-D-arabino-hex-1-enitol 2b
6a, 6b
7a, 80%
7b, 75%
a: P=Bn, R1=OBn, R2=H
b: P=TBDPS, R1=H, R2=OH
A solution of 1b (200.0mg, 1.37mmol) in DMF (2.5mL)
was treated withimidazole (233mg, 3.42mmol) followed
by TBDPSCl (0.39mL, 1.51mmol), under argon at
0ꢁC. The reaction was allowed to warm up to room
Scheme 2. Synthesis of 7a and b. Reagents and conditions: (a) 3equiv
mCPBA, 3equiv BF3ÆEt2O, CH2Cl2, rt, 45min; (b) 1.5equiv Boc2O,
H2, Pd/C, AcOEt, rt, 4h.

A. Squarcia et al. / Tetrahedron: Asymmetry 15 (2004) 3769–3773
3771
J5,6 = 6.6Hz, H-60), 3.35 (s, 3H, CH3O), 1.91 (dd, 2H,
J2,3 = 8.4Hz, J1,2 = 2.2Hz, 2H-2), 1.72 (br s, 1H, OH
disappears after D2O addition). 13C NMR (d, CDCl3):
138.4, 137.9, 128.5, 128.4, 127.9, 127.9, 127.8, 127.7
(Ar), 98.8 (C-1), 76.4 (C-4), 75.1, 73.5 (CH2Ph), 69.3
(C-3), 69.2 (C-6), 65.7 (C-5), 54.8 (OCH3), 34.4 (C-2).
Anal. Calcd for C21H26O5: C, 70.37; H, 7.31. Found:
C, 70.42; H, 7.37.
0
temperature over a period of 1huntil no starting mate-
rial was detected on TLC. The reaction mixture was
diluted withEt O (20mL) and washed with a saturated
2
aqueous NaHCO3 solution (2 · 5mL) and water
(3 · 5mL). The organic phase was dried over Na2SO4
and then concentrated in vacuo. The crude product
was dissolved, under argon, in dry pyridine (3mL) and
BzCl (0.16mL, 1.37mmol) then added dropwise at
ꢀ40ꢁC. The reaction was allowed to warm up to room
temperature and stirred for 1h, then diluted with Et2O
(20mL), washed with a saturated aqueous CuSO4 solu-
tion (2 · 10mL) and water (2 · 10mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo.
The residue was dissolved in dry CH2Cl2 (5mL) and
treated withDIPEA (0.21mL) and MEMCl (0.19mL,
1.72mmol). The reaction was stirred at room tempera-
ture overnight until no starting material was detected
on TLC, then diluted with CH2Cl2 (15mL), washed with
water (3 · 5mL), dried over Na2SO4 and concentrated
in vacuo. The residue was dissolved in MeOH (5mL)
and treated withMeONa (69mg, 2.15mmol) for 3hat
room temperature. The solvent was removed in vacuo,
the residue diluted with AcOEt (20mL) and washed with
water (3 · 5mL). The organic layer was dried over
Na2SO4 and concentrated in vacuo. The crude product
was purified by flash chromatography (SiO2, hexane/
EtOAc 30:1) to give 2b as a colourless oil (0.64mmol,
303mg, 47%). [a]D = ꢀ17.0 (c 1.2, CHCl3). IR mmax
4.4. Methyl 6-O-(tert-butyldiphenylsilyl)-2-deoxy-4-O-(2-
methoxyethoxymetyl)-D-arabino-hexopyranoside 3b, as
an inseparable a,b-anomeric mixture
Compound 3b (112mg, 0.22mmol, 70%) was obtained
from 2b (150mg, 0.32mmol) following the procedure de-
1
scribed for 3a. IR mmax (CHCl3)/cmꢀ1: 3120 (OH). H
NMR (d, CDCl3): (a,b mixture 3:1) 7.82–7.68 (m,
ArH), 7.48–7.35 (m, ArH), 4.87–4.71 (m, OCH2O,
H1a), 4.61–4.50 (br s, OH, disappears after D2O addi-
tion), 4.44 (dd, J1,2eq = 2.2Hz, J1,2ax = 10.2Hz, H-1b),
4.06–3.32, 3.75–3.46 (2m, H-3, H-4, H-5, 2H-6,
OCH2CH2O), 3.41 (s, OCH3), 3.33 (s, CH3O), 2.32
(ddd, J2ax,2 eq = 9.5Hz, J1,2eq = 2.2Hz, J3,2eq = 5.8Hz,
H-2aeq), 2.22 (dd, J2ax,2eq = 13.2Hz, J3,2eq = 5.1Hz,
H-2beq), 1.78–1.51 (m, H2aax, H2bax), 1.08 (s, CH3).
13C NMR (d, CDCl3): (a anomer) 135.8, 134.5, 129.9,
129.8, 128.6, 128.5, 128.3, 127.9 (Ar), 98.3 (C-1), 100.7
(OCH2O), 83.1 (C-4), 75.4 (C-3), 71.4 (OCH2), 67.8
(C-5), 66.5 (OCH2), 63.1 (C-6), 58.9 (CH3O), 54.4
(OCH3), 36.7 (C-2), 26.8 (CH3), 19.3 (Cquat). Anal.
Calcd for C27H40O7Si: C, 64.26; H, 7.99. Found: C,
64.22; H, 8.02.
1
(CHCl3)/cmꢀ1: 3290 (OH). H NMR (d, CDCl3): 7.80–
7.66 (m, 4H, ArH), 7.51–7.27 (m, 6H, ArH), 6.24 (dd,
1H, J1,2 = 5.8Hz, J1,3 = 1.5Hz, H-1), 4.93 (d, 1H,
J = 7.3Hz, OCH2O), 4.83 (d, 1H, J = 7.3Hz, OCH2O),
4.79 (dd, 1H, J1,2 = 5.8Hz, J2,3 = 2.2Hz, H-2), 4.54–
4.42 (br s, 1H, OH, disappears after D2O addition),
4.05–3.55 (m, 9H, OCH2CH2O, 2H-6, H-5, H-4, H-3),
3.41 (s, 3H, CH3O), 1.15 (s, 9H, 3CH3). 13C NMR (d,
CDCl3): 144.1 (C-1), 135.7, 135.5, 133.6, 133.2, 129.6,
128.7, 127.6, 127.5 (Ar), 102.2 (C-2), 97.0 (OCH2O),
80.0 (C-4), 77.1 (C-3), 71.4 (OCH2), 68.5 (C-5), 67.6
(OCH2), 62.3 (C-6), 59.0 (CH3O), 26.8 (CH3), 19.3
(Cquat). Anal. Calcd for C26H36O6Si: C, 66.07; H, 7.68.
Found: C, 66.02; H, 7.73.
4.5. Methyl 4,6-di-O-benzyl-2-deoxy-3-O-mesyl-a-D-
lyxo-hexopyranoside 4a
MsCl (1.8mmol, 0.14mL) was added dropwise to a
solution of 3a (129mg, 0.36mmol) in dry CH2Cl2
(3mL) and dry pyridine (0.15mL), under argon at
0ꢁC. The reaction was allowed to warm up to room
temperature and stirred overnight until no starting
material was detected on TLC. The reaction mixture
was diluted withCH Cl2 (15mL), then washed with a
2
4.3. Methyl 4,6-di-O-benzyl-2-deoxy-a-D-lyxo-hexopyra-
noside 3a
saturated aqueous CuSO4 solution (5mL), brine
(3 · 5mL) and water (3 · 5mL). The organic phase
was dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by flash chromatogra-
phy (SiO2, hexane/EtOAc 8:1) to give 4a as a colourless
oil (138mg, 0.31mmol, 88%). [a]D = +66.0 (c 1.2,
CHCl3). 1H NMR (d, CDCl3): 7.45–7.26 (m, 10H,
ArH), 5.13 (ddd, 1H, J3,2ax = 12.4Hz, J3,2eq = 5.1Hz,
J3,4 = 2.9Hz, H-3), 4.87 (d, 1H, J1,2ax = 3.6Hz, H-1),
4.70–4.40 (m, 4H, 2 · CH2Ph), 4.09–3.93 (m, 2H, H-4,
H-5), 3.59 (d, 2H, J5,6 = 5.9Hz, 2H-6), 3.36 (s, 3H,
A solution of 2a (179mg, 0.55mmol) in dry CH2Cl2
(4mL) was treated withPPh ÆHBr (14mg, 0.041mmol)
3
and MeOH (0.03mL, 0.82mmol). The reaction was stir-
red for 45min at room temperature until no starting
material was detected on TLC. The mixture was diluted
withCH Cl2 (20mL), washed with a saturated aqueous
2
NaHCO3 solution (3 · 5mL) and brine (3 · 5mL), then
dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography
(SiO2, hexane/EtOAc 10:1) to give 3a as a colourless
oil (136mg, 0.38mmol, 70%). [a]D = +73.0 (c 1.3,
OCH3), 2.99 (s, 3H, CH3), 2.43 (td, 1H, J2eq,2ax
=
J3,2ax = 12.4Hz, J1,2ax = 3.6Hz, H-2ax), 2.05 (dd, 1H,
J2eq,2ax = 12.4Hz, J3,2eq = 5.1Hz, H-2eq). 13C NMR (d,
CDCl3): 138.1, 137.7, 128.3, 128.2, 128.1, 128.0, 127.9,
127.6 (Ar), 98.2 (C-1), 76.3 (C-3), 74.8 (CH2Bn), 74.1
(C-4), 73.34 (CH2Ph), 69.2, 68.7 (C-5, C-6), 54.7
(OCH3), 38.3 (CH3), 31.5 (C-2). Anal. Calcd for
C22H28O7S: C, 60.53; H, 6.47; S, 7.35. Found: C,
60.50; H, 6.52; S, 7.31.
1
CHCl3). IR mmax (CHCl3)/cmꢀ1: 3360 (OH). H NMR
(d, CDCl3): 7.43–7.27 (m, 10H, ArH), 4.84 (d 1H,
J1,2 = 2.2Hz, H-1), 4.79–4.49 (m, 4H, 2 · CH2Ph),
4.08–3.94 (m, 2H, H-3, H-5), 3.82 (d, 1H,
0
J3,4 = 2.9Hz, H-4), 3.69 (dd, 1H, J6,6 = 8.8Hz,
0
J5,6 = 7.3Hz, H-6), 3.65 (dd, 1H, J6,6 = 8.8Hz,

3772
A. Squarcia et al. / Tetrahedron: Asymmetry 15 (2004) 3769–3773
1
4.6. Methyl 6-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-
mesyl-4-O-(2-methoxyethoxymetyl)-D-arabino-hexopyr-
anoside 4b, as an inseparable a,b-anomeric mixture
(CHCl3)/cmꢀ1: 2120 (N3). H NMR (d, CDCl3): 1.08
(s, 9H, 3 · CH3) 2.05 (td, 1H, J2eq,2ax = 15.4Hz,
J3,2ax = J1,2ax 4.4Hz, H-2ax); 2.15 (dd, 1H,
J2eq,2ax = 15.4Hz, J2eq,3 = 2.2Hz, H-2eq); 3.37, 3.38 (2s,
6H, OCH3, CH3O); 3.43–3.69, 3.78–4.10 (2m, 8H, H-
4, H-5, 2H-6, OCH2CH2O); 4.21 (m, 1H, J3,4 = 2.9Hz,
H-3); 4.74 (d, 1H, J1,2ax = 4.4Hz, H-1); 4.81, 4.88 (2d,
2H, J = 7.3Hz, OCH2O), 7.32–7.50 (m, 6H, ArH);
7.68–7.82 (m, 4H, ArH). 13C NMR (d, CDCl3): 19.2
(Cquat); 26.7 (CH3); 32.7 (C-2); 54.9, 57.1, 58.82
(CH3O, OCH3, C-3); 63.2 (C-6); 67.5 (C-5); 67.5 (OCH2-
CH2O); 71.5; 73.6 (C-4); 95.5 (OCH2O); 96.5 (C-1);
127.4, 127.5, 128.3, 129.4, 133.1, 133.5, 135.4, 135.7
(Ar). Anal. Calcd for C27H39N3O6Si: C, 61.22; H,
7.42; N, 7.93. Found: C, 61.18; H, 7.50; N, 7.95.
Compound 4b (100mg, 0.18mmol, 92%) was obtained
from 3b (100mg, 0.2m·mol) following the procedure
1
described for 4a. H NMR (d, CDCl3): (3:1 a,b-ano-
meric mixture) 7.79–7.69 (m, ArH), 7.51–7.33 (m,
ArH), 5.04–4.60 (m, OCH2O, H-1a, H-3), 4.44 (dd,
J1,2eq = 2.2Hz, J1,2ax = 9.5Hz, H-1b), 3.98–3.38 (m,
H-4, H-5, 2H-6, OCH2CH2O), 3.53 (s, OCH3), 3.34
(s, CH3O), 3.32 (s, CH3O), 3.30 (s, OCH3), 3.11 (s,
CH3SO2), 3.01 (s, CH3SO2), 2.54 (ddd, J2ax,2eq
=
10.2Hz, J1,2eq = 2.2Hz, J3,2eq = 5.1Hz, H-2beq), 2.46
(ddd, J2ax,2eq = 12.4Hz, J1,2eq = 1.4Hz, J3,2eq = 5.1Hz,
H-2aeq), 1.99 (dd, J2ax,2eq = 12.4Hz, J1,2ax = 3.7Hz, H-
2aax), 1.89 (m, H-2bax), 1.08 (s, CH3). 13C NMR (d,
CDCl3): 135.8, 135.7, 135.5, 133.4, 133.2, 129.6,
127.6, 127.5 (Ar), 103.6 (C-1b), 99.7, 97.4 (OCH2O),
97.2 (C-1a), 80.5, 79.7, 75.6, 75.1, 74.6, 73.9, 71.8,
71.5, 68.2, 67.5, 63.1 (C-6a), 62.8 (C-6b), 58.8 (CH3Oa),
56.5 (CH3Ob), 54.5 (OCH3a), 51.5 (OCH3b), 38.7
(O2SCH3b), 38.3 (O2SCH3a), 37.8 (C-2b), 36.7 (C-2a),
26.7 (CH3), 19.3 (Cquat). Anal. Calcd for C28H42O9SSi:
C, 57.71; H, 7.26; S, 5.50. Found: C, 57.64; H, 7.30; S,
5.45.
4.9. 3-Azido-4,6-di-O-benzyl-2,3-dideoxy-D-idonolactone
6a
To a solution of 5a (165mg, 0.43mmol) in dry CH2Cl2
(5mL) MCPBA (225mg, 1.31mmol) and BF3ÆOEt2
(0.16mL, 1.31mmol) were added at room temperature.
The reaction was stirred for 45min until no starting
material was detected on TLC. The reaction mixture
was diluted withCH Cl2 (15mL) and then washed with
2
a saturated aqueous NaHCO3 solution (3 · 5mL), brine
(3 · 5mL) and water (3 · 5mL). The organic phase was
dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by flashchromatography
(SiO2, hexane/EtOAc 10:1) to give 6a as a colourless oil
(110mg, 0.30mmol, 70%). [a]D = +65.0 (c 1.1, CHCl3).
IR mmax (CHCl3)/cmꢀ1: 2120 (N3), 1750 (CO). 1H
NMR (d, CDCl3): 7.48–7.28 (m, 10H, ArH), 4.75–4.47
(m, 5H, 2 · CH2Ph, H-5), 4.16 (m, 1H, H-3), 3.85–3.80
0
4.7. Methyl 3-azido-4,6-di-O-benzyl-2-deoxy-a-D-xylo-
hexopyranoside 5a
A solution of 4a (287mg, 0.66mmol) in dry toluene
(7mL) was treated withBu 4NCl (550mg, 1.98mmol)
and then with NaN3 (150mg, 2.31mmol). The reaction
was stirred at reflux for 24huntil no starting material
was detected on TLC. The reaction mixture was diluted
(m, 1H, H-4), 3.83 (dd, 1H, J6,6 = 9.7Hz, J6,5
=
0
0
withAcOEt (20mL), then washed withbrine (3
and water (3 · 5mL). The organic phase was dried over
Na2SO4 and concentrated in vacuo. The crude product
· 5mL)
5.4Hz, H-6), 3.75 (dd, 1H, J6,6 = 9.7Hz, J6 ,5 = 4.5Hz,
H-60), 3.01 (dd, 1H, J2 eq,2ax = 18.0Hz, J2eq,3 = 6.1Hz,
H-2eq), 2.54 (dd, 1H, J2eq,2ax = 18.0Hz, J2ax,3 =
was purified by flashchromatography (SiO
2, hexane/
5.4Hz, H-2ax). 13C NMR (d, CDCl3): 167.4 (C-1),
137.3, 136.8, 128.7, 128.5, 128.4, 128.2, 127.9, 127.8
(Ar), 75.9 (C-4), 73.7 (CH2Ph), 73.0 (C-5), 67.3 (C-6),
56.4 (C-3), 32.9 (C-2). Anal. Calcd for C20H21N3O4: C,
65.38; H, 5.76; N, 11.44. Found: C, 65.35; H, 5.80; N,
11.42.
EtOAc 50:1) to give 5a as a colourless oil (169mg,
0.44mmol, 67%). [a]D = +94.0 (c 1.5, CHCl3). IR mmax
1
(CHCl3)/cmꢀ1: 2130 (N3). H NMR (d, CDCl3): 1.87
(dd, 1H, J2eq,2ax = 14.6Hz, J3,2eq = 1.5Hz, H-2eq); 2.26
(td,
1H,
J2eq,2ax = 14.6Hz,
J2ax,3 = 4.4Hz,
J1,2ax = 4.4Hz, H-2ax); 3.42 (s, 3H, OCH3); 3.65 (d,
2H, J5,6 = 6.6Hz, 2H-6); 3.84–3.91 (m, 1H, H-3); 4.27
(dd, 1H, J5,6 = 6.6Hz, J4,5 = 1.5Hz, H-5); 4.46–4.63
(m, 4H, 2 · CH2Ph); 4.67 (dd, 1H, J4,5 = 1.5Hz,
J4,3 = 3.7Hz, H-4); 4.80 (br d, 1H, J1,2ax = 4.4Hz, H-
1); 7.27–7.44 (m, 10H, ArH). 13C NMR (d, CDCl3):
29.1 (C-2); 54.4, 55.1 (OCH3, C-3); 65.2 (C-6); 69.1 (C-
5); 72.8, 73.2, (CH2Ph); 73.3 (C-4); 96.7 (C-1); 127.4,
127.6, 127.9, 128.0, 128.2, 128.3, 137.8, 138.1 (Ar). Anal.
Calcd for C21H25N3O4: C, 65.78; H, 6.57; N, 10.96.
Found: C, 65.75; H, 6.61; N, 11.01.
4.10. 3-Azido-6-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-
D-altronolactone 6b
Compound 6b (64mg, 0.15mmol, 70%) was obtained
from 5b (115mg, 0.21mmol) following the procedure
described for 6a. [a]D = ꢀ42 (c 1.0, CHCl3). IR mmax
1
(CHCl3)/cmꢀ1: 3300 (OH), 2140 (N3), 1760 (CO). H
NMR (d, CDCl3): 7.66–7.44 (m, 4 H, ArH), 7.40–7.24
(m, 6 H, ArH), 4.55–4.38 (m, 2H, H-3, H-5), 3.84–3.73
(m, 3H, H-4, 2H-6), 3.06 (br s, OH, disappears after
0
D2O addition), 2.95 (dd, 1H, J2,2 = 18.3Hz,
0
4.8. Methyl 3-azido-6-O-(tert-butyldiphenylsilyl)-2-de-
oxy-4-O-(2-methoxyethoxymetyl)-a-D-ribo-
hexopyranoside 5b
J2,3 = 7.9Hz, H-2), 2.55 (dd, 1H, J2,2 = 18.3Hz,
J2,3 = 4.0Hz, H-2), 1.1 (s, 9H, CH3). 13C NMR (d,
CDCl3): 173.6 (C-1), 135.6, 133.7, 132.5, 132.4, 130.2,
129.8, 128.3, 127.9 (Ar), 83.8 (C-4), 71.3 (C-5), 64.0
(C-6), 57.9 (C-3), 34.6 (C-2), 26.9 (CH3), 19.3 (SiCCH3).
Anal. Calcd for C22H27N3O4Si: C, 62.09; H, 6.40; N,
9.87. Found: C, 62.03; H, 6.48; N, 9.84.
Compound 5b (144mg, 0.27mmol, 65%) was obtained
from 4b (245mg, 0.42mmol) following the procedure
described for 5a. [a]D = ꢀ35.0 (c 1.3, CHCl3). IR mmax

A. Squarcia et al. / Tetrahedron: Asymmetry 15 (2004) 3769–3773
3773
4.11. 4,6-Di-O-benzyl-3-(tert-butoxycarbonyl)amino-2,3-
dideoxy-D-idonolactone 7a
for C27H37NO6Si: C, 64.90; H, 7.46; N, 2.80. Found: C,
64.95; H, 7.54; N, 2.75.
A solution of 6a (80mg, 0.22mmol) and Boc2O (74mg,
0.34mmol) in AcOEt (5mL) was hydrogenated with H2
in the presence of Pd/C (15mg) for 4h until no starting
material was detected on TLC. The catalyst was filtered
off through a pad of Celite and the solvent evaporated
under reduced pressure. The residue was purified by
flash chromatography (SiO2, hexane/EtOAc 7:1) to give
Acknowledgements
We thank the University ꢀLa Sapienzaꢁ of Rome for
financial support.
7a as
a colourless oil (80mg, 0.18mmol, 80%).
References
[a]D = +42.0 (c 1.1, CHCl3). IR mmax (CHCl3)/
1
cmꢀ1:1750 (CO). H NMR (d, CDCl3): 7.52–7.23 (m,
1. (a) Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86,
35–67; (b) Panfil, I.; Urbanczyk-Lipkowska, Z.; Chmie-
lewski, M. Carbohydr. Res. 1998, 306, 505–515; (c)
Durham, T. B.; Miller, M. J. Org. Lett. 2002, 4, 135–
138, and references therein.
2. (a) Roger, P.; Monneret, C.; Fournier, J.-P.; Choay, P.;
Gagnet, R.; Gosse, C.; Letourneux, Y.; Attasi, G.;
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Dabrowska, A.; Dokurno, P.; Konitz, A.; Smiatacz, Z.
Carbohydr. Res. 2002, 323, 230–234.
10H, ArH), 5.37 (d, 1H, J3,NH = 6.8Hz, NH), 4.76–
4.44 (m, 5H, H-5, 2 · CH2Ph), 4.23 (m, 1H, H-3),
3.95–3.75 (m, 3H, H-4, 2H-6), 3.07 (dd, 1H,
0
J2,2 = 17.5Hz, J2,3 = 7.6Hz, H-2), 2.51 (dd, 1H,
J2,2 = 17.5Hz, J2 ,3 = 4.2Hz, H-20), 1.3 (s, 9H,
3 · CH3). 13C NMR (d, CDCl3): 168.4 (C-1), 154.8
(NCO), 137.4, 135.9, 128.7, 128.6, 128.4, 128.3, 127.9,
127.8 (Ar), 80.9 (OCCH3), 73.7, 73.2, 72.7, 72.3, 68.2
(C-6), 46.7 (C-3), 33.5 (C-2), 31.8 (CH3). Anal. Calcd
for C25H31NO6: C, 68.01; H, 7.08; N, 3.17. Found: C,
68.05; H, 7.04; N, 3.15.
0
0
3. Gauthier, C.; Ramondenc, Y.; Ple, G. Tetrahedron 2001,
57, 7513–7517.
4. See for example: (a) Ref. 3; (b) Hanessian, S.; Kloss, J.
Tetrahedron Lett. 1985, 26, 1261–1264; (c) Danishefsky, S.
J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, 1269–1274;
(d) Jurczak, J.; Kozak, J.; Golebiowski, A. Tetrahedron
1992, 48, 4231–4238.
4.12. 6-O-(tert-Butyldiphenylsilyl)-3-(tert-butoxycarbon-
yl)amino-2,3-dideoxy-D-altronolactone 7b
5. (a) Liberek, B.; Dabrowska, A.; Frankowski, R.; Matu-
szewska, M.; Smiatacz, Z. Carbohydr. Res. 2002, 337,
1803–1810; (b) Liberek, B.; Sikorski, A.; Melcer, A.;
Konitz, A. Carbohydr. Res. 2003, 338, 795–799.
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telli, G. Tetrahedron Lett. 2002, 43, 4613–4615.
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Humphrey, G. R.; De Marco, A. M.; Mathre, D. J.;
Grabowsky, E. J. J. J. Org. Chem. 1993, 58, 5886–5888.
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Compound 7b (60mg, 0.12mmol, 75%) was obtained
from 6b (70mg, 0.16mmol) following the procedure
described for 7a. Colourless oil; [a]D = ꢀ75.0 (c 1.0,
CHCl3). IR mmax (CHCl3)/cmꢀ1: 3300 (OH), 1760
(CO); 1H NMR (d, CDCl3): 7.76–7.24 (m, 10 H,
ArH), 5.01 (d, 1H, J3,NH = 6.1Hz, NH), 4.48–4.41 (m,
2H, H-3, H-5), 3.86–3.80 (m, 3H, H-4, 2H-6), 3.01
0
(dd, 1H, J2,2 = 18.1Hz, J2,3 = 8.4Hz, H-2), 2.9 (br s,
OH, disappears after D2O addition), 2.52 (dd, 1H,
0
J2,2 = 18.1Hz, J2,3 = 4.6Hz, H-2), 1.4 (s, 9H,
3 · CH3), 1.1 (s, 9H, 3 · CH3). 13C NMR (d, CDCl3):
174.6 (C-1), 155.0 (NCO), 135.4, 132.7, 130.0, 129.5,
128.7, 128.5, 127.7, 127.5 (Ar), 84.4 (C-4), 80.5
(OCCH3), 71.8 (C-5), 64.0 (C-6), 48.7 (C-3), 35.6 (C-
2), 28.2 (CH3), 26.8 (CH3), 19.2 (SiCCH3). Anal. Calcd.
10. Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron
Lett. 1989, 30, 6503–6506, and references therein.
11. Mukai, C.; Miyakawa, M.; Hanaoka, M. J. Chem. Soc.,
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