A novel and environmental friendly synthetic route for hydroxypyrrolidines using zeolites

Article abstract of DOI:10.1016/j.carres.2018.11.016

A critical step in the synthesis of the hydroxypyrrolidines, 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-imino-D-lyxitol, from the corresponding D-sugars is the synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses. Instead of applying homogeneous catalysis process with conventional inorganic acid catalysts like HCl and HClO₄, it was found that heterogeneous catalysis using zeolites could be used for the one-pot synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses directly from D-sugars, MeOH and acetone at mild condition. The best catalyst was H-beta zeolite containing a Si/Al molar ratio of 150, where a yield of >83% was obtained. The overall yields of the five-step procedure to 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-imino-D-lyxitol were 57% and 50%, respectively. This synthetic procedure has several advantages such as competitive overall yield, reduced number of steps, and mild reaction conditions. Furthermore, the zeolite catalyst can be easily recovered from the reaction mixture and reused with no loss of activity.

Full text of DOI:10.1016/j.carres.2018.11.016

CarbohydrateResearch472(2019)103–114
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
A novel and environmental friendly synthetic route for hydroxypyrrolidines
using zeolites
A. Fan∗, G.K. Chuah, Stephan Jaenicke
Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore
A B S T R A C T
A critical step in the synthesis of the hydroxypyrrolidines, 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-imino-D-lyxitol, from the corresponding D-sugars is the
synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses. Instead of applying homogeneous catalysis process with conventional inorganic acid catalysts like HCl
and HClO4, it was found that heterogeneous catalysis using zeolites could be used for the one-pot synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses directly
from D-sugars, MeOH and acetone at mild condition. The best catalyst was H-beta zeolite containing a Si/Al molar ratio of 150, where a yield of > 83% was obtained.
The overall yields of the five-step procedure to 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-imino-D-lyxitol were 57% and 50%, respectively. This synthetic
procedure has several advantages such as competitive overall yield, reduced number of steps, and mild reaction conditions. Furthermore, the zeolite catalyst can be
easily recovered from the reaction mixture and reused with no loss of activity.
1. Introduction
all employ standard protecting group manipulations. Dangerfield et al.
[23,31,32] presented a protecting group-free synthetic route to produce
lyxitol hydroxypyrrolidines in competitive yield and high stereo-
selectivity. However, their methodology still has disadvantages, such as
producing highly volatile and toxic HCN from the NaBH3CN used for
the reduction of the imine, tedious work-up procedure (especially for
the synthesis of the O-methyliodoglycosides), and unfavorable eco-
nomics due to the large amount of ammonium acetate waste (∼150
equiv), which when considered in overall, makes the synthetic scheme
environmental unfriendly.
Iminosugars are carbohydrate analogs in which the ring oxygen has
been replaced with nitrogen and are found to be widespread in plants
and microorganisms. Due to their structural similarity to native car-
bohydrates, they are potent inhibitors of many carbohydrate-processing
enzymes involved in biological systems. These unique molecules pro-
mise a new generation of iminosugar-based medicines for a wide range
of diseases such as viral infections, diabetes, tumor metastasis, AIDS
and lysosomal storage disorders [1–11].
Hydroxypyrrolidines are structurally identical to five-membered
iminosugars, which belong to the general class of azasugars.
Hydroxypyrrolidines include the mannosidase inhibitors 1,4-dideoxy-
1,4-imino-D-mannitol [12] and its 6-deoxy analog [13], 1,4-dideoxy-
1,4-imino-D-xylitol [14], phytotoxin swainsonine [15] whose properties
include the inhibition of both lysosomal α-mannosidase [16] and
mannosidase II [17], the antibiotic anisomycin [18], broussonetinine A
[19] and the potent-galactosidase and α-mannosidase inhibitor, gua-
lamycin [20].
As mentioned in our previous work [33], heterogeneous catalysis
have unique advantages, e.g., ease of handling, separation from the
reaction mixtures and recovery of the catalyst. Moreover, hetero-
geneous catalysis often perform well under mild conditions and are
seldom corrosive. Inventing an environmental friendly synthetic
scheme with heterogeneous catalysis process to produce lyxitol hy-
droxypyrrolidines is highly desired. However, heterogeneous catalysis
for the direct transformation of carbohydrates are underexplored [34].
Here, we report an efficient and environmental friendly route to
synthesize 1,4-dideoxy-1,4-imino-L-lyxitol 6 from the cheap starting
material, D-ribose, through the use of heterogeneous catalysis process
and readily available reagents (Scheme 1). The proposed synthetic
route from D-ribose to lyxitol hydroxypyrrolidines 6 consists of five
reactions: (i) one-pot synthesis of O-methyl 2,3-O-isopropylidene-D-ri-
bofuranoside 2, (ii) iodination at C5 of 2, (iii) Vasella reductive ami-
nation to produce 4, (iv) halocyclization/carbonylation of 4 using an
iodine-promoted annulation methodology, and (v) hydrolysis of the
Of the lyxitol pyrrolidines, 1,4-dideoxy-1,4-imino-D-lyxitol (Fig. 1),
which has the structure tentatively assigned to a pyrrolidine isolated
from the marine sponge raispalia [21], was found to be a potent α-
galactosidase inhibitor [14,22], while the enantiomer, 1,4-dideoxy-1,4-
imino-L-lyxitol, has not been isolated or assayed [23]. A number of
strategies to achieve a total synthesis of lyxitol pyrrolidines have been
reported [24–30]. In spite of their elegance and creativity, many of
these strategies are lengthy, some show poor diastereoselectivity, and
∗ Corresponding author.
E-mail address: fanao2013cn@gmail.com (A. Fan).
https://doi.org/10.1016/j.carres.2018.11.016
Received 5 October 2018; Received in revised form 28 November 2018; Accepted 28 November 2018
Availableonline04December2018
0008-6215/©2018ElsevierLtd.Allrightsreserved.

A. Fan et al.
CarbohydrateResearch472(2019)103–114
94%, was obtained after 18 h over H-beta zeolite with a very high
framework Si/Al-ratio of 150. Additionally, the large pore openings and
spacious channel intersections of H-beta zeolite may also contribute to
its catalytic activity (Table 5) [46]. Reducing the temperature led to
long reaction times and after 18 h, the yield of the O-methyl D-ribo-
furanoside was only 65 and 20%, respectively, when the reaction was
conducted at 50 °C and 25 °C.
Fig. 1. Structures of 1,4-dideoxy-1,4-imino-D-lyxitol and 1,4-dideoxy-1,4-
imino-L-lyxitol.
It was reported that the isopropylidenation of D-ribose and O-methyl
D-ribofuranoside can be catalyzed by HY zeolite and 37–75% yields for
di-O- and/or mono-O-isopropylidene derivatives were achieved [47].
As H-beta (150) catalyzed the methoxylation of D-ribose efficiently, it
was interestingly to investigate the reaction from D-ribose to O-methyl
2,3-O-isopropylidene-D-ribofuranoside in one-pot synthesis. The reac-
tion was carried out by the additional presence of acetone. Satisfyingly,
an encouraging 76% yield was achieved after 24 h. Moreover, the sig-
nificant difference in solubility of D-ribose and the 2,3-acetonide 2 al-
lows them to be easily separated with liquid–liquid (ethyl acetate/
water) extraction. In turn, it was possible to recover the unreacted D-
ribose and carry out further batch reactions to improve the yield. About
93% total yield was achieved after another cycle of the reaction.
The used catalyst was recovered by filtration of the reaction mix-
ture, regenerated and used in new batch reactions. Washing of the used
catalyst with water and acetone followed by drying and calcination at
500 °C for 2 h led to almost complete recovery of the initial catalytic
activity (Table 2), where the average and standard deviation of yield
were based on three trials. In the next step, 2,3-O-isopropylidene-5-
iodo-D-furanoside 3 was formed by reacting 2,3-acetonide 2 in pyridine
with methanesulfonyl chloride (MsCl) followed by reacting with so-
dium iodide in 2-butanone [35]. After a very simple work-up procedure
using liquid–liquid (dichloromethane/water) extraction followed by
filtration through a silica gel plug using ethyl acetate/hexane = 1: 3 as
eluent, the iodide 3 was recovered in 95% isolated yield.
carbamate to form the targeted compound 6. The applicability of the
scheme to the synthesis of 1,4-dideoxy-1,4-imino-D-lyxitol 11 starting
from D-lyxose was also attempted (Scheme 2).
2. Results and discussion
2.1. Synthesis 1,4-dideoxy-1,4-imino-L-lyxitol 6 from D-ribose
The synthesis of O-methyl 2,3-O-isopropylidene-D-ribofuranoside
from D-ribose can proceed via two different pathways: Route 1 where D-
ribose is first reacted with MeOH and subsequently with acetone, or
Route 2 where D-ribose is first reacted with acetone and subsequently
with MeOH (Fig. 2). Route 1 is preferred because the increased ele-
trophilicity of the oxygen atom on C3 and C4 resulting from the
methoxylation of the hydroxyl group on C1 will assist in the following
electrophilic addition to acetone.
Several homogeneous inorganic acid catalysts such as CH3COCl
[23,31,32], HCl [35,36], H2SO4 [37] and HClO4 [38] have been used to
catalyze the O-glycosylation of pentoses including D-ribose, L-ribose, D-
xylose and D-arabinose, with methanol. Amongst them, HCl, and HClO4
were
also
used
to
synthesize
O-methyl
2,3-O-iso-
propylidenepentofuranoses in a one-pot transformation. Although the
reactions proceed with relatively high yields and under mild reaction
conditions, they all involve tedious work-up procedures and the cata-
lysts could not be reused. Zeolite catalysts used in heterogeneous cat-
alysis can serve as an environmental friendly alternative to the tradi-
tional synthetic routes. The range of well-defined zeolites available, and
their advantages as easily recoverable and reusable materials, have
prompted their application in green and sustainable procedures for the
conversion of carbohydrates [39]. There are several carbohydrate O-
glycosylation reactions that employ zeolites as catalysts such as
Conversion of iodo-substituted D-furanoside 3 to alkenylamine 4
(Fig. 4) is the next step. The Vasella reaction [48], which involves the
formation of aldehydes from halogeno sugars by induction over metals
such as indium and zinc, is used to convert 3 to 3c.
In their studies on the synthesis of lyxitol pyrrolidines, Dangerfield
et al. [23,31,32] used NaBH3CN for the reduction of the intermediate
imine to amine with the formation of toxic HCN. We modified this re-
duction reaction by using in-situ molecular H2 generated from NH3
solution and Zn dust. The choice of Zn comes from the fact that it is a
very good reducing agent [49] and promoter in the preparation of
amines from imine [50–52] and oximes [53–56]. It is well known that
the use of ammonia or ammonium salts in reductive amination reac-
tions typically results in the formation of amine dimers 3b (Table 3) due
to the lower nucleophilicity of ammonia compared to the primary
amine product of the reductive amination [31]. Therefore, the reaction
has to proceed under an environment where ammonia or ammonium
salts should be largely in excess. Hence, the reaction of converting the
iodo-substituted D-furanoside 3 to olefinic amine 4 was carried out by
using excess Zn, NH3 solution and ammonium salts.
synthesis of O-butyl
D-glucose with n-
butanol [40,41], O-gDly-gclouscyolasitdioens boyf a1c,2et-aynlahtyiodnroofsugars with cyclo-
hexanol [42], and Fischer-type glycosylation of N-acetyl- -D-galacto-
samine (GalNAc) with methanol [43]. In view of the good catalytic
activity in the glycosylation of D-glucose-based sugars, we decided to
investigate use of zeolites for the glycosylation of D-ribose with me-
thanol to O-methyl D-ribofuranoside (Fig. 3). Commercially available
zeolites of H-ZSM-5, HY and H-Beta with different Si/Al ratio were
screened to find the most appropriate one with respect to activity and
selectivity.
The catalytic activities of zeolites for the O-glycosylation of D-ribose
with methanol are shown in Table 1, where the average and standard
deviation of three trials are reported. The reaction conditions are
300 mg D-ribose (2 mmol), 6 mL MeOH, and 350 mg catalyst (catalyst/
reagent: 117% weight). Within each class of zeolite, there is a similar
trend in the relationship between catalytic activity and framework Si/
Al ratios: the catalytic activity increased with increasing Si/Al ratios.
Zeolites with high Si/Al ratio have fewer acid sites but these acid sites
are stronger than in zeolites with low Si/Al. Furthermore, the hydro-
phobicity increases with increasing Si/Al ratio due to the decrease in
the number of hydrophilic charge-compensating ions in the zeolite
structure [44]. Glycosylation of D-ribose with methanol liberates one
mole of water which can poison the acid sites of the catalysts [45]. The
poisoning will be reduced for high Si/Al zeolites despite their smaller
density of acid sites. The highest yield of O-methyl D-ribofuranoside,
Different ammonium salts, (NH4)2SO4, NH4HCO2, NH4Cl,
(NH4)2CO3 and NH4OAc, were investigated for the reductive amination
reaction (Table 3, entries 1–5, the general reaction conditions are iodo-
substituted D-furanoside 3 (160 mg, 0.5 mmol), Zn dust (800 mg, ∼25
equiv), EtOH (10 mL), 25% NH3 aqueous solution (8 mL, 100 equiv)
and 90 °C for 18 h in autoclave). It was found that after the addition of
20 equivalents of (NH4)2SO4 or NH4HCO2, only degradation of the
starting material occurred, but no product could be detected. Although
NH4Cl and (NH4)2CO3 had some activity, both were not satisfactory due
to the excessive formation of the dimer 4a. NH4OAc showed a pro-
mising monomer selectivity, 4: 4a of 2: 1, and total amine (4 + 4a)
yield. Next, taking advantage of the greater solubility of NH4OAc in
EtOH, the concentration of NH4OAc was increased in an attempt to
drive monomer formation. An increase from 20 to 200 equiv NH4OAc
proved beneficial, and the monomer 4 was formed in a 10: 1 ratio
104

A. Fan et al.
CarbohydrateResearch472(2019)103–114
Scheme 1. Synthesis route from D-ribose to 1,4-dideoxy-1,4-imino-l-lyxitol 6.
Scheme 2. Synthesis route from d-lyxose to 1,4-dideoxy-1,4-imino- d-lyxitol 11.
Fig. 3. One-pot synthesis of O-methyl 2,3-O-isopropylidene-D-ribofuranoside
over H-Beta zeolite.
Table 1
Yield of O-methyl d-ribofuranoside over different catalysis conditions.
Temperature (oC)
Time (h)
Isolated yield (%)
a
Catalyst
Ratio(
/
)
H-Beta(150)
65
50
25
65
65
65
65
65
65
18
18
18
18
18
18
18
18
18
94
65
20
82
67
45
70
62
48
2.5
3.1
3.7
3.1
2.2
2.6
2.4
2.2
2.5
2.8
2.8
2.8
2.8
2.6
2.6
2.2
2.2
2.2
H-Beta(75)
HY(15)
HY(2.6)
ZSM-5(60)
ZSM-5(40)
ZSM-5(15)
a
Estimated ratio of O-methyl -D-ribofuranoside: O-methyl -D-ribofurano-
side based on NMR analyses.
Fig. 2. Different synthesis pathways to O-methyl 2,3-O-isopropylidene-D-ribo-
furanoside from D-ribose.
environment, the amine yield dropped from 85 to 25%, although the
high monomer selectivity remained the same. To further investigate
reaction mechanism, the one-pot Vasella-reductive amination was se-
parated into two sequence steps (Scheme 3).
(Table 3, entries 5–7). The ammonia concentration also affected the
monomer selectivity significantly as a reduction from 100 to 30 equiv
led to a decrease in both yield and selectivity. Surprisingly, when the
reaction was proceeded under optimized condition but in an open-air
As shown in Scheme 3, the first step is a classic Vasella reaction
where an aldehyde intermediate 3c was obtained. Then, the unreacted
105

A. Fan et al.
CarbohydrateResearch472(2019)103–114
Table 2
deprotection of isopropylidene with HCl. During the process, one
equivalent of water was generated. Removal of the water from the re-
action system should push the reaction towards imine formation.
However, the large amount of water which is already present in the
reaction mixture due to the use of aqueous ammonia solution as am-
monia source severely hinders the formation of imine. The absence of
imine (4b/4c) in second reaction indicates that the deprotection of
intermediate imine with HCl was not proceeded. So, the only pathway
to form targeted compound amine 4 is through amine 3a, which in-
volves to reduce intermediate imine. The nascent H2 produced from the
Zn dust and ammonia solution is the only reducing agent for the imine
reduction, therefore, no intermediate imine was converted to 3a in the
second step because of the absence of the Zn dust. The low amine yield
obtained when H2 produced in round-bottomed flask can easily diffuse
away in air, resulting in a lack of reducing agent for the intermediate
imine reduction. This problem can be overcome by adding a stable and
selective reducing agent. In contrast to NaBH3CN, sodium triacetox-
yborohydride (NaBH(OAc)3) is a safe, mild, environmental friendly
reducing agent and especially suitable for reductive aminations [57].
By adding 3 equivalents of NaBH(OAc)3 in the second reaction, a sa-
tisfactory high amine yield of 81% was achieved (Table 3, Entry 10).
In contrast to amine 4, amine 3a is easily dissolved in organic sol-
vents such as CH2Cl2 due to the presence of the isopropylidene group
that masked the hydroxyl groups at C2 and C3. The significant differ-
ence in solubility of amine 3a and NH4OAc, which is present in large
excess, allows them to be easily separated by liquid–liquid (CH2Cl2/
water) extraction. The unreacted NH4OAc can be reused for at least five
batches without causing a significant decrease of the monomer se-
lectivity (Fig. 5). Hence, this strategy is favored from perspectives of
economics as well as environmental compatibility.
Yield of O-methyl 2,3-O-isopropylidene-D-ribofuranoside 2 for successive cycles
using regenerated H-beta (150) catalyst.
Run
Time (h)
Isolated Yield (%)
< 5
No catalyst
24
24
24
24
24
24
1st cycle (Fresh catalyst)
2th cycle (catalyst regenerated)
3th cycle (catalyst regenerated)
4th cycle (catalyst regenerated)
5th cycle (catalyst regenerated)
76
74
73
74
73
2.6
2.4
2.5
2.3
2.5
Reaction:
(catalyst/rDe-argibenots:e7(05%00wmegig)h, ta)caentodn6e5(°6Cm(reLfl),uMx)e. OH (6 mL), 350 mg catalyst
Fig. 4. Reaction mechanism for the formation of 4.
Next, olefinic amine 4 was converted to pyrrolidine ring system via
halocyclization [23,31,32]. Subjecting amine 4 to molecular iodine and
NaHCO3 in water led to the formation of a single cyclic carbamate
product 5 in 93% yield. Then, the formed cyclic carbamate 5 was hy-
drolyzed with NaOH, and the desired pyrrolidine 6 was obtained in
excellent yield (∼99%). The overall yield of hydroxypyrrolidine 6 was
57% from D-ribose.
excess Zn dust was removed by filtration before the reaction mixture
was subjected to the second step reaction. Surprisingly, no imine pro-
duct 4b or 4c was detected in second reaction (no residue was obtained
after work-up procedure as in Experimental 4.6). According to the re-
action mechanism (Fig. 4), imine 4b is produced by the condensation of
aldehyde intermediate 3c with NH3 to form 3a followed by the
Table 3
Preparation of olefinic amine 4 under different reaction conditions 4.
Entry
Conditions
Ratio (4: 4a)a
Yield (%)b
1
(NH4)2SO4 (20 equiv)
–
–
2
NH4HCO2 (20 equiv)
–
–
3
(NH4)2CO3 (20 equiv)
1:1
1:1
2:1
4:1
10:1
1:2
10:1
10:1
42
4
NH4Cl (20 equiv)
53
5
NH4OAc (20 equiv)
61
6
NH4OAc (80 equiv)
74
7
NH4OAc (200 equiv)
85, 72c
36
8
NH4OAc (20 equiv), NH3 (30 equiv)
NH4OAc (200 equiv)d
9
25
10e
NH4OAc (20 equiv), NaBH(OAc)3 (3 equiv)
81, 66c
a
b
c
d
e
Estimated ratio is based on NMR analyses.
Combined yield of primary amine 4 and secondary amine 4a.
Isolated yield for primary amine 4.
Round bottle flask and open-air environment.
Vasella reaction to form aldehyde intermediate 3c, followed by addition of NH4OAc, NaBH(OAc)3. The reaction was stirred at RT for 30 h in an
open round-bottomed flask.
106

A. Fan et al.
CarbohydrateResearch472(2019)103–114
Scheme 3. Iodo-substituted D-furanoside 3 to olefinic imine 4b
2.2. Synthesis 1,4-dideoxy-1,4-imino-D-lyxitol 6 from D-lyxose
The generality of the designed route was tested for the synthesis of
D-lyxose to 1,4-dideoxy-1,4-imino-D-lyxitol (Scheme 2). Various zeolite
catalysts and reaction conditions were tested for the transformation of
D-lyxose to O-methyl 2,3-O-isopropylidene-D-lyxofuranoside
7
(Table 4). The general reaction conditions are 500 mg D-lyxose
(3.3 mmol), 6 mL MeOH, 6 mL acetone, 350 mg catalyst (catalyst/re-
agent: 70% weight) and 65 °C. The reported yield were based on the
average of three trials.
As shown in Table 4, strongly acid zeolites such as H-beta (12.5), HY
(2.6) and ZSM-5 (15) did not improve the yield of 2,3-acetonide 7 + 7a
and some unglycosylated 2,3-acetonide 7c were also detected. The best
result was achieved over H-beta (150) and 45% yield of 2,3-acetonide
(7 + 7a) in one batch reaction. After reaction, the reaction mixture
includes unreacted D-lyxose, O-methyl D-lyxofuranoside and 2,3-acet-
onide 7 + 7a. Although ∼45% yield in one batch reaction was rela-
tively low, the significant difference in solubility of the reagents in-
cluding D-lyxose and O-methyl D-lyxofuranoside and products including
2,3-acetonide 7+ 7a allows them to be easily separated with
Fig. 5. Yield of amine products with recovered NH4OAc.
Table 4
Yield of O-methyl 2,3-O-isopropylidene-D-lyxofuranoside 7 over different zeolites.5.
Run
Catalyst
Time (h)
Yield (%)a
Ratioc
1
2
3
4
5
6
7
H-Beta(12.5)
24
24
24
24
24
24
48
24
24
12, 10b
6, 6b
43, 22b
45
> 10
–
HY(2.6)
ZSM-5(15)
4
H-Beta(150)
> 10
4
H-Beta(150) (cycle 2)
H-Beta(150) (cycle 3)
H-Beta(150), MeOH (step 1)
Acetone (step 2)
H-Beta (150), 10 equiv 2,2-
dimethoxypropane
44
44
2.5
65
2.5
8
77, 13b
> 10
(3:2)d
a
b
c
Yield of 7 + 7a + 7b + 7c.
Estimated yield of 7c based on NMR analyses.
Estimated ratio of furanoside product 7 to pyranoside product 7a based on NMR analyses.
Estimated ratio of 2,3-acetonide (7 + 7a) to 3,5-acetonide 7b based on NMR analyses.
d
107

A. Fan et al.
CarbohydrateResearch472(2019)103–114
Scheme 4. O-methyl 2,3-O-isopropylidene-D-lyxofuranoside to aldehyde intermediate 8b
liquid–liquid (ethyl acetate/water) extraction. Therefore, it was pos-
sible to recover those unreacted D-lyxose and O-methyl D-lyxofurano-
side and carry out further batch reactions to improve the yield. About
82% yield was achieved after three cycles of the reaction. Interestingly,
it was found that the ratio of 7a to 7 increased in the subsequent cycles
(see Appendix-1H NMR of O-methyl 2,3-O-isopropylidene-D-lyxofur-
anoside 7). A separate experiment was carried out by allowing the
formation of O-methyl D-lyxofuranoside before the addition of acetone
(Table 4, Run 7). A high molar ratio of 7a to 7 was obtained with this
strategy, which proves that pre-synthesis of the O-methyl D-lyxofur-
anoside led to the preferred formation of the pyranoside product 7a.
Adding 10 equiv 2,2-dimethoxypropane in reaction mixture helps to
improve the total yield to 77%, however, it was also observed that the
significant amount of 3,5-acetonide 7b and unglycosylated 2,3-acet-
onide 7c by-products were formed (Table 4, Run 8).
[23,31]. Besides the competitive yield, the reported strategy also employs
many principles of Green Chemistry such as avoiding toxic or noxious
chemical, and recycling and reusing the reagents.
4. Experimental
4.1. Preparation and characterization of zeolite catalysts
All zeolite catalysts are commercially available and purchased from
Zeolite International. The sample is named as zeolite-type (t) where t is
the framework Si/Al ratios. The nitrogen adsorption/desorption iso-
therms of the zeolite samples were measured with a Micromeritics
Tristar 3000. Before the measurement, each sample was degassed at
500 °C for 4 h to remove physisorbed water. The surface area was de-
termined using the Brunauer–Emmett–Teller (BET) method. The pore
size distribution was calculated from the desorption branch of the iso-
therm using the Barrett–Joyner–Halenda (BJH) equation. The total pore
volume of the sample was taken from the volume of nitrogen adsorbed
at the P/P o of 0.99. The crystal structure and phase of the samples were
Treating the 2,3-acetonide (7 + 7a) with methanesulfonyl chloride
(MsCl) in pyridine followed by reacting with sodium iodide in 2-buta-
none led to a mixture of iodo-substituted
D-
lyxopyranoside 8a (Scheme 4). After a veDr-ylysxiomfuprlaenwosoidrke-u8p abnyd li-
quid–liquid (dichloromethane/water) extraction and filtration through
a silica gel plug using ethyl acetate/hexane = 1: 3 as eluent), a total
92% isolated yield was achieved. Fortunately, based on the mechanism
of Vasella reaction (Scheme 4), it was expected that only a single al-
dehyde intermediate 8b would be obtained from the mixture of iodo-
substituted D-lyxofuranoside 8 and D-lyxopyranoside 8a. By applying
the optimized reaction condition as in Table 3, Entry 7 for the mixture
of D-lyxofuranoside 8 and D-lyxopyranoside 8a, the monomer olefinic
amine 9 was obtained in 68% isolated yield. Finally, halocyclization/
carbonylation of olefinic amine 9 to cyclic carbamate 10 and then hy-
drolysis of the cyclic carbamate 10 afforded the hydroxypyrrolidine 11
in total 50% yield (starting from D-lyxose).
determined with
a Siemens D5005 powder x-ray diffractometer
equipped with a Cu anode and variable primary and secondary beam
slits. The diffractograms were measured from of 5° to 50°, using a step
size of 0.02° and a dwell time of 1 s/step. The average crystallite size D
was calculated using the Scherrer equation as below:
K
cos
D =
,
=
B2 b2
where, K is a constant taken as 0.9, θ is the angle between the X-ray
beam and the normal on the reflecting plane, λ is the wavelength of Cu
Kα = 0.15418 nm, β is the peak line width. The peak line width β is
corrected for the instrumental broadening, where B is the measured
peak width and b is the instrumental broadening. Diffraction data from
standard silicon (Si) powder was used to measure the instrumental
broadening. The silicon (111) reflection at 2θ ∼26.77° was considered
3. Conclusion
and the instrumental broadening
1.413 × 10−3 rad.
b
was determined to be
The novel and environmental friendly synthetic route for hydro-
xypyrrolidines, 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-
imino-D-lyxitol was carried out in a simple 5-steps starting from com-
mercially available D-ribose and D-lyxose, respectively. The one-pot
synthesis of the O-methyl 2,3-O-isopropylidenepentofuranoses of the D-
pentoses was managed over zeolite solid acid catalysts. The best catalyst
was H-beta zeolite containing a Si/Al molar ratio of 150, where a yield
of > 83% was obtained. The catalyst could be reused for subsequent
batch reactions, with no significant loss of activity and selectivity. The
synthetic route resulted in good yields of 1,4-dideoxy-1,4-imino-L-lyxitol
and 1,4-dideoxy-1,4-imino-D-lyxitol of 57% and 50%, respectively. The
yields are comparable to previously reported yields of 55% and 57%
The nitrogen adsorption-desorption isotherms of the different zeo-
lite catalysts are given in Fig. 6.
The textural properties of zeolite catalysts were shown in Table 5,
where the average and standard deviation of three measurements are
reported. The steep increase at low P/Po indicates the presence of mi-
o
cropores. The hysteresis above P/P 0.5 in these zeolite samples does
not indicate the presence of mesopores but originates from the inter-
particle space of the sample. The HY (15) sample has the highest surface
area of 567 m2 g−1 with ∼433 m2 g−1, due to micropores. The surface
area and porosity of the samples were lower for zeolites with higher Al
content.
108

A. Fan et al.
CarbohydrateResearch472(2019)103–114
Fig. 6. Adsorption/desorption isotherms of (a) H-beta (b) HY and (c) ZSM-5 zeolites with different Si/Al ratios (in parenthesis).
4.2. Identification of products
4.3. General procedure for transformation of D-ribose to O-methyl D-
ribofuranoside
1H and 13C NMR spectra were measured at 75, 300 and 400 MHz
with a Bruker Avance 300 NMR spectrometer using tetramethylsilane
(TMS) as the internal standard. Chemical shifts were reported in ppm
downfield from TMS. Mass spectrometry (MS) and high resolution-mass
spectrometry electron ionization (HR-MS EI)were taken with a Finnigan
MAT95XL-T and Micromass VG7035 double focusing mass spectro-
meter of high resolution, respectively. Optical rotations were measured
by a Perkin Elmer 341 polarimeter in a 1 dm cell. Analytical and pre-
parative thin layer chromatography (TLC) were conducted on precoated
TLC plates (silica gel 60 F254, Merck). To detect the sugars, thymol
(0.5 g)/sulfuric acid (5 mL, conc. sulfuric acid in 95 mL ethanol) vi-
sualization reagent was used. After spraying, the TLC plate was heated
to develop pink spots. No crystal structure data was obtained due to the
difficulty in crystal growth for products.
A
25 mL round-bottomed flask was charged with
(Carbosynth, 300 mg, 2 mmol) and MeOH (6 mL). The suspensDio-rnibwoases
heated to reflux (65 °C). After that, zeolite catalyst (350 mg, catalyst/
reagent: 117 wt %) was added into reaction flask. The mixture was
stirred at reflux for 18 h and then cooled to room temperature. The
zeolite catalyst was filtered out and the filtrate was evaporated under
reduced pressure to give a syrup. The resulting syrup was then purified
by column chromatography on silica gel (chloroform/methanol 6: 1)
and 310 mg (94% yield) of O-methyl D-ribofuranoside was obtained as
colourless syrup. For the O-glycosylation of other pentoses with me-
thanol, the same experimental procedure was used. All methoxylated
products were identified by comparing their proton and carbon NMR
spectra with references [23,58–65] and the molar ratios of different
Table 5
Textural properties of Zeolites.
Catalyst
Surf. area (m2 g−1
)
Micropore area(m2 g−1
)
Pore vol. (cm3 g−1
)
Micropore vol. (cm3 g−1
)
Crystallitea size (nm)
H-Beta(150)
H-Beta(75)
HY(15)
496
399
567
451
414
377
331
12.1
10.7
12.6
12.1
8.8
288
221
433
406
274
240
245
8.3
0.52
0.30
0.47
0.35
0.36
0.27
0.32
0.02
0.02
0.03
0.02
0.03
0.02
0.01
0.15
0.12
0.23
0.22
0.15
0.13
0.13
0.01
0.01
0.02
0.02
0.01
0.01
0.01
20.7
13.4
59.6
35.6
61.5
84.7
77.1
0.9
0.7
1.1
0.8
1.0
1.2
1.1
7.6
11.2
10.3
6.6
HY(2.6)
ZSM-5(60)
ZSM-5(40)
ZSM-5(15)
7.5
6.1
6.6
5.2
a
Crystallite sizes were obtained by XRD measurements using the Scherrer equation.
109

A. Fan et al.
CarbohydrateResearch472(2019)103–114
isomer products were estimated from the integral values of the corre-
sponding 1H NMR signals.
dissolved in deionized water (20 mL) and extracted twice with CH2Cl2
(15 mL × 2). The organic phase was rotary evaporated to dryness to
give a syrup. The resulting syrup was dissolved in iPrOH (5 mL) fol-
lowed by dropwise adding 1000 mg (10 mmol) conc. HCl solution. The
suspension was stirred for 2 h and then filtered through celite and
concentrated under reduced pressure. The residue was re-dissolved in
iPrOH (5 mL). The resulting solution was dry loaded onto silica gel and
purified by gradient chromatography (DCM/EtOH/MeOH/30% aqu-
eous NH3, 25/2/2/1 to 5/2/2/1, v/v/v/v) to give the alkenylamine 4 in
72% yield as the HCl salt (55 mg, 0.36 mmol, light yellow powder).
4.4. General procedure for the one-pot synthesis of O-methyl 2,3-O-
isopropylidene-D-ribofuranoside 2 from D-ribose
(Carbosynth, 500 mg, 3.3 mmol), acetone (6 mL) and MeOH D(-6rimboLs)e.
The suspension was heated to reflux (65 °C). After that, zeolite catalyst
(350 mg, catalyst/reagent: 70 wt %) was added into reaction flask. The
mixture was stirred at reflux for 24 h and then cooled to room tem-
perature. The zeolite catalyst was filtered out and the filtrate was
evaporated under reduced pressure to give crude product. The crude
product was dissolved in ethyl acetate (20 mL) and then washed twice
with deionized water (10 mL). The organic phase was rotary evaporated
to dryness to afford 520 mg (76% yield) of colorless syrup. The aqueous
phase was rotary evaporated to dryness followed by adding acetone
(3 mL), MeOH (3 mL), zeolite catalyst (100 mg) and stirring at reflux for
24 h. Applied the same work-up procedure as above, a total of 630 mg
of pure product 2 was obtained (93% overall yield from D-ribose).
[α]D20 − 92.0 (c 0.1, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.13 (s,
3H), 1.28 (s, 3H), 3.20 (s, 3H), 3.43 (d, J = 4.4 Hz, 2H), 4.16 (t,
J = 4.1 Hz, 1H), 4.40 (d, J = 5.9 Hz, 1H), 4.60 (d, J = 5.9 Hz, 1H), 4.77
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 24.3, 25.9, 54.7, 63.2, 81.1, 85.1,
A
25 mL round-bottomed flask was charged with
4.6.2. Method 2
To a solution of iodo-substituted D-furanoside 3 (314 mg, 1 mmol) in
EtOH (20 mL), activated Zn (Sigma-Aldrich, 650 mg, 10 mmol) was
added. The mixture was stirred at reflux for 3 h before cooled down to
room temperature. Then, NH4OAc (15400 mg, 200 mmol), 25% aqu-
eous NH3 (16 mL) and NaBH(OAc)3 (636 mg, 3 mmol) were added to
the reaction mixture. The resulting mixture was stirred at room tem-
perature for 30 h in round-bottomed flask. After that, the mixture was
filtered and rotary evaporated under reduced pressure. The resulting
residue was dissolved in deionized water (30 mL) and extracted twice
with CH2Cl2 (20 mL × 2). The organic phase was rotary evaporated to
dryness to afford a syrup. The resulting syrup was dissolved in iPrOH
(10 mL) followed by dropwise adding 2000 mg (20 mmol) conc. HCl
solution. The suspension was stirred for 2 h and then filtered through
celite and concentrated under reduced pressure. The residue was re-
dissolved in iPrOH (10 mL). The resulting solution was dry loaded on to
silica gel and purified by gradient flash chromatography (DCM/EtOH/
MeOH/30% aqueous NH3, 25/2/2/1 to 5/2/2/1, v/v/v/v) to give the
alkenylamine 4 in 66% yield as the HCl salt. (102 mg, 0.66 mmol, light
87.5, 109.2, 111.7. ESI-MS: m/z 227 [M+Na]+
.
4.5. General procedure for iodination of O-methyl 2,3-O-isopropylidene-D-
ribofuranoside 2 to O-methyl 2, 3-O-isopropylidene-5-iodo-D-ribofuranoside
3
yellow powder). [α]D 8.0 (c 0.1, EtOH). 1H NMR (400 MHz, D2O): δ
20
Methanesulfonyl chloride (0.7 mL, 9 mmol) was added dropwise
with stirring to an ice-cooled solution of O-methyl 2,3-O-iso-
propylidene-D-ribofuranoside (1630 mg, 8.0 mmol) in pyridine (5 mL)
and the mixture was kept for 2 h at 0 °C. The reaction was quenched
with water (5 mL) and then CH2C12 (20 mL) was added. The resulting
solution was washed successively with 10% aq HCl (5 mL) until the
organic layer extract became acidic (pH < 3). After added an addi-
tional portion of 10% aq HCl (5 mL) followed by saturated aq NaHCO3
(5 mL) to the solution, the organic layer was separated and dried with
MgSO4. After filtration, Organic extract was evaporated under reduced
pressure to give semisolid mesylate. To the solution of the semisolid
mesylate in 2-butanone (10 mL), NaI (1800 mg, 12 mmol) was added
and the mixture was stirred and heated at reflux for 24 h. After the
mixture was cooled to room temperature, the precipitate of sodium
methane sulfonate was filtered out and the filtrate was concentrated.
The resulting residue was dissolved in dichloromethane (50 mL) and
then washed twice with water (2 × 40 mL). After dried with MgSO4,
the resulting solution was filtered and evaporated under reduced
pressure to give a syrup. The syrup then was taken up in hexane/EtOAc,
3/1(v/v) and filtered through a silica plug to remove excess NaI to give
iodo-substituted D-furanoside 3 in 95% yield (2380 mg). [α]D20 − 67.0
(c 0.1, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.26 (s, 3H), 1.41 (s, 3H),
3.12 (t, J = 10.0 Hz, 1H), 3.21 (dd, J = 9.9, 6.1 Hz, 1H), 3.30 (s, 3H),
4.36 (dd, J = 9.9, 3.8 Hz, 1H), 4.57 (d, J = 5.9, 1H), 4.70 (d,
J = 5.9 Hz, 1H), 4.98 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 6.61, 24.8,
5.82 (ddd, J = 16.8, 10.4, 6.5 Hz, 1H), 5.31 (dd, J = 16.7, 10.3 Hz,
2H), 4.15 (dd, J = 6.5, 5.5 Hz, 1H), 3.81 (ddd, J = 9.6, 5.5, 2.8 Hz, 2H),
3.25 (dd, J = 13.0, 2.8 Hz, 1H), 2.97 (dd, J = 13.1, 9.5 Hz, 1H). 13C
NMR (75 MHz, D2O): δ 135.2, 118.3, 73.9, 69.7, 41.0. HRMS (ESI) m/z
calcd. for [C5H11O2N + H]+: 118.0863, found: 118.0871.
4.7. Synthesis of carbamate 5
To
a solution of the alkenylamine hydrochloride 4 (154 mg,
1 mmol) in water (5 mL), NaHCO3 (126 mg, 1.5 mmol) and I2 (279 mg,
1.1 mmol) were added. The solution was stirred 18 h at room tem-
perature. After that, the mixture was filtered and rotary evaporated
under reduced pressure to give crude product. The crude product was
purified by silica gel chromatography (EtOAc/MeOH, 99/1, v/v) to
afford amorphous white powder carbamate 5 (148 mg, 0.93 mmol,
93%). [α]D20 32.5 (c 0.3, EtOH). 1H NMR (400 MHz, D2O): δ 4.54–4.73
(m, 3H), 4.18 (ddd, J = 10.3, 7.4, 5.4 Hz, 1H), 4.05 (t, J = 4.4 Hz, 1H),
3.53 (dd, J = 14.5, 10.8 Hz, 1H), 3.17 (dd, J = 14.4, 10.3 Hz, 1H). 13C
NMR (75 MHz, D2O): δ 164.2 (C6), 73.3 (C2), 70.7 (C3), 64.4 (C5), 61.6
(C4), 48.7 (C1). HRMS (ESI) m/z calcd. For [C6H9O4N + Na]+
:
182.0424, found: 182.0429.
4.8. Synthesis of hydroxymethyl-pyrrolidine-3,4-diols 6
26.2, 55.0, 82.8, 85.1, 87.2, 109.4, 112.4. ESI-MS: m/z 337 [M+Na]+
4.6. General procedure for synthesis of alkenylamine 4
4.6.1. Method 1
.
To a solution of carbamate 5 (159 mg, 1 mmol) in EtOH (5 mL),
NaOH (400 mg, 10 mmol) was added. The mixture was stirred at reflux
for 2 h before cooled down to room temperature. Then, Amberlite IR
120H acidic ion exchange resin (1000 mg) was added to the mixture
and the suspension was stirred at room temperature for overnight. After
filtering out the ion exchange resin, the resin was eluted with 5–15%
aqueous NH3. The resulting eluent was concentrated under reduced
pressure. 1, 4-dideoxy-1,4-imino-L-lyxitol 6 was isolated as the HCl salt
(165 mg, 0.97 mmol, 97%). [α]D20 − 22.5 (c 0.3, H2O). 1H NMR
(400 MHz, D2O): δ 4.52 (dt, J = 7.4, 4.1 Hz, 1H), 4.37 (t, J = 4.1 Hz,
1H), 4.00 (dd, J = 12.2, 4.9 Hz, 1H), 3.92 (dd, J = 12.2, 8.4 Hz, 1H),
Activated Zn (Sigma-Aldrich, 800 mg, 12.3 mmol), NH4OAc
(7700 mg, 100 mmol) and 25% aqueous NH3 (8 mL) were added to a
solution of iodo-substituted D-furanoside 3 (160 mg, 0.5 mmol) in EtOH
(10 mL). The mixture was stirred at 90 °C for 18 h in an autoclave. After
cooled to room temperature, the mixture was filtered and rotary eva-
porated under reduced pressure. The resulting residue was then
110

A. Fan et al.
CarbohydrateResearch472(2019)103–114
3.75 (ddd, J = 13.0, 8.8, 4.8 Hz, 1H), 3.55 (dd, J = 12.2, 7.5 Hz, 1H),
3.23 (dd, J = 12.0, 7.3 Hz, 1H). 13C NMR (75 MHz, D2O): δ 69.9 (C2),
69.7 (C3), 62.4 (C4), 57.4 (C5), 47.0 (C1). HRMS (ESI) m/z calcd. for
[C5H11O3N + H]+:134.0812, found: 134.0813.
4.70–4.74 (m, 1H), 4.88 (s, 1H). 13C NMR (75 MHz, CDCl3): (Major) δ
112.6, 107.1, 85.1, 80.4, 79.4, 54.6, 26.0, 24.9, −0.8. ESI-MS: m/z 337
[M+Na]+
.
4.11. General procedure for synthesis of alkenylamine 9
4.9. General procedure for one-pot synthesis O-methyl 2,3-O-
isopropylidene-D-lyxofuranoside 7 from D-lyxose
To a solution of iodo-substituted
8 (160 mg,
0.5 mmol) in EtOH (10 mL), activated DZ-lnyx(oSfuigrmanao-Asildderich, 800 mg,
12.3 mmol), NH4OAc (7700 g, 100 mmol) and 25% aqueous NH3 (8 mL)
were added. The mixture was stirred at 90 °C for 18 h in an autoclave.
After cooled down to room temperature, the mixture was filtered and
concentrated under reduced pressure. The residue was dissolved in
deionized water (20 mL) and extracted twice with CH2Cl2 (15 mL × 2).
The organic phase was rotary evaporated to dryness to afford a syrup.
The resulting syrup was dissolved in iPrOH (5 mL) followed by adding
dropwise 1000 mg (10 mmol) conc. HCl solution. The suspension was
stirred for 2 h and then filtered through celite and concentrated under
reduced pressure. The residue was re-dissolved in iPrOH (5 mL) and
filtered. The solution was dry loaded on to silica gel and purified by
gradient flash chromatography (DCM/EtOH/MeOH/30% aqueous NH3,
25/2/2/1 to 5/2/2/1, v/v/v/v) to give the alkenylamine 9 in 68% yield
as the HCl salt (52 mg, 0.34 mmol, light yellow powder). [α]D20 − 8.0
(c 0.1, EtOH). 1H NMR (400 MHz, D2O): δ 5.72–6.08 (m, 1H),
5.15–5.55 (m, 2H), 4.15 (dd, J = 6.5, 5.4 Hz, 1H), 3.81 (ddd, J = 9.5,
5.4, 2.8 Hz, 2H), 3.25 (dd, J = 13.3, 3.0 Hz, 1H), 2.97 (dd, J = 13.2,
9.6 Hz, 1H). 13C NMR (75 MHz, D2O): δ 135.4, 118.6, 74.2, 69.9, 41.3.
HRMS (ESI) m/z calcd. for [C5H11O2N + H]+: 118.0868, found:
118.0873.
A
25 mL round-bottomed flask was charged with
(Carbosynth, 500 mg, 3.3 mmol), acetone (6 mL) and MeOHD(-6lymxoLs)e.
The suspension was heated to reflux (65 °C). After that, zeolite catalyst
(350 mg, catalyst/reagent: 70 wt %) was added into reaction flask. The
mixture was stirred at reflux for 24 h and then cooled to room tem-
perature. The zeolite catalyst was filtered out and the filtrate was
evaporated under reduced pressure to give crude product. The crude
product was dissolved in ethyl acetate (20 mL) and then washed twice
with deionized water (10 mL). The organic phase was rotary evaporated
to dryness to afford 310 mg (45% yield) of colorless syrup. The aqueous
phase was rotary evaporated to dryness followed by adding Acetone
(6 mL), MeOH (6 mL) and zeolite catalyst (350 mg). The resulting
mixture was stirred at reflux for 24 h. Applied the same work-up pro-
cedure as above to give another batch of colorless syrup product.
Repeated the same reaction and work-up process for those unreacted D-
lyxose and O-methyl D-lyxofuranoside in aqueous extract for another 2
cycles, a total of 560 mg of pure product was obtained (82% overall
yield from D-lyxose). D-lyxofuranoside product 7: 1H NMR (300 MHz,
CDCl3): (Major) δ 1.28 (s, 3H), 1.42 (s, 3H), 3.30 (s, 3H), 3.85–4.04 (m,
2H), 4.02 (dd, J = 8.6, 2.8 Hz, 1H), 4.55 (d, J = 4.4 Hz, 1H), 4.74 (dd,
J = 4.8, 2.7 Hz, 1H), 4.89 (s, 1H). 13C NMR (75 MHz, CDCl3): (Major) δ
112.7, 107, 85.1, 80.3, 79.3, 61.0, 54.6, 25.9, 24.5. D-lyxopyranoside
product 7a: 1H NMR (300 MHz, CDCl3): (Minor) δ 1.33 (s, 3H), 1.49 (s,
4.12. Synthesis of carbamate 10
3H), 3.40 (s, 3H), 3.59–4.0 (m, 2H), 4.0–4.33 (m, 3H), 4.62 (s, 1H). 13
C
To a solution of the alkenylamine hydrochloride 9 (154 mg,
NMR (75 MHz, CDCl3): (Minor) δ 112.7, 99.9, 76.3, 74.4, 63.9, 62.9,
1 mmol) in water (5 mL), NaHCO3 (126 mg, 1.5 mmol) and I2 (279 mg,
1.1 mmol) were added. The solution was stirred 18 h at room tem-
perature. After that, the mixture was filtered and rotary evaporated
under reduced pressure to give crude product. The crude product was
purified by silica gel chromatography (EtOAc/MeOH, 99/1, v/v) to
afford carbamate 10 (157 mg, 0.99 mmol, 99%) as an amorphous white
powder. [α]D20 − 30.2 (c 0.3, EtOH). 1H NMR (400 MHz, D2O): δ
4.54–4.80 (m, 3H), 4.18 (ddd, J = 8.0, 5.2, 2.8 Hz, 1H), 4.05 (t,
J = 3.4 Hz, 1H), 3.54 (dd, J = 10.8, 8.0 Hz, 1H), 3.18 (dd, J = 10.8,
8.0 Hz, 1H). 13C NMR (75 MHz, D2O): δ 164.3 (C6), 73.3 (C2), 70.7
(C3), 64.4 (C5), 61.6 (C4), 48.7 (C1). HRMS (ESI) m/z calcd. For
[C6H9O4N + Na]+: 182.0429, found: 182.0433.
55.8, 27.5, 25.6. ESI-MS: m/z 337 [M+Na]+
.
4.10. General procedure for iodination of O-methyl 2,3-O-isopropylidene-D-
lyxofuranoside 7 to O-methyl 2, 3-O-isopropylidene-5-iodo-D-
lyxofuranoside 8
Methanesulfonyl chloride (0.7 mL, 9 mmol) was added dropwise
with stirring to an ice-cooled solution of O-methyl 2,3-O-iso-
propylidene-D-lyxofuranoside (1630 mg, 8.0 mmol) in pyridine (5 mL)
and the mixture was kept for 2 h at 0 °C. The reaction was quenched
with water (5 mL) and then CH2C12 (20 mL) was added. The resulting
mixture was washed successively with 10% aq HCl (5 mL) until the
organic layer extract became acidic (pH < 3). After added an addi-
tional portion of 10% aq HCl (5 mL) followed by saturated aq NaHCO3
(5 mL) to the solution, the organic layer was separated and dried with
(MgSO4). After filtration, organic extract was concentrated to give
semisolid mesylate. To the solution of the mesylate in 2-butanone
(20 mL), NaI (12000 mg, 80 mmol) was added. The mixture was stirred
and heated at reflux for 36 h. After the mixture was cooled to room
temperature, the precipitate of sodium methane sulfonate and un-
reacted NaI were filtered out and the filtrate was concentrated under
reduced pressure. The residual oil was dissolved in dichloromethane
(50 mL) and washed with water (2 × 40 mL). After dried with MgSO4,
the resulting solution was evaporated under reduced pressure to give a
syrup. The resulting syrup then was taken up in hexane/EtOAc, 3/1 (v/
v) and filtered through a silica plug to remove excess NaI to give iodo-
4.13. Synthesis of hydroxymethyl-pyrrolidine-3,4-diols 11
To a solution of carbamate 10 (159 mg, 1 mmol) in EtOH (5 mL),
NaOH (400 mg, 10 mmol) was added. The mixture was stirred at reflux
for 2 h before cooled down to room temperature. Amberlite IR 120H
acidic ion exchange resin (1000 mg) was added to the mixture and the
resulting suspension was stirred at room temperature for overnight.
After filtering out the ion exchange resin, the resin was eluted with
5–15% aqueous NH3. The resulting eluent was concentrated under re-
duced pressure. 1,4-dideoxy-1,4-imino-L-lyxitol 11 was isolated as the
HCl salt (166 mg, 97 mmol, 97%). [α]D 21.5 (c 0.3, H2O). 1H NMR
20
(400 MHz, D2O): δ 4.50–4.54 (m, 1H), 4.37 (t, J = 1.6 Hz, 1H), 4.00
(dd, J = 3.3, 1.3 Hz, 1H), 3.96 (dd, J = 5.6, 2.1 Hz, 1H), 3.74–3.80 (m,
1H), 3.55 (dd, J = 13.2, 3.0 Hz, 1H), 3.27 (dd, J = 13.3, 9.5 Hz, 1H).
13C NMR (75 MHz, D2O): δ 69.3 (C2), 69.1 (C3), 61.4 (C4), 57.1 (C5),
46.5 (C1). HRMS (ESI) m/z calcd. for [C5H11O3N + H]+:134.0817,
found: 134.0815.
20
substituted D-lyxofuranoside 8 in 92% yield (2310 mg). [α]D 65.0 (c
0.1, CHCl3). 1H NMR (300 MHz, CDCl3): (Major) δ 1.30 (s, 3H), 1.42 (s,
3H), 3.25–3.35 (m, 4H), 4.14–4.19 (m, 1H), 4.57 (d, J = 5.8 Hz, 1H),
111

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CarbohydrateResearch472(2019)103–114
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.carres.2018.11.016.
Appendix
1H NMR (300 MHz, CDCl3) of O-methyl 2,3-O-isopropylidene-D-lyxofuranoside 7.
112

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CarbohydrateResearch472(2019)103–114
[25] P. Merino, I. Delso, T. Tejero, F. Cardona, M. Marradi, E. Faggi, C. Parmeggiani,
A. Goti, Eur. J. Org Chem. (2008) 2929–2947.
References
[26] D. Díez, M.T. Bebéitez, M.J. Gil, R.F. Moro, I.S. Marcos, N.M. Garrido, G.P. Basabe,
Synthesis 4 (2005) 565–568.
[1] P. Compain, O.R. Martin (Eds.), Iminosugars: from Synthesis to Therapeutic
Applications, John Wiley & Sons, 2007.
[27] A.S. Davis, N.J. Gates, K.B. Lindsay, M. Tang, S.G. Pyne, Synlett 1 (2004) 49–52.
[28] L. Espelt, T. Parella, J. Bujons, C. Solans, J. Joglar, A. Delgado, P. Clapés, Chem. Eur
J. 9 (2003) 4887–4899.
[2] T.D. Butters, R.A. Dwek, F.M. Platt, Curr. Top. Med. Chem. 3 (2003) 561–574.
[3] E.B.D. Melo, A.D.S. Gomes, I. Carvalho, Tetrahedron 62 (2006) 10277–10302.
[4] D. Durantel, C. Alotte, F. Zoulim, Curr. Opin. Invest. Drugs 8 (2007) 125–132.
[5] K. Whitby, D. Taylor, D. Patel, P. Ahmed, A.S. Tyms, Antiviral Chem. Chemother.
15 (2004) 141–151.
[29] A.L. Lei, G. Liu, X. Lu, J. Org. Chem. 67 (2002) 974–980.
[30] C.-C. Wang, S.-Y. Luo, C.-R. Shie, S.-C. Hung, Org. Lett. 4 (2002) 847–849.
[31] E.M. Dangerfield, M.S.M. Timmer, B.L. Stocker, Org. Lett. 11 (2009) 535–538.
[32] E.M. Dangerfield, C.H. Plunkett, B.L. Stocker, M.S.M. Timmer, Molecules 14 (2009)
5298–5307.
[6] A.A. Watson, G.W.J. Fleet, N. Asano, R.J. Molyneux, R.J. Nash, Photochemistry 56
(2001) 265–397.
[7] R.A. Dwek, T.D. Butters, F.M. Platt, N. Zitzmann, Nat. Rev. Drug Discov. 1 (2002)
65–75.
[33] A. Fan, S. Jaenicke, G.K. Chuah, Org. Biomol. Chem. 9 (2011) 7720–7726.
[34] M.J. Climent, A. Corma, S. Iborra, Green Chem. 13 (2011) 520–540.
[35] L.M. Lerner, Carbohydr. Res. 53 (1977) 177–185.
[8] T.D. Butters, R.A. Dwek, F.M. Platt, Glycobiology 15 (2005) 43–53.
[9] P. Greimel, J. Spreitz, A.E. Stutz, T.M. Wrodnigg, Curr. Top. Med. Chem. 3 (2003)
513–523.
[36] V. Popsavin, S. Grabež, B. Stojanović, M. Popsavin, V. Pejanović, D. Miljković,
Carbohydr. Res. 321 (1999) 110–115.
[10] M.E.C. Caines, S.M. Hancock, C.A. Tarling, T.M. Wrodnigg, R.V. Stick, A.E. Stutz,
A. Vasella, S.G. Withers, N.C.J. Strynadka, Angew. Chem. Int. Ed. 46 (2007)
4474–4476.
[37] J.J. Forsman, J. Wärnå, D.Y. Murzin, R. Leino, Eur. J. Org Chem. (2009)
5666–5676.
[38] L.G. Dickson, E. Leroy, J.-L. Reymond, Org. Biomol. Chem. 2 (2004) 1217–1226.
[39] N.M. Xavier, S.D. Lucas, A.P. Rauter, J. Mol. Catal. 305 (2009) 84–89.
[40] A. Corma, S. Iborra, S. Miquel, J. Primo, J. Catal. 161 (1996) 713–719.
[41] J.-F. Chapat, A. Finiels, J. Joffre, C. Moreau, J. Catal. 185 (1999) 445–453.
[42] Y. -i. Matsushita, K. Sugamoto, Y. Kita, T. Matsui, Tetrahedron Lett. 38 (1997)
8709–8712.
[11] T.M. Wrodnigg, A.J. Steiner, B.J. Ueberbacher, Anti Cancer Agents Med. Chem. 8
(2008) 77–85.
[12] M.S. Butler, Nat. Prod. Rep. 25 (2008) 475–516.
[13] M.J. Eis, C.J. Rule, B.A. Würzburg, B. Ganem, Tetrahedron Lett. 26 (1985)
5397–5398.
[14] J.P. Saludes, S.C. Lievens, T.F. Molinski, J. Nat. Prod. 70 (2007) 436–438.
[15] F.P. Guengerich, S.J. DiMari, H.P. Broquist, J. Am. Chem. Soc. 95 (1973)
2055–2056.
[43] B. Helferich, E. Schmitz-Hillebrecht, Chem. Ber. 66B (1933) 378–383.
[44] A. Corma, J. Catal. 216 (2003) 298–312.
[45] S. Namba, Y. Wakushima, T. Shimizu, H. Masumoto, T. Yashima, B. Imelik,
C. Naccache, G. Condurier, Y. Ben Taarit (Eds.), Catalysis by Acids and Bases, vol.
20, Elsevier, Amsterdam, 1985, pp. 205–211.
[16] Y.F. Liao, A. Lal, K.W. Moreman, J. Biol. Chem. 271 (1996) 28348–28358.
[17] G.P. Kaushal, T. Szumilo, I. Pastuszak, A.D. Elbein, Biochemistry 29 (1990)
2168–2176.
[46] B.S. Balaji, M. Sasidharan, R. Kumar, B. Chanda, Chem. Commun. (1996) 707–708.
[47] A.P. Rauter, F. Ramôa-Ribeiro, A.C. Fernandes, J.A. Figueiredo, Tetrahedron 51
(1995) 6529–6540.
[18] B.A. Sobin, F.W. Tanner Jr., J. Am. Chem. Soc. 76 (1954) 4053.
[19] M. Shibano, S. Kitagawa, S. Nakamura, N. Akazawa, G. Kusano, Chem. Pharm. Bull.
45 (1997) 700–705.
[48] E. Henon, A. Bercier, R. Plantier-Royon, D. Harakat, C. Portella, J. Org. Chem. 72
(2007) 2271–2278.
[20] K. Tsuchiya, S. Kobayashi, T. Harada, T. Kurokawa, T. Nakagawa, N. Shimada,
K. Kobayashi, J. Antibiot. 48 (1995) 626–642.
[49] W. Boland, N. Schroer, C. Sieler, M. Feigel, Helv. Chim. Acta 70 (1987) 1025–1040.
[50] R.A.D. Silva, I.H.S. Estevam, L.W. Bieber, Tetrahedron Lett. 48 (2007) 7680–7682.
[51] R.A.D. Silva, L.W. Bieber, Tetrahedron Lett. 51 (2010) 689–691.
[52] K. Abiraj, B. Dinesh, G.R. Srinivasa, D. Channe Gowda, J. Chem. Res-S. (2006)
534–535.
[21] G.W.J. Fleet, S.J. Nicholas, P.W. Smith, S.V. Evans, L.E. Fellows, R.J. Nash,
Tetrahedron Lett. 26 (1985) 3127–3130.
[22] M.-J. Blanco, F.J. Sardina, J. Org. Chem. 63 (1998) 3411–3414.
[23] E.M. Dangerfield, S.A. Gulab, C.H. Plunkett, M.S.M. Timmer, B.L. Stocker,
Carbohydr. Res. 345 (2010) 1360–1365.
[53] P. Falus, Z. Boros, G. Hornyánszky, J. Nagy, F. Darvas, L. Ürge, L. Poppe,
Tetrahedron Lett. 52 (2011) 1310–1312.
[24] B.L. Fera, F. Nicotra, Synthetic methods for the preparation of iminosugars, in:
A.E. Stütz (Ed.), Iminosugars as Glycosidase Inhibitors: Norjirimycin and beyond,
Wiley-VCH, Weinheim, Germany, 1999, pp. 68–92 (Chapter 4).
[54] K. Abiraj, D.C. Gowda, J. Chem. Res., Synop. (2003) 332–334.
[55] S. Robin, G. Rousseau, Eur. J. Org Chem. 17 (2000) 3007–3011.
113

A. Fan et al.
CarbohydrateResearch472(2019)103–114
[56] J.C. Jochims, Monatsh. Chem. 94 (1963) 677–680.
[57] A.F. Abdel-Magid, K.G. Carson, B.D. Harris, C.A. Maryanoff, R.D. Shah, J. Org.
Chem. 61 (1996) 3849–3862.
[62] W.V. Dahlhoff, W. Fenzl, R. Köster, Liebigs Ann. Chem. 8 (1990) 807–810.
[63] K. Paradowska, T. Gubica, A. Temeriusz, M.K. Cyrański, I. Wawer, Carbohydr. Res.
343 (2008) 2299–2307.
[58] N.-S. Li, J. Lu, J.A. Piccirilli, Org. Lett. 9 (2007) 3009–3012.
[59] G. Lopeza, C. Nugier-Chauvina, C. Rémondb, M. O'Donohue, Carbohydr. Res. 342
(2007) 2202–2211.
[64] P. Prabhakar, S. Rajaram, D.K. Reddy, V. Shekar, Y. Venkateswarlu, Tetrahedron
Asymmetry 21 (2010) 216–221.
[65] M. Bennett, G.B. Gill, G. Pattenden, A.J. Shuker, A. Stapleton, J. Chem. Soc. Perkin
Trans. 1 (1991) 929–937.
[60] G.W.J. Fleet, P.W. Smith, Tetrahedron 42 (1986) 5685–5692.
[61] W.V. Dahlhoff, Liebigs Ann. Chem. 11 (1990) 1093–1097.
114