Efficient synthesis of 1-deoxy-azasugars as useful synthetic tools

Article abstract of DOI:10.1016/S0040-4039(03)00512-4

1-Deoxy-azasugars are efficiently prepared from sugar-lactones using a stereoinversion process and they are applied to the synthesis of a natural product.

Full text of DOI:10.1016/S0040-4039(03)00512-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3085–3088
Efficient synthesis of 1-deoxy-azasugars as useful synthetic tools
Daisuke Sawada, Hideyo Takahashi and Shiro Ikegami*
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko Kanagawa 199-0195, Japan
Received 1 February 2003; revised 21 February 2003; accepted 21 February 2003
Abstract—1-Deoxy-azasugars are efficiently prepared from sugar-lactones using a stereoinversion process and they are applied to
the synthesis of a natural product. © 2003 Elsevier Science Ltd. All rights reserved.
Azasugars, monosaccharide analogues having a nitro-
gen atom instead of the ring oxygen atom, have inter-
esting activities for glycoside-related enzymes, and they
have been intensively studied as glycosidase inhibitors1
with potential therapeutic utility. Some strong
inhibitors such as (+)-nojirimycin and (+)-deoxynoji-
rimycin are representative.2 1-Deoxy-azasugars are
chemically more stable than normal azasugars due to a
lack of a hydroxyl group at the C1 position, and thus
they must be suitable compounds for practical use.3 As
a result, it becomes necessary to supply a large amount
of various 1-deoxy-azasugars by chemical synthesis.
Although numerous synthetic methods have been devel-
oped,4 they sometimes needed lengthy steps, and
resulted in mixtures of the stereoisomers in low yields.
Here we report a more efficient synthetic method for
1-deoxy-azasugars, and its applications to natural
product synthesis as useful tools.
reaction5 as a key step.6 The present synthetic plan is
also based on the SN2 type cyclization procedures. At
first, we describe the synthesis of six-membered 1-
deoxy-azasugars. We started with three kinds of
D-gly-
cono-1,5-lactones 1, 2, 3, which are easily derived from
glucose, galactose and mannose, respectively7 (Scheme
1). The lactones 1, 2, 3 were converted to the amides 4,
5, 68 by treatment with NH3 in nearly quantitative
yields. Reduction of the amides by refluxing in THF
with LiAlH4 gave the amines 7, 8, 9, and then, the
cyclization reactions were tried under the Mitsunobu
conditions after converting to sulfonamide derivatives.
According to the methods developed by Fukuyama et
al.,9 the amines 7, 8, 9 were reacted with 2-nitrobenz-
enesulfonyl chloride (NsCl) and triethylamine in
CH2Cl2 to afford the corresponding 2-nitrobenzenesul-
fonamides 10, 11, 12. Successively, they underwent the
Mitsunobu conditions (triphenylphosphine and diethyl
azodicarboxylate in THF), and the cyclization reactions
easily proceeded through complete inversion to afford
We have already developed the selective synthesis of
L
-sugars from
D
-sugar-lactones using the Mitsunobu
the L-1-deoxy-azasugar derivatives 13, 14, 15 in good
Scheme 1.
Keywords: amino sugars; carbohydrate mimics; indolizidine; Mitsunobu reaction.
* Corresponding author. Tel.: +81-42-658-3728; fax: +81-42-685-1872; e-mail: shi-ike@pharm.teikyo-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00512-4

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D. Sawada et al. / Tetrahedron Letters 44 (2003) 3085–3088
Scheme 2. Reagents and conditions: (a) NH3, MeOH; 80%; (b) LiAlH4, THF, reflux; 76%; (c) NsCl, Et3N, CH2Cl2; 93%; (d) PPh3,
DEAD, THF; quant.; (e) PhSH, K2CO3, DMF; 79%.
yields. After removing an Ns group using PhSH, the
corresponding azasugars 16, 17, 1810 were obtained in
65, 66, 71% overall yields from 1, 2, 3, respectively.
Thus, we were able to develop an excellent method for
idene-
converted from
D
-mannono-1,4-lactone11 (19), which is easily
-mannono-1,4-lactone, was used as
D
the starting material (Scheme 2). The g-lactone 19 was
converted to the amide 20 by reacting with NH3 and
then reduced to the amine 21. After nosylation of the
amine, the Mitsunobu reaction was conducted to give
the cyclized product 23 in quantitative yield. Finally,
the removal of an Ns group resulted in the formation of
the synthesis of the 1-deoxy-aza-derivaives of
(16), -altrose (17), and -gulose (18) converted from
-glucose, -galactose and -mannose, respectively, in
excellent yields.
L-idose
L
L
D
D
D
the five-membered -1-deoxy-azasugar derivative 24.
L
Next, we turned our attention to the synthesis of five-
membered 1-deoxy-azasugars. 2,3,5,6-Di-O-isopropyl-
This material 24 is provided as the starting material for
the synthesis of biologically important compounds, in
which one example is described. Intermediate 23 was
selectively hydrolyzed to the diol 25 by TFA in 70%
yield (conv. y. 82%), which was oxidized to the alde-
hyde 26 by the NaIO4-cleavage (Scheme 3). Reduction
of the aldehyde, then the removal of an Ns group
afforded 27 in good yields. Finally, it was hydrolyzed
with 1N HCl to give the 1-deoxy-aza-analogue of
L-
ribose 28, that is
L
-iminoribitol.4j–m,12 Also, the alde-
hyde 26 could be applicable as the key compound for
natural product synthesis (Scheme 4). Wittig reaction to
26 using the reagent 29 afforded the adduct 30 in 69%
yield as an E–Z mixture. The nosyl group was removed,
and the resultant amine was protected as a trifluoroac-
etamide to give 31 in 91% yield (two steps). Both the
hydrogenation of the olefin part and the removal of the
benzyl group resulted in an alcohol, which was trans-
Scheme 3. Reagents and conditions: (a) TFA, THF, H2O; 70%
(conv. y. 82%); (b) NaIO4, silica gel, CH2Cl2, H2O; 96%; (c) 1,
NaBH4, MeOH; quant; 2, PhSH, K2CO3, CH3CN; 75%; (d)
1N, HCl, reflux; quant.
Scheme 4. Reagents and conditions: (a) NaHMDS, THF, 29, −78 to 0°C; 69%; (b) 1, PhSH, K2CO3, DMF; 95%; 2, (CF3CO)2O,
Py, CH2Cl2; 96%; (c) 1, Pd·C, MeOH, H2; 79%; 2, TsCl, DABCO, CH2Cl2, quant.; (d) K2CO3, MeOH, H2O, 50°C; 75%; (e) 1N
HCl, reflux; 90%.

D. Sawada et al. / Tetrahedron Letters 44 (2003) 3085–3088
3087
formed to the tosylate (32). Then, treatment with
K2CO3 in MeOH and H2O caused both the hydrolysis
of the trifluoroacetamide of 32 and the continuous
cyclization. The bicyclic product 33 was successfully
obtained in 75% yield. Finally, the deprotection of an
acetonyl group afforded 2-epilentiginosine.13
Am. Chem. Soc. 2000, 122, 2995; (b) Takahashi, H.; Iwai,
Y.; Hitomi, Y.; Ikegami, S. Org. Lett. 2002, 4, 2401.
7. Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 4976.
8. Overkleeft, H. S.; van Wiltenburg, J.; Pandit, U. K.
Tetrahedron 1994, 50, 4215.
9. (a) Fukuyama, T.; Jow, C.-K.; Cheng, M. Tetrahedron
Lett. 1995, 36, 6373; (b) Fukuyama, T.; Cheng, M.; Jow,
C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38,
5831.
In summary, we have developed a novel method to
prepare 1-deoxy-azasugars more efficiently from sugar-
lactones with the inversion of stereochemistry. This
method could be applied to numerous lactones, and
would afford biologically important compounds.
10. 16: [h]2D1 −11.6 (c 1.65, CHCl3); IR (neat) 3088, 3063,
3030, 2918, 2862, 1604, 1587, 1497, 1455, 1366, 1206,
1094, 1073, 1028, 735, 698 cm−1 1H NMR (400 MHz,
;
CDCl3) l 7.22–7.33 (m, 20H), 4.64 (s, 2H), 4.60–4.52 (m,
6H), 3.68 (dd, J=9.5, 9.5 Hz, 1H), 3.60–3.64 (m, 2H),
3.55 (dd, J=5.3, 9.5 Hz, 1H), 3.41–3.47 (m, 1H), 3.36–
3.41 (m, 1H), 3.02 (dd, J=4.2, 13.0 Hz, 1H), 2.86 (dd,
J=6.6, 13.0 Hz, 1H), 2.35 (brs, 1H); 13C NMR (100
MHz, CDCl3) l 138.4, 138.3, 138.2, 138.1, 128.2, 128.1,
128.1, 127.7, 127.6, 127.5, 127.5, 127.4, 127.4, 127.3, 77.9,
77.0, 76.8, 74.0, 73.3, 72.5, 72.0, 67.1, 54.6, 44.2; EI-S m/z
523 (M+); EI-HRMS calcd for C34H37NO4 (M+):
523.2722, found: 523.2717. 17: [h]1D8 −11.9 (c 0.325,
CHCl3); IR (neat) 3063, 3030, 2924, 2862, 1732, 1651,
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1585, 1496, 1454, 1364, 1208, 1100, 1028, 741, 698 cm−1
;
1H NMR (400 MHz, CDCl3) l 7.23–7.35 (m, 20H), 4.71
(d, J=14.0 Hz, 1H), 4.40–4.59 (m, 7H), 3.81–3.89 (m,
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1H), 3.07 (dd, J=1.8, 14.2 Hz, 1H), 2.97 (m, 1H), 2.42
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2858, 1604, 1587, 1495, 1454, 1365, 1207, 1101, 1028, 742,
698 cm−1; H NMR (400 MHz, CDCl3) l 7.22–7.35 (m,
1
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4.34–4.57 (m, 7H), 3.80–3.82 (m, 1H), 3.73–3.79 (m, 1H),
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D. Sawada et al. / Tetrahedron Letters 44 (2003) 3085–3088
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