A general methodology for the asymmetric synthesis of 1-deoxyiminosugars

Article abstract of DOI:10.1016/S0040-4039(03)00218-1

A general methodology for the stereoselective synthesis of 1-deoxymannojirimycin and its three other stereoisomers is described. The achiral olefin 6 was converted through the common olefin intermediate 12 to the target compounds in a highly stereocontrol

Full text of DOI:10.1016/S0040-4039(03)00218-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2387–2391
A general methodology for the asymmetric synthesis of
1-deoxyiminosugars
Om V. Singh and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX 78249, USA
Received 11 December 2002; revised 20 January 2003; accepted 21 January 2003
Abstract—A general methodology for the stereoselective synthesis of 1-deoxymannojirimycin and its three other stereoisomers is
described. The achiral olefin 6 was converted through the common olefin intermediate 12 to the target compounds in a highly
stereocontrolled manner. The regioselective asymmetric aminohydroxylation (AA) and diastereoselective dihydroxylation reactions
were used for the introduction of all four stereocenters in the targets, and the ring-closing metathesis (RCM) reaction was utilized
for the construction of the required six-membered ring. © 2003 Elsevier Science Ltd. All rights reserved.
Glycosidases catalyze cleavage/formation of the glyco-
sidic bonds in carbohydrates and related molecules.1
1-Deoxyiminosugars such as 1, 2, 3, 4, and 5 are potent
glycosidase inhibitors (Fig. 1).2 When protonated, they
mimic charge and shape of the cationic intermediates
generated in the glycosidase catalyzed reactions.
glucosyltransferase8 and currently in clinical trials as a
potential therapy for Gaucher disease. As such, much
effort has been put forth in developing methodologies
for the asymmetric synthesis of 1-deoxyiminosugars.
However, most syntheses reported so far relied on
chiral pools such as carbohydrates and amino acid
derivatives, and/or required chiral auxiliaries for the
asymmetric induction.2,9 Truly asymmetric methodolo-
gies, which are amenable to stereochemical manipula-
tion and derivatization, have been scarcely reported.10
Glycosidases are implicated in various diseases such as
diabetes,3 metastatic cancer,4 malaria,5 and viral infec-
tion,6 making glycosidases good targets for drug devel-
opment. N-Butyl-1-deoxynojirimycin, for example, is
an inhibitor of glucosidase I7 and ceramide
We recently developed a substrate-based methodology
that allowed the regioselective control of the Sharpless
asymmetric aminohydroxylation (AA) reaction of
olefins.11 In this approach, steric, electronic, and aryl–
aryl stacking interactions between olefins and the AA
catalyst were utilized to control regioselectivity. We
have been interested in applying this methodology to
the asymmetric synthesis of biologically important com-
pounds.12 As depicted in Scheme 1, it is envisioned that
1-deoxyimino-sugars can be prepared from the achiral
olefin V in a highly stereoselective fashion. The regiose-
lective asymmetric aminohydroxylation11,13 (V to IV)
and diastereoselective dihydroxylation14 (II to I) reac-
tions will respectively install the vicinal aminoalcohol
and diol functionalities in the targets, and the ring-clos-
ing metathesis15 (III to II) will furnish the required
six-membered ring. Herein, we report a successful
implementation of this strategy to the asymmetric syn-
thesis of 1-deoxymannojirimycin (2) and its three other
stereoisomers 3, 4, and 5.
Figure 1.
Keywords: 1-deoxyiminosugar; regioselective aminohydroxylation;
ring-closing metathesis.
As shown in Scheme 2, our synthesis started with the
olefin 6, which was readily prepared from ethyl 4-bro-
* Corresponding author. Tel.: +1-210-458-4958; fax: +1-210-458-4958;
e-mail: hhan@utsa.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00218-1

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O. V. Singh, H. Han / Tetrahedron Letters 44 (2003) 2387–2391
KH, and potassium t-butoxide as a base, the starting
material 8 was recovered unchanged. Deprotection of
the TBDPS group by tetrabutyl ammonium fluoride
(TBAF) and the subsequent oxidation of the alcohol
under the Des–Martin conditions22 yielded the aldehyde
10. Terminal olefination reaction of 10 with the Wittig
reagent23 suffered from a poor reaction yield (ꢀ30%),
and thus the modified Horner–Wadsworth–Emmones
olefination24 was attempted. Olefination of the aldehyde
10 with triethyl phosphonoacetate and DBU in the
presence of lithium bromide produced the a,b-unsatu-
rated ester 11 in 94% yield. The RCM reaction of 11
using the Grubbs’ catalyst [bis(tricyclohexylphos-
phine)benzylidineruthenium(IV)dichloride] required ele-
vated temperature (90°C) to generate the key olefin
intermediate 12 in 80% yield.
Scheme 1.
Scheme 3 shows how the key olefin intermediate 12 was
utilized to generate 1-deoxygulonojirimycin (4) and 1-
deoxyidonojirimycin (5). Dihydroxylation reaction of
12 by OsO4 gave 13 as a sole diol product, since steric
congestion at the top face of 12 preferred approach of
OsO4 from the bottom face of the molecule. The diol 13
was isolated as an acetonide from the reaction mix-
ture,25 which upon two successive deprotection reac-
tions by cerric ammonium nitrate (CAN)26 and then 6N
HCl converted to the HCl salt of 1-deoxygulonojir-
imycin (4).27 Contrary to the literature,28 the p-
methoxybenzyl group remained intact under the CAN
deprotection conditions. trans-Diol stereochemistry at
C2 and C3 for 1-deoxyidonojirimycin (5) was intro-
duced by applying cyclic sulfate chemistry29 to the
cis-diol 13. Thus, treatment of 13 with thionyl chloride
followed by oxidation of the resulting cyclic sulfite
using RuCl3 and NaIO4 produced the cyclic sulfate 14.
Ring opening reaction of the cyclic sulfate 14 by
sodium benzoate took place almost exclusively at C2,
Scheme 2. Reagents and conditions: (a) K2OsO4·2H2O (5
mol%), (DHQD)2PHAL (6 mol%), LiOH, N-bromoac-
etamide, t-BuOH–H2O 3:2, 4°C, 8 h, 70%; (b) (i) NaH,
PMBCl, DMF, 0°C, 8 h, 80%, (ii) LiBH4, ether, 15 min,
quantitative, (iii) TBDPSCl, TEA, DMAP, CH2Cl2, 25°C, 4
h, quantitative; (c) KH, 18-crown-6-ether, allyl bromide,
THF, 25°C, 5 h, 95%; (d) (i) TBAF, THF, 25°C, 1 h,
quantitative, (ii) periodinane, CH2Cl2, 25°C, 1 h, 90%; (e)
triethyl phosphonoacetate, LiBr, DBU, THF, 25°C, 2 h, 94%;
(f) Grubbs’ catalyst (10 mol%), toluene, 90°C, 2 h, 80%.
mocrotonate and p-methoxyphenol. The olefin 6 was
designed in such a way that electronic and aryl–aryl
stacking interactions between 6 and the AA catalyst
could reinforce each other to increase regioselectivity in
the AA reaction of 6.16 Thus, the osmium catalyzed
regioselective AA reaction of 6 afforded the aminoalco-
hol 7 in an excellent regioselectivity (>20:1),17 and a
single recrystallization of the column purified product
from ethyl acetate–hexane gave analytically pure 7 in
70% yield and >99% ee. A reaction sequence of protec-
tion of the hydroxyl group with p-methoxybenzyl chlo-
ride,18 reduction of the resulting ester with LiBH4 in the
ether solution containing a trace amount of methanol,19
and TBDPS protection20 of the alcohol furnished 8.
Scheme 3. Reagents and conditions: (a) OsO4, NMO, t-
BuOH–H2O 1:1, 12 h, 96%; (b) (i) DMP, PPTS, CH2Cl2,
25°C, 12 h, 94%, (ii) CAN, MeCN–H2O 4:1, 0°C, 10 min,
92%, (iii) 6N HCl, 120°C, 12 h, 98%; (c) (i) SOCl2, TEA,
CH2Cl2, −15°C, 30 min, (ii) RuCl3, NaIO4, MeCN–CH2Cl2–
H2O 1:1:1, 25°C, 1 h, 85% for two steps; (d) (i) NaOBz,
DMF, 105°C, 3 h, (ii) 20% aq. H2SO4–CH2Cl2 1:1, 25°C, 12
h, 85% for two steps; (e) b-(ii) and then b-(iii), 90% for two
steps.
Allylation of 8 with allyl bromide and KH in THF
proceeded to give 9 in a good yield only when a
catalytic amount of crown ether was present in the
reaction mixture.21 In all initial attempts using NaH,

O. V. Singh, H. Han / Tetrahedron Letters 44 (2003) 2387–2391
2389
since both trans-diaxial ring opening rule30 and steric
congestion at C3 favored ring opening at that carbon.
Deprotection of p-methoxyphenyl group of the alcohol
15 by CAN and a final exhaustive acidic hydrolysis
gave 1-deoxyidonojirimycin (5) as HCl salt.27
unbalance might improve selectivity in the dihydroxyla-
tion reaction, the benzoyl group of 17a was converted
to the much bigger TBDPS group. Gratifyingly, dihy-
droxylation reaction of 17c produced two inseparable
diastereomers 19a and 19b in a good selectivity (10:1).
After acetylation reaction, 19a and 19b were separated
as the corresponding triacetates by column chromatog-
raphy. Deprotection of the PMP group by CAN and
acidic deprotection of the acetyl and TBDPS groups
transformed the triacetate of 19a to 1-deoxymannojir-
imycin (2).27 In order to synthesize 1-deoxyaltronojir-
imycin (3), the mixture of the diols 19a and 19b was
converted to the corresponding cyclic sulfates, which
were separated by column chromatography. The major
cyclic sulfate 20 was subjected to ring opening reaction
by sodium benzoate in DMF to generate 21a as well as
21b that formed from the partial deprotection of the
TBDPS group under the reaction conditions. Deprotec-
tion of the p-methoxyphenyl group of 21a and 21b by
CAN followed by acid hydrolysis finished the asymmet-
ric synthesis of 1-deoxyaltronojirimycin (3).27
The olefin 12 was also used as an intermediate for the
synthesis of 1-deoxymannojirimycin (2) and 1-deoxyal-
tronojirimycin (3) (Scheme 4). p-Methoxybenzyl group
of 12 was deprotected by 5% trifluoroacetic acid/
CH2Cl2.31 Configuration at C4 of the alcohol 16 was
inverted by Mitsunobu reaction.32 Dihydroxylation of
the resulting benzoate ester 17a under the Sharpless–
Upjohn conditions14d,e generated an inseparable mix-
ture of the diols 18a and 18b in 3:2 ratio as determined
1
by H NMR of the reaction mixture. It was reasoned
that a low selectivity in the above dihyroxylation reac-
tion might be attributed to the fact that the p-
methoxyphenyl and benzoate groups in 17a were
similar in size and thus both faces of the molecule were
almost equally hindered. Hoping that increasing steric
In summary 1-deoxymannojirimycin and its three other
stereoisomers were synthesized from the readily avail-
able olefin 6 via the regioselective AA, ring closing
metathesis, and diastereoselective dihydroxylation reac-
tions in a highly stereoselective manner. The methodol-
ogy developed (vide supra) is extremely divergent and
flexible to stereochemical manipulation and synthetic
modification. Extension of this methodology to the
asymmetric synthesis of the remaining other stereoiso-
mers and related azasugars is currently under
investigation.
Acknowledgements
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully acknowledged.
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1
2·HCl: [h]589=−9.9 (c 1.5, MeOH), H NMR (500 MHz,
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12.5 Hz, H-6), 3.93–3.87 (m, 2H, H-6% and H-4), 3.75
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and 13.7 Hz, H-1), 3.30 (dd, 1H, J=1.0 and 13.5 Hz),

O. V. Singh, H. Han / Tetrahedron Letters 44 (2003) 2387–2391
2391
3.24–3.13 (m, 1H, H-5); 13C NMR (75 MHz, D2O): l
72.24, 65.73, 65.57, 60.18, 57.95, 47.40.
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D2O): l 4.20 (m, 1H, H-2), 4.08 (dd, 1H, J=3.0 and 15.7
Hz, H-3), 4.07 (br s, 1H, H-4), 4.02 (dd, 1H, J=3.5 and
12.8 Hz, H-6), 3.88 (dd, 1H, J=6.5 and 12.8 Hz, H-6%),
3.45–3.39 (m, 2H, H-5 and H-1), 3.273 (dd, 1H, J=3.0
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