Enantiospecific synthesis of a glycoside of D-epi-purpurosamine

Article abstract of DOI:10.1016/S0957-4166(00)00483-3

2-Propyl D-epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthesized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-α-D-erythro-hex-3-enopyranosid-2-ulose 2 as the key precursor. The f

Full text of DOI:10.1016/S0957-4166(00)00483-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4945–4954
Enantiospecific synthesis of a glycoside of
-epi-purpurosamine
D
Christian A. Iriarte Capaccio and Oscar Varela*
CIHIDECAR-CONICET, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabello´n II, 1428 Buenos Aires, Argentina
Received 30 October 2000; accepted 21 November 2000
Abstract
2-Propyl
D
-epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthe-
-erythro-hex-
sized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-a-
D
3-enopyranosid-2-ulose 2 as the key precursor. The first approach through the saturated diol 4, prepared
by reduction of the enone system of 2, was unsuccessful as the C-2 position of 2,6-di-O-sulfonyl
derivatives 5 and 6 resisted substitution by azide. Therefore, an alternative sequence starting from the
allylic alcohol 3, also derived from 2, was developed. In this case, the 2,6-di-O-tosyl derivative 9 gave the
expected 2,6-diazide 10 with additional unwanted rearrangement of the double bond to the 2-propyl
4,6-diazido-2,3,4,6-tetradeoxy-a- -threo-hex-2-enopyranoside 11 isomer. However, the ditriflate derivative
D
13, analogous to 9, underwent substitution to afford the diazide 10 in good yield. Upon reduction of the
azide functions and saturation of the double bond of 10 by catalytic hydrogenation under acidic
conditions, the dihydrochloride salt 14 was obtained as a crystalline product (43% overall yield from 3).
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Sannamycin-type aminoglycoside antibiotics are a relatively simple class of pseudodisaccha-
rides in which
D
-purpurosamine sugars are a-glycosidically linked to a 1,4-diaminocyclitol
derivative.1 In order to ascertain structure–activity relationships, Prinzbach and co-workers2
prepared sets of variously protected derivatives of purpurosamine and its 2-epi- analogue as
glycosyl donors, using a sequence based on pioneering work by Brimacombe.3 The procedure,
which starts from acrolein dimer (racemic 3,4-dihydro-2H-pyran-2-carbaldehyde), involves a
low yielding step (nitrosochlorination, azidonitration) to introduce the amino function at C-2.
Further studies4 led to an improvement in this reaction employing an ‘indirect aziridination’
process; enzymatic resolution was then employed to separate the racemates which were formed.
* Corresponding author. E-mail: varela@qo.fcen.uba.ar
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00483-3

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C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
The resulting glycosyl donors were coupled with a convenient sannamine acceptors affording the
structurally modified binuclear aminoglycosides.5,6
On the other hand, for the confirmation of the structure of the diaminosugar component of
the antibiotics sisomicin and dihydrosisomicin, Guthrie and Williams7,8 reported a multi-step
synthesis of di-N-acetylated
D
-epi-purpurosamine diethyl dithioacetal. The key step was the
rearrangement of an allylic 4-thiocyanate to the isomeric 2-isothiocyanate. Gero et al.9 described
a similar rearrangement of an allylic 4-azido derivative that led to methyl di-N-acetyl- -epi-pur-
D
purosamide as an intermediate precursor of the same dithioacetal derivative.
As part of our project on the synthesis of diamino tetradeoxy sugars,10 we wish to report here
an expeditious and enantiospecific synthesis of a glycoside of
D
-epi-purpurosamine starting from
-galactose. As far as we know,
2-acetoxy-3,4,6-tri-O-acetyl- -galactal 1 readily prepared from
D
D
this is the first synthesis of a simple, crystalline glycoside of the free diamino sugar.
2. Results and discussion
The two approaches described here for the synthesis of a glycoside of
D
-epi-purpurosamine
employed the sugar enone 2 as a chiral template. This compound can be readily prepared,11 in
about 90% yield, by the tin(IV) chloride-promoted glycosylation of the galactal derivative 1. The
reduction of the carbonyl function of 2 with sodium borohydride in methanol, followed by
O-deacetylation with sodium methoxide, took place with partial saturation of the double bond
to afford a 1:3.6 ratio of the saturated diol 4 and the allylic alcohol 3. Therefore, the mixture
was hydrogenated in the presence of catalytic palladium to give 4 as the main product (84%
yield from 2). The reduction of the carbonyl function of compound 2 afforded the diastereoiso-
mer having the
-erythro configuration.12 The diastereofacial selectivity may be attributed to the
D
sterical hindrance of the anomeric substituent which blocks the a-face and induces the attack of
the hydride from the opposite side. The stereocenters in 4 have the required configuration for
the substitution (upon sulfonylation) of a nitrogen nucleophile, to give a precursor of epi-pur-
purosamine. Tosylation of 4, in a 3:1 mixture of chloroform–pyridine,13 gave the ditosylate 5 in
82% yield but the attempted substitution of both O-tosyl groups of 5 by sodium azide was
unsuccessful. When the reaction was performed in DMF at high temperature, TLC analysis
1
showed the formation of a main product which was less polar than the starting material. The H
NMR spectrum of this compound revealed that a tosyl group remained intact. The chemical
shift of H-2 indicated that the sulfonate at this position was not substituted. Furthermore, the
upfield shift of H-6,6% with respect to the same signals in 5 was indicative that, as expected, the
tosyl group at the primary C-6 position had been replaced by azide. This monosubstituted
product 7 was rather stable, but when heated under reflux in DMF using concentrated solutions
of sodium azide extensive decomposition occurred. Since the trifluoromethanesulfonate group
(triflate) has better properties as nucleofuge, compound 4 was converted into the ditriflate 6,
which could be readily purified by column chromatography. However, the disubstitution of the
sulfonyl groups of 6 by azide was unsuccessful under all the conditions studied, and again a
monoazide derivative 8 was spectroscopically identified as the main product (Scheme 1).
In view of these results we decided to prepare the diol 3, by chemoselective reduction of the
carbonyl group in the enone system of 2. Such a diol could be derivatized as the corresponding
disulfonate, and it should be expected that the allylic nature of the secondary sulfonate would
help its nucleophilic displacement by azide. The reduction of the carbonyl group of 2 was

C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
4947
AcO
AcO
OH
OAc
OH
OH
OAc
O
O
O
1)
2)
NaBH4
O
+
NaOMe,
MeOH
SnCl4
OiPr
OiPr
OH
AcO
OiPr
O
OH
3
1
2
4
N3
OR
H2/Pd
O
O
NaN3
DMF
OR
OR
OiPr
OiPr
4 R = H
7 R = Ts
8 R = Tf
5 R = MeC6H4SO2 (Ts)
6 R = F3CSO2 (Tf)
Scheme 1.
performed with sodium borohydride in the presence of cerium(III) chloride, in order to avoid
the saturation of the double bond.14 Under these conditions the diol 3 was obtained in an 81%
yield. The corresponding 2,6-di-O-tosyl derivative 9 was then prepared in an 86% yield by the
procedure applied previously in the synthesis of 5; compound 9 was treated with sodium azide
in DMF at 80°C, and the reaction mixture was monitored by TLC which indicated two main
products of lower polarity than the starting material 9. These product spots were not detectable
by exposure to UV light, suggesting an absence of the tosyl groups. Column chromatography
1
allowed the separation of the two products and their structures were determined by H NMR
spectroscopy, using 2D COSY and single frequency decoupling experiments. The least polar
product was found to be the expected diazide 10, produced by straightforward substitution of
1
both tosyl groups. In addition to the upfield shift for the signals of H-2 and H-6,6% in the H
NMR spectrum of 10, the change in the J1,2 coupling constant value from 4.1 Hz (in 9) to <1
Hz (in 10) indicated the change in the configuration of the C-2 stereocenter.
The other product isolated from the azide substitution reaction was the 4-azido-2-enopyra-
noside 11, which resulted from an allylic rearrangement of the azido group from C-2 to C-4.
This kind of rearrangement has been reported for similar allylic thiocyanates7,8 and azides.6,9,15
Transfer of chirality takes place during the rearrangement, and the configuration of the new
stereocenter at C-4 was determined on the basis of the J4,5 coupling constant. Its small value (2.4
Hz) indicates a gauche relationship for H-4 and H-5 and hence a
D
-threo configuration for the
chiral centers of 11. As allylic rearrangements are often promoted thermally, low temperature
conditions for the azide substitution reaction were investigated. At lower temperature, the
formation of a new product was observed. It was shown by TLC to have intermediate polarity
to 9 and the diazides 10 and 11. The product from the low temperature reaction was isolated by
1
column chromatography and spectroscopically identified as the allylic azide 12. Thus, its H
NMR spectrum showed a strong upfield shift for the H-2 signal, whereas the H-6,6% signals were
only slightly altered with respect to the same resonances in 9. Interestingly, the allylic tosylate
was substituted more easily than the primary tosylate. The latter required higher temperatures
and when the reaction temperature was increased the formation of both diazides 10 and 11 was
observed (Scheme 2).

4948
C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
N3
N3
OR
N3
NaBH4
Ce3+
NaN3
O
O
O
2
+
OiPr
N3
DMF, 80°C
OiPr
OiPr
OR
11
10
3 R = H
9 R = Ts
TsCl
NaN3
DMF, 60°C
NaN3
OTs
O
DMF, 35°C
N3
OiPr
12
Scheme 2.
In order to overcome the rearrangement the ditriflate derivative 13 was prepared. This was
very unstable and readily decomposed at room temperature. Therefore, the crude sulfonylation
product mixture was exposed directly to sodium azide in DMF at low temperature (from −42 to
0°C). Under these conditions the conversion of 13 into the desired diazide derivative 10 was
almost complete in about 1 hour (Scheme 3). Compound 10 was isolated by column chromatog-
raphy in 67% yield from 3, and subjected to catalytic hydrogenation at 45 psi in methanolic
hydrochloric acid solution. Simultaneous saturation of the double bond and reduction of the
azide functions took place affording the glycoside of -epi-purpurosamine dihydrochloride 14 in
D
crystalline form. The 1H NMR spectrum of 14 showed broad singlets for H-1 and H-2; the small
J1,2, J2,3, and J2,3% values were indicative of the S configuration of C-2. This result was further
1
confirmed by acetylation of compound 14 to the di-N-acetyl derivative 15. In its H NMR
spectrum, the resonance of H-1 appeared as a broad singlet (J1,2<1 Hz) in contrast with the
larger value (J1,2=3.4 Hz) found for the analogous glycoside derivative of purpurosamine C,
which has opposite configuration at C-2.
N3
OTf
OH
NaN3
Tf2O, CH2Cl2
O
O
N3
O
-42 to 0
DMF, 0°C
°C
OiPr
OiPr
OiPr
OTf
OH
10
13
3
NHAc
O
NH2
O
H2N
AcHN
H2/Pd
HCl
Ac2O
· 2 HCl
C5H5N
OiPr
OiPr
14
15
Scheme 3.
In summary, the alkyl
D
-epi-purpurosaminide 14 was prepared by an operationally straight-
forward and enantiospecific synthesis in 43% overall yield from 3. As the glycosidic linkage is
constructed at the beginning of the sequence, and the next steps require gentle conditions, we
anticipate that the procedure developed could be employed for the coupling to the conveniently
protected cyclitol aglycon to obtain sannamycin-type antibiotics.

C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
4949
3. Experimental
3.1. General methods
Solvents were reagent grade and in most cases were dried and distilled prior to use, according
to standard procedures. Melting points were determined with a Fisher–Johns apparatus and are
uncorrected. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel
60 F254 (Merck) aluminum supported plates. Visualization of the spots was effected by exposure
to UV light or charring with a solution of 5% sulfuric acid in EtOH, containing 0.5%
p-anisaldehyde. Column chromatography was performed with silica gel 60 (230–400 mesh,
Merck). Optical rotations were measured with a Perkin–Elmer 343 polarimeter at 25°C. Nuclear
magnetic resonance (NMR) were recorded on a Bruker AC 200 spectrometer (1H at 200 MHz,
13C at 50.3 MHz) or on a Bruker AMX-500 (1H at 500 MHz) in CDCl3 solutions (unless
otherwise indicated) with TMS as an internal standard. Assignments were corroborated by
appropriate 2D experiments.
3.2. 2-Propyl 3,4-dideoxy-h-
D
-erythro-hexopyranoside 4
-erythro-hex-3-enopyranosid-2-ulose11 (2,
A solution of 2-propyl 6-O-acetyl-3,4-dideoxy-a-
D
146 mg, 0.64 mmol) in dry MeOH (8 mL) was cooled to 0°C and NaBH4 (140 mg, 3.70 mmol)
was slowly added. After 1 h of stirring at 0°C no starting material was detected by TLC. The
reaction mixture was treated with a 0.5 M solution of NaOMe in MeOH (1.3 mL) and stirred
at room temperature for 30 min. The solution was neutralized with Dowex 50W (H+) resin, then
filtered and concentrated. Boric acid was eliminated by successive evaporations with MeOH
(3×15 mL). The resulting oil was shown by NMR to be a 3.6:1 mixture of the unsaturated 3 and
saturated 4 derivatives; TLC (EtOAc): 3 and 4 had Rf 0.57 and 0.53, respectively. The oil was
dissolved in EtOAc (10 mL), cooled to 0°C, and then treated with 10% Pd/C (30 mg) and
hydrogen under atmospheric pressure. After 16 h TLC showed a single product had formed (Rf
0.53). The product was purified by column chromatography using a polarity gradient of
toluene:EtOAc from 3:1 to 1:1. Compound 4 (102 mg, 84% from 2) was isolated as a colorless
1
oil; [h]D=+129.7 (c 1.0, CHCl3); lit.12 [h]D=+128; identical H and 13C NMR spectra to those
described.12
3.3. 2-Propyl 3,4-dideoxy-2,6-di-O-tosyl-h- -erythro-hexopyranoside 5
D
Compound 4 (305 mg, 1.60 mmol) was dissolved in a mixture of anhydrous CHCl3 (3 mL)
and pyridine (1 mL, 12.4 mmol). The solution was cooled to 0°C and tosyl chloride (1.20 g, 6.29
mmol) was added. After stirring at room temperature for 16 h, TLC (3:1 toluene:EtOAc)
indicated that no starting material 4 remained and a less polar product, having Rf 0.73, had
formed. The mixture was diluted with CH2Cl2 (50 mL) and successively washed with 10%
aqueous HCl, saturated aqueous NaHCO3 and water. The organic extract was dried (MgSO4)
and concentrated. The residue was purified by column chromatography using a polarity gradient
(hexane:EtOAc from 20:1 to 5:1) affording the ditosylate 5 as an oil (652 mg, 82%); [h]D=+63.6
1
(c 1.0, CHCl3); H NMR l 7.78 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.33 (d, 4H, J=8.3
Hz), 4.78 (d, 1H, J=3.5 Hz), 4.33 (ddd, 1H, J=3.5, 4.8, 12.0 Hz), 4.03–3.90 (m, 3H), 3.75
(septet, 1H, J=6.2 Hz, CHMe2), 2.45 (s, 6H), 2.03 (dddd, 1H, J=4.8, :12 Hz), 1.67 (m, 2H),

4950
C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
1.44 (m, 1H), 1.15 (d, 3H, J=6.2 Hz), 1.07 (d, 3H, J=6.2 Hz); 13C NMR l 144.8, 129.9 (×2),
129.8 (×2), 128.0 (×2), 127.8 (×2), 94.3, 76.2, 71.4, 70.6, 65.5, 26.6, 23.4, 21.7, 21.5. Anal. calcd
for C23H30O8S2: C, 55.40; H, 6.06. Found: C, 55.84; H, 6.56.
3.4. 2-Propyl 3,4-dideoxy-2,6-di-O-trifluoromethanesulfonyl-h- -erythro-hexopyranoside 6
D
To a solution of 4 (132 mg, 0.69 mmol) in dry CH2Cl2 (40 mL) was added 2,6-di-tert-butyl-4-
methylpyridine (0.892 g, 4.34 mmol). The solution was cooled to −42°C (CH3CN–dry ice) and
trifluoromethanesulfonic anhydride (0.38 mL, 2.26 mmol) was slowly added. The mixture was
stirred at 0°C for 4 h when TLC (6:1 toluene:EtOAc) showed conversion of 4 into a less polar
product (Rf 0.70). The reaction mixture was poured into cold water (30 mL) and extracted twice
with CH2Cl2 (50 mL). The organic layer was dried (MgSO4) and concentrated, and the resulting
syrup purified by flash chromatography (20:1 hexane:EtOAc). Pure compound 6 was obtained
as a colorless oil (230 mg, 73%); [h]D=+73.1 (c 1.3, CHCl3); 1H NMR l 5.02 (d, 1H, J=3.6 Hz),
4.75 (ddd, 1H, J=3.6, 5.0, 12.0 Hz), 4.36 (d, 2H, J=4.7 Hz), 4.14 (dddd, 1H, J=2.7, 4.7, 4.7,
12.0 Hz), 3.89 (septet, 1H, J=6.2 Hz), 2.24 (dddd, 1H, J=4.7, 12.0, 12.2, 15.5 Hz), 1.98 (m,
1H), 1.78 (m, 1H), 1.56 (dddd, 1H, J=4.3, 11.8, 13.4, 15.5 Hz), 1.20 (d, 3H, J=6.2 Hz), 1.13
(d, 3H, J=6.2 Hz); 13C NMR l 118.5 (q, J:316 Hz), 93.9, 82.3, 76.6, 71.6, 65.3, 26.0, 23.5,
23.0, 21.4. Anal. calcd for C11H16F6O8S2: C, 29.08; H, 3.55. Found: C, 29.27; H, 3.53.
3.5. 2-Propyl 6-azido-2-O-tosyl-3,4,6-trideoxy-h- -erythro-hexopyranoside 7
D
To a solution of 5 (389 mg, 0.78 mmol) in dry DMF (3.2 mL) was added sodium azide (101
mg, 1.55 mmol). The mixture was stirred at 60°C for 16 h, and then at 125°C for 2 h. TLC (6:1
toluene:EtOAc) showed complete conversion of 5 into a less polar product (Rf 0.54, UV active
spot). The reaction mixture was diluted with water (20 mL) and extracted twice with ether (50
mL). The ethereal extract was dried (MgSO4) and concentrated. The residue was purified by
column chromatography (20:1 hexane:EtOAc) affording 7 as a viscous oil (231 mg, 80%);
1
[h]D=+80.0 (c 0.8, CHCl3); H NMR l 7.79 (d, 2H, J=8.3 Hz), 7.34 (d, 2H, J=8.3 Hz), 4.84
(d, 1H, J=3.5 Hz), 4.41 (dddd, 1H, J=3.5, 4.8, 12.0 Hz), 4.00 (m, 1H), 3.85 (septet, 1H, J=6.2
Hz), 3.22 (dd, 1H, J=6.6, 12.9 Hz), 3.12 (dd, 1H, J=4.0, 12.9 Hz), 2.45 (s, 3H), 2.07 (dddd, 1H,
J=4.5, :12.2 Hz), 1.78–1.60 (m, 2H), 1.46 (dddd, 1H, J:4.2, 11.5, 13.3 Hz), 1.23 (d, 3H,
J=6.2 Hz), 1.15 (d, 3H, J=6.2 Hz); 13C NMR l 145.0, 134.2, 133.0, 129.8 (×2), 127.7 (×2), 94.2,
76.4, 70.6, 67.1, 54.4, 27.8, 23.5, 23.1, 21.6, 21.5. Anal. calcd for C16H23N3O5S: C, 52.02; H, 6.27.
Found: C, 52.01; H, 6.21.
3.6. 2-Propyl 6-azido-2-O-trifluoromethanesulfonyl-3,4,6-trideoxy-h- -erythro-hexopyranoside 8
D
The crude 6 product mixture obtained by sulfonylation of 4 (130 mg, 0.68 mmol) was
dissolved in DMF (3 mL) previously cooled to −18°C. At this temperature sodium azide (200
mg, 3.08 mmol) was slowly added. The mixture was stirred at −10°C for 1 h, when TLC showed
complete consumption of the starting material. The product was extracted and chro-
1
matographed as indicated for 7, affording compound 8 (72 mg, 30% from 4); H NMR l 5.09
(d, 1H, J=4.5 Hz), 4.84 (ddd, 1H, J=4.5, 5.0, 12.0 Hz), 4.07 (m, 1H), 4.01 (septet, 1H, J=6.2
Hz), 3.28 (dd, 1H, J=6.5, 13.0 Hz), 3.19 (dd, 1H, J=4.1, 13.0 Hz), 2.29 (ddd, J=4.6, :12.2
Hz), 2.02 (m, 1H), 1.86–1.51 (m, 2H), 1.30 (d, 3H, J=6.2 Hz), 1.21 (d, 3H, J=6.2 Hz); 13C
NMR l 93.8, 83.1, 71.2, 67.3, 54.3, 27.8, 23.8, 23.2, 21.5.

C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
4951
Compound 8 was rather unstable and the attempted substitution of the triflate group at C-2
by azide by increasing the temperature resulted in complete decomposition.
3.7. 2-Propyl 3,4-dideoxy-h- -erythro-hex-3-enopyranoside 3
D
To a solution of 2 (315 mg, 1.38 mmol) in dry MeOH (17 mL) was added cerium(III) chloride
heptahydrate (514 mg, 1.38 mmol). The solution was cooled to 0°C and NaBH4 (209 mg, 5.52
mmol) was added. The mixture was stirred for 1 h at 0°C and then treated with a 0.5 M solution
of sodium methoxide in MeOH (12 mL) at room temperature for 30 min, when TLC (EtOAc)
showed a main spot having Rf 0.57. The solid formed was filtered, and the filtrate treated with
Dowex 50W (H+) resin. The work up was the same as was described in the preparation of
compound 4. Upon purification by column chromatography (toluene:EtOAc from 3:1 to 1:1) the
1
unsaturated diol 3 was obtained as a viscous oil (211 mg, 81%); [h]D=+34.6 (c 1.0, CHCl3); H
NMR l 5.78 (bd, 1H, J=10.7 Hz), 5.67 (d, 1H, J=10.7 Hz), 5.09 (d, 1H, J=4.1 Hz), 4.20 (m,
2H), 4.00 (septet, 1H, J=6.2 Hz), 3.70 (dd, 1H, J=3.4, 11.4 Hz), 3.57 (dd, 1H, J=5.9, 11.4 Hz),
2.16 (bs, 2H, interchanges with D2O), 1.25 (d, 3H, J=6.2 Hz), 1.20 (d, 3H, J=6.2 Hz); 13C
NMR l 129.0, 126.4, 95.3, 70.7, 69.2, 65.0, 64.0, 23.3, 21.9. Anal. calcd for C9H16O4: C, 57.43;
H, 8.57. Found: C, 57.05; H, 8.63.
3.8. 2-Propyl 3,4-dideoxy-2,6-di-O-tosyl-h- -erythro-hex-3-enopyranoside 9
D
Tosylation of 3 (302 mg, 1.60 mmol) under the conditions described for the preparation of 5
afforded the ditosyl derivative 9 (687 mg, 86%) as a crystalline product; mp 69–69.5°C;
1
[h]D=+11.4 (c 0.8, CHCl3); H NMR l 7.78 (d, 2H, J=8.2 Hz), 7.76 (d, 2H, J=8.2 Hz), 7.34
(d, 4H, J=8.2 Hz), 5.71 (dt, 1H, J=1.9, 10.6 Hz), 5.55 (bd, 1H, J=10.6 Hz), 5.02 (d, 1H,
J=4.1 Hz), 4.89 (ddd, J=1.9, 4.1, 5.5 Hz), 4.34 (m, 1H), 4.06 (dd, 1H, J=3.6, 10.6 Hz), 4.01
(dd, 1H, J=5.5, 10.6 Hz), 3.82 (septet, 1H, J=6.2 Hz), 2.44 (s, 6H), 1.16 (d, 3H, J=6.2 Hz),
1.12 (d, 3H, J=6.2 Hz); 13C NMR l 145.1, 133.7, 133.0, 130.0 (×2), 129.9 (×2), 128.0 (×2), 127.8
(×2), 124.3, 93.6, 71.5, 70.6, 66.5, 23.2, 21.6. Anal. calcd for C23H28O8S2: C, 55.63; H, 5.68.
Found: C, 55.01; H, 5.92.
3.9. 2-Propyl 2,6-diazido-2,3,4,6-tetradeoxy-h-
D
-threo-hex-3-enopyranoside 10 and 2-propyl
4,6-diazido-2,3,4,6-tetradeoxy-h- -threo-hex-2-enopyranoside 11
D
To a solution of 9 (1.30 g, 2.62 mmol) in dry DMF (10 mL) was added sodium azide (1.49
g, 22.9 mmol). The mixture was heated to 80°C and stirred at this temperature for 3 h. TLC (6:1
toluene:EtOAc) showed two main product spots having Rf 0.66 and 0.63, which were not
fluorescent to the UV light. The reaction mixture was diluted with ethyl ether (100 mL) and
washed with water (2×50 mL). The organic extract was dried (MgSO4) and concentrated. The
residue was subjected to column chromatography using mixtures of increasing polarity of
hexane:EtOAc (from 70:1 to 40:1). The fractions from the column which had Rf 0.66 were
1
concentrated to afford 10 as an oil (0.32 g, 51%); [h]D=+396.5 (c 1.2, CHCl3); H NMR l 6.01
(dd, 1H, J=1.1, 10.5 Hz), 5.82 (dddd, 1H, J=1.1, 2.0, 5.0, 10.5 Hz), 5.00 (s, 1H), 4.32 (m, 1H),
3.93 (septet, 1H, J=6.2 Hz), 3.35 (dd, 1H, J=7.1, 12.7 Hz), 3.27 (m, 1H), 3.24 (dd, 1H, J=4.6,
12.7 Hz), 1.17 (d, 3H, J=6.2 Hz), 1.12 (d, 3H, J=6.2 Hz); 13C NMR l 131.2, 120.9, 96.9, 70.3,
67.8, 55.3, 54.4, 23.2, 21.6. Anal. calcd for C9H14N6O2: C, 45.37; H, 5.92. Found: C, 45.64; H,
5.82.

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Concentration of the next fractions from the column afforded 11 as an oil (0.19 g, 30%);
1
[h]D=−379.9 (c 1.0, CHCl3); H NMR l 6.07 (dd, 1H, J=2.5, 10.0 Hz, H-2), 5.98 (dd, 1H,
J=5.1, 10.0 Hz, H-3), 5.10 (d, 1H, J=2.5 Hz, H-1), 4.20 (ddd, 1H, J=2.4, 4.9, 8.0 Hz, H-5),
3.99 (septet, 1H, J=6.2 Hz, CHMe2), 3.55 (dd, 1H, J=8.0, 12.8 Hz, H-6), 3.26 (dd, 1H, J=4.9,
12.8 Hz, H-6%), 3.22 (dd, 1H, J=2.4, 5.1 Hz, H-4), 1.19 (d, 3H, J=6.2 Hz, CH3), 1.13 (d, 3H,
J=6.2 Hz, CH3); 13C NMR l 131.6, 123.6, 92.1, 70.2, 69.4, 52.8, 52.0, 23.4, 21.6. Anal. calcd
for C9H14N6O2: C, 45.37; H, 5.92. Found: C, 45.63; H, 6.03.
3.10. 2-Propyl 2-azido-6-O-tosyl-2,3,4-trideoxy-h- -threo-hex-3-enopyranoside 12
D
A solution of 9 (230 mg, 0.46 mmol) and sodium azide (71 mg, 1.09 mmol) in dry DMF (2
mL) was heated at 35°C. TLC (6:1 toluene:EtOAc) showed gradual conversion of 9 into a less
polar product having Rf 0.56. A 1 mL aliquot of the mixture was taken, diluted with water and
extracted with ethyl ether. The extract was dried (MgSO4) and concentrated to afford a viscous
oil, which was the product with Rf 0.56, and starting material (Rf 0.45). The former was isolated
1
by column chromatography (hexane:EtOAc 30:1) and spectroscopically identified as 12; H
NMR l 7.82 (d, 2H, J=8.2 Hz), 7.35 (d, 2H, J=8.2 Hz), 5.86 (dddd, J=1.0, 2.1, 5.0, 10.3 Hz),
4.96 (s, 1H), 4.44 (m, 1H), 4.12 (dd, 1H, J=6.1, 10.4 Hz), 4.08 (dd, 1H, J=5.5, 10.4 Hz), 3.91
(septet, 1H, J=6.2 Hz), 3.30 (m, 1H), 2.46 (s, 3H), 1.19 (d, 3H, J=6.2 Hz), 1.16 (d, 3H, J=6.2
Hz); 13C NMR l 144.8, 134.0, 132.8, 129.8 (×2), 129.6, 128.0 (×2), 121.5, 96.7, 70.8, 70.3, 66.5,
55.2, 23.1, 21.5.
The original mixture was then heated at 60°C for 1.5 h when TLC revealed the formation of
the spot of Rf 0.56 together with those corresponding to the diazides 10 and 11. The mixture was
1
processed as described above and the resulting crude product was monitored by H NMR
spectroscopy showing the signals characteristic of compounds 10, 11 and 12.
3.11. 2-Propyl 3,4-dideoxy-2,6-di-O-trifluoromethanesulfonyl-h-
D
-erythro-hex-3-enopyranoside
13 and its conversion into 10
To a solution of compound 3 (198 mg, 1.05 mmol) in anhydrous CH2Cl2 (60 mL) was added
2,6-di-tert-butyl-4-methylpyridine (1.15 g, 5.6 mmol) and the mixture was cooled at about
−42°C (CH3CN–dry ice). Trifluoromethanesulfonic anhydride (0.66 mL, 3.92 mmol) was added
to the solution, which was allowed to warm slowly until 0°C. After 30 min TLC (6:1
toluene:EtOAc) showed complete conversion of 3 into a faster moving product having Rf 0.56.
The mixture was concentrated at 0°C and the residue dissolved in DMF (20 mL) previously
cooled at −42°C, and at this temperature sodium azide (860 mg, 13.23 mmol) was added. The
temperature was slowly increased until 0°C, and in about 1 h, TLC showed that the intermediate
ditriflate 13 was completely converted into a major product having identical polarity to 10. The
reaction mixture was diluted with cold water (20 mL) and extracted with ethyl ether (3×50 mL),
dried (MgSO4) and chromatographed to give 10 (168 mg, 67% from 3); which showed the same
physical and spectroscopic properties as the product previously synthesized from 9.
3.12. 2-Propyl 2,6-diamino-2,3,4,6-tetradeoxy-h-
D
-threo-hexopyranoside dihydrochloride
(2-propyl -epi-purpurosaminide dihydrochloride) 14
D
Compound 10 (68 mg, 0.29 mmol) dissolved in MeOH (5 mL) containing conc. HCl (0.15

C. A. Iriarte Capaccio, O. Varela / Tetrahedron: Asymmetry 11 (2000) 4945–4954
4953
mL) was hydrogenated at 45 psi in the presence of 10% Pd on carbon (20 mg). After 2 h TLC
revealed complete consumption of the starting 10; the catalyst was removed by filtration and
ethyl ether was slowly added to induce crystallization of the hydrochloride salt, which precipi-
tated as a white solid. Compound 14 (48 mg, 64%) gave mp >230°C; [h]D=+102.4 (c 0.8,
1
MeOH); H NMR (DMSO-d6) l 8.62 (bs, 3H, NH3-2), 8.26 (bs, 3H, NH3-6), 5.04 (s, 1H, H-1),
4.00 (m, 1H, H-5), 3.94 (septet, 1H, J=6.1 Hz, CHMe2), 3.03 (bs, 1H, H-2), 2.90 (m, 2H,
H-6,6%), 1.98–1.74 (m, 3H), 1.48 (m, 1H), 1.18 (d, 3H, J=6.1 Hz, CH3), 1.09 (d, 3H, J=6.1 Hz,
1
CH3); H NMR (D2O) l 5.08 (s, 1H, H-1), 4.20 (m, 1H, H-5), 4.06 (septet, 1H, J=6.2 Hz,
CHMe2), 3.38 (bs, 1H, H-2), 3.22–3.00 (m, 2H, H-6,6%), 2.26 (m, 1H), 1.92 (m, 1H), 1.75–1.59
(m, 2H), 1.26 (d, 3H, J=6.2 Hz, CH3), 1.20 (d, 3H, J=6.2 Hz, CH3); 13C NMR (DEPT) l 92.8
(C-1), 68.2 (CHMe2), 64.6 (C-5), 46.8 (C-2), 42.3 (C-6), 23.0, 20.9 (C-3,4), 20.6, 19.8 (CH3).
Anal. calcd for C9H22Cl2N2O2: C, 41.39; H, 8.49; N, 10.73. Found: C, 41.63; H, 8.40; N, 10.68.
3.13. 2-Propyl 2,6-N,N-diacetamido-2,3,4,6-tetradeoxy-h- -threo-hexopyranoside 15
D
Compound 14 (50 mg, 0.19 mmol) was dissolved in dry pyridine (1 mL) and to the solution,
cooled at 0°C, was added acetic anhydride (1 mL) under argon. The mixture was stirred at 0°C
for 1 h, and then at room temperature for an additional 5 h, when TLC (4:1 EtOAc:MeOH)
showed complete conversion of 14 into a product which had Rf 0.43. To the reaction mixture,
cooled at 0°C, was added MeOH (8 mL) and the resultant solution was stirred at room
temperature for 1 h, and then concentrated. The residue was dissolved in toluene (10 mL) and
concentrated in vacuum, in order to remove the excess of pyridine (this process was repeated
four times). The resulting oil was purified by column chromatography (from EtOAc to 10:1
EtOAc:MeOH). Compound 15 (38 mg, 73%) was obtained as a crystalline product; mp 31°C;
1
[h]D=+100.4 (c 1.0, MeOH); H NMR l 6.16 (d, 1H, J=8.3, NH), 6.03 (bt, 1H, NH), 4.65 (s,
1H, H-1), 3.89 (m, 2H, H-2,5), 3.84 (septet, 1H, J=6.2 Hz, CHMe2), 3.46 (ddd, 1H, J=3.7, 6.9,
13.6 Hz, H-6), 3.05 (ddd, 1H, J=4.9, 7.9, 13.6 Hz, H-6%), 2.00 (m, 1H), 1.97 (s, 3H), 1.94 (s, 3H),
1.59 (m, 1H), 1.42 (m, 2H), 1.17 (d, 3H, J=6.2 Hz), 1.11 (d, 3H, J=6.2 Hz); 13C NMR (DEPT)
l 170.0, 169.4 (CO), 96.7 (C-1), 69.4, 67.3 (C-5, CHMe2), 46.2 (C-2), 43.8 (C-6), 23.4, 23.2, 23.1,
21.7 (CH3), 23.3, 22.3 (C-3,4). Anal. calcd for C13H24N2O4: C, 57.33; H, 8.88; N, 10.29. Found:
C, 56.93; H, 8.79; N, 10.26.
Acknowledgements
Financial support from ANPCyT (National Agency for Promotion of Science and Technol-
ogy, PICT 01698) and from the University of Buenos Aires (Project TW70) is gratefully
acknowledged. O.V. is a Research Member of the National Research Council of Repu´blica
Argentina (CONICET).
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