New entry for asymmetric deoxyazasugar synthesis: Syntheses of deoxymannojirimycin, deoxyaltrojirimycin and deoxygalactostatin

Article abstract of DOI:10.1039/a807532h

Deoxyazasugars such as deoxymannojirimycin, deoxyaltrojirimycin and deoxygalactostatin were stereoselectively synthesized starting from (R)-(+)-4-methoxycarbonyloxazolidinoe via a bicyclic oxazolidinylpiperidine as a common synthetic intermediate.

Full text of DOI:10.1039/a807532h

New entry for asymmetric deoxyazasugar synthesis: syntheses of
deoxymannojirimycin, deoxyaltrojirimycin and deoxygalactostatin
Koji Asano, Toshikazu Hakogi, Seiji Iwama and Shigeo Katsumura*
School of Science, Kwansei Gakuin University, Uegahara, Nishinomiya 662-8501, Japan.
E-mail: katumura@kwansei.ac.jp
Received (in Cambridge, UK) 28th September 1998, Accepted 9th November 1998
Deoxyazasugars such as deoxymannojirimycin, deoxyal-
trojirimycin and deoxygalactostatin were stereoselectively
synthesized starting from (R)-(+)-4-methoxycarbonylox-
azolidinone via a bicyclic oxazolidinylpiperidine as a com-
mon synthetic intermediate.
of 6 along with its stereoisomer with Lindlar catalyst produced
cis-allyl alcohol 7,‡ which was isolated, then treated with
sodium in liquid ammonia followed by acid to give the
corresponding diol. Unfortunately, cyclization attempts utiliz-
ing the obtained diol via the tosylate of the primary alcohol were
unsuccessful. The secondary hydroxy group of 7 was then
protected with a TBDMS group, and the terminal silyl group
was selectively removed by treatment with aq. HF in MeCN to
give allyl alcohol 8.9 The cyclization proceeded successfully
upon treatment of 8 with MsCl followed by NaH to produce
Recently, polyhydroxylated piperidine alkaloids have received
much attention due to their importance as glycosidase in-
hibitors.1 Among them, deoxymannojirimycin 1 isolated from
Lonchocarpus sp.,2 deoxyaltrojirimycin 23 and deoxygalacto-
statin 34 can be regarded as deoxyazasugars based on their
structural relationship to deoxysugars. Deoxy compound 1 is a
moderate inhibitor of a-mannosidases and a good inhibitor of
mammalian a-fucosidase, compound 2 is known as an analogue
of 1 and is named in the relation with altrose, and compound 3
is a potent inhibitor of galactosidase. Because of the significant
biological activities of these compounds as well as their
characteristic structure, a number of synthetic efforts have been
reported.5†
O
O
Bn
Bn
N
O
N
O
i
MeO
TBDMSO
O
O
4
5
O
O
ii
We previously developed both enantiomers of 4-methoxy-
carbonyloxazolidinone 4 as a chiral building block for the
synthesis of natural amino alcohols, and realized the stereo-
selective syntheses of both g-hydroxy-b-amino alcohols6 and
sphingolipids.7 As part of our continuing interest in the
synthetic utility of 4, we have applied this methodology to the
synthesis of deoxyazasugars. As a new flexible deoxyazasugar
synthesis, we now report the stereoselective asymmetric
syntheses of deoxymannojirimycin 1, deoxyaltrojirimycin 2 and
deoxygalactostatin 3 from common intermediate 9.
Bn
Bn
iii
N
O
N
O
O
TBDMSO
TBDMSO
OH
OH
O
6
7
iv–vi
HN
N
O
vii, viii
O
Synthesis of deoxymannojirimycin 1 via the common
intermediate 9 is shown in Scheme 1. Reaction of (R)-(+)-ester
4 with the lithium anion of propargyl alcohol silyl ether at 2100
OTBDMS
OH
OTBDMS
8
9
23
°C in THF gave ketone 5 [mp 31.0–32.0 °C; [a]D +32.2
ix
(c 0.88, CHCl3)]. The successful stereoselective reduction of
the ketone to produce the desired anti alcohol 6 was achieved
with diisobutylaluminium 2,6-di-tert-butyl-4-methylphenoxide
O
HO
HO
O
NH
N
x, xi
OH
O
1
in 92% yield; the anti:syn selectivity was 11:1 by H NMR
O
analysis. Reduction with NaBH4 and L-Selectride® gave a 5:3
and 1:2 mixture of anti- and syn-derivatives, respectively, and
triisobutylaluminium reduction showed 9:1 selectivity. The
obtained stereoselectivity can be understood by considering the
reaction intermediates as shown in Fig. 1. In the case of
diisobutylaluminium 2,6-di-tert-butyl-4-methylphenoxide re-
duction, two possible conformers A and B in the transition state
were considered based on an intramolecular fashion of this
reagent. Compared to intermediate A, intermediate B is
disfavored due to steric interactions between the bulky
aluminium reagent and the methylene group of the ox-
azolidinone ring, and hence this reaction resulted in high anti-
selectivity. On the other hand, conformers C and D were
anticipated in sodium borohydride and L-Selectride® reduc-
tion. There was considered to be no significant difference in
steric interactions between these conformers due to the
intermolecular fashion of the hydride attack of these reagents,
and they resulted in poor selectivity, despite the fact that the L-
Selectride® is sterically more demanding than NaBH4.
OR
R = OTBDMS
OTBDMS
11
11′ R = H
10
xii, xiii
HO
NH
OH
HO
OH
1-Deoxymannojirimycin 1
Scheme 1 Reagents and conditions: i, TBDMSOCH2C·CLi, THF, 2100
°C (82%); ii, diisobutylaluminium 2,6-di-tert-butyl-4-methylphenoxide,
toluene, 0 °C (92%); iii, Lindlar catalyst, H2, MeOH (90%); iv, Na, liquid
NH3, 278 °C; v, TBDMSCl, imidazole, DMF (67% for 2 steps), vi, 55% aq.
HF, MeCN, 220 °C (98%); vii, MsCl, Et3N, DMAP, DMF; viii, NaH,
DMF, 0 °C (80% for 2 steps); ix, OsO4, NMO, ButOH, H2O (86%); x,
Me2C(OMe)2, PPTS, acetone (92%); xi, 6
M aq. NaOH, dioxane, reflux, 24
With anti-alcohol 6 in hand, our attention turned to the
construction of the bicyclic oxazolidinylpiperidine. Reduction
h (71%); xii, conc. HCl, MeOH, reflux, 4 h (quant.); xiii, basic ion-exchange
resin.
Chem. Commun., 1999, 41–42
41

Diisobutylaluminum 2,6-di-tert-butyl-4-methylphenoxide
Al Al
+49.9 (c 0.48, CHCl3)] resulting from diaxial opening of the
epoxide ring. Synthesis of 2 from 13 was achieved by the same
procedures as those in the deoxymannojirimycin synthesis (6
aq. NaOH, conc. HCl; 85% for two steps).¶
Ph
O
Ph
O
M
R
O
N
O
N
O
The synthetic strategy for deoxyaltrojirimycin was applied to
the synthesis of deoxygalactostatin 3 (Scheme 2), which is not
a natural product but was synthesized as an analogue of
deoxygalactose. Oxidation of 9 with PDC after removal of the
silyl group gave the corresponding ketone. Reduction of the
ketone obtained with L-Selectride® in the presence of cerium
chloride produced syn alcohol 14 with a high degree of
H
Al
O
H
H
H
H
R
H
Al
B
A
(disfavored) (to syn)
(favored) (to anti)
1
stereoselectivity (20:1 by H NMR analysis; 77%). Although
epoxidation of 14 with MCPBA was very slow (room temp., 3
days, CHCl3), we obtained the desired a-oriented epoxide 15 in
65% conversion yield. The synthesis of deoxygalactostatin 3
was achieved from 15 by the same procedure employed in the
synthesis of deoxyaltrojirimycin. Thus, formation of acetonide
(52%), hydrolysis of oxazolidinone (67%), and then acid
treatment (quant.) yielded deoxygalactostatin 3.¶
In conclusion, 4-methoxycarbonyloxazolidinone 4 has been
proved to be a versatile chiral building block for the syntheses
of deoxyazasugars via bicyclic oxazolidinylpiperidine 9 as a
common synthetic intermediate.
NaBH4 or L-Selectride®
O
Ph
Ph
O
O
N
O
R
N
O
H
H
O
H–
H
H
R
H–
D
C
( no significant selectivity)
Fig. 1
This work was supported by a Grant-in-Aid for Scientific
Research from Monbusho (No.09480145). S. I. is grateful to the
Japan Promotion of Science for a postdoctoral fellowship.
bicyclic oxazolidinylpiperidine 9§. This compound was used as
the common intermediate for the present deoxyazasugar
synthesis. Oxidation of 9 with OsO4 yielded diol 10 as the sole
product, the stereochemistry of which was assumed to be anti to
the neighbouring siloxy group at this stage. Acetonide forma-
tion followed by cleavage of the oxazolidinone ring with aq.
NaOH in dioxane gave a mixture of monosilyl ether 11 and diol
11A. Upon treatment of the mixture with acid, deoxymannojir-
imycin 1 was quantitatively obtained after purification with
basic ion-exchange resin.¶
Notes and references
† Recently, Cinfolini and co-workers described an elegant synthesis of
deoxyazasugars via the aza-Achmatowicz reaction: M. A. Cinfolini,
C. Y. W. Hermann, Q. Dong, T. Shimizu, S. Swaminathan and N. Xi,
Synlett, 1998, 105.
24
‡ Selected data for 7: mp 83.0–84.0 °C; [a]D 223.9 (c 0.19, CHCl3);
n(KBr)/cm21 3262, 1778, 1119; dH(400 MHz, CDCl3) 0.067 (3H, s), 0.073
(3H, s), 0.90 (9H, s), 3.10 (1H, br s), 3.61–3.65 (1H, a pair of ddd, J 2.9, 6.1,
9.0), 4.26 (5H, m), 4.58 (1H, br d, J 6.1), 4.82 (1H, d, J 15.1), 5.37 (1H, ddt,
J 1.7, 7.3, 11.5), 5.72 (1H, m), 7.34 (5H, m).
Next is the synthesis of deoxyaltrojirimycin 2 (Scheme 2).
Epoxidation of bicyclic compound 9 after removal of the silyl
group gave epoxy alcohol 12, which was treated with BF3–Et2O
23
§ Selected data for 9: mp 92.5–93.0 °C; [a]D +26.0 (c 1.00, CHCl3);
n(KBr)/cm21 2953, 1786, 1630; dH(400 MHz, CDCl3) 0.11 (3H, s), 0.13
(3H, s), 0.90 (9H, s), 3.51 (1H, ddd, J 4.2, 8.1, 8.1), 3.65 (1H, m), 4.09 (1H,
m), 4.15 (1H, m), 4.22 (1H, dd, J 4.2, 8.9), 4.51 (1H, dd, J 8.1, 8.9), 5.72
(2H, s); dC(100 MHz, CDCl3) 24.68, 24.20, 17.86, 25.61, 40.82, 56.42,
67.21, 68.37, 123.83, 130.48, 157.24.
22
in acetone to produce acetonide 13 [mp 123.0–124.0 °C; [a]D
O
2
i,ii
N
27
9
O
O
¶ Selected data for 1: mp 186.0–186.5 °C; [a]D 235.7 (c 0.07, MeOH)
[lit.,5a mp 183–185 °C; [a]D 236.2 (c 0.342, MeOH)]. For 2: [a]D23 +16.3
20
3
(c 0.8, H2O) [lit. (of enantiomer),3b [a]D 214.5(c 0.7, CHCl3)]. For 3:
20
OH
12
[a]D27 +40.3 (c 0.38, H2O) [lit.,5c [a]25D +44.6(c 1.1, H2O)].
1 E. W. Baxter and A. B. Reitz, J. Org. Chem., 1994, 59, 3175; F. M. Platt,
G. R. Neises, R. A. Dwek and T. D. Butters, J. Biol. Chem., 1994, 269,
8362 and references cited therein.
2 L. E. Fellows, E. A. Bell, D. G. Lynn, F. J. Pilkiewcz, I. Miura and K.
Nakanishi, J. Chem. Soc., Chem. Commun., 1979, 977.
3 (a) X. Yi-Ming and Z. Wei-Shan, J. Chem. Soc., Perkin Trans. 1, 1997,
741; (b) R. Grandel and U. Kazmaier, Tetrahedron Lett., 1997, 38,
8009.
iii
O
HO
HO
HO
NH
N
iv–vi
O
OH
O
OH
O
1-Deoxyaltrojirimycin 2
13
4 Y. Miyake and M. Ebata, J. Antibiol., 1987, 40, 122; Y. Miyake and M.
Ebata, Agric. Biol. Chem., 1988, 52, 153.
O
N
5 Deoxymannojirimycin: (a) K. H. Yong, Y. J. Yoon and S. G. Lee,
J. Chem. Soc., Perkin Trans. 1, 1994, 2621; (b) X.-D. Wu, S.-K. Khim,
X. Zhang, E. M. Cederstrom and P. S. Mariano, J. Org. Chem., 1998, 63,
841 and references cited therein. Deoxyaltrojirimycin: see ref. 3.
Deoxygalactostatin: (c) P. L. Barili, G. Berti, G. Catelani, F. D’Andrea,
F. D. Rensis and L. Puccioni, Tetrahedron, 1997, 53, 3407; (d) J. P.
Shilvock and G. W. J. Fleet, Synlett, 1998, 554 and references cited
therein.
i,vii,viii
O
9
OH
14
ix
O
HO
NH
iv–vi
N
6 S. Katsumura, N. Yamamoto, M. Morita and Q. Han, Tetrahedron:
Asymmetry, 1994, 5, 161 and references cited therein.
O
O
OH
HO
7 S. Katsumura, Y. Yamamoto, E. Fukuda and S. Iwama, Chem. Lett.,
1995, 393; M. Murakami, S. Iwama, S. Fujii, K. Ikeda and S. Katsumura,
Bioorg. Med. Chem. Lett., 1997, 7, 1725.
8 S. Iguchi, H. Nakai, M. Hayashi and H. Yamamoto, J. Org. Chem., 1979,
44, 1363.
OH
1-Deoxygalactostatin 3
Scheme 2 Reagents and conditions: i, TBAF, THF (98%); ii, MCPBA,
CH2Cl2 (78%); iii, BF3–OEt2, acetone, 0 °C (70%); iv, 6 aq. NaOH,
dioxane, reflux, 24 h; v, conc. HCl, MeOH, reflux, 4 h (85% for 2 steps); vi,
basic ion-exchange resin; vii, PDC, 4 Å molecular sieves, CH2Cl2 (73%);
viii, L-Selectride®, CeCl3, THF (77%); ix, MCPBA, CHCl3, 3 d (65%).
OH
15
M
9 S. J. Danishefsky, D. M. Armistead, F. E. Wincott, H. G. Selnick and R.
Hungate, J. Am. Chem. Soc., 1989, 111, 2967.
Communication 8/07532H
42
Chem. Commun., 1999, 41–42