Propane-1,3-diyl dithioacetals of carbohydrates; part 7: Preparation of aminocyclitols and iminosugars by intramolecular cyclizations of D-glucosamine propane-1,3-diyl dithioacetal derivatives

Article abstract of DOI:10.1055/s-2006-942430

Versatile 3,4,5-tri-O-protected 2-acylamino-2-deoxy-6-O-tosyl-D-glucose propane-1,3-diyl dithioacetal intermediates were efficiently synthesized from D-glucosamine propane-1,3-diyl dithioacetal or its derivatives. Intramolecular cyclizations from these in

Full text of DOI:10.1055/s-2006-942430

2242
PAPER
Propane-1,3-diyl Dithioacetals of Carbohydrates; Part 7: Preparation of
Aminocyclitols and Iminosugars by Intramolecular Cyclizations of
D-Glucosamine Propane-1,3-diyl Dithioacetal Derivatives
A
minocyclitols
an
u
d Iminosuga
e
-
olecular
L
Cyclizations
o
e
f
D
-Glucosa
i
mine
D
ithioa
C
cetals hen,a,b Robin Leguijt,a Hartmut Redlich*a
a
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)839772; E-mail: redlich@uni-muenster.de
NRW Graduate School of Chemistry, Corrensstraße 36, 48149 Münster, Germany
b
Received 27 April 2006
Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday
As it will be shown in this paper, certain D-glucosamine
propane-1,3-diyl dithioacetal derivatives 2, 3, and 4 bear-
ing a 6-O-tosyl group will serve as suitable common pre-
cursors for both aminocyclitols and iminosugars
Abstract: Versatile 3,4,5-tri-O-protected 2-acylamino-2-deoxy-6-
O-tosyl-D-glucose propane-1,3-diyl dithioacetal intermediates were
efficiently synthesized from D-glucosamine propane-1,3-diyl
dithioacetal or its derivatives. Intramolecular cyclizations from
these intermediates produced biologically important aminocyclitols (Figure 2).
as well as iminosugars. The 3,4-O-methylene protection on the in-
termediates did not hinder the cyclizations. The resultant aminocy-
OR1
S
clitols and iminosugars bearing orthogonal protecting groups are
R2O
ideal for regioselective modification. Hence, deprotection method-
S
ology is also discussed.
NHR
OTs
2, R = Ac, R1 = R2 = R3 = MOM
3, R = Ac, R1,R2 = -CH2-, R3 = MOM
4, R = Tfa, R1,R2 = -CH2-, R3 = MOM
R3O
Key words: chiral pool, intramolecular cyclizations, aminocycli-
tol, iminosugar, protecting-group cleavage
Figure 2
As important bioactive compounds, nitrogen-containing
carbohydrate mimics, such as aminocyclitols (i.e., 2-
deoxystreptamine derivatives) and iminosugars (i.e.,
nojirimycin analogues) have been the subject of intense
interest over the last decade.1 In the preceding paper we
described the protecting group manipulation and lithiated
dianion chemistry of derivatives of D-glucosamine pro-
pane-1,3-diyl dithioacetal (1) (Figure 1), herein we report
a very short synthetic route to aminocyclitols and imino-
sugars from D-glucosamine propane-1,3-diyl dithioacetal
derivatives.2 Highlights of the synthetic design are effi-
cient intramolecular cyclization3 and a single common in-
termediate, derived from D-glucosamine propane-1,3-diyl
dithioacetal, to both aminocyclitols and iminosugars. As
D-glucosamine propane-1,3-diyl dithioacetal is an inex-
pensive chiral pool substrate and building block that is
readily available from renewable mass (e.g. chitin), this
makes the synthesis more attractive.
Starting from the previously reported compounds 5 and
6,2 two-step synthesis of the versatile intermediates 2 and
3 will be briefly described (Scheme 1). The 6-O-ester pro-
tection on compounds 5 and 6 was removed by sodium
methoxide, and the resulting alcohols 7 and 8 were con-
verted into O-tosyl derivatives 2 and 3, respectively; the
3,4,5-O-methoxymethyl or 5-O-methoxymethyl-3,4-O-
methylene protection tolerates very basic conditions
which will be presented in the cyclization procedures.
Compound 4 bearing N-trifluoroacetyl (Tfa) protection,
which has been used for lithiated dianion chemistry,4 was
also readily synthesized from compound 1 using the same
protecting group manipulation methodology (Scheme 2).
Compound 2 was subjected to similar lithiating condition
reported previously2 [n-BuLi (2.2 equiv), THF, –78 °C].
Without disturbing the O-tosyl group, the imidate–
dithiane dianion 13 was formed and, in principle, both
have a chance to attack C6 to yield the cyclized products.
But the resultant compound was identified as an aminocy-
clitol 14, which is formed by coupling of C1 and C6 . No
C–N coupling compound was found under such reaction
conditions. Interestingly, when compound 2 was refluxed
in tetrahydrofuran with sodium hydride, the iminosugar
16 was the main product (Scheme 3). This is easily under-
stood as the sodium hydride deprotonated amide readily
forms the imidate anion 15 and this is not sufficiently ba-
sic to deprotonate the dithiane. Synthesis of the imino-
sugar by monolithiation of the amide was also
unsuccessful.
OH OH
S
HO
S
OH NH2
1
Figure 1
SYNTHESIS 2006, No. 13, pp 2242–2250
x
x.
x
x
.
2
0
0
6
Advanced online publication: 23.06.2006
DOI: 10.1055/s-2006-942430; Art ID: C02006SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Aminocyclitols and Iminosugars by Intramolecular Cyclizations of D-Glucosamine Dithioacetals
2243
MOMO
MOMO
S
MOMO
MOMO
S
TsCl, DMAP,
py, r.t.
MeOH,
NaOMe
S
2
S
57%
quant.
NHAc
NHAc
MOMO
MOMO
5
OAc
7
OH
O
TsCl, Et3N,
DMAP,
CH2Cl2, r.t.
S
O
S
MeOH,
NaOMe
O
O
S
3
S
80%
73%
NHAc
NHAc
MOMO
MOMO
6
8
OPv
OH
Scheme 1
PvCl, DMF,
py, –50 °C
then r.t.
n-BuLi
THF, –78 °C
to –20 °C
NaH
THF,
reflux
OH OH
S
S
CF3CO2Et,
MeOH
Ac
N
S
S
HO
NHAc
O
1
S
S
70%
3
quant.
52%
78%
OH NHTfa
MOMO
O
MOMO
17
9
S
O
O
O
(MeO)2CH2,
BF3⋅Et2O
CH2Cl2, r.t.
OH OH
S
O
18
PvO
S
S
NHTfa
Scheme 4
63%
OH NHTfa
MOMO
10
OPv
11
lecular cyclization reactions, and may even be used to pre-
vent such cyclizations.3,5 However, in this case, the
cyclizations to both aminocyclitol and iminosugar work
well even with the 3,4-O-trans-formaldehyde protection
in place.
TsCl, Et3N,
DMAP,
CH2Cl2, r.t.
S
O
NaOMe,
MeOH
O
S
4
57%
NHTfa
56%
MOMO
12
OH
According to our recent investigations, compound 4, as a
newly developed system, works excellently in the lithiat-
ed dianion chemistry. Compared to N-acetyl derivatives,
i.e., compound 2 and 3, the lithiated dianion from com-
pound 4 is produced at a lower temperature (ca. –100 °C)
and reacts with various electrophiles more rapidly and
with higher yield. Furthermore, removing N-trifluoro-
acetyl protection should be much easier compared to re-
moving N-acetyl protection. This will be extremely
important in the later phase of the synthesis.
Scheme 2
Compound 3 was subjected to both cyclization conditions
used for 2. Aminocyclitol 17 was produced in 52% yield,
which is lower than the yield for the cyclization of 2 to
give 14, but the iminosugar 18 was formed in 78% yield,
which is better than the yield for the cyclization of 2 to
give 16 (Scheme 4). It is worth mentioning that the trans-
acetal arrangement, in general, does not support intramo-
n-BuLi
THF, –78 °C
to – 20 °C
S
MOMO
MOMO
NaH
THF, reflux
OMOM
S
N
S
MOMO
MOMO
2
O
N
MOMO
2Li
ONa
OTs
S
OTs
15
13
63%
71%
S
Ac
N
S
S
S
NHAc
MOMO
OMOM
OMOM
MOMO
OMOM
OMOM
14
16
Scheme 3
Synthesis 2006, No. 13, 2242–2250 © Thieme Stuttgart · New York

2244
Y.-L. Chen et al.
PAPER
The cyclization of compound 4 to aminocyclitol 19 is drochloric acid failed due to decomposition. However, re-
shown in Equation 1; compound 19 is formed in high moving acid-labile protecting groups on iminosugar 18
yield as expected. However, when compound 4 was treat- using hydrochloric acid works well to yield compound 22
ed with sodium hydride in refluxing tetrahydrofuran, (Scheme 5).
elimination of the O-tosyl group and cleavage of the N-tri-
fluoroacetyl group was observed and none of the desired
product was formed.
S
S
BCl3, CH2Cl2,
–90 °C to r.t
NHAc
OH
17
64%
HO
n-BuLi
S
S
THF, –100 °C
to –50 °C
NHTfa
O
OH
4
21
78%
MOMO
S
Ac
N
14% HCl–THF,
r.t.
O
19
S
18
71%
HO
OH
Equation 1
OH
22
Highly functionalized aminocyclitols and iminosugars
bearing different protecting groups can be produced in
high yield according to our new methodology. The fol-
lowing part discusses the deprotection manipulation and
brings the work closer to natural products or bioactive
compounds.
Scheme 5
N-Acyl deprotection is demonstrated in Scheme 6, where
N-trifluoroacetyl protection on 19 was readily removed
using sodium methoxide to give the free amine 23. On the
other hand, N-acetyl protection on 22 can be removed by
refluxing 6 M hydrochloric acid–ethanol (in this proce-
dure, cleavage of dithiane was also detected) to give 24 af-
ter basification (Scheme 6).
The most interesting feature of the highly functionalized
aminocarbocycles 14, 17, and 19 as well as iminosugars
16 and 18 produced by our new methodology is the or-
thogonal protection. Typically, dithiane, O-acetal, and N-
acyl protection can be classified as oxidation/heavy metal,
acid-, and base-sensitive protection, respectively. Each
can be removed by established methods without interfer-
ing with other protecting groups. In principle, even the
3,4-O-methylene group can be discriminated from the O-
methoxymethyl protection if the correct conditions are
used. This is a great advantage for synthesis directed at
bioactivity investigation because it allows selective mod-
ification at a certain site. Three different types of protect-
ing groups are present on compounds 14, 16, 17, 18, and
19 and a large number of deprotection manipulations can
be visualized, but we will only demonstrate several typi-
cal cases.
S
S
NaOMe, MeOH,
100 °C
NH2
O
19
67%
MOMO
O
23
1. 33% HCl in
EtOH–H2O, reflux
2. NH3, MeOH
S
H
N
S
22
48%
HO
OH
OH
24
Conversion of the dithiane protection to a carbonyl func-
tion can be realized on compounds 17 and 18 by oxidative
cleavage (the mercury salt method is only feasible for 17).
Equation 2 shows the formation of ketone 20 with N-chlo-
rosuccinimide and silver nitrate from aminocyclitol 17.
Scheme 6
In conclusion, versatile synthetic intermediates 2, 3, and 4
were readily prepared in a few steps from D-glucosamine
propane-1,3-diyl dithioacetal (1), which is inexpensive
and readily available from renewable mass, for example,
chitin. From the common intermediates 2, 3, and 4, ami-
nocyclitols 14, 17, and 19 and iminosugars 16 and 18,
members of the two main categories of nitrogen-contain-
ing carbohydrate mimics and the subject of recent a re-
search hot spot, were efficiently synthesized by
intramolecular cyclization reactions. In particular, N-tri-
fluoroacetyl derivative 4 proved excellent for preparation
of aminocyclitol 19 (78% yield) by lithiated dianion
chemistry, while N-acetyl derivative 3 was good for pro-
ducing the iminosugar 18 (78% yield). The 3,4-O-methyl-
O
NCS, AgNO3
NHAc
CaCO3, MeCN, H2O
17
40%
MOMO
O
O
20
Equation 2
Acid-labile protecting groups on aminocyclitol 17 can be
removed by boron trichloride at low temperature to yield
compound 21; attempts to produce compound 21 with hy-
Synthesis 2006, No. 13, 2242–2250 © Thieme Stuttgart · New York

PAPER
Aminocyclitols and Iminosugars by Intramolecular Cyclizations of D-Glucosamine Dithioacetals
2245
2-Acetamido-2-deoxy-3,4,5-tri-O-methoxymethyl-6-O-tosyl-
D-glucose Propane-1,3-diyl Dithioacetal (2)
ene protection on intermediates 3 and 4 did not hinder the
cyclization procedures. The resultant orthogonally pro-
tected aminocyclitols 14, 17, and 19 as well as iminosug-
ars 16 and 18 serve as ideal precursors for regioselective
modification. Typical selective deprotection reactions
proved viable when the correct conditions were used. The
whole work demonstrates that derivatives of D-glu-
cosamine propane-1,3-diyl dithioacetal (1) are powerful
and versatile building blocks and established a new and
efficient methodology to both aminocyclitols and imino-
sugars.
To a soln of the 3,4,5-tri-O-methoxymethyl compound 7 (2.58 g,
5.8 mmol) in anhyd pyridine (50 mL) was added p-TsCl (1.66 g, 8.7
mmol); the mixture was stirred overnight at r.t.. Another portion of
p-TsCl (0.88 g, 4.36 mmol) and catalytic amount of DMAP was
added and the mixture was stirred for 2 h. The reaction was
quenched with H2O and the mixture was extracted with CH2Cl2.
Evaporation of the solvent under reduced pressure and purification
by MPLC (cyclohexane–EtOAc, 2:1) yielded the 6-O-tosylate 2 as
a white solid; yield: 1.96 g (57%); mp 97 °C.
[a]D20 +7.4 (c 1.00, MeOH).
1H NMR (300 MHz, C6D6): d = 7.76 (d, J = 8.2 Hz, 2 H, Hortho-Ts),
7.29 (d, J = 8.2 Hz, 2 H, Hmeta-Ts), 5.85 (d, J = 10.1 Hz, 1 H,
NHC=O), 4.65 (d, J = 6.6 Hz, 1 H, OCH2O), 4.63 (d, J = 6.6 Hz, 1
H, OCH2O), 4.62 (d, J = 6.5 Hz, 1 H, OCH2O), 4.54 (d, J = 6.7 Hz,
1 H, OCH2O), 4.58 (d, J = 6.5 Hz, 1 H, OCH2O), 4.59 (d, J = 6.7
Hz, 1 H, OCH2O), 4.43 (dd, J = 10.1 Hz, J = 9.3 Hz, 1 H, H2), 4.19
(d, J = 7.9 Hz, 1 H, H3), 4.18 (dd, J = 10.5 Hz, J = 3.4 Hz, 1 H,
H6a), 4.12 (dd, J = 10.5 Hz, J = 7.0 Hz, 1 H, H6b), 3.99 (dd, J = 6.9
Hz, J = 3.3 Hz, J = 2.8 Hz, 1 H, H5), 3.73 (dd, J = 7.9 Hz, J = 2.8
Hz, 1 H, H4), 3.74 (d, J = 9.3 Hz, 1 H, H1), 3.32 (s, 3 H, OCH3),
3.28 (s, 6 H, OCH3), 3.05–2.98 (m, 1 H, SCHax-a), 2.94–2.87 (m, 1
H, SCHax-b), 2.54–2.46 (m, 2 H, SCHeq), 2.39 (s, 3 H, CH3-Ts), 1.97
(s, 3 H, NCOCH3), 1.95–1.89 (m, 2 H, SCCH2CS).
13C NMR (75 MHz, C6D6): d = 170.3 (NC=O), 144.9 (Cq-Ts), 130.0
(Cq-Ts), 129.9 (2C, Cmeta-Ts), 128.1 (2C, Cortho-Ts), 98.9 (OCH2O),
97.6 (OCH2O), 96.7 (OCH2O), 78.9 (C4), 77.0 (C3), 75.7 (C5), 69.4
(C6), 56.6 (OCH3), 56.2 (OCH3), 55.9 (OCH3), 50.7 (C2), 46.2
(C1), 27.2 (SCH2C), 26.4 (SCH2C), 25.5 (SCCH2CS), 23.2 (CH3-
Ac), 21.7 (CH3-Ts).
NMR spectra were recorded on Bruker AMX 400 spectrometer.
The chemical shift is specified as d (ppm) and the signal of the sol-
vent was used as the internal standard (CDCl3 1H: d = 7.24, 13C: d =
77.23, C6D6 1H: d = 7.16, 13C: d = 128.39, CD3OD 1H: d = 4.85, 13C:
d = 49.15). ESI-MS were recorded on a Quattro LCZ or on a Mi-
croTof. MALDI-TOF MS were recorded on a Reflex IV.
O-Acetylation; General Procedure
The compound with free hydroxy groups was dissolved in anhyd
pyridine–Ac2O (2:1). The mixture was stirred at r.t. until the starting
material was completely converted into the O-acetyl product, which
can take hours to several days (monitored by TLC). The reaction
may be accelerated by the addition of a catalytic amount of DMAP.
The solvent was then evaporated under reduced pressure and traces
of pyridine were removed by coevaporation with toluene. The crude
product was purified by extraction from H2O with CH2Cl2 and, if
necessary, by column chromatography.
ESI-MS: m/z = 598.3 [M + H]+, 620.4 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C24H39NNaO10S3: 620.1631;
2-Acetamido-2-deoxy-3,4,5-tri-O-methoxymethyl-D-glucose
Propane-1,3-diyl Dithioacetal (7)
The 3,4,5-tri-O-methoxymethyl derivative 5 was de-O-acylated
with NaOMe in MeOH. The reaction was followed by TLC and
when it showed complete conversion, the mixture was neutralized
with ion-exchange resin (Amberlyst 15, Acros) and filtered. The
liquid phase was evaporated to dryness to yield the 6-hydroxy com-
pound 7 as an oil in quantitative yield. It was used in the next step
without further purification.
found: 620.1628.
2-Acetamido-2-deoxy-5-O-methoxymethyl-3,4-O-methylene-
D-glucose Propane-1,3-diyl Dithioacetal (8)
To a soln of 6 (5.00 g, 11.1 mmol) in MeOH (50 mL), NaOMe (4.00
g, 74.1 mmol) was added at r.t. The mixture was stirred overnight
and then neutralized by addition of AcOH. The volatile components
were removed under reduced pressure. EtOAc and H2O were added
to the residue and the organic phase was separated and concentrated
under reduced pressure. The residue was purified by MPLC
(EtOAc–cyclohexane, 2:1) to give 8 as a colorless oil that crystal-
lized slowly during storage; yield: 3.25 g (80%). An analytical sam-
ple was recrystallized (EtOAc); mp 123.7–124.1 °C.
[a]D20 –2.9 (c 1.00, MeOH).
1H NMR (400 MHz, C6D6): d = 5.64 (d, J = 10.1 Hz, 1 H, NHC=O),
4.82 (ddd, J = 10.1 Hz, J = 10.1 Hz, J = 1.1 Hz, 1 H, H2), 4.79 (d,
J = 6.1 Hz, 1 H, 3-OCH2O), 4.76 (d, J = 6.4 Hz, 1 H, 4-OCH2O),
4.73 (d, J = 6.6 Hz, 1 H, 5-OCH2O), 4.71 (d, J = 6.4 Hz, 1 H, 4-
OCH2O), 4.68 (dd, J = 7.9 Hz, J = 1.1 Hz, 1 H, H3), 4.64 (d, J = 6.1
Hz, 1 H, 3-OCH2O), 4.63 (d, J = 6.6 Hz, 1 H, 5-OCH2O), 4.13–4.08
(m, 2 H, H4/5), 4.04 (dd, J = 11.9 Hz, J = 4.1 Hz, 1 H, H6a), 3.96
(d, J = 9.4 Hz, 1 H, H1), 3.93 (dd, J = 11.9 Hz, J = 5.4 Hz, 1 H,
H6b), 3.26 (s, 3 H, 4-OCH3), 3.18 (s, 3 H, 5-OCH3), 3.12 (s, 3 H, 3-
OCH3), 3.10–3.02 (m, 1 H, SCHax-a), 2.86–2.79 (m, 1 H, SCHax-b),
2.21–2.10 (m, 2 H, SCHeq), 1.66 (s, 3 H, NCOCH3), 1.50–1.43 (m,
2 H, SCCH2CS), 0.88 (br s, 1 H, OH).
13C NMR (100 MHz, C6D6): d = 170.3 (NC=O), 99.4 (3-OCH2O),
98.0 (4-OCH2O), 97.5 (5-OCH2O), 81.7 (C5), 79.6 (C4), 78.0 (C3),
62.8 (C6), 56.5 (3-OCH3), 56.2 (4-OCH3), 55.8 (5-OMe), 51.6 (C2),
46.4 (C1), 27.2 (SCH2C), 26.4 (SCH2C), 26.0 (SCCH2CS), 23.0
(CH3-Ac).
[a]D20 +0.7 (c 1.00, CHCl3).
1H NMR (400 MHz, C6D6): d = 5.88 (d, J = 10.1 Hz, 1 H, NH), 4.99
(s, 1 H, 3,4-OCH2O), 4.87 (s, 1 H, 3,4-OCH2O), 4.70 (d, J = 6.9 Hz,
1 H, CH2-MOM), 4.68 (d, J = 6.9 Hz, 1 H, CH2-MOM), 4.60–4.51
(m, 2 H, H4, H2), 3.99 (d, J = 8.4 Hz, 1 H, H1), 3.75 (dd, J = 3.1
Hz, J = 12.4 Hz, 1 H, H6a), 3.71–3.65 (m, 2 H, H3, H5), 3.60 (dd,
J = 4.4 Hz, J = 12.4 Hz, 1 H, H6b), 3.36 (s, 3 H, CH3-MOM), 3.16
(br s, 1 H, OH), 2.96–2.81 (m, 2 H, dithiane), 2.69–2.62 (m, 2 H,
dithiane), 2.00 (s, 3 H, Ac), 1.97–1.76 (m, 2 H, dithiane).
13C NMR (100 MHz, C6D6): d = 170.5 (Ac), 97.0 (3,4-OCH2O),
95.4 (CH2-MOM), 80.8 (C5), 77.1 (C3), 76.8 (C4), 62.7 (C6), 56.0
(CH3-MOM), 51.3 (C2), 48.3 (C1), 28.4 (dithiane), 28.0 (dithiane),
25.5 (dithiane), 23.2 (Ac).
ESI-MS: m/z = 466.2 [M + Na]+, 909.3 [2 M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H33NNaO8S2: 466.1540;
HRMS (ESI): m/z [M + Na]+ calcd for C14H25NNaO6S2: 390.1016;
found: 390.1058.
found: 466.1540.
Anal. Calcd for C14H25NO6S2: C, 45.76; H, 6.86; N, 3.81. Found: C,
45.80; H, 6.72; N, 3.66.
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Y.-L. Chen et al.
PAPER
2-Acetamido-2-deoxy-5-O-methoxymethyl-3,4-O-methylene-6-
O-tosyl-D-glucose Propane-1,3-diyl Dithioacetal (3)
To a soln of 8 (1.00 g, 2.7 mmol), Et3N (1.0 mL, 7.1 mmol), and
DMAP (0.30 g, 2.4 mmol) in CH2Cl2 (40 mL) at r.t. was added TsCl
(1.20 g, 6.3 mmol) and the mixture was stirred overnight. The reac-
tion was quenched by addition of MeOH and all solvent was re-
moved under reduced pressure. The residue was purified by MPLC
(EtOAc–cyclohexane, 2:3) to give 3 as a colorless oil; yield: 1.02 g
(73%).
purified by MPLC (EtOAc–cyclohexane, 1:1); yield: 861 mg
(70%).
[a]D20 –7.0 (c 1.00, MeOH).
1H NMR (400 MHz, CDCl3): d = 6.88 (d, J = 9.4 Hz, 1 H, NH), 4.48
(m, 1 H, H2), 4.61 (dd, 1 H, J = 1.3 Hz, J = 6.1 Hz, H3), 4.25(br s,
1 H, 4-OH), 4.20 (dd, J = 5.2 Hz, J = 12.0 Hz, 1 H, H6a), 4.09 (dd,
J = 3.0 Hz, J = 12.0 Hz, 1 H, H6b), 3.39 (br s, 1 H, 3-OH), 3.96 (d,
J = 8.0 Hz, 1 H, H1), 3.67 (m, 1 H, H5), 3.29 (m, 1 H, H4), 2.96 (br
s, 1 H, 5-OH), 2.81–2.73 (m, 2 H, dithiane), 2.58–2.49 (m, 2 H,
dithiane), 1.90–1.73 (m, 2 H, dithiane), 1.03 (s, 9 H, CH3-Pv).
[a]D20 +14.8 (c 1.00, CHCl3).
1H NMR (400 MHz, C6D6): d = 7.75 (d, J = 8.2 Hz, 2 H, Haryl), 7.29
(d, J = 8.2 Hz, 2 H, Haryl), 5.81 (d, J = 9.8 Hz, 1 H, NH), 4.96 (s, 1
H, 3,4-OCH2O), 4.79 (s, 1 H, 3,4-OCH2O), 4.62 (d, J = 6.8 Hz, 1 H,
CH2-MOM), 4.57 (d, J = 6.8 Hz, 1 H, CH2-MOM), 4.50 (m, 1 H,
H3), 4.46 (m, 1 H, H2), 4.24 (dd, J = 2.9 Hz, J = 11.0 Hz, 1 H, H6a),
4.05 (dd, J = 4.6 Hz, J = 11.0 Hz, 1 H, H6b), 3.96 (d, J = 8.2 Hz, 1
H, H1), 3.82–3.77 (m, 1 H, H5), 3.67 (dd, J = 6.4 Hz, J = 6.9 Hz, 1
H, H4), 3.26 (s, 3 H, CH3-MOM), 2.96–2.84 (m, 2 H, dithiane),
2.67–2.61 (m, 2 H, dithiane), 2.38 (s, 3 H, CH3-Ts), 1.97 (s, 3 H,
Ac), 1.94–1.84 (m, 2 H, dithiane).
13C NMR (100 MHz, CD3Cl): d = 179.9 (CO-Pv), 157.8 (d, J = 37.5
Hz, 1 C, CO-Tfa), 115.5 (d, J = 287.8 Hz, 1 C, CF3-Tfa), 71.9 (C5),
71.2 (C4), 69.6 (C3), 65.7 (C6), 53.9 (C2), 46.5 (C1), 38.9 (Cq-Pv),
27.9 (dithiane), 27.7 (dithiane), 27.0 (3C, CH3-Pv), 25.2 (dithiane).
HRMS (ESI): m/z [M + Na]+ calcd for C16H26F3NNaO6S2:
472.1046; found: 472.1047.
Anal. Calcd for C16H26F3NO6S2: C, 42.75; H, 5.83; N, 3.12. Found:
C, 43.21; H, 6.10; N, 2.90.
13C NMR (100 MHz, C6D6): d = 170.2 (Ac), 144.8 (Caryl), 132.7
(Caryl), 129.7 (2C, Caryl), 127.9 (2C, Caryl), 96.5 (3,4-OCH2O), 95.4
(CH2-MOM), 77.5 (C3), 76.4 (C4), 75.1 (C5), 69.1 (C6), 56.1 (CH3-
MOM), 51.6 (C2), 48.2 (C1), 28.4 (dithiane), 28.0 (dithiane), 25.5
(dithiane), 23.2 (Ac), 21.5 (CH3-Ts).
HRMS (ESI): m/z [M + Na]+ calcd for C21H31NNaO8S3: 544.1104;
found: 544.1110.
2-Deoxy-5-O-methoxymethyl-3,4-O-methylene-6-O-pivaloyl-2-
trifluoroacetamido-D-glucose Propane-1,3-diyl Dithioacetal
(11)
6-O-Pivaloyl derivative 10 (1.00 g, 2.2 mmol) was added to CH2Cl2
(10 mL) and dimethoxymethane (10 mL), then BF3·OEt2 (2.0 mL,
15.8 mmol) was added. The mixture was stirred at r.t. for 1 h. Sat.
aq NaHCO3 was then added to quench the reaction. The two phases
were separated and the aqueous phase was washed with Et2O. The
combined organic phases were washed with brine and concentrated
under reduced pressure. The residue was purified by MPLC
(EtOAc–cyclohexane, 1:10) to give 11 as a colorless oil; yield: 0.71
g (63%).
Anal. Calcd for C21H31NO8S3: C, 48.35; H, 5.99; N, 2.68. Found: C,
48.54; H, 6.08; N, 2.39.
2-Deoxy-2-trifluoroacetamido-D-glucose Propane-1,3-diyl
Dithioacetal (9)
Compound 1 (3.0 g, 11.2 mmol) was suspended in a mixture of an-
hyd MeOH (20 mL) and ethyl trifluoroacetate (5 mL). The mixture
was stirred overnight at r.t. All volatile components were removed
under vacuum to give 9 as a white solid in quantitative yield; mp
176.0–177.0 °C.
[a]D20 –7.0 (c 1.00, MeOH).
1H NMR (600 MHz, CDCl3): d = 6.62 (d, J = 10.2 Hz, 1 H, NH),
5.08 (s, 1 H, 3,4-OCH2O), 4.91 (s, 1 H, 3,4-OCH2O), 4.79 (d,
J = 6.8 Hz, 1 H, CH2-MOM), 4.70 (dd, J = 0.9 Hz, J = 6.3 Hz, 1 H,
H3), 4.66 (d, J = 6.8 Hz, 1 H, CH2-MOM), 4.59 (pseudo t,
J1 = J2 = 9.6 Hz, 1 H, H2), 4.45 (dd, J = 3.5 Hz, J = 12.2 Hz, 1 H,
H6), 4.13 (dd, J = 4.4 Hz, J = 12.1 Hz, 1 H, H6), 3.92 (d, J = 9.6 Hz,
1 H, H1), 3.85 (dt, J = 3.6 Hz, J = 3.6 Hz, J = 7.5 Hz, 1 H, H5), 3.77
(dd, J = 6.3 Hz, J = 7.5 Hz, 1 H, H4), 3.39 (s, 3 H, CH3-MOM),
3.02–2.94 (m, 2 H, dithiane), 2.70–2.63 (m, 2 H, dithiane), 2.04–
2.00 (m, 2 H, dithiane), 1.18 (s, 9 H, Pv).
[a]D20 –48.1 (c 1.00, MeOH).
1H NMR (400 MHz, CD3OD): d = 3.59 (br s, 2 H, H6), 3.59 (m, 2
H, H2, H1), 2.85 (m, 1 H, H3), 2.51 (m, 1 H, H4), 2.36 (m, 1 H, H5),
1.76–1.70 (m, 2 H, dithiane), 1.51–1.39 (m, 2 H, dithiane), 0.77–
0.68 (m, 2 H, dithiane).
13C NMR (100 MHz, CD3OD): d = 158.2 (q, J = 37.0 Hz, 1 C, CO-
Tfa), 116.6 (q, J = 286.8 Hz, 1 C, CF3-Tfa), 73.2 (C5), 72.5 (C4),
68.3 (C6), 63.6 (C3), 54.8 (C2), 46.6 (C1), 27.7 (dithiane), 27.3
(dithiane), 25.8 (dithiane).
HRMS (ESI): m/z [M + Na]+ calcd for C11H18F3NNaO5S2:
388.0471; found: 388.0473.
13C NMR (150 MHz, CDCl3): d = 178.1 (CO-Pv), 157.5 (q, J = 37.5
Hz, 1 C, CO-Tfa), 115.7 (q, J = 287.8 Hz, 1 C, CF3-Tfa), 95.9 (CH2-
MOM), 96.6 (3,4-OCH2O), 77.2 (C3), 75.9 (C4), 74.9 (C5), 62.2
(C6), 56.1 (CH3-MOM), 52.1 (C2), 46.3 (C1), 38.8 (Me3C-Pv), 27.3
(dithiane), 27.0 (3C, CH3-Pv), 26.9 (dithiane), 25.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H30F3NNaO7S2:
528.1308; found: 528.1315.
Anal. Calcd for C11H18F3NO5S2: C, 36.16; H, 4.97; N, 3.83. Found:
C, 36.39; H, 4.80; N, 3.69.
Anal. Calcd for C19H30F3NO7S2: C, 45.14; H, 5.98; N, 2.77. Found:
C, 45.45; H, 6.14; N, 2.76.
2-Deoxy-6-O-pivaloyl-2-trifluoroacetamido-D-glucose
Propane-1,3-diyl Dithioacetal (10)
2-Deoxy-5-O-methoxymethyl-3,4-O-methylene-2-trifluoro-
acetamido-D-glucose Propane-1,3-diyl Dithioacetal (12)
To a soln of 11 (1.0 g, 1.98 mmol) in MeOH (10 mL) was added
30% NaOMe in MeOH (3.0 mL) at r.t. The mixture was stirred
overnight and then neutralized by addition of AcOH. The volatile
components were removed under reduced pressure. EtOAc and H2O
were added to the residue and the organic phase was separated and
concentrated under reduced pressure. The residue was purified by
MPLC (EtOAc–cyclohexane, 1:5) and gave 12 as a colorless oil that
crystallized slowly during storage; yield: 475 mg (57%); mp 144 °C
(dec.).
The acetamido compound 9 (1.0 g, 2.74 mmol) was dissolved in py-
ridine (8 mL) and DMF (3 mL) and cooled to –50 °C, a soln of piv-
aloyl chloride (0.47 mL, 3.8 mmol, 1.4 equiv) in DMF (3 mL) was
added dropwise over a period of 1 h. The mixture was kept stirring
at this temperature for a further 1 h and warmed to r.t.. Then it was
stirred overnight at r.t. and quenched by addition of MeOH. All vol-
atile components were then removed under reduced pressure. The
remaining syrup was separated between CH2Cl2 and H2O. The or-
ganic phase was washed sequentially with dil aq HCl, sat. NaHCO3,
and brine. Then the organic phase was evaporated to dryness and
Synthesis 2006, No. 13, 2242–2250 © Thieme Stuttgart · New York

PAPER
Aminocyclitols and Iminosugars by Intramolecular Cyclizations of D-Glucosamine Dithioacetals
2247
[a]D20 –13.4 (c 1.00, MeOH).
J = 6.4 Hz, 2 H, OCH2O), 4.56 (dd, J = 6.5 Hz, J = 3.9 Hz, 2 H,
OCH2O), 4.53 (dd, J = 6.7 Hz, J = 4.7 Hz, 2 H, OCH2O), 4.46 (ddd,
J = 8.4 Hz, J = 5.8 Hz, J = 2.5 Hz, 1 H, H5), 4.13 (dd, J = 4.3 Hz,
J = 3.3 Hz, 1 H, H3), 4.11 (dd, J = 4.3 Hz, J = 2.5 Hz, 1 H, H4), 3.20
(s, 3 H, OCH3), 3.16 (s, 3 H, OCH3), 3.15 (s, 3 H, OCH3), 3.15–3.06
(m, 1 H, SCHax-a), 2.64–2.56 (m, 1 H, SCHax-b), 2.50–2.31 (m, 2 H,
SCHeq), 2.41 (d, J = 8.4 Hz, 2 H, H6), 1.78 (s, 3 H, NCOCH3), 1.55–
1.52 (m, 2 H, SCCH2CS).
13C NMR (100 MHz, C6D6): d = 169.9 (NC=O), 97.4 (OC=O), 97.1
(OC=O), 95.9 (OC=O), 78.4 (C4), 77.2 (C3), 71.4 (C5), 56.0
(OCH3), 55.9 (OCH3), 55.6 (OCH3), 54.2 (C1), 52.7 (C2), 37.0
(C6), 27.7 (SCH2C), 26.9 (SCH2C), 25.2 (SCCH2CS), 23.5 (CH3-
Ac).
1H NMR (400 MHz, CDCl3): d = 6.75 (d, J = 9.8 Hz, 1 H, NH), 5.1
(s, 1 H, 3,4-OCH2O), 5.0 (s, 1 H, 3,4-OCH2O), 4.78 (d, J = 7.0 Hz,
1 H, CH2-MOM), 4.76 (d, J = 6.9 Hz, 1 H, CH2-MOM), 4.72 (dd,
J = 0.8 Hz, J = 6.5 Hz, 1 H, H4), 4.67 (pseudo t, J = 9.5 Hz, 1 H,
H2), 4.00 (d, J = 9.0 Hz, 1 H, H1), 3.88 (dd, J = 2.5 Hz, J = 12.1 Hz,
1 H, H6a), 3.77–3.74 (m, 1 H, H3), 3.70–3.64 (m, 2 H, H5, H6b),
3.46 (s, 3 H, CH3-MOM), 3.04–2.95 (m, 2 H, dithiane), 2.75–2.66
(m, 2 H, dithiane), 2.10–1.99 (m, 2 H, dithiane), 1.75 (br s, 1 H, 6-
OH).
13C NMR (100 MHz, CDCl3): d = 157.6 (d, J = 37.5 Hz, 1 C, CO-
Tfa), 115.7 (d, J = 288.0 Hz, 1 C, CF3-Tfa), 97.0 (3,4-OCH2O), 95.5
(CH2-MOM), 80.9 (C5), 77.1 (C3), 76.8 (C4), 62.8 (C6), 56.0 (CH3-
MOM), 51.9 (C2), 46.7 (C1), 27.6 (dithiane), 27.2 (dithiane), 25.1
(dithiane).
ESI-MS: m/z = 426.2 [M + H]+, 448.2 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H31NNaO7S2: 448.1434;
HRMS (ESI): m/z [M + Na]+ calcd for C14H22F3NNaO6S2:
found: 448.1434.
444.0733; found: 444.0736.
2-Acetamido-2,6-anhydro-2-deoxy-3,4,5-tri-O-methoxymethyl-
D-glucose Propane-1,3-diyl Dithioacetal (16)
Anal. Calcd for C14H22F3NO6S2: C, 39.90; H, 5.26; N, 3.32. Found:
C, 40.03; H, 5.03; N, 3.17.
To a soln of 6-O-tosyl compound 2 (302 mg, 0.51 mmol) in anhyd
THF (10 mL) was added 60% NaH in oil (50 mg, 1.25 mmol) at
0 °C. The mixture was heated to reflux temperature and stirred for
2 h and then quenched by addition of EtOH and H2O. The mixture
was extracted with Et2O (3 ×) and the combined organic phases
were dried (MgSO4) and filtered. The solvent was evaporated under
reduced pressure and resulting residue purified by MPLC (EtOAc–
cyclohexane, 2:1) to give 16 as a colorless syrup; yield: 135 mg
(63%).
2-Deoxy-5-O-methoxymethyl-3,4-O-methylene-6-O-tosyl-2-tri-
fluoroacetamido-D-glucose Propane-1,3-diyl Dithioacetal (4)
To a soln of 12 (1.5 g, 3.6 mmol), Et3N (1.5 mL, 10.6 mmol), and
DMAP (0.45 g, 3.6 mmol) in CH2Cl2 (30 mL) was added TsCl (1.50
g, 7.8 mmol) at r.t. and the mixture was stirred overnight. The reac-
tion was quenched by addition of MeOH and the solvent was re-
moved under reduced pressure. The residue was purified by MPLC
(EtOAc–cyclohexane, 1:5) to give 4 as a colorless oil; yield: 1.2 g
(56%).
[a]D20 –71.0 (c 1.00, CHCl3).
[a]D20 +18.7 (c 1.00, MeOH).
Isomers from the rotating restriction of amide were observed and re-
solved by NMR. For the sake of clarity they are listed here as sepa-
rate compounds.
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 8.3 Hz, 2 H, Haryl),
7.29 (d, J = 8.3 Hz, 2 H, Haryl), 6.56 (d, J = 9.8 Hz, 1 H, NH), 4.95
(s, 1 H, 3,4-OCH2O), 4.80 (s, 1 H, 3,4-OCH2O), 4.64 (d, J = 6.8 Hz,
1 H, CH2-MOM), 4.58 (d, J = 6.8 Hz, 1 H, CH2-MOM), 4.49 (pseu-
do t, J = 9.2 Hz, 1 H, H2), 4.61 (dd, 1 H, J = 1.3 Hz, J = 6.1 Hz, H3),
4.27 (dd, J = 3.1 Hz, J = 10.9 Hz, 1 H, H6a), 4.05 (dd, J = 4.5 Hz,
J = 10.9 Hz, 1 H, H6b), 3.91 (d, J = 9.2 Hz, 1 H, H1), 3.81–3.77 (m,
1 H, H5), 3.61 (dd, J = 6.1 Hz, J = 7.1 Hz, 1 H, H4), 3.28 (s, 3 H,
CH3-MOM), 2.96–2.87 (m, 2 H, dithiane), 2.66–2.59 (m, 2 H,
dithiane), 2.38 (s, 3 H, CH3-Ts), 1.99–1.90 (m, 2 H, dithiane).
13C NMR (100 MHz, CDCl3): d = 157.5 (d, J = 37.5 Hz, 1 C, CO-
Tfa), 117.1 (CF3-Tfa), 129.8 (3 C, Caryl), 129.0 (3 C, Caryl), 96.5
(3,4-OCH2O), 95.6 (CH2-MOM), 77.0 (C3), 76.5 (C4), 75.0 (C5),
68.5 (C6), 56.2 (CH3-MOM), 52.3 (C2), 46.4 (C1), 27.6 (dithiane),
27.2 (dithiane), 25.1 (dithiane), 21.5 (CH3-Ts).
Isomer 1:
1H NMR (600 MHz, CDCl3): d = 5.38 (dd, J = 6.4 Hz, J = 6.1 Hz,
1 H, H2), 4.80 (d, J = 6.7 Hz, 1 H, OCH2O), 4.77 (d, J = 6.7 Hz, 1
H, OCH2O), 4.72 (d, J = 6.7 Hz, 1 H, OCH2O), 4.68 (d, J = 6.6 Hz,
1 H, OCH2O), 4.66 (d, J = 6.6 Hz, 1 H, OCH2O), 4.65 (d, J = 6.7
Hz, 1 H, OCH2O), 4.44 (d, J = 6.8 Hz, 1 H, H1), 4.10 (dd, J = 10.3
Hz, J = 6.3 Hz, 1 H, H3), 4.04 (dd, J = 10.2 Hz, J = 3.2 Hz, 1 H,
H4), 3.96 (br s, 1 H, H5), 3.77 (br d, J = 14.9 Hz, 1 H, H6a), 3.54
(br d, J = 14.9 Hz, 1 H, H6b), 3.38 (s, 6 H, OCH3), 3.34 (s, 3 H,
OCH3), 2.86–2.78 (m, 2 H, SCHax), 2.76–2.69 (m, 2 H, SCHeq), 2.12
(s, 3 H, NCOCH3), 2.00–1.94 (m, 1 H, SCCH2CS), 1.89–1.84 (m, 1
H, SCCH2CS).
13C NMR (150 MHz, CDCl3): d = 171.1 (NC=O), 96.9 (OCH2O),
96.8 (OCH2O), 96.6 (OCH2O), 75.2 (C4), 72.9 (2C, C3/5), 56.2
(OCH3), 55.9 (OCH3), 55.9 (OCH3), 53.9 (C2), 47.6 (C6), 46.2
(C1), 30.2 (SCH2C), 29.8 (SCH2C), 25.5 (SCCH2CS), 21.8 (CH3-
Ac).
HRMS (ESI): m/z [M + Na]+ calcd for C21H28F3NNaO8S3:
598.0821; found: 598.0822.
(2R,3R,4R,5R)-2-Acetamido-3,4,5-tris(methoxymethoxy)cyclo-
hexanone Propane-1,3-diyl Dithioacetal (14)
Isomer 2:
To a soln of the 6-O-tosyl compound 2 (98 mg, 0.16 mmol) in anhyd
THF (5 mL) was added dropwise a 1.6 M n-BuLi in hexane (0.31
mL, 0.5 mmol) at –78 °C. The pink soln was warmed to –40 °C over
1 h and and this point the soln became yellowish. At –20 °C after
stirring for a total of 2 h, the mixture was quenched with H2O. The
phases were separated, the aqueous phase was extracted with Et2O
(3 ×), and the combined organic phases were dried (MgSO4). The
solvent was evaporated and the residue was purified by MPLC
(EtOAc–cyclohexane 1:2) to give 14 as a colorless syrup; yield: 48
mg (71%).
1H NMR (600 MHz, CDCl3): d = 4.80 (d, J = 6.7 Hz, 1 H, OCH2O),
4.80 (br d, J = 15.1 Hz, 1 H, H6a), 4.73 (d, J = 6.9 Hz, 1 H,
OCH2O), 4.70 (d, J = 7.1 Hz, 1 H, OCH2O), 4.68 (d, J = 6.9 Hz, 1
H, OCH2O), 4.67 (d, J = 6.9 Hz, 1 H, OCH2O), 4.61 (d, J = 7.2 Hz,
1 H, H1), 4.58 (d, J = 6.9 Hz, 1 H, OCH2O), 4.26 (dd, J = 6.5 Hz,
J = 6.1 Hz, 1 H, H2), 4.16 (dd, J = 10.5 Hz, J = 6.1 Hz, 1 H, H3),
4.05 (dd, J = 6.4 Hz, J = 3.3 Hz, 1 H, H4), 3.98 (br s, 1 H, H5), 3.43
(s, 3 H, OCH3), 3.38 (s, 3 H, OCH3), 3.34 (s, 3 H, OCH3), 2.99–2.94
(m, 1 H, SCHax-a), 2.91 (br d, J = 14.8 Hz, 1 H, H6b), 2.90–2.85 (m,
1 H, SCHax-b), 2.81–2.73 (m, 2 H, SCHeq), 2.21 (s, 3 H, NCOCH3),
2.05–2.02 (m, 1 H, SCCH2CS), 1.84–1.78 (m, 1 H, SCCH2CS).
[a]D20 –25.1 (c 1.00, MeOH).
1H NMR (400 MHz, C6D6): d = 6.41 (d, J = 10.2 Hz, 1 H, NHC=O),
5.05 (dd, J = 10.2 Hz, J = 3.3 Hz, 1 H, H2), 4.67 (dd, J = 8.4 Hz,
13C NMR (150 MHz, CDCl3): d = 171.0 (NC=O), 97.4 (OCH2O),
96.4 (OCH2O), 95.2 (OCH2O), 74.6 (C4), 74.1 (C3), 71.2 (C5), 60.8
Synthesis 2006, No. 13, 2242–2250 © Thieme Stuttgart · New York

2248
Y.-L. Chen et al.
PAPER
(C2), 56.4 (OCH3), 55.8 (OCH3), 55.7 (OCH3), 47.8 (C1), 41.0
(C6), 31.4 (2C, SCH2C), 25.5 (SCCH2CS), 22.2 (CH3-Ac).
ESI-MS: m/z = 448.1 [M + Na]+, 873.3 [2 M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H31NNaO7S2: 448.1434;
found: 448.1426.
Isomer 2:
1H NMR (400 MHz, CDCl3): d = 5.14 (s, 1 H, 3,4-OCH2O), 5.07 (s,
1 H, 3,4-OCH2O), 4.93 (dd, J = 2.3 Hz, J = 15.2 Hz, 1 H, H6), 4.66
(d, J = 6.8 Hz, 1 H, MOM), 4.62 (d, J = 6.8 Hz, 1 H, MOM), 4.52–
4.44 (m, 2 H, H2, H1), 4.28 (m, 1 H, H5), 3.98 (dd, J = 4.8 Hz,
J = 9.9 Hz, 1 H, H3), 3.72 (dd, J = 2.7 Hz, J = 9.9 Hz, 1 H, H4), 3.31
(s, 3 H, MOM), 2.92–2.71 (m, 4 H, dithiane), 2.69 (dd, J = 1.4 Hz,
J = 15.2 Hz, 1 H, H6), 2.22 (s, 3 H, CH3-Ac), 2.09–2.00 (m, 1 H,
dithiane), 1.87–1.75 (m, 1 H, dithiane).
13C NMR (100 MHz, CDCl3): d = 171.3 (CO-Ac), 96.3 (3,4-
OCH2O), 95.2 (MOM), 75.7 (C4), 72.3 (C3), 68.9 (C5), 60.2 (C2),
55.5 (MOM), 45.1 (C1), 41.8 (C6), 30.7 (dithiane), 30.3 (dithiane),
25.2 (dithiane), 22.5 (CH3-Ac).
(2R,3R,4R,5R)-2-Acetamido-5-(methoxymethoxy)-3,4-(methyl-
enedioxy)cyclohexanone Propane-1,3-diyl Dithioacetal (17)
To a soln of 3 (1.38 g, 2.6 mmol) in anhyd THF (70 mL) at –78 °C
under argon was added 1.6 M n-BuLi in hexane (7 mL, 11.2 mmol).
The mixture was slowly warmed to –20 °C over 5 h and then it was
quenched by addition of sat. aq NH4Cl. The organic phase was sep-
arated and the aqueous phase was washed with EtOAc. The com-
bined organic phases were washed with brine and evaporated under
reduced pressure. The residue was purified by MPLC (EtOAc–cy-
clohexane, 1:1) to give 17 as a colorless oil that occasionally crys-
tallized during storage; yield: 0.48 g (52%). An analytical sample
was recrystallized (EtOAc); mp 179.4–180.0 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C14H23NNaO5S2: 372.0910;
found: 372.0925.
Anal. Calcd for C14H23NO5S2: C, 48.12; H, 6.63; N, 4.01. Found: C,
47.74; H, 6.67; N, 3.58.
[a]D20 –8.9 (c 1.00, CHCl3).
(2R,3R,4R,5R)-5-(Methoxymethoxy)-3,4-(methylenedioxy)-2-
(trifluoroacetamido)cyclohexanone Propane-1,3-diyl Dithio-
acetal (19)
1H NMR (400 MHz, CDCl3): d = 6.21 (d, J = 9.6 Hz, 1 H, NH), 5.09
(s, 1 H, 3,4-OCH2O), 5.03 (s, 1 H, 3,4-OCH2O), 4.69 (d, J = 6.7 Hz,
1 H, MOM), 4.65 (d, J = 6.7 Hz, 1 H, MOM), 4.43 (pseudo t,
J = 10.4 Hz, 1 H, H2), 4.33–4.28 (m, 1 H, H5), 3.98 (dd, J = 9.5 Hz,
J = 10.9 Hz, 1 H, H3), 3.40 (dd, J = 2.7 Hz, J = 9.5 Hz, 1 H, H4),
3.36 (s, 3 H, MOM), 2.99 (dd, J = 2.8 Hz, J = 15.5 Hz, 1 H, H6a),
2.96–2.87 (m, 2 H, dithiane), 2.78–2.64 (m, 2 H, dithiane), 2.06 (dd,
J = 3.2 Hz, J = 15.5 Hz, 1 H, H6b), 2.05 (s, 3 H, CH3-Ac), 1.98–
1.85 (m, 2 H, dithiane).
13C NMR (100 MHz, CDCl3): d = 170.0 (CO-Ac), 96.5 (3,4-
OCH2O), 95.7 (MOM), 80.3 (C4), 73.6 (C3), 69.6 (C5), 58.5 (C2),
55.5 (MOM), 55.4 (C1), 42.4 (C6), 27.0 (dithiane), 25.9 (dithiane),
24.0 (dithiane), 23.2 (CH3-Ac).
To a soln of 4 (150 mg, 0.26 mmol) in anhyd THF (2 mL) at –100
°C under argon was added 1.6 M n-BuLi in hexane (0.48 mL, 0.78
mmol). The mixture was slowly warmed to –50 °C over 3 h and then
it was quenched by the addition of sat. aq NH4Cl. The organic phase
was separated and the aqueous phase was washed with EtOAc. The
combined organic phases were washed with brine and evaporated
under reduced pressure. The residue was purified by MPLC
(EtOAc–cyclohexane, 1:5) to give 19 as a white solid; yield: 82 mg
(78%); mp 160.0 °C (dec.).
[a]D20 +8.0 (c 1.00, MeOH).
1H NMR (600 MHz, CDCl3): d = 7.07 (d, J = 9.6 Hz, 1 H, NH), 5.17
(d, J = 0.75 Hz, 1 H, 3,4-OCH2O), 5.13 (d, J = 0.75 Hz, 1 H, 3,4-
OCH2O), 4.76 (d, J = 6.7 Hz, 1 H, CH2-MOM), 4.73 (d, J = 6.7 Hz,
1 H, CH2-MOM), 4.44–4.39 (m, 2 H, H2, H5), 4.11 (dd, J = 9.4 Hz,
J = 10.8 Hz, 1 H, H3), 3.47 (dd, J = 2.7 Hz, J = 9.4 Hz, 1 H, H4),
3.44 (s, 3 H, MOM), 3.09 (dd, J = 2.9 Hz, J = 15.6 Hz, 1 H, H6a),
3.03–2.96 (m, 2 H, dithiane), 2.80–2.73 (m, 2 H, dithiane), 2.16 (dd,
J = 2.9 Hz, J = 15.6 Hz, 1 H, H6b), 2.03–1.97 (m, 2 H, dithiane).
13C NMR (150 MHz, CDCl3): d = 157.0 (very weak d, J = 35.3 Hz,
1 C, CO-Tfa), 116.0 (very weak q, J = 223.5 Hz, 1 C, CF3-Tfa), 96.8
(3,4-OCH2O), 95.7 (MOM), 80.2 (C4), 73.1 (C3), 69.3 (C5), 59.4
(C2), 55.7 (MOM), 55.0 (C1), 43.0 (C6), 27.0 (dithiane), 25.8
(dithiane), 23.5 (dithiane).
HRMS-ESI(+): m/z [M + Na]+ 372.0907. C14H23NNaO5S2 requires
372.0910.
Anal. Calcd for C14H23NO5S2: C, 48.12; H, 6.63; N, 4.01. Found: C,
47.81; H, 6.99; N, 3.96.
2-Acetamido-2,6-anhydro-2-deoxy-5-O-methoxymethyl-3,4-O-
methylene-D-glucose Propane-1,3-diyl Dithioacetal (18)
To a soln of 3 (300 mg, 0.58 mmol) in anhyd THF (10 mL) at r.t.
under argon was added 60% NaH in oil (30 mg, 0.75 mmol). Then
the mixture was refluxed for 2 h and then it was cooled to r.t. and
quenched by addition of sat. aq NH4Cl. The organic phase was sep-
arated and the aqueous phase was washed with EtOAc. The com-
bined organic phases were washed with brine and evaporated under
reduced pressure. The residue was purified by MPLC (EtOAc–cy-
clohexane, 2:3) to give 18 as a colorless oil; yield: 157 mg (78%).
HRMS (ESI): m/z [M + Na]+ calcd for C14H20F3NNaO5S2:
426.0627; found: 426.0623.
[a]D20 –67.9 (c 1.00, CHCl3).
(2R,3R,4R,5R)-2-Acetamido-5-(methoxymethoxy)-3,4-(methyl-
enedioxy)cyclohexanone (20)
Similar to compound 16, isomers of compound 18 were observed
and recorded by NMR.
A soln of the dithiane 17 (150 mg, 0.43 mmol) in MeCN (0.5 mL)
was added quickly to a well-stirred mixture of NCS (225 mg, 1.7
mmol), AgNO3 (327 mg, 1.9 mmol), and CaCO3 (300 mg, 3 mmol)
in aq 80% MeCN (4 mL). After 30 min, the mixture was filtered and
the solvent was concentrated. The residue was purified by column
(EtOAc–cyclohexane, 1:1) to give 20 as a white solid; yield: 45 mg
(40%); mp 156–158 °C (dec.).
Isomer 1:
1H NMR (400 MHz, CDCl3): d = 5.81 (dd, J = 5.7 Hz, J = 9.4 Hz,
1 H, H2), 5.10 (s, 1 H, 3,4-OCH2O), 4.99 (s, 1 H, 3,4-OCH2O), 4.76
(d, J = 6.7 Hz, 1 H, MOM), 4.61 (d, J = 6.7 Hz, 1 H, MOM), 4.28
(m, 1 H, H5), 4.05 (d, J = 9.4 Hz, 1 H, H1), 3.90–3.81 (m, 2 H, H3,
H6), 3.60 (dd, J = 2.6 Hz, J = 10.0 Hz, 1 H, H4), 3.32 (s, 3 H,
MOM), 3.16 (dd, J = 1.5 Hz, J = 15.1 Hz, 1 H, H6), 3.05–2.84 (m,
2 H, dithiane), 2.77–2.52 (m, 2 H, dithiane), 2.13 (s, 3 H, CH3-Ac),
1.97–1.88 (m, 2 H, dithiane).
13C NMR (CDCl3, 100 MHz): d = 171.2 (CO-Ac), 96.2 (MOM),
95.8 (3,4-OCH2O), 75.5 (C4), 72.1 (C3), 70.4 (C5), 53.4 (C2), 55.8
(MOM), 47.1 (C6), 41.5 (C1), 27.8 (dithiane), 27.7 (dithiane), 25.2
(dithiane), 22.1 (CH3-Ac).
[a]D20 –21.5 (c 1.00, MeOH).
1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 8.5 Hz, 1 H, NH), 5.26
(s, 1 H, 3,4-OCH2O), 5.18 (s, 1 H, 3,4-OCH2O), 4.90 (dd, J = 8.5
Hz, J = 12.0 Hz, 1 H, H2), 4.78 (d, J = 6.7 Hz, 1 H, CH2-MOM),
4.71 (d, J = 6.7 Hz, 1 H, CH2-MOM), 4.57 (m, 1 H, H5), 4.17 (dd,
J = 9.4 Hz, J = 2.2 Hz, 1 H, H4), 3.99 (dd, J = 9.4 Hz, J = 12.0 Hz,
1 H, H3), 3.35 (s, 3 H, CH3-MOM), 2.99 (dd, J = 3.7 Hz, J = 15.9
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Aminocyclitols and Iminosugars by Intramolecular Cyclizations of D-Glucosamine Dithioacetals
2249
Hz, 1 H, H6a), 2.06 (dd, J = 3.7 Hz, J = 15.9 Hz, 1 H, H6b), 2.1 (s,
3 H, CH3-Ac).
13C NMR (100 MHz, CDCl3): d = 204.1 (C1), 170.7 (CO-Ac), 98.4
(3,4-OCH2O), 97.1 (CH2-MOM), 80.7 (C4), 76.5 (C3), 69.9 (C5),
61.8 (C2), 56.1 (CH3-MOM), 45.5 (C6), 23.4 (CH3-Ac).
13C NMR (100 MHz, CDCl3): d = 170.5 (CO-Ac), 170.0 (CO-Ac),
169.9 (CO-Ac), 169.8 (CO-Ac), 68.2 (C4), 67.9 (C5), 67.1 (C3),
51.2 (C2), 45.3 (C6), 42.5 (C1), 27.8 (dithiane), 27.5 (dithiane),
25.0 (dithiane), 21.4 (CH3-Ac), 21.1 (CH3-Ac), 20.7 (CH3-Ac), 20.6
(CH3-Ac).
Isomer 2:
HRMS (ESI): m/z [M + Na]+ calcd for C11H17NNaO6: 282.0953;
found: 282.0931.
1H NMR (400 MHz, CDCl3); d = 5.32 (dd, J = 3.4 Hz, J = 11.1 Hz,
1 H, H4), 5.30–5.26 (m, 1 H, H5), 5.15 (dd, J = 4.8 Hz, J = 11.1 Hz,
1 H, H3), 4.73 (dd, J = 1.8 Hz, J = 15.4 Hz, 1 H, H6a), 4.50–4.41
(m, 2 H, H2, H1), 3.02–2.93 (m, 1 H, H6b), 2.98–2.71 (m, 4 H,
dithiane), 2.21 (s, 3 H, CH3-Ac), 2.15–1.71 (m, 1 H, dithiane), 2.06
(s, 3 H, CH3-Ac), 1.99 (s, 3 H, CH3-Ac), 1.94 (s, 3 H, CH3-Ac).
13C NMR (100 MHz, CDCl3): d = 170.7 (CO-Ac), 170.1 (CO-Ac),
170.0 (CO-Ac), 169.9 (CO-Ac), 68.3 (C3), 67.9 (C4), 67.2 (C5),
57.5 (C2), 46.2 (C1), 40.6 (C6), 30.7 (dithiane), 30.6 (dithiane),
25.0 (dithiane), 21.8 (CH3-Ac), 21.1 (CH3-Ac), 20.7 (CH3-Ac), 20.5
(CH3-Ac).
(2R,3R,4R,5R)-2-Acetamido-3,4,5-trihydroxycyclohexanone
Propane-1,3-diyl Dithioacetal (21)
To a soln of 17 (50 mg, 0.14 mmol) in CH2Cl2 (5 mL) at –90 °C un-
der argon was added 10% BCl3 in 2-chloroethanol (1.6 mL, 1.4
mmol).The mixture was then warmed to r.t. over a period of 20 min
and stirred for a further 3 h. Sat. NaHCO3 was added to neutralize
the mixture and then all the volatile components were removed un-
der reduced pressure. The residue was extracted with MeOH and fil-
tered. The filtrate was concentrated under reduced pressure again
and the residue was purified by MPLC (acetone–cyclohexane, 1:1)
to give 21 as a white powder; yield: 27 mg (64%). An analytical
sample was recrystallized (MeOH–EtOAc); mp 200.9–201.5 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NNaO4S2: 316.0648;
found: 316.0665.
[a]D20 –36.4 (c 1.00, MeOH).
Anal. Calcd for C11H19NO4S2: C, 45.03; H, 6.53; N, 4.47. Found: C,
44.80; H, 6.59; N, 4.46
The NMR data were recorded from the peracetylated derivative of
the product by general acetylation procedure.
(2R,3R,4R,5R)-2-Amino-5-(methoxymethoxy)-3,4-(methylene-
dioxy)cyclohexanone Propane-1,3-diyl Dithioacetal (23)
1H NMR (400 MHz, CDCl3,): d = 5.94 (d, J = 10.1 Hz, 1 H, NH),
5.41 (t, J = 10.1 Hz, 1 H, H3), 5.24–5.21 (m, 1 H, H5), 4.99 (dd,
J = 3.6 Hz, J = 10.1 Hz, 1 H, H4), 4.36 (t, J = 10.1 Hz, 1 H, H2),
3.03 (dd, J = 3.6 Hz, J = 15.8 Hz, 1 H, H6), 2.95–2.86 (m, 2 H,
dithiane), 2.72–2.61 (m, 2 H, dithiane), 2.14 (dd, J = 2.8 Hz,
J = 15.8 Hz, 1 H, H6), 2.04 (s, 3 H, CH3-Ac), 1.97 (s, 3 H, CH3-Ac),
1.96 (s, 3 H, CH3-Ac), 1.94 (s, 3 H, CH3-Ac), 1.90–1.82 (m, 2 H,
dithiane).
Compound 19 (60 mg, 0.15 mmol) was dissolved in MeOH (1 mL)
and 30% NaOMe in MeOH (1 mL) was added. The clear soln was
heated in a sealed tube at 100 °C for 10 h. Then the solvent was
evaporated and the residue was partitioned between H2O and
EtOAc. The organic phase was collected, washed with brine, and
evaporated. The resulted syrup was purified by MPLC (EtOAc–cy-
clohexane, 1:1) to give 23 as colorless oil; yield: 31 mg (67%).
13C NMR (100 MHz, CDCl3): d = 170.8 (CO-Ac), 170.2 (CO-Ac),
169.8 (CO-Ac), 169.4 (CO-Ac), 71.4 (C4), 69.0 (C3), 68.1 (C5),
58.2 (C2), 53.9 (C1), 38.9 (C6), 26.7 (dithiane), 25.7 (dithiane),
22.6 (dithiane), 23.1 (CH3-Ac), 21.1 (CH3-Ac), 20.6 (CH3-Ac), 20.5
(CH3-Ac).
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NNaO4S2: 316.0648;
found: 316.0649.
[a]D20 –39.0 (c 1.00, MeOH).
1H NMR (500 MHz, C6D6): d = 4.96 (d, J = 2.0 Hz, 2 H, 3,4-
OCH2O), 4.68 (dd, J = 6.6 Hz, J = 28.6 Hz, 2 H, CH2-MOM), 4.21
(pseudo t, J = 9.9 Hz, 1 H, H3), 4.07 (m, 1 H, H5), 3.10 (d, J = 10.2
Hz, 1 H, H2), 2.88 (dd, J = 2.7 Hz, J = 9.5 Hz, 1 H, H4), 3.27 (s, 3
H, CH3-MOM), 2.65 (dd, J = 2.9 Hz, J = 15.4 Hz, 1 H, H6a), 3.02–
2.92 (m, 2 H, dithiane), 2.45–2.40 (m, 1 H, dithiane), 2.20–2.16 (m,
1 H, dithiane), 1.58–1.50 (m, 3 H, dithiane, H6b).
13C NMR (125 MHz, C6D6): d = 96.6 (3,4-OCH2O), 95.6 (CH2-
MOM), 80.3 (C4), 77.1 (C3), 70.1 (C5), 66.8 (C2), 55.3 (CH3-
MOM), 54.6 (C1), 43.4 (C6), 27.81 (dithiane), 25.76 (dithiane),
24.8 (dithiane).
Anal. Calcd for C11H19NO4S2: C, 45.03; H, 6.53; N, 4.47. Found: C,
44.91; H, 6.50; N, 4.61.
(2S,3R,4R,5R)-2-Acetamido-2,6-anhydro-2-deoxy-D-glucose
Propane-1,3-diyl Dithioacetal (22)
To a soln of 18 (207 mg, 0.59 mmol) in THF (25 mL) at 0 °C was
added concd HCl (4 mL). The mixture was then stirred overnight at
r.t.. Solid Na2CO3 was added to quench the reaction and the slurry
was stirred for 10 min before it was filtered. The filtrate was con-
centrated under reduced pressure. The residue was purified by
MPLC (acetone–cyclohexane, 5:4) to give 22 as a white powder;
yield: 123 mg (71%). An analytical sample was recrystallized
(CH2Cl2–EtOAc); mp 179.0–180.5 °C (dec.).
HRMS (ESI): m/z [M + Na]+ calcd for C12H21NNaO4S2: 330.0804;
found: 330.0807.
2-Amino-2,6-anhydro-2-deoxy-D-glucose Propane-1,3-diyl
Dithioacetal (24)
Compound 22 (293 mg, 1 mmol) was dissolved in a mixture of H2O
(3 mL) and EtOH (2 mL). 6 M HCl (1 mL) was added and the mix-
ture was refluxed for 3 h. All the volatile components were removed
from the mixture under vacuum. Methanolic NH3 was added to the
residue and the mixture was evaporated to dryness again. The resi-
due was purified by MPLC (cyclohexane–acetone, 1:3) to give 24
as a light yellow solid; yield: 120 mg (48%); mp 112 °C.
[a]D20 –36.5 (c 1.00, CHCl3).
The NMR data were recorded from the peracetylated derivative of
the product by general acetylation procedure. Isomers were ob-
served and recorded.
[a]D20 +3.7 (c 1.00, MeOH).
Isomer 1:
The compound was then peracetylated according to the standard
procedure. NMR analysis was performed on the peracetylated de-
rivative, and was found identical to the NMR spectrum of the per-
acetylated derivative of compound 22.
HRMS (ESI): m/z [M + H]+ calcd for C9H18NO3S2: 252.0728;
found: 252.0713.
1H NMR (400 MHz; CDCl3): d = 5.65 (dd, J = 4.6 Hz, J = 8.6 Hz,
1 H, H2), 5.30–5.26 (m, 1 H, H5), 5.25–5.21 (m, 2 H, H4, H3), 4.07
(d, J = 8.6 Hz, 1 H, H1), 3.78 (d, J = 15.5 Hz, 1 H, H6), 3.48 (d,
J = 15.5 Hz, 1 H, H6), 2.99–2.83 (m, 2 H, dithiane), 2.73–2.52 (m,
2 H, dithiane), 2.06 (s, 3 H, CH3-Ac), 2.02 (s, 3 H, CH3-Ac), 1.99
(s, 3 H, CH3-Ac), 1.97 (s, 3 H, CH3-Ac), 1.93–1.86 (m, 2 H,
dithiane).
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Y.-L. Chen et al.
PAPER
Wiley-VCH: Weinheim, 2003.
Acknowledgment
(2) See the preceding papers: (a) Chen, Y.-L.; Leguijt, R.;
Redlich, H. Synthesis 2006, submitted. (b) Chen, Y.-L.;
Leguijt, R.; Redlich, H. J. Carbohydr. Chem. 2006,
submitted.
The work was supported by the Deutsche Forschungsgemeinschaft
(R.L.) and NRW Graduate School of Chemistry (Y.-L.C.). Christi-
an Schulz took part in this project; his excellent work is appreciated.
(3) (a) Krohn, K.; Börner, G. J. Org. Chem. 1991, 56, 6038.
(b) Krohn, K.; Börner, G. J. Org. Chem. 1994, 59, 6063.
(c) Krohn, K.; Gringard, S.; Börner, G. J. Org. Chem. 1994,
59, 6069. (d) Krohn, K.; Gringard, S.; Börner, G.
Tetrahedron: Asymmetry 1994, 5, 2485.
References
(1) See for example: (a) Carbohydrate Mimics, Concepts and
Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998.
(b) Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Stütz, A. E., Ed.; Wiley-VCH: Weinheim, 1999.
(c) Carbohydrates in Chemistry and Biology; Ernst, B.;
Hart, G. W.; Sinaÿ, P., Eds.; Wiley-VCH: Weinheim, 2000.
(d) Carbohydrate-based Drug Discovery; Wong, C.-H., Ed.;
(4) Graham, J.; Ninan, A.; Reza, K.; Sainsbury, M.; Shertzer, H.
Tetrahedron 1992, 48, 167.
(5) Redlich, H.; Sudau, W.; Szardenings, A. K.; Vollerthun, R.
Carbohydr. Res. 1992, 226, 57.
Synthesis 2006, No. 13, 2242–2250 © Thieme Stuttgart · New York