An efficient synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol and 1,4-dideoxy-1,4-imino-d- and l-xylitol from chiral aziridines

Article abstract of DOI:10.1016/j.tetlet.2013.08.040

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The g

Full text of DOI:10.1016/j.tetlet.2013.08.040

Tetrahedron Letters 54 (2013) 5775–5777
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Tetrahedron Letters
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An efficient synthesis of 1,4-dideoxy-1,4-imino-D- and L-arabinitol
and 1,4-dideoxy-1,4-imino-D- and L-xylitol from chiral aziridines
Hwan Geun Choi a, Dong-Sik Park a, Won Koo Lee b, Taebo Sim a,c,
⇑
a Future Convergence Research Division, Korea Institute of Science and Technology, PO Box 131,Cheongryang, Seoul 130-650, Republic of Korea
b Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
c KU-KIST Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul 136-713, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-
D
- and
L-arabinitol (D-AB1, 1 and
Received 14 May 2013
Revised 1 August 2013
Accepted 6 August 2013
Available online 20 August 2013
L
-AB1, 3) and 1,4-dideoxy-1,4-imino-D- and L-xylitol (D-DIX, 2 and L-DIX, 4) starting from commercially
available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon
homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered
iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the
routes more amenable to large-scale synthesis.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
D
-AB1/
-DIX/
L
-AB1
D
L
-DIX
Natural product
Efficient synthesis
Chiral aziridines
Iminosugars, which contain a ring-nitrogen atom instead of the
endocyclic oxygen present in monosaccharides, have received
great attention owing to their attractive biological activities.1 The
H
N
H
N
H
N
H
N
HO
HO
HO
HO
HO
OH
HO
OH
HO
OH
HO
OH
iminosugar, 1,4-dideoxy-1,4-imino-
first isolated from the fruits of Angylocalyx boutiqueanus in 19852
and its diastereomer, 1,4-dideoxy-1,4-imino- -xylitol ( -DIX, 2),
was recently isolated from marine sponges.3
-AB1 was found to
be a potent inhibitor of glycogen phosphorylase and -glucosi-
D-arabinitol (D-AB1, 1), was
1
2
3
4
D-AB1,
(2R, 3R, 4R)
D-DIX,
(2R, 3S, 4S)
L-AB1,
(2S, 3S, 4S)
L-DIX,
(2S, 3R, 4R)
D
D
D
Figure 1. Structure of five-membered iminosugars.
a
dases.4–6 Glucosidase inhibitors have been utilized as therapeutic
agents for the treatment of several diseases including diabetics,
viral infections, cancer, and genetic disorders.7–9 Oncogene activa-
tion has been shown to trigger aberrant glycosylation owing to an
altered cascade for the expression of glycosyltransferases.10 More-
over, the level of glycosidases is also elevated in many types of can-
cer cells (Fig. 1).11
pathway involving Vasella reductive amination followed by
halocyclization/carbonylation.22 A sequence culminating in the
preparation of
Sharpless asymmetric dihydroxylation as a key step.19 A reductive
cleavage reaction of the bis-benzylidene acetal of -mannitol
was employed in an approach to the synthesis of
-DIX.27 Pseudo-
L-AB1 began with Garner’s aldehyde and utilized
D
L
hemiketal lactams, derived from sucrose, were utilized as key
intermediates in sequences culminating in the preparation of
Because of its broad spectrum of biological activities and phar-
macological properties, especially anti-cancer activity7–9
D
-AB1,12–16
-ara-
-xylitol
L
-DIX,14,15,23–28 4) became the targets of our
D
-AB1 and
-fructose-6-phosphate aldolase and
L
-DIX.15 Chemo-enzymatic synthesis strategy using
as well as its three stereoisomers, 1,4-dideoxy-1,4-imino-
binitol ( and
-AB1,13,17–19 3) and 1,4-dideoxy-1,4-imino-
-DIX,20–22 2 and
L
D
L
-rhamnulose-1-phosphate
-AB1 and
-AB1.29,30
SmI2-mediated benzyloxymethylation of dibenzyltartarimide
resulted in -AB1 and
-AB1.31 Finally, a stereoselective palladium
catalyzed oxazine forming reaction of -serine served as the key
component of the synthesis of
-AB1.16
L
D
L
aldolase was adopted for the synthesis of
D
L
(D
effort aimed at developing highly efficient synthetic strategies.
Recently reported synthetic routes for the preparation of the four
iminosugars follow a number of different approaches. For example,
D
L
D
D
D
-DIX has been synthesized starting from D-xylose through a
Although a significant effort has been given to devising efficient
syntheses of the four iminosugars highlighted above, some of the
routes developed are lengthy owing to the need for tedious
protection/deprotection protocols. Herein, we describe the results
⇑
Corresponding author. Tel.: +82 2 958 6347; fax: +82 2 958 5189.
E-mail addresses: tbsim@kist.re.kr, tbsim@korea.ac.kr (T. Sim).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.040

5776
H. G. Choi et al. / Tetrahedron Letters 54 (2013) 5775–5777
of a recent study, which has led to highly efficient and conve-
niently performed syntheses of the iminosugar stereoisomers
Reductions of the amide and acetate groups in (2S)-8A and (2R)-
8A were carried out using borane–dimethyl sulfide to generate the
corresponding pyrrolidines (2R)-9A and (2S)-9A (Scheme 3). The
(2R,3R,4R)-2-(hydroxymethyl)pyrrolidine-3,4-diol, (2R)-9A, gener-
ated in this manner, was subjected to silica gel chromatography
(DCM:7 N ammonia in MeOH solution = 10:1) to afford pure
(2R)-9A in 95% yield.
D-AB1 (1), D-DIX (2), L-AB1 (3), and L-DIX (4). Each of the sequences
started from a commercially and readily available chiral aziridine,
and a facile recrystallization procedure was employed in each case
to generate pure product.
As shown in Scheme 1, the total syntheses of diastereomerically
pure
D
-AB1, 1 and
L
-AB1, 3 and
D
-DIX, 2 and
L
-DIX, 4 commenced
Although the crude (2S,3R,4R)-2-(hydroxymethyl)pyrrolidine-
3,4-diol, (2S)-9A arising from the reduction reaction was also
subjected to silica gel chromatography, pure (2S)-9A could not be
obtained presumably because of the presence of a tight boron-
(2S)-9A adduct. Therefore, the chromatographed substance was
used for the ensuing hydrogenolysis step (Pd(OH)2, methanol,
1 atm hydrogen in the absence of acid) to cleave the benzyl pro-
tecting group. Silica gel chromatography (DCM:MeOH:EtOH:30%
NH4OH = 5:2:2:1) of the resulting product mixture afforded pure
with the commercially available 2R- and 2S-enantiomers of 1-
methylbenzylaziridine-2-methanols, (2R)-5 and (2S)-5, respec-
tively. These substances were prepared from the corresponding
aziridine-2-carboxylates by using LiAlH4 reduction. In accord with
our previous report,32–34 independent Swern oxidations of (2R)-5
and (2S)-5 gave the corresponding 1-methylbenzylaziridine-2-
carboxaldehydes that were then transformed to trans-3-aziridin-
2-yl-acrylates (2S)-6 and (2R)-6 in 98:2 trans:cis ratios by using
Horner–Wadsworth–Emmons olefination with ethyl diethylphos-
phonoacetate. The desired trans-diastereomers of each enantiomer
were readily purified by using silica gel column chromatography.
Cis-Dihydroxylation reactions of (2S)-6 and (2R)-6 using OsO4 in
the presence of NMO afforded diastereomers (2S)-7 and (2R)-7 in
77% and 73% respective yields. Based on the analysis of crude 1H
NMR spectra, diastereomeric ratios of (2S)-7 and (2R)-7 were
1:1.7 and 1:1, respectively. Neither diastereomer of diastereomers
(2S)-7 or (2R)-7 were separable by employing silica gel chromatog-
raphy. The C-3 bonds present in the aziridine rings of (2S)-7 and
(2R)-7 were regioselectively cleaved by treatment with AcOH in
CH2Cl2 to produce the corresponding acyclic acetate ester prod-
ucts, which then underwent lactam ring forming cyclization in
the presence of AcOH at 50 °C to produce (2S)-8 and (2R)-8. The
diastereomeric ratios of (2S)-8 and (2R)-8 would be same as those
of (2S)-7 and (2R)-7.
L-DIX, 4. It is interesting to note that the reduction conditions
transform the boron-(2S)-9A complex into -DIX, 4 which is boron
L
free. This finding parallels the results of a previous study by
Couturier et al.,35 that showed that palladium catalyzes the
methanolysis of borane–amine adducts. (2R)-9A was also sub-
jected to the same hydrogenolysis and purification step as applied
to (2S)-9A to form pure
Utilizing the same general approach employed to synthesize
-AB1, 1 and -DIX, 4, we have also prepared -AB1, 3 and -DIX,
D-AB1, 1 in 91% yield.
D
L
L
D
2 from pyrrolidinones (2S)-8B and (2R)-8B (Scheme 4). It should
be noted that (2R,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol,
(2R)-9B did not form boron-adducts in contrast to the (2S)-9A. As
a result, both substances, (2S)-9B and (2R)-9B in scheme 4 were
generated in a pure form by using silica gel chromatography.
The study described above has led to the development of a gen-
eral strategy for the highly facile and efficient synthesis of imino-
The facile recrystallization of each product mixture containing
(2S)-8 and (2R)-8 from ethanol at 0 °C afforded the individual dia-
stereomers of (2S)-8B and (2R)-8A in a pure form as white crystal-
line substances (Scheme 2). This facile recrystallization could
render our synthetic route more amenable to large-scale prepara-
tion of the final compounds 1–4. The mother liquors from each
were subjected to flash column chromatography to furnish diaste-
reomerically pure (2S)-8A and (2R)-8B.
sugar D-AB1 and three of its diastereomers. The six-step routes,
beginning with commercially and readily available chiral aziri-
dines, are comprised of steps involving a two-carbon homologation,
dihydroxylation, and regioselective aziridine ring opening/intra-
molecular five-membered iminosugar ring formation. Moreover,
the facile use of recrystallization to separate easily diastereomers
Me
Ph
Me
Ph
Pd(OH)2 (10 wt%)
H2 (1 atm)
H
N
BH3SMe2 (10 equiv)
THF, 0 oC to RT, 12 h
N
N
O
AcO
HO
HO
MeOH. RT, 3 h
Ph
Ph
Ph
HO
OH
HO
OH
HO
OH
i) Swern oxidation
or
Me
(2S)-
N
Me
(2R)-
N
Me
N
2
(2R)-8A
(2R)-9A (95%)
D-AB1, 1 (91%)
2
ii) Triethyl phosphonoacetate
(1.1 equiv),
K2CO3 (5 equiv),
OH
OH
O
5
5
H
H
O
Me
Ph
Me
Ph
Pd(OH)2 (10 wt%)
H2 (1 atm)
(2R)-6 : 53%,two steps from (2S)-5
EtOH, RT, 8 h
H
N
BH3SMe2 (10 equiv)
THF, 0 oC to RT, 12 h
6
5
(2S)- : 70%,two steps from (2R)-
N
N
O
AcO
HO
HO
MeOH. RT, 3 h
HO
OH
HO
OH
HO
OH
L-DIX, 4
i) AcOH (10 equiv) ,
DCM ( 0.3 M)
RT, 18 h
(2S)-8A
(2S)-9A
Ph
Me
Ph
63%, two steps from (2S)-8A
OsO4 (0.04 equiv),
NMO (1.1 equiv)
OH
Me
N
2
N
2
O
O
Scheme 3. Synthesis of
D
-AB1, 1 and
L
-DIX, 4.
AcO
THF : H2O = 3 : 1
RT, 12 h
ii) Toluene (0.03 M),
50 oC, 12 h
OH
O
HO
OH
(2S)-7 : 78%
(2S)-8 : 92%
7
8
(2R)- : 72%
(2R)- : 73%
Me
Ph
Me
Ph
Pd(OH)2 (10 wt%)
H2 (1 atm)
H
N
BH3SMe2 (10 equiv)
Scheme 1. Synthesis of the pyrrolidinones, (2S)-8 and (2R)-8.
N
N
O
AcO
HO
HO
THF, 0 oC to RT, 12 h
MeOH. RT, 3 h
HO
(2S)-
OH
8B
HO
OH
HO
OH
9B
3
(2S)-
(67%)
L-AB1, (76%)
Me
Ph
Me
Ph
Me
Ph
N
N
N
O
recrystallization
O
O
Me
Ph
Me
Ph
+
Pd(OH)2 (10 wt%)
AcO
AcO
AcO
H
N
BH3SMe2 (10 equiv)
THF, 0 oC to RT, 12 h
H2 (1 atm)
EtOH, 0 o
C
N
N
O
HO
OH
HO
OH
HO
OH
AcO
HO
HO
MeOH. RT, 3 h
(2S)-8 / 600 mg
(2R)- / 980 mg
(2S)-8A / 220 mg
8A /
(2S)-8B / 270 mg (recrystallized)
8B /
HO
OH
HO
OH
HO
OH
8
(2R)-
350 mg (recrystallized)
(2R)-
264 mg
(2R)-8B
(2R)-9B (72%)
D-DIX, 2 (86%)
Scheme 2. Separation of the diastereomeric pyrrolidinones (2S)-8 and (2R)-8 by
recrystallization.
Scheme 4. Synthesis of L-AB1, 3 and D-DIX, 2.

H. G. Choi et al. / Tetrahedron Letters 54 (2013) 5775–5777
5777
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This research was supported by Korea Institute of Science and
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Supplementary data
Supplementary data (1H NMR/13C NMR, HRMS, optical rotation)
associated with this article can be found, in the online version, at
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