Synthesis of C2-Methylene Glycitols from 1,2-Cyclopropanated Sugars: En Route to Iminosugar Analogues

Article abstract of DOI:10.1055/s-0033-1340617

C2-Methylene glycitols were synthesized in three steps by halonium ion mediated solvolytic ring opening of 1,2-cyclopropanated sugars, dehydrohalogenation using potassium carbonate in aqueous acetonitrile, and reduction with sodium borohydride. The generality of the methodology was evaluated by applying it to a series of 1,2-cyclopropanated pyranoses as well as furanoses to give the corresponding C2-methylene glycitol derivatives. Furthermore, the obtained glycitols were converted into 1-deoxy-C2-methylene iminosugar derivatives. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340617

PAPER
▌923
paper
Synthesis of C2-Methylene Glycitols from 1,2-Cyclopropanated Sugars:
En Route to Iminosugar Analogues
Imino Sugars from 1,2-Cyclopropanated Carbohydrates
Kalapati Seshadri, Perali Ramu Sridhar*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Fax +91(40)23012460; E-mail: p_ramu_sridhar@uohyd.ac.in
Received: 05.11.2013; Accepted after revision: 19.12.2013
which are found in several complex natural products.5
Moreover, C2-methylene nucleosides6 are efficient inhib-
itors of ribonucleotide phosphate reductase,6c a key en-
zyme in tumor progression. In spite of their importance,
Abstract: C2-Methylene glycitols were synthesized in three steps
by halonium ion mediated solvolytic ring opening of 1,2-cyclo-
propanated sugars, dehydrohalogenation using potassium carbonate
in aqueous acetonitrile, and reduction with sodium borohydride.
The generality of the methodology was evaluated by applying it to very few synthetic methods are available for the prepara-
tion of these sugar derivatives (Scheme 1).7 The most
common method involves Lewis acid mediated Ferrier re-
a series of 1,2-cyclopropanated pyranoses as well as furanoses to
give the corresponding C2-methylene glycitol derivatives. Further-
more, the obtained glycitols were converted into 1-deoxy-C2-meth-
arrangement of C2-acetoxymethyl glycal derivatives;8
ylene iminosugar derivatives.
Pd(PPh3)4 is also effective in carrying out a similar trans-
formation.8c Recently, gold-catalyzed glycosylation of
Key words: azasugars, carbohydrates, electrophilic addition, pi-
peridines, cyclization
C2-[(propargyloxy)methyl] glycals was reported.9
On the other hand, C2-methylene iminosugar derivatives
have been explored for the synthesis of a number of gly-
The application of C2-methylene sugars in the synthesis
cosidase inhibitors10 including natural ones.11 However,
of novel iminosugar derivatives1 in search of potential in-
the synthesis of the cyclic amine precursor was achieved
hibitors of glycosidases and glycosyl transferases,2 antivi-
by photoinduced electron transfer (PET)-promoted cycli-
ral and anticancer agents, is an interesting and active area
zation of an α-[(trimethylsilyl)methyl]amine radical cat-
in synthetic and medicinal chemistry research.3 C2-Meth-
ylene sugars also serve as precursors in the stereoselective
ion to a tethered acetylene functionality.12
In continuation of our investigations of the applications of
1,2-cyclopropanated sugar derivatives,13 we envisaged
that electrophilic ring opening of cyclopropane followed
synthesis of bioactive natural products and their ana-
logues.4 The methylene group at the C2 position is a pro-
chiral center in the preparation of C2-methyl glycosides,
OBn
OBn R2
N
O
OR1
O
BnO
BnO
OBn
Wittig
olefination
OBn
imino sugars
O
NH
OBn
OBn
O
Ferrier
rearrangement
O
OR1
OBn
N
O
O
OR2
BnO
BnO
OBn
OBn
BnO
this
work
R2 = OAc, propargyl
R1 = H or alkyl or aryl
OBn
C2-methylene
nucleosides
OBn
OBn
O
O
OR1
BnO
BnO
OBn
OBn
C2-methyl sugars
Scheme 1 Preparation of C2-methylene sugars and their application in bioactive natural product synthesis
SYNTHESIS 2014, 46, 0923–0932
Advanced online publication: 30.01.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340617; Art ID: SS-2013-Z0729-OP
© Georg Thieme Verlag Stuttgart · New York

924
K. Seshadri, P. R. Sridhar
PAPER
OBn
O
OBn
K2CO3
MeCN–H2O
(5:1)
OBn
NBS
dioxane–H2O
(2:1)
O
OH
O
OH
Br
8 h, 61%
6 h, 89%
BnO
BnO
BnO
OBn
OBn
OBn
1
2
3α/3β
OBn
OBn
OH OH
OBn
OH
CHO
NaBH4, MeOH
30 min, 84%
BnO
BnO
OBn
4
5
Scheme 2 Stereoselective synthesis of a C2-methylene glucitol derivative
by dehydrohalogenation could provide an easy access in oxygen, in the presence of a protic solvent to provide C2-
the synthesis of C2-methylene sugar derivatives.
branched glycosides.14 Based on this strategy, 1,5-an-
hydro-3,4,6-tri-O-benzyl-2-deoxy-1,2-C-methylene-α-D-
glucitol (1)14a on reaction with N-bromosuccinimide in a
mixture of dioxane–water (2:1) provided 3,4,6-tri-O-ben-
zyl-2-C-(bromomethyl)-2-deoxy-D-glucopyranoside (2)14a
in 61% yield. Treatment of 2 with potassium carbonate in
acetonitrile–water (5:1) provided a complex mixture. De-
tailed spectral analysis of this mixture revealed that the
Herein we report the synthesis of 2-deoxy-C2-methylene
glycitols and their further conversion into C2-methylene
iminosugar derivatives starting from 1,2-cyclopropanated
sugar derivatives.
It is well known that 1,2-cyclopropanated sugars will un-
dergo electrophilic ring opening, assisted by endocyclic
Table 1 Synthesis of 2-Deoxy-C2-methylene Glycitol Derivatives from 1,2-Cyclopropanated Sugar Precursors
Entry
1
1,2-Cyclopropanated sugar
Bromohydrina (yieldb)
C2-Methylene glycosidec (yieldb)
Glycitol (yieldb)
O
O
OH
OH OH
BnO
BnO
BnO
BnO
BnO
BnO
OBn
7 (62%)
OBn
OBn
6
8 (85%)
9 (85%)
O
O
OH
OH
OH
OH OH
BnO
OBn
BnO
BnO
2
3
11 (65%)
15 (65%)
OBn
OBn
10
12 (84%)
13 (87%)
OH OH
O
O
BnO
BnO
OBn
BnO
OBn
OBn
14
16 (84%)
17 (87%)
O
O
OH OH
BnO
OBn
BnO
BnO
4
5
19 (64%)
23 (71%)
OBn
OBn
18
20 (70%)
21 (84%)
O
O
OH
OH
OH
BnO
BnO
BnO
BnO
BnO
BnO
22
24 (79%)
25 (82%)
a Obtained as an anomeric mixture.
b Yield refers pure and isolated products.
c Obtained as an equilibrium mixture of α/β and ring-opened aldehyde derivatives.
Synthesis 2014, 46, 923–932
© Georg Thieme Verlag Stuttgart · New York

PAPER
Imino Sugars from 1,2-Cyclopropanated Carbohydrates
925
compound is a mixture of 3α, 3β, and 4.1a Reduction of hand, selective protection of the primary hydroxyl group
this crude mixture with sodium borohydride gave 2-de- in glucitol 5 with TBS gave alcohol 28, inversion of con-
oxy-2-C-methylene glucitol derivative 51a as a single dia- figuration at C5 using the Mitsunobu reaction15 via 29 and
stereomer in excellent yield (Scheme 2).
30, and deprotection of the silyl protective group provided
C2-methylene-L-iditol derivative 31. Mesylation of both
the hydroxyls in 31 to give 32 followed by reaction with
benzylamine provided 1-deoxy-C2-methylene-D-gluco-
nojirimycin derivative 33 (Scheme 3).
The methodology could also be extended to other 1,2-cy-
clopropanated sugar derivatives. Thus, 1,2-cyclo-
propanated pyranoses 6,14a 10, 14, and 18 upon reaction
with N-bromosuccinimide in dioxane–water provided the
corresponding bromohydrins 7, 11, 15, and 19 in good This methodology for the synthesis of iminosugar deriva-
yields. Potassium carbonate mediated dehydrohalogena- tives could also be extended to the other glycitols 13, 17,
tion of these bromohydrins provided the corresponding and 21. Thus, dimesylation of these diols gave the corre-
C2-methylene sugar derivatives 8, 12, 16, and 20 that sponding disulfonates 34, 36, and 38 followed by substi-
were further reduced to the corresponding glycitol deriv- tution with benzylamine provided the corresponding 1-
atives 9, 13, 17, and 21 in excellent yields (Table 1, entries deoxy-C2-methylene iminosugar derivatives 35, 37, and
1–4). Interestingly, the methodology also can be applied 39 in good yield (Table 2, entries 1–3). Similarly, C2-
to the synthesis of C2-methylene pentitol derivatives. methylene-D-ribitol derivative 25 upon dimesylation pro-
Thus, N-bromosuccinimide-mediated electrophilic ring vided disulfonate 40, which further reacted with benzyl-
opening of 1,4-anhydro-3,5-di-O-benzyl-2-deoxy-1,2-C- amine produced the five-membered C2-methylene
methylene-α-D-ribitol (22) gave the bromohydrin 23 that iminosugar 41 (Table 2, entry 4). The C2-methylene
on reaction with potassium carbonate provided the C2- group present in these iminosugars can serve as an excel-
methylene derivative 24.
lent prochiral function for the preparation of stereoiso-
mers of potent α-glycosidase inhibitors10 and
isofagomine.11
It is worthwhile to mention that compound 24 can serve as
an excellent synthon for the synthesis of C2-methylene
nucleosides analogues. Further reduction of the hemiace- In conclusion, a general methodology was developed for
tal 24 gave the expected C2-methylene-D-ribitol deriva- the synthesis of hexose and pentose derived C2-methy-
tive 25 (Table 1, entry 5).
lene glycitols starting from the corresponding 1,2-cyclo-
propanated sugar precursors. The obtained products were
successfully converted into C2-methylene iminosugar de-
rivatives that can be used for the synthesis of a variety of
iminosugar inhibitors.
Our further efforts were focused on the synthesis of L- and
D-iminosugars using C2-methylene glycitols. Thus, dime-
sylation of glucitol derivative 5 gave 26 that upon reaction
with benzylamine provided C2-methylene-L-idonojirimy-
cin derivative 271a as a single diastereomer. On the other
OBn
OBn
OBn
TBSCl
imidazole
CH2Cl2
Ph3P, p-NBA
DEAD, THF
OPNB
OTBS
OH OH
OH OTBS
8 h, 85%
12 h
BnO
BnO
BnO
OBn
OBn
OBn
5
28
29
MsCl, Et3N
30 min, 91%
(two steps)
NaOMe
2 h, 89%
OBn
CH2Cl2, 0 °C
MeOH
OBn
OBn
BnO
Bn
N
OMs OMs
OH OTBS
BnNH2, 90 °C
16 h, 75%
BnO
BnO
OBn
OBn
OBn
OBn
30
26
27
p-TsOH
MeOH
20 min, 96%
OBn
OBn
Bn
N
MsCl, Et3N
OMs OMs
OH OH
BnNH2, 90 °C
16 h, 74%
CH2Cl2, 0 °C
2 h, 89%
BnO
BnO
BnO
OBn
OBn
32
OBn
31
33
Scheme 3 Synthesis of 1-deoxy-2-C-methylene-L-idonojirimycin and 1-deoxy-C2-methylene-D-gluconojirimycin derivatives
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 923–932

926
K. Seshadri, P. R. Sridhar
PAPER
separated and the aqueous layer was extracted with CH2Cl2 (2 × 20
mL). The combined organic layers were then dried (anhyd Na2SO4),
filtered, and concentrated. Purification by column chromatography
(silica gel, EtOAc–hexane) afforded the corresponding C2-methy-
lene sugar derivative as an equilibrium mixture of isomers.
Table 2 Synthesis of 1-Deoxy-C2-methylene Iminosugar Deriva-
tives
Entry Glycitol Dimesylate
(yielda)
C2-Methylene
iminosugar (yieldb)
Sodium Borohydride Reduction, Synthesis of C2-Methylene
Glycitols; General Procedure
Bn
N
OMs OMs
OBn
An equilibrium mixture of C2-methylene compound (1 mmol, 1
equiv) was dissolved in anhyd MeOH (10 mL). NaBH4 (1.2 equiv)
was added slowly at 0 °C to the mixture and it was allowed it to
warm to 25 °C and stirring was continued for 30 min. When TLC
indicated the complete disappearance of starting material, the reac-
tion was quenched by the addition of sat. aq NH4Cl (20 mL). MeOH
was removed under reduced pressure and the suspension was ex-
tracted with CHCl3 (3 × 50 mL). The combined extracts were
washed with sat. aq NaHCO3, dried (anhyd Na2SO4), filtered, and
concentrated. The crude product was purified by column chroma-
tography (EtOAc–hexane) to afford the diol.
1
2
13
17
BnO
BnO
OBn
34 (82%)
35 (72%)
Bn
N
OMs OMs
BnO
BnO
OBn
OBn
36 (81%)
37 (74%)
3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-D-arabino-hexopy-
ranose (3 and 4)
A mixture of 3/4 (89:11, 75 mg, 89%) was obtained from bromohy-
drin 2 (100 mg, 0.19 mmol) as a colorless gum; Rf = 0.36 (30%
EtOAc–hexane); [α]D25 +6.3 (c 1.1, CHCl3).
Bn
N
OMs OMs
BnO
3
4
21
25
BnO
OBn
OBn
IR (neat): 3402, 3030, 2922, 2866, 1726, 1496, 1454, 1359, 1265,
1105, 736 cm–1.
38 (79%)
39 (68%)
1H NMR (400 MHz, CDCl3): δ (major isomer) = 7.38–7.16 (m, 15
H), 5.59 (s, 1 H), 5.30 (s, 1 H), 5.18 (s, 1 H), 4.86 (d, J = 10.8 Hz, 1
H), 4.73 (d, J = 11.1 Hz, 1 H), 4.67 (d, J = 11.1 Hz, 1 H), 4.60–4.53
(m, 4 H), 4.21 (m, 1 H), 3.64 (m, 2 H), 3.51 (m, 1 H), 3.30 (br s, 1
H).
13C NMR (100 MHz, CDCl3): δ = 142.7, 138.2, 137.9, 136.8, 128.6,
128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 110.8, 95.9, 80.6, 80.3,
74.8, 73.3, 73.1, 71.4, 69.2.
Bn
N
OMs
OMs
BnO
BnO
BnO
BnO
40 (85%)
41 (76%)
a Yield refers crude product after workup.
b Yield refers pure and isolated product.
HRMS (ESI): m/z [M + Na]+ calcd for C28H30O5Na: 469.1991;
found: 469.1991.
(3R,4R,5R)-3,4,6-Tris(benzyloxy)-2-methylenehexane-1,5-diol
(5)
Compound 5 (168 mg, 84%) was obtained from a mixture of 3 and
4 (200 mg, 0.45 mmol) as a colorless gum; Rf = 0.21 (30% EtOAc–
hexane); [α]D25 +2.9 (c 1.0, CHCl3).
All reactions were carried out under an inert atmosphere with dry
solvents under anhydrous conditions unless otherwise mentioned.
CH2Cl2, MeOH, and Et3N were initially dried and stored over 4-Å
molecular sieves. TLC [silica gel 60 F254 (Merck)] was developed
by staining with 5% H2SO4 in MeOH or 5% phosphomolybdic acid
in EtOH and heat. Silica gel (100–200 mesh) was used as a station-
ary phase for column chromatography. NMR spectra were recorded
at 25 °C on a Bruker Avance III 400 (400 MHz for 1H and 100 MHz
for 13C) instrument; CDCl3 internal standard [residual CHCl3 (δH =
7.26), and CDCl3 (δC = 77.0)]. IR spectra were recorded on Jasco
FT-IR-5300. HRMS were recorded on a Bruker maXis ESI-TOF
spectrometer.
IR (neat): 3425, 2916, 2866, 1813, 1649, 1454, 1358, 1267, 1091,
736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.25 (m, 15 H), 5.38 (s, 1 H),
5.28 (s, 1 H), 4.68 (d, J = 10.8 Hz, 1 H), 4.62 (m, 2 H), 4.53 (s, 2 H),
4.34 (d, J = 12.0 Hz, 1 H), 4.20–4.10 (m, 3 H), 3.99 (m, 1 H), 3.77
(m, 1 H), 3.63 (m, 2 H), 2.91 (br s, 1 H), 2.58 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.3, 137.9, 137.7, 128.5, 128.4,
128.3, 128.2, 127.9, 127.8, 115.7, 81.4, 80.6, 74.5, 73.4, 71.2, 70.9,
70.4, 63.8.
Ring Opening of 1,2-Cyclopropanated Sugar with NBS/Water;
General Procedure
HRMS (ESI): m/z [M + Na]+ calcd for C28H32O5Na: 471.2148;
found: 471.2148.
To a solution of 1,2-cyclopropanated glycal (1 mmol, 1 equiv) in di-
oxane–H2O (2:1, 6 mL) was added NBS (1.2 equiv) at 25 °C and
stirring was continued for 8 h. The mixture was then concentrated
to half its volume in vacuo and extracted with CH2Cl2 (3 × 20 mL).
The combined extracts were dried (anhyd Na2SO4), filtered, and
concentrated. Purification of the crude product by column chroma-
tography (silica gel, EtOAc–hexane) afforded pure bromohydrin.
3,4,6-Tri-O-benzyl-2-C-(bromomethyl)-2-deoxy-D-talopyra-
nose (7)
Bromohydrin 7 (300 mg, 61%) was obtained from cyclopropane de-
rivative 6 (400 mg, 0.93 mmol) as a colorless gum; Rf = 0.48 (30%
EtOAc–hexane).
IR (neat): 3393, 2887, 1726, 1496, 1361, 1095, 736 cm–1.
Potassium Carbonate Mediated Dehydrohalogenation, Synthe-
sis of C2-Methylene Sugar Derivatives; General Procedure
To a solution of bromohydrin (1 mmol, 1 equiv) in MeCN–H2O
(5:1, 12 mL) was added K2CO3 (2 equiv). The mixture was stirred
at 25 °C for a period of ~6–8 h (in case of 20 the reaction took 24
h). After completion of the reaction (by TLC) the mixture was dilut-
ed with CH2Cl2 (20 mL) and H2O (10 mL). The organic layer was
1H NMR (400 MHz, CDCl3): δ = 7.40–7.25 (m, 15 H), 5.50 (s, 1 H),
4.88 (d, J = 11.2 Hz, 1 H), 4.68 (d, J = 12.0 Hz, 1 H), 4.62–4.42 (m,
4 H), 4.21 (m, 1 H), 4.01–3.99 (m, 1 H), 3.88–3.85 (m, 1 H), 3.81
(m, 1 H), 3.77–3.64 (m, 3 H), 3.54–3.50 (m, 1 H), 2.61 (m, 1 H).
Synthesis 2014, 46, 923–932
© Georg Thieme Verlag Stuttgart · New York

PAPER
Imino Sugars from 1,2-Cyclopropanated Carbohydrates
927
13C NMR (100 MHz, CDCl3): δ = 138.5, 138.0, 137.7, 128.5, 128.4,
128.3, 128.0, 127.8, 127.7, 127.5, 127.3, 93.6, 76.1, 74.5, 74.4,
73.5, 70.7, 69.8, 69.7, 67.1, 45.9, 32.1.
HRMS (ESI): m/z [M + Na]+ calcd for C28H31O5BrNa: 549.1253;
found: 549.1253.
IR (neat): 3406, 2870, 1724, 1494, 1454, 1356, 1267, 1107, 738,
698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.28 (m, 10 H), 5.12 (d, J =
10.8 Hz, 1 H), 5.01 (m, 1 H), 4.73–4.64 (m, 4 H), 4.45 (s, 1 H), 4.10
(t, J = 10.8 Hz, 1 H), 3.91 (m, 1 H), 3.82 (dd, J = 5.2, 11.2 Hz, 1 H),
3.66 (m, 2 H), 3.47 (m, 2 H), 2.13 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.8, 138.3, 137.8, 137.5, 128.6,
128.5, 128.4, 128.3, 128.0, 127.8, 127.7, 127.5, 127.0, 94.3, 93.1,
76.2, 75.9, 75.5, 73.8, 71.7, 71.6, 62.0, 56.4, 48.6, 45.9, 31.0, 30.2.
3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-D-lyxo-hexopyra-
nose (8)
C2-Methylene sugar derivatives 8/ring-opened aldehyde (1:2, 72
mg, 85%) were obtained from bromohydrin 7 (100 mg, 0.19 mmol)
as a colorless gum; Rf = 0.45 (30% EtOAc–hexane); [α]D25 –10.1 (c
1.0, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H23O4BrNa: 429.0678;
found: 429.0678.
IR (neat): 3414, 2920, 2868, 1726, 1689, 1496, 1454, 1361, 1086,
738 cm–1.
3,4-Di-O-benzyl-2-deoxy-2-C-methylene-L-ribopyranose (12)
C2-Methylene sugar derivative 12/ring-opened aldehyde (1:3, 135
mg, 84%) were obtained from bromohydrin 11 (200 mg, 0.49
mmol) as a colorless gum; Rf = 0.45 (30% EtOAc–hexane).
1H NMR (400 MHz, CDCl3): δ = 9.59 (s, 1 H), 7.39–7.27 (m, 26 H),
6.62 (s, 1 H), 6.25 (s, 1 H), 5.65 (s, 0.5 H), 5.42 (s, 0.5 H), 5.28 (s,
0.5 H), 4.82 (d, J = 4.0 Hz, 1 H), 4.70 (m, 2 H), 4.67–4.39 (m, 6 H),
3.96 (m, 1 H), 3.72 (m, 1 H), 3.60 (m, 1 H), 3.51 (m, 1 H), 3.49–3.40
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 193.4, 147.0, 140.0, 138.5, 138.4,
138.0, 137.8, 137.3, 136.0, 128.5, 128.3, 127.9, 127.8, 127.6, 111.5,
96.3, 78.4, 75.7, 73.4, 73.3, 72.1, 71.7, 70.8, 69.0.
IR (neat): 3414, 2920, 2868, 1726, 1689, 1496, 1454, 1361, 1086,
738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.64 (s, 1 H), 7.38–7.27 (m, 22 H),
6.61 (s, 1 H), 6.30 (s, 1 H), 5.52 (s, 0.3 H), 5.37 (s, 0.3 H), 5.26 (d,
J = 6.4 Hz, 1 H), 5.06 (s, 1 H), 4.82–4.76 (m, 1 H), 4.72–4.68 (m, 6
H), 4.56 (m, 3 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.28 (m, 1 H), 3.76–
3.70 (m, 3 H), 3.61 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 193.7, 147.1, 139.9, 138.0, 137.8,
137.6, 137.0, 136.6, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.5, 115.8, 95.2, 94.7, 80.5, 77.6, 76.0, 75.5, 74.9,
72.4, 71.9, 71.4, 70.9, 70.3, 62.3, 61.0, 57.0.
HRMS (ESI): m/z [M + Na]+ calcd for C28H30O5Na: 469.1991;
found: 469.1991.
(3R,4S,5R)-3,4,6-Tris(benzyloxy)-2-methylenehexane-1,5-diol
(9)
C2-Methylene-D-galactitol derivative 9 (43 mg, 85%) was obtained
from 8 (50 mg, 0.11 mmol) as a colorless gum; Rf = 0.21 (30%
EtOAc–hexane); [α]D25 –13.3 (c 1.0, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O4Na: 349.1416;
found: 349.1416.
IR (neat): 3443, 2926, 2862, 1730, 1651, 1496, 1454, 1394, 1211,
1091, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.24 (m, 15 H), 5.40 (s, 1 H),
5.29 (s, 1 H), 4.67 (d, J = 11.2 Hz, 1 H), 4.60–4.47 (m, 4 H), 4.33
(d, J = 11.6 Hz, 1 H), 4.19–4.14 (m, 3 H), 4.11–4.04 (m, 1 H), 3.79–
3.76 (m, 1 H), 3.55–3.52 (m, 2 H), 2.70 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 145.6, 137.9, 137.7, 137.6, 128.4,
128.0, 127.9, 127.8, 116.4, 80.6, 79.7, 74.5, 73.4, 70.9, 70.8, 69.7,
63.8.
(2S,3R)-2,3-Bis(benzyloxy)-4-methylenepentane-1,5-diol (13)
C2-Methylene-L-arabitol derivative 13 (87 mg, 87%) was obtained
from 12 (100 mg, 0.30 mmol) as a colorless gum; Rf = 0.22 (30%
EtOAc–hexane); [α]D25 –35.4 (c 1.2, CHCl3).
IR (neat): 3416, 2928, 1726, 1651, 1496, 1456, 1356, 1267, 1028,
736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 10 H), 5.42 (s, 1
H), 5.28 (s, 1 H), 4.65–4.58 (m, 4 H), 4.35 (d, J = 12.0 Hz, 1 H),
4.14 (d, J = 8.0 Hz, 1 H), 4.08 (d, J = 6.8 Hz, 1 H), 3.75 (d, J = 4.8
Hz, 2 H), 3.70–3.66 (m, 1 H), 2.45 (br s, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H32O5Na: 471.2148;
found: 471.2148.
13C NMR (100 MHz, CDCl3): δ = 145.4, 137.7, 137.6, 128.5, 128.2,
128.1, 128.0, 127.9, 116.7, 81.0, 80.6, 73.1, 70.7, 63.4, 61.9.
HRMS (ESI): m/z [M + Na]+ calcd for C20H24O4Na: 351.1573;
found: 351.1573.
3,4-Di-O-benzyl-1,2-dideoxy-1,2-C-methylene-α-L-ribopyra-
nose (10)
Compound 10 (510 mg, 81%) was obtained by cyclopropanation of
3,4-di-O-benzyl-L-arabinal (600 mg, 2.02 mmol) as a colorless
gum; Rf = 0.51 (20% EtOAc–hexane).
3,4-Di-O-benzyl-1,2-dideoxy-1,2-C-methylene-α-D-ribopyra-
nose (14)
Compound 14 (600 mg, 82%) was obtained by cyclopropanation of
3,4-di-O-benzyl-D-arabinal (700 mg, 2.36 mmol) as a colorless
gum; Rf = 0.50 (20% EtOAc–hexane).
IR (neat): 3468, 2860, 1739, 1645, 1496, 1454, 1361, 1097, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.29 (m, 10 H), 4.78–4.68
(m, 3 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.03 (t, J = 10.0 Hz, 1 H), 3.82
(dd, J = 4.0, 12.0 Hz, 1 H), 3.72 (m, 1 H), 3.69 (t, J = 4.4 Hz, 1 H),
3.30 (d, J = 12.0 Hz, 1 H), 1.53 (td, J = 3.2, 6.8 Hz, 1 H), 1.22 (m,
1 H), 0.76 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.6, 138.5, 128.4, 128.3, 127.8,
127.7, 127.6, 127.5, 72.8, 71.2, 70.9, 69.5, 64.7, 53.8, 13.9, 11.3.
IR (neat): 3468, 2860, 1739, 1645, 1496, 1454, 1361, 1097, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.29 (m, 10 H), 4.76–4.67
(m, 3 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.03 (dt, J = 1.2, 4.8 Hz, 1 H),
3.81 (dd, J = 4.4, 12.0 Hz, 1 H), 3.73 (m, 1 H), 3.68 (t, J = 4.4 Hz,
1 H), 2.98 (dd, J = 1.2, 12.0 Hz, 1 H), 1.50 (td, J = 3.2, 6.8 Hz, 1 H),
1.21 (m, 1 H), 0.75 (m, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3Na: 333.1467;
found: 333.1467.
13C NMR (100 MHz, CDCl3): δ = 138.5, 138.4, 128.4, 128.3, 127.8,
127.7, 127.6, 127.5, 72.8, 71.2, 70.9, 69.5, 64.6, 53.8, 13.9, 11.2.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3Na: 333.1467;
found: 333.1467.
3,4-Di-O-benzyl-2-C-(bromomethyl)-2-deoxy-L-ribopyranose
(11)
Bromohydrin 11 (366 mg, 65%) was obtained from cyclopropane
derivative 10 (430 mg, 1.38 mmol) as a colorless gum; Rf = 0.46
(30% EtOAc–hexane).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 923–932

928
K. Seshadri, P. R. Sridhar
PAPER
3,4-Di-O-benzyl-2-C-(bromomethyl)-2-deoxy-D-ribopyranose
(15)
Bromohydrin 15 (383 mg, 65%) was obtained from cyclopropane
derivative 14 (450 mg, 1.45 mmol) as a colorless gum; Rf = 0.43
(30% EtOAc–hexane).
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3Na: 333.1467;
found: 333.1467.
3,4-Di-O-benzyl-2-C-(bromomethyl)-2-deoxy-D-lyxopyranose
(19)
Bromohydrin 19 (672 mg, 64%) was obtained from cyclopropane
derivative 18 (800 mg, 2.58 mmol) as a colorless gum; Rf = 0.45
(30% EtOAc–hexane).
IR (neat): 3406, 2870, 1724, 1494, 1454, 1356, 1267, 1107, 738,
698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.32 (m, 10 H), 5.10 (d, J =
10.8 Hz, 1 H), 4.99 (m, 1 H), 4.70–4.64 (m, 4 H), 4.43 (s, 1 H), 4.07
(t, J = 10.8 Hz, 1 H), 3.89 (m, 1 H), 3.80 (dd, J = 5.2, 11.2 Hz, 1 H),
3.65 (m, 2 H), 3.49 (m, 2 H), 2.11 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.7, 138.2, 137.8, 137.5, 128.6,
128.5, 128.4, 128.3, 128.0, 127.8, 127.7, 127.5, 127.0, 94.3, 93.1,
76.2, 75.9, 75.5, 73.8, 71.7, 71.6, 62.0, 56.4, 48.6, 45.9, 31.0, 30.2.
IR (neat): 3406, 2870, 1724, 1494, 1454, 1356, 1267, 1107, 738,
698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.27 (m, 10 H), 5.15 (d, J =
8.0 Hz, 1 H), 4.89 (d, J = 8.0 Hz, 1 H), 4.71–4.50 (m, 5 H), 4.11 (m,
3 H), 3.91 (m, 1 H), 3.86 (m, 1 H), 3.80 (m, 1 H), 3.64 (m, 2 H), 3.53
(m, 3 H), 2.60 (m, 1 H), 2.39 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.0, 137.7, 136.6, 128.8, 128.6,
128.5, 128.2, 128.0, 127.9, 127.8, 127.7, 94.3, 93.4, 75.1, 74.5,
73.7, 73.0, 71.9, 71.5, 71.1, 70.8, 63.1, 56.5, 46.1, 41.1, 30.7, 30.2.
HRMS (ESI): m/z [M + Na]+ calcd for C20H23O4BrNa: 429.0678;
found: 429.0678.
3,4-Di-O-benzyl-2-deoxy-2-C-methylene-D-ribopyranose (16)
C2-Methylene sugar derivative 16/ring-opened aldehyde (1:3, 67
mg, 84%) were obtained from bromohydrin 15 (100 mg, 0.24
mmol) as a colorless gum; Rf = 0.41 (30% EtOAc–hexane); [α]D
+17.6 (c 1.0, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H23O4BrNa: 429.0678;
found: 429.0678.
25
3,4-Di-O-benzyl-2-deoxy-2-C-methylene-D-lyxopyranose (20)
C2-Methylene sugar derivative 20/ring-opened aldehyde (2.3:1,
197 mg, 70%) was obtained from bromohydrin 19 (350 mg, 0.86
mmol) as a colorless gum; Rf = 0.42 (30% EtOAc–hexane).
IR (neat): 3437, 2926, 2872, 1687, 1496, 1454, 1358, 1099, 738
cm–1.
IR (neat): 3400, 2930, 1724, 1687, 1496, 1358, 1207, 1097, 738
cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.63 (s, 1 H), 7.38–7.26 (m, 21 H),
6.61 (s, 1 H), 6.29 (s, 1 H), 5.52 (s, 0.3 H), 5.37 (s, 0.3 H), 5.25 (d,
J = 6.4 Hz, 2 H), 5.06 (s, 1 H), 4.83–4.75 (m, 1 H), 4.72–4.62 (m, 4
H), 4.55 (m, 3 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.28 (m, 1 H), 4.05–
3.90 (m, 0.8 H), 3.75–3.68 (m, 3 H), 3.62 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 193.7, 147.1, 139.9, 138.0, 137.8,
137.6, 137.0, 136.6, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9,
127.8, 127.5, 115.8, 95.2, 94.7, 80.5, 76.0, 75.5, 75.0, 72.4, 72.0,
71.3, 71.0, 70.9, 70.4, 62.3, 61.0, 57.0.
1H NMR (400 MHz, CDCl3): δ = 9.58 (s, 0.4 H), 7.40–7.27 (m, 15
H), 6.65 (s, 0.4 H), 6.30 (s, 0.4 H), 5.45 (s, 1 H), 5.28 (d, J = 8.4 Hz,
1 H), 4.79–4.60 (d, J = 11.2 Hz, 5 H), 4.52 (d, J = 11.6 Hz, 1 H),
4.35 (d, J = 4.8 Hz, 1 H), 4.24 (m, 1 H), 3.98–3.88 (m, 2 H), 3.75–
3.71 (m, 1 H), 3.61 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 193.6, 146.6, 142.6, 139.2, 138.2,
137.9, 137.4, 137.2, 136.9, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 116.3, 112.2, 95.2, 95.1, 94.7, 79.5, 79.0, 78.0,
75.8, 73.5, 72.8, 72.0, 71.3, 71.0, 70.8, 62.2, 61.9, 58.5.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O4Na: 349.1416;
found: 349.1416.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O4Na: 349.1416;
(2R,3S)-2,3-Bis(benzyloxy)-4-methylenepentane-1,5-diol (17)
C2-Methylene-D-arabitol derivative 17 (44 mg, 87%) was obtained
from 16 (50 mg, 0.15 mmol) as a colorless gum; Rf = 0.21 (30%
EtOAc–hexane); [α]D25 +29.0 (c 1.0, CHCl3).
found: 349.1416.
(2R,3R)-2,3-Bis(benzyloxy)-4-methylenepentane-1,5-diol (21)
C2-Methylene-D-xylitol derivative 21 (152 mg, 84%) was obtained
from 20 (180 mg, 0.55 mmol) as a colorless gum; Rf = 0.19 (30%
EtOAc–hexane); [α]D25 –28.4 (c 0.7, CHCl3).
IR (neat): 3416, 2928, 1726, 1651, 1496, 1456, 1356, 1267, 1028,
736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 10 H), 5.42 (s, 1 H),
5.28 (s, 1 H), 4.65–4.58 (m, 4 H), 4.35 (d, J = 12.0 Hz, 1 H), 4.14
(d, J = 8.0 Hz, 1 H), 4.08 (d, J = 6.8 Hz, 1 H), 3.75 (d, J = 4.8 Hz, 2
H), 3.70–3.66 (m, 1 H), 2.45 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 145.3, 137.7, 137.6, 128.5, 128.2,
128.1, 128.0, 127.9, 116.5, 81.0, 80.6, 73.1, 70.7, 63.4, 61.9.
HRMS (ESI): m/z [M + Na]+ calcd for C20H24O4Na: 351.1573;
found: 351.1573.
IR (neat): 3416, 2928, 1726, 1651, 1496, 1456, 1356, 1267, 1028,
736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 10 H), 5.38 (s, 1 H),
5.26 (s, 1 H), 4.81 (d, J = 12.0 Hz, 1 H), 4.60–4.70 (m, 3 H), 4.38
(d, J = 12.0 Hz, 1 H), 4.16–4.12 (m, 2 H), 3.76–3.68 (m, 2 H), 3.58–
3.54 (m, 1 H), 2.65 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 144.9, 138.1, 137.8, 128.5, 128.4,
128.0, 127.9, 127.8, 116.2, 82.5, 80.9, 73.7, 71.0, 63.5, 62.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H24O4Na: 351.1573;
3,4-Di-O-benzyl-1,2-dideoxy-1,2-C-methylene-β-D-lyxopyra-
nose (18)
Compound 18 (838 mg, 80%) was obtained by cyclopropanation of
3,4-di-O-benzyl-D-xylal (1.0 g, 3.37 mmol) as a colorless gum; Rf =
0.48 (20% EtOAc–hexane).
found: 351.1573;
3,5-Di-O-benzyl-1,2-dideoxy-1,2-C-methylene-α-D-ribofura-
nose (22)
Compound 22 (438 mg, 83%) was obtained by cyclopropanation of
3,5-di-O-benzyl-D-ribital (500 mg, 1.68 mmol) as a colorless gum;
Rf = 0.58 (20% EtOAc–hexane).
IR (neat): 3468, 2860, 1739, 1645, 1496, 1454, 1361, 1097, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.34 (m, 10 H), 4.90 (d, J =
12.0 Hz, 1 H), 4.80 (d, J = 12.0 Hz, 1 H), 4.70 (m, 2 H), 4.16 (t, J =
6.8 Hz, 1 H), 3.85–3.81 (td, J = 3.2, 6.0 Hz, 1 H), 3.72–3.68 (dd, J =
4.0, 6.4 Hz, 1 H), 3.47 (m, 1 H), 3.24 (t, J = 10.8 Hz, 1 H), 1.42 (m,
1 H), 0.86 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 138.7, 138.6, 128.4, 128.2, 127.8,
127.7, 127.6, 77.8, 77.3, 72.8, 70.3, 66.4, 55.7, 15.7, 11.8.
IR (neat): 3468, 2860, 1739, 1645, 1496, 1454, 1361, 1097, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.30 (m, 10 H), 4.72 (d, J =
12.0 Hz, 1 H), 4.63–4.50 (m, 3 H), 4.32 (t, J = 5.6 Hz, 1 H), 4.17 (m,
1 H), 3.82 (m, 1 H), 3.60 (dd, J = 3.2, 10.4 Hz, 1 H), 3.54 (dd, J =
5.2, 10.4 Hz, 1 H), 1.74 (td, J = 4.4, 9.2 Hz, 1 H), 1.27 (m, 1 H), 0.58
(m, 1 H).
Synthesis 2014, 46, 923–932
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PAPER
Imino Sugars from 1,2-Cyclopropanated Carbohydrates
929
13C NMR (100 MHz, CDCl3): δ = 138.3, 138.2, 128.4, 128.3, 127.8,
127.7, 127.7, 127.6, 81.5, 81.0, 73.4, 71.4, 69.9, 60.3, 18.1, 8.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3Na: 333.1467;
found: 333.1467.
(3R,4S,5R)-3,4,6-Tris(benzyloxy)-1,5-bis(mesyloxy)-2-methyl-
enehexane (26)
Crude dimesylate 26 (300 mg, 89%) was obtained from diol 5 (250
mg, 0.55 mmol) as a yellow oil; Rf = 0.23 (40% EtOAc–hexane).
IR (neat): 3553, 3032, 2937, 1730, 1496, 1454, 1356, 1267, 1176,
1097, 966, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 15 H), 5.58 (s, 1 H),
5.27 (s, 1 H), 4.94 (m, 1 H), 4.81–4.72 (m, 4 H), 4.66–4.51 (m, 5 H),
4.41 (d, J = 12.0 Hz, 1 H), 4.14 (d, J = 8.0 Hz, 1 H), 4.04 (d, J = 4.0
Hz, 1 H), 3.85 (m, 2 H), 3.00 (s, 3 H), 2.96 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 138.9, 137.6, 137.5, 137.4, 128.6,
128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 119.8, 82.2, 81.3,
81.2, 75.4, 73.5, 73.3, 71.4, 68.7, 68.3, 38.4, 37.3.
3,5-Di-O-benzyl-2-C-(bromomethyl)-2-deoxy-D-ribofuranose
(23)
Bromohydrin 23 (326 mg, 71%) was obtained from cyclopropane
derivative 22 (350 mg, 1.12 mmol) as a colorless gum; Rf = 0.47
(30% EtOAc–hexane); [α]D25 –3.7 (c 0.9, CHCl3).
IR (neat): 3410, 2926, 1724, 1604, 1454, 1363, 1222, 1028, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.31 (m, 10 H), 5.33 (m, 1
H), 4.69–4.48 (m, 5 H), 4.23 (d, J = 4.4 Hz, 1 H), 4.11 (d, J = 5.2
Hz, 1 H), 3.67–3.46 (m, 4 H), 3.43–3.33 (m, 1 H), 2.67 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 137.8, 137.4, 137.3, 136.9, 128.6,
128.5, 128.2, 128.0, 127.9, 127.8, 127.6, 102.0, 99.1, 82.4, 81.7,
80.3, 80.2, 73.6, 73.5, 72.6, 72.5, 70.6, 70.1, 53.2, 50.3, 28.4, 26.5.
HRMS (ESI): m/z [M + Na]+ calcd for C30H36O9S2Na: 627.1699;
found: 627.1699.
Synthesis of C2-Methylene Iminosugars; General Procedure
Dimesylate crude (1 mmol) was added to a round-bottomed flask
and BnNH2 (50 mL) was added to it. The mixture was stirred at 90
°C for a period of 16–20 h. The mixture was then quenched with dil
HCl (20 mL) and extracted with CHCl3 (3 × 20 mL). The combined
organic layers were washed with sat. NaHCO3, then with H2O, and
dried (anhyd Na2SO4). The product was purified by column chro-
matography (hexanes–EtOAc, 9:1) to give unsaturated iminosugars
(68–75%).
HRMS (ESI): m/z [M + Na]+ calcd for C20H23O4BrNa: 429.0678;
found: 429.0678.
3,5-Di-O-benzyl-2-deoxy-2-C-(methylene)-D-erythro-pentofura-
nose (24)
C2-Methylene sugar derivative 24/ring-opened aldehyde (1:10, 126
mg, 79%) was obtained from bromohydrin 23 (200 mg, 0.49 mmol)
as a colorless gum; Rf = 0.44 (30% EtOAc–hexane).
(2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-methylenepiperidine (27)
IR (neat): 3466, 2922, 1689, 1454, 1361, 1091, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.66 (s, 1 H), 7.37–7.25 (m, 16 H),
6.59 (s, 1 H), 6.29 (s, 1 H), 5.55 (s, 0.1 H), 5.48 (d, J = 10.8 Hz, 1
H), 5.38 (s, 0.1 H), 4.63–4.47 (m, 6 H), 4.35 (m, 2 H), 3.92 (m, 1 H),
3.65–3.52 (m, 3 H), 2.53 (d, J = 6.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.9, 149.9, 147.6, 137.8, 137.7,
137.6, 136.9, 135.9, 128.6, 128.4, 128.1, 127.9, 127.8, 114.8, 114.2,
98.5, 82.8, 81.5, 80.2, 79.6, 74.8, 73.7, 73.3, 72.8, 71.6, 71.2, 70.7,
70.4, 69.8.
C2-Methylene iminosugar derivative 27 (77 mg, 75%) was obtained
from dimesylate 26 (120 mg, 0.20 mmol) as a colorless gum; Rf =
0.45 (10% EtOAc–hexane); [α]D25 –5.9 (c 1.2, CHCl3).
IR (neat): 3402, 3030, 2920, 2860, 1657, 1602, 1494, 1454, 1361,
1265, 1097, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 20 H), 5.23 (s, 1 H),
5.07 (s, 1 H), 4.73 (d, J = 12.0 Hz, 1 H), 4.67 (d, J = 12.0 Hz, 1 H),
4.56–4.50 (m, 4 H), 4.09 (d, J = 8.0 Hz, 1 H), 3.93–3.90 (m, 1 H),
3.86–3.83 (m, 2 H), 3.79–3.76 (m, 2 H), 3.49 (m, 1 H), 3.28 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 140.5, 139.7, 138.6, 138.5, 138.5,
129.1, 128.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 126.8, 114.0,
79.8, 78.7, 73.2, 72.7, 71.0, 68.5, 59.5, 56.0, 52.5.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O4Na: 349.1416;
found: 349.1416.
(3S,4R)-3,5-Bis(benzyloxy)-2-methylenepentane-1,4-diol (25)
C2-Methylene-D-ribitol derivative 25 (58 mg, 82%) was obtained
from 24 (70 mg, 0.21 mmol) as a colorless gum; Rf = 0.23 (30%
EtOAc–hexane); [α]D25 +37.3 (c 0.6, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C35H38NO3: 520.2851; found:
520.2851.
IR (neat): 3416, 2928, 1726, 1651, 1496, 1456, 1356, 1267, 1028,
736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 10 H), 5.45 (s, 1 H),
5.25 (s, 1 H), 4.57–4.53 (m, 4 H), 4.27 (m, 2 H), 4.11 (d, J = 12.8
Hz, 1 H), 4.00 (m, 1 H), 3.58 (m, 2 H), 3.12 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 144.8, 137.9, 137.8, 128.4, 127.9,
127.8, 127.8, 127.7, 118.7, 81.6, 73.4, 71.5, 70.9, 70.5, 62.7.
(2R,3R,4R)-1,3,4-Tris(benzyloxy)-5-[(tert-butyldimethylsil-
oxy)methyl]hex-5-en-2-ol (28)
To a solution of diol 5 (1.00 g, 2.23 mmol, 1 equiv) in anhyd CH2Cl2
(20 mL) was added imidazole (167 mg, 2.45 mmol) and TBSCl
(334 mg, 2.23 mmol) successively at 0 °C. Then the mixture was
stirred at 25 °C overnight. It was then diluted with CH2Cl2 (50 mL)
and washed with H2O (2 × 20 mL). The combined organic layers
were then dried (anhyd Na2SO4), filtered, and concentrated. Purifi-
cation by column chromatography (silica gel, hexanes–EtOAc, 4:1)
afforded 28 (1.06 g, 85%) as a colorless gum; Rf = 0.69 (20%
EtOAc–hexane); [α]D25 +17.3 (c 1.3, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H24O4Na: 351.1573;
found: 351.1573.
Dimesylation of C2-Methylene Glycitol Derivatives; General
Procedure
IR (neat): 3485, 2930, 1651, 1496, 1454, 1390, 1263, 1091, 839,
736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 15 H), 5.45 (s, 1 H),
5.29 (s, 1 H), 4.69–4.58 (m, 4 H), 4.55 (m, 2 H), 4.33 (d, J = 12.0
Hz, 1 H), 4.23–4.13 (m, 2 H), 3.99 (m, 1 H), 3.73 (m, 1 H), 3.61 (d,
J = 4.8 Hz, 2 H), 2.67 (m, 1 H), 0.9 (s, 9 H), 0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 138.3, 138.1, 137.9, 128.4,
128.2, 128.1, 127.9, 127.8, 127.7, 127.6, 113.6, 80.7, 80.0, 74.5,
73.3, 70.9, 70.8, 70.4, 63.7, 25.9, 25.8, 18.4, –5.3.
Diol (1 mmol, 1 equiv) was dissolved in anhyd CH2Cl2 (10 mL).
Et3N (2.5 equiv) was then added and the mixture was cooled to 0 °C.
After 5 min, MsCl (2.2 equiv) was added and the mixture was
stirred for 2 h at 0 °C. The mixture was then quenched with sat.
NH4Cl (20 mL) and extracted with CHCl3 (3 × 50 mL). The com-
bined organic layers were washed with sat. NaHCO3 and then with
H2O. The organic layer was dried (anhyd Na2SO4), filtered, and
concentrated to give the crude dimesylate as a yellow liquid.
HRMS (ESI): m/z [M + Na]+ calcd for C34H46O5SiNa: 585.3013;
found: 585.3013.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 923–932

930
K. Seshadri, P. R. Sridhar
PAPER
(2S,3R,4R)-1,3,4-Tris(benzyloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]hex-5-en-2-ol (30)
(2R,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-methylenepiperidine (33)
C2-Methylene iminosugar derivative 33 (76 mg, 74%) was obtained
from crude dimesylate 32 (120 mg, 0.20 mmol) as a colorless gum;
Rf = 0.42 (10% EtOAc–hexane); [α]D25 –30.6 (c 1.0, CHCl3).
To a solution of 28 (1.0 g, 1.77 mmol) in anhyd THF (30 mL) was
added Ph3P (1.40 g, 5.33 mmol) and 4-nitrobenzoic acid (0.89 g,
5.33 mmol) at 25 °C. Then flask was cooled to 0 °C and DEAD
(0.84 mL, 5.33 mmol) was added dropwise at 0 °C; stirring was con-
tinued for 12 h at 25 °C. Then the mixture was diluted with Et2O
(100 mL) and washed with sat. aq NaHCO3 (2 × 50 mL). The aque-
ous layers were combined and extracted with Et2O (50 mL). The
combined organic layers were dried (anhyd Na2SO4), filtered, con-
centrated, and dried. The crude product was dissolved in anhyd
MeOH (30 mL), 0.5 M NaOMe–MeOH (20 mL) was added drop-
wise at 0 °C, and the mixture was stirred for 30 min. After comple-
tion of the reaction (TLC), the solvent was evaporated and the crude
product was purified by column chromatography (silica gel, hex-
anes–EtOAc, 4:1) to afford 30 (905 mg, 91%, 2 steps) as a colorless
gum; Rf = 0.57 (20% EtOAc–hexane); [α]D25 –4.4 (c 0.4, CHCl3).
IR (neat): 3423, 2926, 2856, 1660, 1494, 1454, 1361, 1265, 1097,
738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.24 (m, 20 H), 5.27 (s, 1 H),
4.94 (s, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.74 (d, J = 12.0 Hz, 1 H),
4.64–4.56 (m, 2 H), 4.51 (s, 2 H), 4.02 (d, J = 4.0 Hz, 1 H), 3.90 (d,
J = 12.0 Hz, 1 H), 3.85–3.79 (m, 2 H), 3.72–3.69 (m, 2 H), 3.31 (d,
J = 12.0 Hz, 1 H), 2.95 (m, 1 H), 2.90 (d, J = 12.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 140.3, 139.2, 138.6, 138.4, 138.2,
129.1, 128.4, 128.3, 128.2, 127.8, 127.7, 127.6, 126.8, 110.8, 84.3,
79.6, 74.3, 73.2, 72.6, 68.3, 64.0, 55.0, 54.4.
HRMS (ESI): m/z [M + H] calcd for C35H38NO3: 520.2851; found:
520.2851.
IR (neat): 3468, 2928, 1653, 1496, 1454, 1359, 1253, 1097, 839,
698 cm–1.
(2S,3R)-2,3-Bis(benzyloxy)-1,5-bis(mesyloxy)-4-methylenepen-
tane (34)
Crude dimesylate 34 (115 mg, 82%) was obtained from diol 13 (95
mg, 0.29 mmol) as a yellow oil; Rf = 0.28 (40% EtOAc–hexane);
[α]D25 –54.5 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.37–7.30 (m, 15 H), 5.49 (s, 1 H),
5.35 (s, 1 H), 4.97 (d, J = 8.0 Hz, 1 H), 4.64–4.57 (m, 2 H), 4.49–
4.39 (m, 3 H), 4.31–4.26 (m, 3 H), 3.90 (m, 1 H), 3.78 (m, 1 H), 3.45
(m, 1 H), 3.38 (m, 1 H), 2.50 (br s, 1 H), 0.97 (s, 9 H), 0.12 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 138.5, 138.4, 138.1, 128.4,
128.3, 127.9, 127.7, 127.6, 115.0, 83.4, 79.6, 75.4, 73.2, 71.2, 70.8,
69.7, 62.9, 26.0, 18.4, –5.3.
IR (neat): 3544, 3032, 2937, 1730, 1496, 1454, 1356, 1267, 1176,
1097, 966, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.32 (m, 10 H), 5.60 (s, 1 H),
5.51 (s, 1 H), 4.76–4.67 (m, 4 H), 4.62–4.47 (m, 5 H), 4.37 (m, 2 H),
4.05 (m, 1 H), 3.85 (m, 1 H), 3.77 (m, 1 H), 3.65 (m, 1 H), 3.50 (m,
1 H), 2.95 (s, 3 H), 2.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.4, 137.7, 137.2, 137.0, 128.6,
128.5, 128.3, 128.2, 128.1, 128.0, 127.8, 120.1, 78.6, 78.0, 74.4,
74.0, 73.0, 72.6, 72.5, 72.0, 71.0, 69.4, 68.0, 67.5, 53.5, 42.2, 37.7,
37.5.
HRMS (ESI): m/z [M + Na]+ calcd for C34H46O5SiNa: 585.3013;
found: 585.3013.
(3R,4R,5S)-3,4,6-Tris(benzyloxy)-2-methylenehexane-1,5-diol
(31)
To a solution of 30 (200 mg, 0.35 mmol) in MeOH (20 mL), was
added catalytic amount of TsOH (~25 mg) at 0 °C. The mixture was
stirred at 0 °C for 20 min. After completion of the reaction (TLC),
the solvent was evaporated and the residue was purified by column
chromatography (silica gel, hexanes–EtOAc, 2:1) to afford 31 (151
mg, 96%) as a colorless gum; Rf = 0.18 (30% EtOAc–hexane);
[α]D25 –4.5 (c 0.9, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O8S2Na: 507.1124;
found: 507.1129.
(3S,4R)-1-Benzyl-3,4-bis(benzyloxy)-5-methylenepiperidine
(35)
C2-Methylene iminosugar derivative 35 (45 mg, 72%) was obtained
from crude dimesylate 34 (75 mg, 0.15 mmol) as a colorless gum;
Rf = 0.52 (10% EtOAc–hexane); [α]D25 –13.6 (c 1.0, CHCl3).
IR (neat): 3450, 2926, 1649, 1496, 1454, 1265, 1093, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 15 H), 5.42 (s, 1 H),
5.34 (s, 1 H), 4.94 (d, J = 12.0 Hz, 1 H), 4.61 (m, 2 H), 4.48–4.41
(m, 3 H), 4.30 (d, J = 8.0 Hz, 1 H), 4.23 (s, 2 H), 3.89 (m, 1 H), 3.83
(m, 1 H), 3.46 (m, 1 H), 3.43 (m, 1 H), 2.59 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 138.3, 138.1, 137.9, 128.5,
128.4, 128.3, 127.9, 127.8, 116.7, 83.5, 79.6, 75.3, 73.3, 71.2, 71.1,
69.6, 63.5.
IR (neat): 3468, 2926, 1660, 1494, 1454, 1358, 1267, 1093, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.28 (m, 15 H), 5.10 (s, 1 H),
5.03 (s, 1 H), 4.67–4.49 (m, 4 H), 4.38 (d, J = 12.0 Hz, 1 H), 4.07
(d, J = 3.2 Hz, 1 H), 3.68–3.55 (m, 2 H), 3.06–2.99 (m, 2 H), 2.84
(m, 1 H), 2.74 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.1, 138.5, 138.4, 137.8, 129.2,
128.9, 128.3, 128.2, 128.1, 127.8, 127.6, 127.5, 127.4, 127.1, 127.0,
115.2, 76.7, 76.1, 70.5, 69.0, 62.1, 55.0, 52.0.
HRMS (ESI): m/z [M + Na]+ calcd for C28H32O5Na: 471.2148;
found: 471.2148.
(3R,4S,5S)-3,4,6-Tris(benzyloxy)-1,5-bis(mesyloxy)-2-methyl-
enehexane (32)
Crude dimesylate 32 (120 mg, 89%) was obtained from diol 31 (100
mg, 0.22 mmol) as a yellow oil; Rf = 0.22 (40% EtOAc–hexane).
HRMS (ESI): m/z [M + H]+ calcd for C27H30NO2: 400.2276; found:
400.2274.
IR (neat): 3543, 3032, 2937, 1730, 1496, 1454, 1356, 1267, 1176,
1097, 966, 738 cm–1.
(2R,3S)-2,3-Bis(benzyloxy)-1,5-bis(mesyloxy)-4-methylenepen-
tane (36)
Crude dimesylate 36 (173 mg, 81%) was obtained from diol 17 (145
mg, 0.44 mmol) as a yellow oil; Rf = 0.26 (40% EtOAc–hexane);
[α]D25 +31.8 (c 1.3, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 15 H), 5.58 (d, J =
4.0 Hz, 2 H), 4.88 (m, 1 H), 4.70–4.67 (m, 4 H), 4.54 (d, J = 12.0
Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.35 (d, J = 12.0 Hz, 1 H), 4.24
(d, J = 12.0 Hz, 1 H), 4.17 (d, J = 4.0 Hz, 1 H), 3.86 (m, 1 H), 3.65
(m, 1 H), 3.55 (m, 1 H), 2.96 (s, 3 H), 2.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.3, 138.2, 137.3, 137.1, 128.5,
128.4, 128.1, 128.0, 127.9, 121.2, 114.1, 81.3, 79.0, 78.8, 75.2,
73.3, 71.2, 69.2, 69.0, 38.5, 37.3.
IR (neat): 3550, 3030, 2937, 2874, 1734, 1496, 1454, 1356, 1176,
1099, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.32 (m, 10 H), 5.60 (s, 1 H),
5.51 (s, 1 H), 4.77–4.67 (m, 4 H), 4.63–4.47 (m, 5 H), 4.37 (m, 2 H),
4.05 (m, 1 H), 3.91 (m, 1 H), 3.87 (m, 1 H), 3.77 (m, 1 H), 3.50 (d,
J = 5.2 Hz, 1 H), 2.91 (s, 3 H), 2.90 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C30H36O9S2Na: 627.1699;
found: 627.1699.
Synthesis 2014, 46, 923–932
© Georg Thieme Verlag Stuttgart · New York

PAPER
Imino Sugars from 1,2-Cyclopropanated Carbohydrates
931
13C NMR (100 MHz, CDCl3): δ = 139.4, 137.2, 137.0, 128.7, 128.6,
128.5, 128.3, 128.2, 128.1, 128.0, 127.8, 120.1, 78.6, 78.0, 74.4,
73.0, 72.6, 72.0, 71.5, 71.0, 69.4, 68.4, 68.1, 67.5, 53.5, 42.2, 37.7,
37.5, 37.0.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O8S2Na: 507.1124;
found: 507.1129.
J = 7.2 Hz, 1 H), 3.76 (m, 1 H), 3.40 (m, 1 H), 2.92 (s, 3 H), 2.91 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 139.3, 137.2, 128.5, 128.2, 128.1,
128.0, 120.2, 78.5, 77.9, 73.0, 71.0, 69.4, 68.1, 37.4, 31.6.
(2S,3S)-1-Benzyl-3-(benzyloxy)-2-(benzyloxymethyl)-4-methyl-
enepyrrolidine (41)
C2-Methylene iminosugar derivative 41 (39 mg, 76%) was obtained
from crude dimesylate 40 (63 mg, 0.13 mmol) as a colorless gum;
Rf = 0.55 (10% EtOAc–hexane); [α]D25 –5.80 (c 0.2, CHCl3).
(3R,4S)-1-Benzyl-3,4-bis(benzyloxy)-5-methylenepiperidine
(37)
C2-Methylene iminosugar derivative 37 (43 mg, 74%) was obtained
from crude dimesylate 36 (70 mg, 0.14 mmol) as a colorless gum;
Rf = 0.48 (10% EtOAc–hexane); [α]D25 +23.3 (c 1.0, CHCl3).
IR (neat): 3452, 2918, 1667, 1491, 1449, 1363, 1252, 1097, 728
cm–1.
IR (neat): 3470, 3030, 2868, 1658, 1494, 1454, 1352, 1267, 1120,
914, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.27 (m, 15 H), 5.12 (s, 1 H),
5.05 (s, 1 H), 4.69–4.39 (m, 4 H), 4.10 (d, J = 2.4 Hz, 1 H), 3.68–
3.59 (m, 3 H), 3.08–3.00 (m, 2 H), 2.85 (m, 1 H), 2.77 (m, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.41–7.28 (m, 15 H), 5.11 (s, 1 H),
5.03 (s, 1 H), 4.66 (d, J = 12.4 Hz, 1 H), 4.62–4.49 (m, 2 H), 4.40
(d, J = 12.4 Hz, 1 H), 4.08 (d, J = 2.8 Hz, 1 H), 3.66–3.58 (m, 3 H),
3.03 (dd, J = 4.0, 12.0 Hz, 2 H), 2.84 (dd, J = 4.0, 6.8 Hz, 1 H), 2.75
(t, J = 10.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.2, 138.5, 138.4, 137.9, 129.2,
128.3, 127.8, 127.7, 127.5, 127.4, 127.3, 127.2, 115.2, 76.7, 76.1,
70.5, 69.0, 62.1, 55.0, 52.0.
13C NMR (100 MHz, CDCl3): δ = 141.2, 138.5, 138.4, 137.9, 129.2,
128.3, 127.8, 127.6, 127.5, 127.4, 127.1, 115.3, 76.6, 76.1, 70.5,
68.9, 62.1, 55.0, 52.1.
HRMS (ESI): m/z [M + H]+ calcd for C27H30NO2: 400.2276; found:
400.2274.
HRMS (ESI): m/z [M + H]+ calcd for C27H30NO2: 400.2276; found:
400.2276
(2R,3R)-2,3-Bis(benzyloxy)-1,5-bis(mesyloxy)-4-methylenepen-
tane (38)
Crude dimesylate 38 (88 mg, 79%) was obtained from diol 21 (75
mg, 0.23 mmol) as a yellow oil; Rf = 0.28 (40% EtOAc–hexane).
Acknowledgment
P.R.S. thanks University Grants Commission (UGC), New Delhi,
India for grant No. 40-56/2011 (SR). K.S. thanks CSIR for a senior
research fellowship.
IR (neat): 3430, 2937, 1732, 1496, 1454, 1356, 1267, 1176, 1097,
966, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.32 (m, 10 H), 5.60 (s, 1 H),
5.50 (s, 1 H), 4.75–4.67 (m, 4 H), 4.63–4.45 (m, 5 H), 4.40–4.35 (m,
3 H), 4.04 (m, 1 H), 3.93–3.85 (m, 3 H), 3.77 (m, 1 H), 3.50 (d, J =
5.2 Hz, 1 H), 2.92 (s, 3 H), 2.90 (s, 3 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
13C NMR (100 MHz, CDCl3): δ = 139.4, 137.7, 137.2, 137.0, 128.7,
128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.8, 120.2, 78.6, 78.0,
74.2, 73.0, 72.6, 72.0, 69.4, 68.4, 67.5, 53.5, 42.2, 37.5, 37.4, 34.9,
31.4.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O8S2Na: 507.1124;
found: 507.1124.
References
(1) (a) Nagaraj, P.; Ganesan, M.; Ramesh, N. G. Tetrahedron
2011, 67, 769. (b) Gupta, P.; Vankar, Y. D. Eur. J. Org.
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(3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-5-methylenepiperidine
(39)
C2-Methylene iminosugar derivative 39 (48 mg, 68%) was obtained
from crude dimesylate 38 (85 mg, 0.17 mmol) as a colorless gum;
Rf = 0.51 (10% EtOAc–hexane); [α]D25 +17.6 (c 0.8, CHCl3).
(4) Bischofberger, K.; Brink, A. J.; de Villiers, O. G.; Hall, R.
H.; Jordaan, A. J. Chem. Soc., Perkin Trans. 1 1977, 1472.
(5) See the Supporting Information.
IR (neat): 3468, 2926, 1660, 1494, 1454, 1358, 1267, 1093, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 15 H), 5.21 (s, 1 H),
5.06 (s, 1 H), 4.70–4.57 (m, 4 H), 3.87 (d, J = 6.8 Hz, 1 H), 3.63–
3.53 (m, 3 H), 3.19–3.14 (m, 2 H), 2.89 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 141.2, 138.5, 138.4, 137.8, 129.1,
128.3, 128.2, 128.0, 127.7, 127.6, 127.5, 127.1, 127.0, 112.2, 81.8,
78.1, 73.7, 72.2, 61.7, 57.0, 54.6.
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HRMS (ESI): m/z [M + H]+ calcd for C27H30NO2: 400.2276; found:
400.2274.
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(3S,4R)-3,5-Bis(benzyloxy)-1,4-bis(mesyloxy)-2-methylenepen-
tane (40)
Crude dimesylate 40 (63 mg, 85%) was obtained from diol 25 (50
mg, 0.15 mmol) as a yellow oil; Rf = 0.27 (40% EtOAc–hexane).
IR (neat): 3423, 2931, 1728, 1485, 1453, 1354, 1269, 1181, 1092,
965, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 10 H), 5.59 (s, 1 H),
5.50 (s, 1 H), 4.69 (m, 3 H), 4.52 (m, 3 H), 4.35 (m, 2 H), 4.04 (d,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 923–932

932
K. Seshadri, P. R. Sridhar
PAPER
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Synthesis 2014, 46, 923–932
© Georg Thieme Verlag Stuttgart · New York