Synthesis of Protected EPI-2-Deoxystreptamine and Analogs

Article abstract of DOI:10.1081/CAR-120026471

A protected C-3 epi-2-deoxystreptamine was synthesized starting with the intermediate 2-L-1,3/2,4,5-1-acetamido-2,3,4-tri-O-benzyl-2,3,4,5- cyclohexanetetrol 8, derived from D-glucose.

Full text of DOI:10.1081/CAR-120026471

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Synthesis of Protected EPI‐2‐Deoxystreptamine and
Analogs
Mauro V. De Almeida a , Emerson T. Da Silva a , Mireille Le Hyaric a , Antônio S. Machado a ,
Marcus V. N. De Souza a & Raquel M. Santiago a
a Departamento de Química , ICE , U.F.J.F, Juiz de Fora, MG, 36036‐330, Brazil
Published online: 23 Feb 2007.
To cite this article: Mauro V. De Almeida , Emerson T. Da Silva , Mireille Le Hyaric , Antônio S. Machado , Marcus V. N. De
Souza & Raquel M. Santiago (2003) Synthesis of Protected EPI‐2‐Deoxystreptamine and Analogs , Journal of Carbohydrate
Chemistry, 22:7-8, 733-742, DOI: 10.1081/CAR-120026471
To link to this article: http://dx.doi.org/10.1081/CAR-120026471
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 7 & 8, pp. 733–742, 2003
Synthesis of Protected EPI-2-Deoxystreptamine
and Analogsy
*
Mauro V. De Almeida, Emerson T. Da Silva, Mireille Le Hyaric,
Antoˆnio S. Machado, Marcus V. N. De Souza, and Raquel M. Santiago
Departamento de Qu´ımica, ICE, Juiz de Fora, MG, Brazil
ABSTRACT
A protected C-3 epi-2-deoxystreptamine was synthesized starting with the inter-
mediate 2-L-1,3/2,4,5-1-acetamido-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol 8,
derived from D-glucose.
Key Words: Streptamine; Aminocyclitols; Aminoglycoside; Antibiotic.
INTRODUCTION
Aminocyclitols and diaminocyclitols are subunits of the aminoglycoside anti-
biotics, which are among the longest used and best known antibiotics. They have
activities against a variety of aerobic bacteria[1] and are clinically important due to their
effectiveness against certain bacterial infections, such as pneumonia and septicemia.[2]
yThis paper is dedicated to Professor Ge´rard Descotes on the occasion of his 70th birthday.
*
Correspondence: Mauro V. De Almeida, Departamento de Qu´ımica, ICE, U.F.J.F, 36036-330,
Juiz de Fora, MG, Brazil; E-mail: mvieira@quimica.ufjf.br.
733
DOI: 10.1081/CAR-120026471
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

734
De Almeida et al.
Figure 1.
Aminoglycoside antibiotics interact with RNA molecules, and those containing a 2-
deoxystreptamine unit bind specifically to HIV RRE, which block binding of the HIV
Rev protein to this RNA, and inhibit HIV replication in tissue culture cells.[3–5]
2-Deoxystreptamine is an aminocyclitol contained in many antibiotics such as
neomycin B, paranomycin, kanamycin and amikacin (Figure 1).[6] The emergence of
multiple resistant bacteria has created the need for new antibiotics. The structural
stability and abundant functionality of 2-deoxystreptamine make it an attractive scaf-
fold for the combinatorial generation of small molecules, and a large panel of
compounds, derivatized with various substituents on the hydroxyl and amino groups of
2-deoxystreptamine have been synthesized for biological screening.[6–10]
In this paper, we wish to report the synthesis of the protected C-3 analogue of 2-
deoxystreptamine, 2-L-1,3/2,4,5 1,5-diacetamido-2,3,4-tri-O-benzyl-2,3,4-cyclohexane-
triol (18). This compound can be useful for synthesizing new aminoglycoside antibiotics.
RESULTS AND DISCUSSION
The oxime 2 was prepared from D-glucose via carbohydrate-inosose Ferrier rear-
rangement as previously described.[11,12] As reduction of 2 with LiAlH4 does not
proceed,[12] compound 2 was first converted to its benzyloxime 3 derivative
(Scheme 1).[13] Reduction of 3 with LiAlH4 gave a mixture of amine 4 (8%) and its
epimer 5 (74%), along with the benzylhydroxylamine 6 (8%). These three compounds
were purified by column chromatography. Compound 6 was quantitatively reduced to 5
using sodium borohydride and nickel chloride in methanol.
The N-acylated amines 7 and 8 were both obtained in 90% yield, by reaction of 4
and 5, respectively, with acetic anhydride in methanol. Substitution of the hydroxyl
groups of 7 was performed using DAST in methylene chloride. The expected fluori-
nated compound 9 was obtained in 70% yield. In a similar way compound 10 was
prepared from 8 in the same yield.
Compound 8 was converted to the mesylate 11 in 88% yield (Scheme 2)[13] by
treatment with methanesulfonyl choride in pyridine. Treatment of 11 with sodium azide

Synthesis of Protected EPI-2-Deoxystreptamine and Analogs
735
Scheme 1. a) PhCH2Cl, NaH, DMF, 0°C, 24 h; b) LiAlH4, THF, reflux, 12 h; c) NaBH4,
NiCl2.6H2O, MeOH, À10°C ! rt, 8 h; d) Ac2O, MeOH, rt, 4 h; e) DAST, CH2Cl2, 0°C ! rt, 6 h.
in DMSO gave the compound 12 in 88% yield. The latter was reduced by triphenyl-
phosphine in THF/H2O giving the target compound 13 in 73% yield. Reaction of the
mesylate 11 with potassium thioacetate in DMF afforded the desired compound 14 in
64% yield.
Oxidation of alcohol 8[13] with PCC in dichloromethane furnished the cyclohexanone
15 in 86% yield (Scheme 3). Treatment of 15 with O-benzylhydroxylamine hydrochloride
in pyridine afforded the syn benzyloxime 16 in quantitative yield, as a single isomer. The
epi-deoxystreptamine 17[14] was obtained in 60% yield by reduction of 16 with LiAlH4 in
Scheme 2. a) MsCl, Py, 0°C ! rt, 12 h; b) NaN3, DMSO, 120°C, 48 h; c) PPh3, THF, 0°C ! rt,
24 h; d) KSAc, DMF, 100°C, 48 h.

736
De Almeida et al.
Scheme 3. a) PCC, CH2Cl2, rt, 48 h; b) HCl.H2NOBn, Py, rt, 2 h; c) LiAlH4, THF, reflux, 24 h;
d) Ac2O, Py, 0°C ! rt, 8 h.
THF. Next, acetylation of 17 by treatment with acetic anhydride in pyridine produced the
target compound 18[14] in 90% yield.
1
The structures of all new compounds were unequivocally established by H, COSY
1
(1H x H) and 13C NMR analyses. For practical purposes, atom number of all com-
pounds, in their nomenclature and NMR analyses, is the same as that adopted for
compounds 8 and 15 (Scheme 3).
EXPERIMENTAL
Melting points were determined with a Thomas-Hoover apparatus and are un-
1
corrected. H NMR (200 and 400 MHz) and 13C NMR (50.3 and 100.6 MHz) spectra
were determined in deuterated chloroform or deuterated acetone containing ca. 1%
tetramethylsilane as an internal standard on a Brucker DRX 200 and DRX 400
spectrometers. Coupling constants (J) are given in Hertz (Hz). The [a]D were
recorded on Perkin-Elmer 241-MC sodium absorption at 20°C. Infrared spectra were
obtained on a Bomem FT IR MB-102 spectrometer in KBr pellets. Mass spectra
(m/z) were recorded on atlas CH4 or AEI MS9 spectrometers. Elemental analyses
were carried at ‘‘Laboratoire Central de Microanalyse du CNRS, ICSN, Gif sur
Yvette, France.’’
The progress of all reactions was monitored by thin-layer chromatography, which
was performed on 2.0 cm X 6.0 cm aluminum sheets precoated with silica gel 60
(HF-254, Merck) to a thickness of 0.25 mm. The developed chromatograms were
viewed under an ultraviolet light. For column chromatography, Merck silica gel
(70–230 mesh) was used. Solvents used in the reactions were generally redistilled
prior to use.

Synthesis of Protected EPI-2-Deoxystreptamine and Analogs
737
2-L-2,4,5/3 1-Benzyloximino-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol
(3). To a mixture of 2 (1 g, 2.3 mmol) in DMF (10 mL) was added at 0°C a
dispersion of NaH (0.11 g, 2.6 mmol) in mineral oil (60%), and then benzyl chloride
(0.3 g, 2.4 mmol). The reaction mixture was stirred at 90°C for 3 h. Water was added
(20 mL), and the resulting mixture was extracted with dichloromethane (3 ꢀ 50 mL).
The organic layer was dried over anhydrous MgSO4, and concentrated under reduced
pressure to furnish a crude residue. Purification by flash chromatography (hexane/ethyl
acetate) yielded 1.1 g (91%) of benzyloxime 3 as a crystalline material, mp 82–84°C
20
1
(hexane/ethyl acetate); [a]D –16 (c 1.0; CHCl3). H NMR (200 MHz; CDCl3) d 2.70
(dd, 1H, H-6a, J6a–6e = 15.0, J6aÀ5 = 5.0 Hz), 3.00 (dd, 1H, H-6e, J6eÀ5 = 7.0 Hz),
3.70 (s, 1H, H-4), 4.00 (m, 3H, H-2, H-3, H-5), 4.20–4.80 (m, 6H, 3CH2Ph), 5.20 (s,
2H, NOCH2Ph), 7.30 (m, 20H, Ph); 13C NMR (50.3 MHz; CDCl3) d 27.7 (C-6), 66.6
(C-5), 71.5, 72.3, 73.7, 75.9 (CH2Ph), 78.1, 79.0, 80.2 (C-2, C-3, C-4), 127.7, 127.9,
128.0, 128.3, 137.9, 138.1 (Ph), 153.6 (C1).
Anal. Calcd for C34H35NO5: C, 75.95; H, 6.56; N, 2.60; Found: C, 75.76; H, 6.53;
N, 2.50.
2-L-1,2,4,5/3 1-Amino-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol (4); 2-L-1,
3/2,4,5 1-amino-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol (5) and 2-L-1,3/2,4,5 1-
benzylhydroxylamino-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol (6). To a solu-
tion of benzyloxime 3 (5.37 g, 10 mmol) in 30 mL of anhydrous THF was added
LiAlH4 (0.8 g, 21 mmol). The reaction mixture was stirred 12 h at reflux under an
atmosphere of N2. Methanol was added and the mixture was filtered through a pad of
Celite. The solvent was removed under reduced pressure. The crude residue was pu-
rified by chromatography yielding epimeric amines 4 (8%) and 5 (74%) (characterized
as acetamide 7 and 8) along with the benzylhydroxylamine 6 (8%). Compound 6 was
characterized as its hydrochloride salt, dec.172–174°C (hexane/diethyl ether);
20
1
[a]D + 33 (c 0.5, CHCl3); H NMR (400 MHz; CDCl3) d 1.80 (m, 1H, H-6a), 2.60
(m, 1H, H-6e, J6a–6e = 12.7 Hz), 3.35 (s, 1H, H-4), 3.80 (s, 3H, H-1, H-2, H-3), 4.05
(s, 1H, H-5), 4.50–4.90 (m, 6H, CH2Ph), 5.20 (m, 2H, NOCH2Ph), 7.00–7.40 (m, 20H,
Ph); 13C NMR (100.6 MHz; CDCl3) d 28.0 (C-6), 58.1 (C-1), 65.4 (C-4), 77.7 (C-3),
82.5, 82.7 (C-2, C-5). MS (E. I): m/z 540 [M + H]+.
Anal. Calcd for C34H37NO5.HCl: C, 70.88; H, 6.47; N, 2.43; Found: C, 70.56; H,
6.51; N, 2.53.
2-L-1,2,4,5/3 1-Acetamido-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol
(7). The amine 4 (866 mg, 2 mmol) was treated with acetic anhydride (408 mg, 4 mmol)
in methanol (15 mL) for 4 h at rt. Then 15 mL of water was added and the mixture was
extracted with dichloromethane (3 ꢀ 20 mL). The organic layer was concentrated
furnishing a crude residue. Purification by column chromatography (hexane/ethyl acetate)
20
gave 855 mg (90%) of compound 7 as an oil. [a]D À 5 (c 2.7; CH2Cl2).
Anal. Calcd for C29H33NO5.H2O: C, 70.56; H, 7.15; N, 2.84; Found: C, 70.48; H,
6.91; N, 2.91.
2-L-1,3/2,4,5 1-Acetamido-2,3,4-tri-O-benzyl-2,3,4,5-cyclohexanetetrol
(8). The amine 5 (866 mg, 2 mmol) was treated with acetic anhydride (408 mg, 4 mmol)
in methanol (15 mL) for 4 h at rt. Then 15 mL of water was added and the mixture was

738
De Almeida et al.
extracted with dichloromethane (3 ꢀ 20 mL). The organic layer was concentrated fur-
nishing a crude residue. Purification by column chromatography (hexane/ethyl acetate)
gave 855 mg (90%) of the compounds 8 as a solid, mp 194–196°C (hexane/ethyl acetate);
[a]D + 36 (c 1.1; CHCl3). 1H NMR (200 MHz; DMSO d6) d 1.20–1.60 (m, 1H, H-6a),
20
1.80–2.20 (m, 1H, H-6e), 3.40–3.50 (m, 2H, H-2, H-4), 3.50–3.80 (m, 1H, H-3), 4.10 (m,
2H, H-1, H-5), 4.40–5.00 (m, 6H, 3CH2Ph), 7.00–7.60 (m, 15H, Ph), 8.43 (m, 2H, NH2);
13C NMR (50.3 MHz; DMSO d6) d 32.8 (C-6), 48.4 (C-5), 63.7 (C-1), 71.0, 74.3, 74.7
(CH2Ph), 81.7, 82.8 (C-2, C-3, C-4), 127.8, 128.4, 138.9 (Ph).
Anal. Calcd for C29H33NO5: C, 73.26; H, 6.95; N, 2.95; Found: C, 72.96; H, 6.99;
N, 2.90.
Conversion of 6 in 5. To a solution of compound 6 (827 mg, 1.43 mmol) in
methanol (30 mL) was added slowly 1.36 g (5.7 mmol) of NiCl2.6H2O and then 1.63 g
(42.8 mmol) of NaBH4 at À10°C. The resulting mixture was stirred at this temperature
for 8 h. The solvent was removed at reduced pressure and the residue was purified by
flash chromatography to furnish 662 mg of the compound 5 (quantitative yield),
characterized as acetamide 8.
2-L-1,2,4/3,5 1-Acetamido-5-fluoro-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(9). A mixture of compound 7 (475 mg, 1 mmol) and DAST (0.4 mL, 3 mmol) in
dichloromethane (20 mL) was stirred at 0°C for 4 h and at rt for further 2 h. Then,
was added 5 mL of water and this mixture was extracted with dichloromethane
(3 ꢀ 20 mL). The organic layer was submitted to the usual work-up furnishing a
crude residue. Purification by column chromatography (hexane/ethyl acetate) yielded
20
the compound 9 (70% yield). mp 73–75°C (hexane/ethyl acetate); [a]D À 6 (c 1.3;
1
CH2Cl2). H NMR (400 MHz; C6D6) d 0.67 (m, 1H, H-6a), 0.95 (s, 3H, CH3), 1.85
(m, 1H, H-6e), 2.62 (dd, 1H, H-2, J2–1 = 4.7, J2–3 = 9.0 Hz), 2.77 (m, 1H, H-4), 2.98
(t, 1H, H-3, J3–4 = 8.5 Hz), 3.90 (m, 1H, H-1), 4.08 (m, 1H, H-5, J5ÀF = 49,
J5À4 = 8.5, J5–6e = 3.5, J5–6a = 9.8 Hz), 3.63–4.26 (m, 6H, CH2Ph), 5.20 (d,1H, NH,
J
NH-1= 6.9 Hz), 6.44–6.73 (m, 15H, Ph); 13C NMR (100.6 MHz, CDCl3) d 23,3
(CH3), 30.5, 30.7 (C-6), 44.2, 44.4 (C-1), 79.3 (C-2), 80.0, 80.1 (C-3), 82.8, 83.0 (C-
4), 90.3, 92.1 (C-5,J5ÀF = 177), 170.7 (C O).
Anal. Calcd for C29H32NO4F: C, 72.93; H, 6.75; N, 2.93; Found: C, 72.56; H,
6.77; N, 2.78.
2-L-1,3,5/2,4 1-Acetamido-5-fluoro-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(10). Compound 10 was prepared from 8 as described for the preparation of fluoride 9
20
from 7. Yield: 70%. mp 169–171°C (hexane/ethyl acetate); [a]D + 20 (c 0.4; CHCl3).
1H NMR (400 MHz; CDCl3) d 1.44 (m, 1H, H-6a, J6a–6e = 12 Hz), 2.49 (m, 1H, H-6e),
3.35 (dd, 1H, H-2, J2–3 = 8.6, J2À1 = 10 Hz), 3.55 (t, 1H, H-3, J3–4 = 8.6 Hz), 3.60 (m,
1H, H-4, J4–5 = 8.5 Hz), 3.74 (m, 1H, H1), 4.60 (m, 1H, H-5, J5ÀF = 49, J5–6a = 9.3
Hz), 4.60–4.92 (m, 7H, CH2Ph, NH), 7.25–7.40 (m, 15H, Ph); 13C NMR (100.6 MHz,
CDCl3) d 23.3 (CH3), 33.0, 33.2 (C-6), 47.1, 47.2 (C-1), 80.9 (C-2), 82.8, 82.9 (C-3),
83.7, 83.9 (C-4), 90.5, 92.3 (C5, J5ÀF = 179 Hz), 169.9 (C O).
Anal. Calcd for C29H32NO4F.1/2 H2O: C, 71.58; H, 6.83; N, 2.83; Found: C,
71.87; H, 6.81; N, 2.86.

Synthesis of Protected EPI-2-Deoxystreptamine and Analogs
739
2-L-1,3/2,4,5 1-Acetamido-2,3,4-tri-O-benzyl-5-O-methanesulfonyl-2,3,4,5-cyc-
lohexanetetrol (11). To a solution of 8 (237 mg, 0.5 mmol) in pyridine (10 mL) was
added 0.1 mL (1.4 mmol) of methanesulfonyl chloride. The mixture was stirred at 0°C
for 12 h. Then 15 mL of water was added and this mixture was extracted with
dichloromethane (3 ꢀ 20 mL). The organic layer was concentrated and the residue
purified by flash cromatography to furnish 241 mg of 11 (88% yield). mp 175–177°C
(hexane/ethyl acetate); [a]D + 75 (c 0.7; CHCl3). 1H NMR (400 MHz; CDCl3) d
20
1.72 (dt, 1H, H-6a), 1.75 (s, 1H, CH3CONH), 2.42 (dt, 1H, H-6e, J6e–6a = 14.6,
J6e–1 = J6eÀ5 = 4.3 Hz), 3.07 (s, 3H, CH3SO3R), 3.53 (dd, 1H, H-4, J4–3 = 9.2,
J4–5 = 2.9 Hz), 3.57 (dd, 1H, H-2, J2À1 = 10, J2–3 = 9.0 Hz), 3.85 (t, 1H, H-3), 3.88
(m, 1H, H1), 4.60–4.93 (m, 6H, CH2Ph), 5.13 (m, 1H, H-5), 5.20 (d, 1H, NH), 7.27–
7.38 (m, 15H, Ph); 13C NMR (100.6 MHz, CDCl3) d 23.5 (CH3CO), 31.6 (C-6), 39.3
(CH3SO3R), 48.4 (C-1), 76.7, 80.2, 80.7, 81.8 (C-2, C-3, C-4, C-5), 170.3 (C O).
Anal. Calcd for C30H34NO7S: C, 65.20; H, 6.20; N, 2.53; Found: C, 65.03; H,
6.47; N, 2.41.
2-L-1,3,5/2,4 1-Acetamido-5-azido-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(12). A solution of compound 11 (240 mg, 0.43 mmol) in DMSO (5 mL) was treated
with sodium azide (113 mg, 1.74 mmol) at 120°C for 48 h. After addition of water (5
mL), the precipitate was collected and washed with water. This solid was recrystallized
from a mixture of diethyl ether/hexane to gave 189 mg of 12 (88% yield). mp 211–
20
1
213°C; [a]D + 63 (c 0.9; CHCl3). H NMR (400 MHz; C6D6) d 0.58 (q, 1H, H-6a,
J6a–6e = 13 Hz), 1.68 (dt, 1H, H-6e, J6eÀ5 = J6eÀ1 = 4.5 Hz), 1.86 (s, 3H, CH3), 2.53
(m, 1H, H-5, J5À4 = 9.8 Hz), 2.73 (dd, 1H, H-2, J2À1= 10.2, J2À3 = 9.3 Hz), 2.88 (t,
1H, H-4, J4À3 = 9.8 Hz), 3.01 (t, 1H, H-3), 3.46 (m, 1H, H-1), 3.98 (d, 1H, NH, JNH-1 = 7.2
Hz), 4.17–4.57 (m, 6H, CH2Ph), 6.70–7.10 (m, 15H, Ph); 13C NMR (100.6 MHz; CDCl3)
d 23.3 (CH3), 33.1 (C-6), 48.8 (C-1), 60.8 (C-5), 81.2 (C-2), 84.6, 84.9 (C-3, C-4), 169.9
(C O).
Anal. Calcd for C29H31N4O4: C, 69.72; H, 6.26; N, 11.21; Found: C, 69.61; H,
6.46; N, 11.04.
2-L-1,3,5/2,4 1-Acetamido-5-amino-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(13). To a solution of 12 (300 mg, 0.6 mmol) in anhydrous THF (5 mL) was added
PPh3 (312 mg, 1.2 mmol). The mixture was stirred for 1 h at rt and water (1 mL) was
added. After 12 h solvents were removed and the crude residue was purified by column
chromatography (hexane/ethyl acetate) yielding 207 mg (73%) of 13. Dec. 220–227°C
20
(hexane/ethyl acetate); [a]D + 22 (c 2.3; CH2Cl2).
Anal. Calcd for C29H34N2O4.HCl.H2O: C, 65.83; H, 7.05; N, 5.29; Found: C,
65.75; H, 6.91; N, 5.25.
2-L-1,3,5/2,4 1-Acetamido-5-thioacetyl-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(14). A mixture of 180 mg (0.33 mmol) of 11 and 75 mg (0.65 mmol) of potassium
thioacetate in 25 mL of DMF was stirred at 100°C for 48 h. Water (30 mL) was added, and
the mixture was extracted with diethyl ether (4 ꢀ 30 mL). The organic layer was sub-
mitted to the usual work-up furnishing a crude residue. Purification by column chroma-
tography (hexane/ethyl acetate) gave 110 mg (64%) of compound 14. Dec. 204–206°C

740
De Almeida et al.
20
(hexane/ethyl acetate); [a]D + 30 (c 1.4; CHCl3). 1H NMR (400 MHz; CDCl3) d 1.50 (q,
1H, H-6a), 1.71 (s, 3H, CH3CON), 2.24 (s, 3H, CH3COS), 2.35 (dt, 1H, H-6e, J6e–6a
13.0 Hz), 3.40 (dd, 1H, H-2, J2–1 = 10, J2–3 = 9.1 Hz), 3.50 (m, 2H, H-4, H-5, J4À3
=
=
J4–5 = 9.0 Hz), 3.64 (t, 1H, H-3), 3.75 (m, 1H, H-1), 4.60–4.93 (m, 6H, CH2Ph), 4.95 (d,
1H, NH, JNH-1 = 7.0), 7.25–7.37 (m, 15H, Ph); 13C NMR(100.6 MHz; CDCl3) d 23.4
(CH3CONH), 30.7 (CH3COS), 33.9 (C-6), 43.4 (C-5), 50.8 (C-1), 81.3, 82.3, 86.4 (C-2,
C-3, C-4), 169.8 (HNC O), 194.4 (SC O).
Anal. Calcd for C31H35NO5S: C, 69.77; H, 6.61; N, 2.63; Found: C, 69.85; H,
6.91; N, 2.66.
2-L-1,3/2,4 1-Acetamido-5-oxo-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(15). To a solution of acetamide 8 (475 mg, 1 mmol) in CH2Cl2 (10 mL) was added
PCC (1.08 g, 5 mmol). The reaction mixture was stirred at rt for 48 h, water was added
(20 mL) and the mixture was extracted with diethyl ether (3 ꢀ 10 mL). The organic
layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to
furnish the crude residue, that was purified by flash chromatography (ethyl acetate),
yielding 407 mg (86%) of crystalline 15. mp 200–202°C (hexane/ethyl acetate);
20
1
[a]D + 29 (c 1.5; CHCl3); H NMR (200 MHz; CDCl3) d 2.57 (dd,1H, H-6a, J6a–6e
=
14.0, J6aÀ5 = 10.0 Hz), 3.00 (dd,1H, H-6e, J6eÀ6a = 14.0, J6aÀ5 = 5.0 Hz), 3.83 (m, 2H,
H-2, H-4), 4.00 (m, 1H, H-3), 4.10 (m, 1H, H-5), 4.40–5.00 (m, 6H, 3CH2Ph), 5.60 (d,
1H, NH, JNH-5 = 7.0 Hz), 7.30 (m, 15H, Ph); 13C NMR (50.3 MHz; CDCl3) d 23.4
(CH3CONH), 41.8 (C-6), 49.3 (C-1), 73.3–75.1 (3 CH2Ph), 78.9 (C-3), 82.9 (C-2),
84.8 (C-4), 128.0À138.0 (Ph), 170.1 (HNC O), 204.1 (C O). MS (E.I): m/z 368
[M + H]+.
Anal. Calcd for C29H31NO5: C, 73.55; H, 6.59; N, 2.96; Found: C, 73.25; H, 6.59;
N, 3.02.
2-L-1,3/2,4 1-Acetamido-5-benzyloximino-2,3,4-tri-O-benzyl-2,3,4-cyclohexane-
triol (16). To a solution of 15 (473 mg, 1 mmol) in methanol (5 mL) and pyridine (1
mL) was added O-benzylhydroxylamine hydrochloride (240 mg, 1.5 mmol). The re-
action mixture was stirred during 2 h at rt. The solvent was removed under reduced
pressure, and water was added to the residue. After extraction with dichloromethane the
organic layer was dried over anhydrous MgSO4 and concentrated under reduced
pressure to furnish 16 (570 mg, quantitative yield). The product was purified by re-
20
1
crystallization (hexane/diethyl ether), mp 176–178°C; [a]D À 4 (c 0.5; CHCl3); H
NMR (400 MHz; CDCl3) d 1.60 (s, 3H, CH3), 2.80 (dd, 1H, H-6a, J6aÀ6a = 14,
J6aÀ1 = 4.0 Hz), 2.70 (dd, 1H, H6e, J6eÀ1 = 5.2 Hz), 3.60 (t, 1H, H-2, J2–3 = 2.8 Hz),
4.00 (t, 1H, H-3), 4.10 (d, 1H, H-4, J4À3 = 2.8 Hz), 4.41–4.45 (m, 1H, H-1), 6.02 (d,
1H, NH, J1-NH = 8.0 Hz), 7.21–7.31 (m, 20H, Ph); 13C NMR (50.3 MHz; CDCl3) d
23.9 (CH3CONH), 25.2 (C-6), 48.7 (C-1), 71.1–73.2 (3 CH2Ph), 76.6 (C NOCH2Ph),
77.1 (C-2), 77.2 (C-3), 80.1 (C-4), 128.2–138.8 (Ph), 154.6 (C-5), 170.1 (CO).
Anal. Calcd for C36H38N2O5.1/2 H2O: C, 73.57; H, 6.69; N, 4.77; Found: C, 73.56;
H, 6.71; N, 4.65.
2-L-1,3/2,4,5 1,5-Diamino-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol (17). To a
solution of oxime 16 (290 mg, 0.5 mmol) in anhydrous THF (20 mL) was added
LiAlH4 (152 mg; 4 mmol). The reaction mixture was stirred during 24 h at reflux.

Synthesis of Protected EPI-2-Deoxystreptamine and Analogs
741
The reaction mixture was cooled to 0°C and water was added slowly. After filtration
over a pad of Celite the solvent was evaporated and the residue was purified by flash
chromatography (CH2Cl2/MeOH) to afford 130 mg of the desired amine (60% yield)
as an oil; 1H NMR (400 MHz; Acetone-d6) d 1.39 (ddd, 1H, H-6a, J6a–6e = 13.6,
J6aÀ1 = 11.0, J6aÀ5 = 3.0 Hz), 1.76 (dt, 1H, H-6e, J6eÀ1 = J6eÀ5 = 3.6 Hz), 2.81 (s, 4H,
NH2), 3.20 (ddd, 1H, H-1, J1–2 = 9.2 Hz), 3.39 (t, 1H, H-3, J3À2 = J3–4 = 9.2 Hz), 3.61
(dd, 1H, H-4, J4–5 = 3.6 Hz), 4.07 (m, 1H, H-5), 4.19 (t, 1H, H-2), 4.60–5.00 (m, 6H,
CH2Ph), 7.20–7.35 (m, 15H, Ph); 13C NMR (100.6 MHz; Acetone-d6) d 34.3 (C-6),
56.0, 56.7 (C-1,C-5), 72.8, .75.5, 75.6 (3 CH2Ph), 83.9, 85.2, 86.7, (C-2, C-3, C-4),
127.8–140.7 (Ph).
Anal. Calcd for C27H32N2O3: C, 74.97; H, 7.46; N, 6.47; Found: C, 74.67; H, 7.66;
N, 10.87.
2-L-1,3/2,4,5 1,5-Diacetamido-2,3,4-tri-O-benzyl-2,3,4-cyclohexanetriol
(18). The amine 17 (216 mg, 0.5 mmol) was treated with acetic anhydride (204 mg,
2.0 mmol) in pyridine (10 mL) for 4 h at rt. Then, 15 mL of water were added and the
mixture was extracted with dichloromethane (3 ꢀ 20 mL). The organic layer was
concentrated furnishing a crude residue. Purification by column chromatography (ethyl
1
acetate/methanol) gave 230 mg of the compound 18 (90%) as an oil. H NMR (400
MHz; CDCl3) d 1.57 (dt, 1H, H-6a, J6a–6e = 14, J6aÀ1 = 10.4 Hz), 2.53 (dt, 1H, H-6e,
J6eÀ1 = J6eÀ5 = 3.6 Hz), 3.44 (dd, 1H, H-3, J3À2 = 8.0, J3À4 = 10.0 Hz), 3.63 (m, 2H,
H-2, H-4), 3.81 (ddd, 1H, H-1, J1–2 = 9.6 Hz), 4.35 (m, 1H, H-5), 4.50–5.00 (m, 6H,
CH2Ph), 7.15–7.35 (m, 15H, Ph); 13C NMR (100.6 MHz; CDCl3) d 22.4, 23.6 (CH3),
30.1 (C-6), 46.3 (C-5), 55.5 (C-1), 71.9, 75.7, 75.9 (CH2Ph), 80.0, 80.2, 83.2 (C-2, C-3,
C-4), 127.6-138.8 (Ph), 170.9, 171.1 (C O).
Anal. Calcd for C31H36N2O5: C, 72.09; H, 6.98; N, 5.43; Found: C, 72.01; H, 6.92;
N, 5.64.
ACKNOWLEDGMENT
We wish to thank Drs. J. Cleophax and R. H. Dodd for many fruitful discussions.
This research was supported by CNPq.
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Received February 12, 2003
Accepted August 5, 2003