A divergent synthesis of (+)-muscarine and (+)-epi-muscarine from D-glucose

Article abstract of DOI:10.1016/S0040-4020(00)00482-8

A novel stereospecific synthesis of (+)-muscarine and (+)-epi-muscarine has been achieved by utilizing D-glucose as a chiral precursor. The key steps of the synthesis involved stereospecific cyclization of 3,5-di-O-sulfonyl-D-glucofuranose derivatives into the corresponding 2,5-anhydrides, and stereospecific hydrogenation of 2,5-anhydro-L-threo-hex-2-enose ethylene acetal derivatives, thus providing an access to divergent intermediates for the preparation of both target molecules in a fully stereospecific manner. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00482-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5929±5940
A Divergent Synthesis of (1)-Muscarine and
(1)-epi-Muscarine from d-Glucose
*
Velimir Popsavin, Ostoja Beric, Mirjana Popsavin, Ljubica Radic, Janos Csanadi
Â
and Vera Cirin-Novta
 Â
Â
Â
Â
University of Novi Sad, Faculty of Sciences, Institute of Chemistry, Trg D. Obradovica 3, 21000 Novi Sad, Yugoslavia
Received 2 March 2000; revised 12 May 2000; accepted 1 June 2000
AbstractÐA novel stereospeci®c synthesis of (1)-muscarine and (1)-epi-muscarine has been achieved by utilizing d-glucose as a chiral
precursor. The key steps of the synthesis involved stereospeci®c cyclization of 3,5-di-O-sulfonyl-d-glucofuranose derivatives into the
corresponding 2,5-anhydrides, and stereospeci®c hydrogenation of 2,5-anhydro-l-threo-hex-2-enose ethylene acetal derivatives, thus
providing an access to divergent intermediates for the preparation of both target molecules in a fully stereospeci®c manner. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
In the course of our recent studies related to the preparation
of enantiomerically pure muscarine stereoisomers by
chirality transfer from d-glucose, the syntheses of (1)-
epiallo-muscarine12 (4) and (2)-allo-muscarine13 (3) were
already completed. Herein we report a divergent synthesis
of (1)-muscarine (1) and (1)-epi-muscarine (2) based on
d-glucose as a chiral precursor.14
(1)-Muscarine (1; Fig. 1) is a principal alkaloid of the
poisonous mushroom Amanita muscaria, which shows a
strong and speci®c cholinomimetic activity.1 Consequently,
its structure, chemistry and biological activity have been
extensively studied.2 There is a renewed interest in the
muscarinic ®eld due to the discovery of a relationship
between cholinergic de®cits and the pathology of
Alzheimer's disease.3 Hence, synthetic activity in this area
has been considerable, and numerous syntheses of mus-
carine4±9 and of many of its analogs10,11 have been accom-
plished from different precursors. Major drawbacks of most
of these approaches are either lack of selectivity or the usage
of relatively expensive reagents and/or starting compounds.
Apart from a recent synthesis of (2)-muscarine from
S-malic acid,9 none of the reported routes are suitable for
the preparation of 5-substituted muscarine analogs.
Results and Discussion
The key steps in the synthesis of both targets 1 and 2 are: (i)
the formation of the 2,5-anhydro-l-idose ethylene acetal
derivatives 8 and 9 (Scheme 1) by an intramolecular SN2
process which is expected to occur during an acid catalyzed
alcoholysis of the protected furanoses12,15 6 and 7; and (ii) a
stereoselective catalytic reduction of the conformationally
constrained dihydrofurans 12 and 15 which should be
Figure 1. (1)-Muscarine and its biologically active stereoisomers.
Keywords: 2,5-anhydro sugars; d-glucose; (1)-muscarine; (1)-epi-muscarine; stereospeci®c synthesis.
* Corresponding author. Fax: 138-121-54-065; e-mail: popsavin@ih.ns.ac.yu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00482-8

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V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
Scheme 1. (a) TrCl, Py, rt, 3 days, then MsCl, 148C, 24 h, 100%; (b) TrCl, Py, rt, 3 days, then TsCl, rt 10 days, 100%; (c) ethylene glycol, TsOH, 808C, 5 h,
53% of 8; 54% of 9; (d) Me2C(OMe)2, TsOH, rt, 24 h, 87% of 10, 77% of 11; (e) Bu4NF, MeCN, N2, re¯ux, 48 h, 76% of 12 from 10, 82% of 12 from 11, 67%
of 15 from 13, 86% of 15 from 14; (f) PhCH(OMe)2, TsOH, DMF, 708C, 20 h, 60% of 13, 86% of 14; (g) H2, PtO2, EtOH, rt, 24 h, 94% of 16, 91% of 17.
available from the completely protected 2,5-anhydro-l-
idose derivatives 10 and 11, as well as from 13 and 14.
76 and 82% yield, respectively. Condensation of 8 with
a,a0-dimethoxytoluene in DMF, in the presence of catalytic
amounts of toluene-4-sulfonic acid, gave the corresponding
4,6-O-benzylidene derivative 13 (60%), which was subse-
quently treated with tetrabutylammonium ¯uoride to yield
the ole®n 15 (40% from 8). However, successive treatment
of 9 with a,a0-dimethoxytoluene and tetrabutylammonium
¯uoride led to the formation of 15 with considerably better
overall yield (74% from 9). Catalytic hydrogenation of both
12 and 15 (PtO2, EtOH) took place stereospeci®cally, from
the less hindered b-face, allowing the isolation of the corre-
sponding 3-deoxy derivatives 16 (94%) and 17 (91%) as the
only stereoisomers. The stereochemistry of 17 was unam-
biguously con®rmed by NOE differential 1H NMR spectro-
scopy, and the characteristic NOE relations are shown in
Scheme 1. Upon irradiation of the multiplet at 4.48 ppm
(2H, H-4 and H-6b), a signi®cantly stronger NOE was
observed with H-3b (2.35 ppm) than with H-3a
(2.27 ppm). This result is consistent with a cis arrangement
of H-4 and H-3b as well as with a trans relationship of H-4
and H-3a. However, an irradiation of H-1 (5.12 ppm) gave a
strong NOE with H-3a thus proving a spatial vicinity of
these protons, and consequently an a-orientation of the
dioxolane acetal ring. Finally, the large vicinal coupling
between H-2 and H-3b (J2,3bˆ9.2 Hz) that is compatible
with cis relationship of these protons additionally con®rmed
the l-xylo con®guration of the molecule 17. Compared to
the target 2, both intermediates 16 and 17 have the correct
stereochemistry at all chiral centers. For the sake of better
For the cyclization studies both suitable protected 3,5-di-O-
mesyl (6) and 3,5-di-O-tosyl (7) d-glucofuranose deriva-
tives were ®rst prepared. Monoacetone glucose (5),16 was
tritylated and subsequently mesylated in a one-pot pro-
cedure to afford the corresponding 3,5-di-O-mesyl-6-O-
trityl derivative 6 in quantitative yield. Similarly, the
3,5-di-O-tosyl derivative 7 was prepared by successive
treatment of 5 with trityl chloride and tosyl chloride. Both
1
products 6 and 7 were isolated in pure form (TLC, H and
13C NMR) after the usual workup and used in the next step
without further puri®cation. Thus, treatment of crude 6 with
ethylene glycol in the presence of toluene-4-sulfonic acid as
a catalyst gave the 2,5-anhydro-l-idose derivative 8 (53%
from 5), while the 3,5-di-O-tosyl ester 7, under the same
reaction conditions, furnished the corresponding 3-O-tosyl
derivative 9 in 54% overall yield.
In the next steps studies were performed with both iso-
propylidene and benzylidene protection. Thus the reaction
of 8 with 2,20-dimethoxypropane under the toluene-4-
sulfonic acid catalysis afforded the expected 4,6-O-iso-
propylidene derivative 10 in 87% yield. The 3-O-tosyl
ester 9 under the same reaction conditions gave 77% yield
of 11. Both 3-sulfonates 10 and 11 readily reacted with
tetrabutylammonium ¯uoride, in boiling acetonitrile, to
afford the corresponding 2,3-unsaturated derivative 12 in

V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
5931
Scheme 2. (a) NBS, BaCO3, CCl4, N2, re¯ux, 1.5 h, 63% of 18, 66% of 19.
functional resemblance to the target, they must be further
subjected to a C-6 deoxygenation process. This would lead
to the 6-deoxy derivative 22 (Scheme 2), a potential
divergent intermediate for the synthesis of both targets 1
and 2. At ®rst it has been planned to deoxygenate the C-6
via the 6-bromodeoxy derivative 17a. It was further
assumed that the compound 17 could be converted to 17a
by using the well known Hanessian±Hullar reaction, which
was successfully used for the conversion of numbered
4,6-O-benzylidene sugar acetals into the corresponding
4-O-benzoyl-6-bromo-6-deoxy derivatives.17 However,
when the recommended reaction conditions were applied
to the 3-deoxy-l-xylo-hexose 17 (NBS, BaCO3, CCl4"#),17
the 4-bromodeoxy derivative 18 was unexpectedly formed
in 63% yield; no traces of the expected 6-bromodeoxy
derivative 17a was observed. Conversely, l-ido derivative
13a,18 under the same reaction conditions, gave the
expected 6-bromodeoxy derivative 19 as the only reaction
product in 66% yield. The same reaction course was
observed upon treatment of 3-O-mesyl derivative 13 with
NBS in boiling tetrachloromethane.18
The difference in product distribution between the l-xylo
and l-ido series may be due to different steric and presum-
ably electronic effects. According to a proposed mecha-
nism19 of the process, the initial attack of a free radical at
the benzylic hydrogen atom in both molecules 17 and 13a
would occur ®rst. The resulting bromoacetals (17b and 13b)
could further collapse to the cyclic benzoxonium ions (18a
and 19a) and bromide anion. The reaction would then
assume ionic character and the more-susceptible carbon
atom would be attacked preferentially by bromide ion to
give the corresponding O-benzoylated bromohydrin. It
seems that the preferential nucleophilic attack at C-4 in
the intermediate 18a (leading to the formation of 18) is
due to the overcrowding of the primary center by the syn-
oriented dioxolane acetal function. On the contrary, the
C-4 in 19a is presumably more crowded by the b-oriented
Figure 2. Stereochemical relationships in the optimized structures 18a and 19a. The numbers in parentheses denote values of formal charge at C-4 and C-6,
respectively.

5932
V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
Scheme 3. (a) TFA, MeOH, rt, 0.5 h, 79%; (b) AcOH, H2O, re¯ux, 7 h, 81%; (c) H2, 10% Pd/C, EtOH, AcOH, rt, 16 h, 83%; (d) TsCl, Py, 2288C, 6 days,
80%; (e) LiAlH4 THF, N2, re¯ux, 4 h 90%; (f) TsCl, Py, rt, 48 h, 80%; (g) KOBz, DMF, 1008C, 24 h, 66%; (h) DEAD, PhCO2H, Ph3P, THF, 08±rt, 20 h; (i)
TFA, 6 M HCl, 148C, 24 h; (j) NaBH4, MeOH, rt, 2 h, 60% from 24, 27% from 22; (k) imidazole, Ph3P, I2, toluene, N2, re¯ux, 3 h, 84%; (l) K2CO3, MeOH,
THF, rt, 1.5 h, 83%; (m) Me3N, EtOH, 808C, 3 h, 93%.
dioxolane functionality, thus directing the nucleophilic
attack towards the less-hindered C-6, whereupon the
observed product 19 was formed. These assumptions were
veri®ed by molecular modeling studies.20
into the molecules 16 and 17 has been developed. Selective
removal of the 4,6-O-isopropylidene protective group in 16,
achieved with 10% tri¯uoroacetic acid in methanol, gave
the corresponding diol 20 in 79% yield, while the action of
diluted acetic acid onto 17 afforded 81% yield of 20
(Scheme 3). Finally, the intermediate 20 was more con-
veniently prepared directly from 15 in 83% yield, by a
one-pot procedure which included a catalytic hydrogenation
of the double bond, and a hydrogenolytic removal of the
benzylidene protection over 10% Pd/C. Monotosylation of
the diol 20 at 2288C produced 6-O-tosyl derivative 21
(80%) which was subsequently treated with lithium alu-
minum hydride in boiling tetrahydrofuran, to give the key
chiral intermediate 22 in 90% yield.
Preliminary molecular mechanics calculations (MM1)
gave the low energy conformations of 18a and 19a with
the tetrahydrofuran rings having the 4T3 and the 4T3
geometry, respectively (Fig. 2). These ®ndings certainly
do not exclude the existence of the other conformations,
but apparently suggest that both intermediates 18a and
19a may occupy conformations suitable to explain the
experimental results. Indeed, a careful examination of the
optimized structure 18a clearly indicated that the dioxolane
acetal function does prevent approach of the nucleophile to
C-6. On the contrary, the spatial arrangement of both C-2
and C-3 substituents in 19a obviously causes serious
overcrowding of the C-4. Moreover, semiempirical PM3
calculations performed on 18a gave signi®cantly different
values for the formal charge at C-4 (0.050) and C-6
(20.039), thus indicating a higher electrophilicity of C-4
in the intermediate 18a. Conversely, concerning the calcu-
lated formal charges in 19a, the C-6 (0.052) was shown to
be somewhat more electrophilic than the C-4 (0.020). These
®ndings appear to convincingly explain the experimental
results.
The seven-step synthetic sequence, which uses the tosyloxy
leaving group as well as the benzylidene protection,
obviously represents the most convenient route towards
the divergent intermediate 22, since it provided the highest
overall yield of the desired product (24% from 5). Reaction
of 22 with tosyl chloride in pyridine gave the corresponding
4-O-tosyl derivative 23 in 80% yield. Compound 23 readily
reacted with potassium benzoate, to give the chiral synthon
24 (66%) with an absolute con®guration of all stereocenters
corresponding to (1)-muscarine (1). Compound 24 was
alternatively prepared directly from 22 by using the standard
Mitsunobu conditions.21 However, thus obtained sample 24
was slightly contaminated with unidenti®ed aromatic
impurities that remained in the sample even after repeated
Due to the undesirable outcome of the last reaction, an
alternative procedure for introduction of 6-deoxy functions

V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
5933
Scheme 4. (a) BzCl, Py, rt, 24 h, 86%; (b) TFA, 6 M HCl, 148C, 24 h; (c) NaBH4, MeOH, rt, 2 h, 59% from 29; (d) imidazole, Ph3P, I2, toluene, N2, re¯ux, 3 h,
90%; (e) K2CO3, MeOH, THF, rt, 1.5 h, 65%; (f) Me3N, EtOH, 808C, 3 h, 95%.
chromatographic puri®cation. Fortunately, these impurities
did not affect the course of the following reaction directed to
the hydrolytic removal of the dioxolane protective group.
Thus, treatment of 24 with a 4:1 mixture of tri¯uoroacetic
and 6 M hydrochloric acid gave the unstable aldehyde 25,
which was immediately reduced with sodium borohydride
to afford the primary alcohol 26. It appeared that the four-
step sequence realized via the 4-O-tosyl derivative 23 repre-
sents a slightly more convenient procedure for the prepa-
ration of 26, since it provided a somewhat higher overall
yield (32% from 22) compared to the three-step sequence
based on Mitsunobu reaction (27% from 22). Reaction of 26
with iodine, imidazole and triphenylphosphine, according to
the methodology developed by Garegg and Samuelsson,22
gave the known7 iodo derivative 27 in 84% yield. O-Deben-
zoylation of 27 with potassium carbonate in methanol
afforded 83% yield of the corresponding iodo alcohol 28.
Finally, compound 28 was converted to (1)-muscarine
iodide (1) by treatment with trimethylamine in ethanol.
Conversion of the intermediate 22 into the (1)-epi-mus-
carine iodide (2) is outlined in Scheme 4.
The sequence started with O-benzoylation of 22 whereupon
the corresponding 4-O-benzoyl derivative 29 was obtained
in 86% yield. Hydrolytic removal of the dioxolane protec-
tive group in 29, followed by subsequent sodium boro-
hydride reduction of the unstable aldehyde 30 gave the
corresponding primary alcohol 31 in 59% yield (51%
from 22). Alternatively, when the last three-step process
was carried out without chromatographic puri®cation of
the 4-O-benzoyl derivative 29, the desired product 31 was
obtained in an overall yield of 53% with respect to
compound 22. The intermediate 31 was ®nally converted
to the (1)-epi-muscarine iodide (2) by using the same
three-step sequence which was already applied for the
conversion of 26 into the (1)-muscarine iodide (1; Scheme
3). The 1H and 13C NMR spectral data (Table 1) as well as
physical constants of both 1 and 2 thus obtained were in
reasonable agreement with those already reported.7,8
In conclusion, this paper describes a divergent 11-step
synthesis of (1)-muscarine (1) and (1)-epi-muscarine (2)
from commercially available monoacetone glucose (5) in 5
1
Table 1. H and 13C NMR spectral data for 1 and 2 (in D2O)
Comp.
Chemical shift (d) and J (Hz)
Reference
H-1a
H-1b
H-2
H-3a
H-3b
H-4
H-5
H-6
1
2
3.48
3.39
3.62
3.49
4.66
4.57
2.01
1.91
2.12
2.01
4.13
4.03
4.06
3.96
1.21
1.11
This work
7
3.56
3.42
3.60
3.46
4.46
4.37
1.60
1.51
2.61
2.51
4.24
4.14
3.95
3.85
1.22
1.13
This work
7
J1a,lb
J1a,2
J1b,2
J2,3a
J2,3b
J3a,3b
J3a,4
J3b,4
J4,5
1
2
14.0
14.0
9.1
9.2
1.8
1.8
9.5
9.6
6.4
6.3
13.7
13.7
5.9
5.7
2.4
2.3
2.5
2.5
This work
7
13.9
13.9
3.1
3.3
9.7
8.2
5.9
5.7
8.7
8.7
14.3
14.3
1.9
1.9
6.0
6.0
3.5
3.5
This work
7
C-1
C-2
C-3
C-4
C-5
C-6
NMe3
1
2
73.21
73.51
72.96
73.00
74.66
74.85
73.99
73.95
40.23
40.53
41.97
41.96
77.87
78.13
74.16
74.16
86.77
86.91
83.45
83.43
21.89
22.11
16.18
16.15
56.70
57.09
56.84
56.82
This work
7
This work
7

5934
V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
and 7% overall yield, respectively. Although this new
synthesis of 1 consists of more synthetic steps and has a
lower overall yield than the earlier preparation from
l-rhamnose (10% from seven steps),5 it uses a less expen-
sive and readily available starting material.23 Compared
with the previous carbohydrate based approaches4 (each
containing at least one non-speci®c synthetic step), the
new synthesis of both targets 1 and 2 from d-glucose was
realized in a fully regio- and stereospeci®c manner.
Moreover, appropriate C-6 modi®cations of the 2,5-anhydro
derivatives of type 20 or 21, may provide access to potential
divergent intermediates for the preparation of a variety of
5-substituted (1)-muscarine analogs.
was left at 148 overnight, then ®ltered through a Celite pad,
and the precipitate washed with ethylene glycol. Combined
®ltrate and washings were poured into saturated NaCl
solution (44 mL), neutralized with NaHCO3, and extracted
with EtOAc (6£20 mL). The extracts were combined, dried
and evaporated to pale yellow oil. Flash column chroma-
tography (EtOAc) of the residue afforded pure 8 (0.931 g,
53% from 5) as a colorless syrup: [a]Dˆ129.6 (c, 0.19 in
CHCl3); Rf 0.24 (19:1 CH2Cl2±MeOH), Rf 0.27 (EtOAc);
nmax (®lm): 3430 (broad), 2940, 2880, 1370, 1200, 1100,
930 cm21; 1H NMR (CDCl3): d 2.72 (bs, 1H, exchangeable
with D2O, OH-6), 3.11 (s, 3H, MeSO2), 3.84±4.15 (m, 6H,
2£H-6 and CH2-dioxolane), 4.24 (dd, 1H, J1,2ˆ6.3 Hz,
J2,3ˆ3.9 Hz, H-2), 4.28 (m, 1H, J4,5ˆ4.0 Hz, H-5), 4.38
(d, 1H, exchangeable with D2O, J4,OHˆ4.1 Hz, OH-4),
4.64 (m, 1H, J3,4ˆ2.0 Hz, H-4), 5.01 (dd, 1H, H-3), 5.11
(d, 1H, H-1); 13C NMR (CDCl3): d 38.10 (MeSO2), 61.53
(C-6), 65.24 and 65.46 (2£CH2-dioxolane), 77.51 (C-4),
79.46 (C-2), 79.52 (C-5), 85.43 (C-3), 101.91 (C-1); CI-
MS: m/z 569 (2M111), 285 (M111). HR-MS: Calcd for
C9H16O8S: 284.0566. Found: m/z 284.0571.
Experimental
General methods
Melting points were determined on a BuÈchi 510 apparatus
and were not corrected. Optical rotations were measured on
a Perkin±Elmer 141 MC polarimeter. IR spectra were
recorded with a Specord 75IR spectrophotometer. NMR
spectra were recorded on a Bruker AC 250 E instrument
and chemical shifts are expressed in ppm down®eld from
tetramethylsilane. Mass spectra were recorded on Finnigan-
MAT 8230 and VG AutoSpec mass spectrometers. TLC was
performed on DC Alufolien Kieselgel 60 F254 (E. Merck).
Column chromatography was carried out using Kieselgel 60
(under 0.063 mm; E. Merck). Flash column chroma-
tography was performed using ICN silica 32±63. All
organic extracts were dried with anhydrous Na2SO4.
Organic solutions were concentrated in a rotary evaporator
under diminished pressure at a bath temperature below
358C.
2,5-Anhydro-3-O-p-toluenesulfonyl-l-idose
ethylene
acetal (9). Compound 5 (7.5 g, 34.06 mmol) was dissolved
in anhydrous pyridine (75 mL), and trityl chloride (15.0 g,
53.8 mmol) was added. After 3 days at room temperature, to
the solution was added tosyl chloride (20.25 g,
106.22 mmol) and the mixture was left at room temperature
for 10 days. The mixture was poured into a stirred and
cooled (08C) solution of 6 M HCl (300 mL), whereupon a
white precipitate was formed. The precipitate was collected
by ®ltration, washed with cold water and dried at 358C for
48 h. Chromatographically homogenous 7 (26.2 g, 100%)
was thus obtained as a white amorphous solid: mp 128±
1298C (decomp.); Rf 0.86 (2:1 EtOAc±light petroleum), Rf
1
0.65 (7:1 toluene±Me2CO): H NMR (CDCl3): d 1.27 and
1.42 (2£s, 3H, each, CMe2), 2.43 and 2.48 (2£s, 3H, each
2£MeC6H4SO2), 3.22 (dd, 1H, J6a,6bˆ11.0 Hz, J5,6aˆ2.8 Hz,
H-6a), 3.33 (dd, 1H, J5,6bˆ5.5 Hz, H-6b), 4.55 (dd, 1H,
J3,4ˆ2.8 Hz, J4,5ˆ5.2 Hz, H-4), 4.75 (ddd, 1H, H-5), 4.79
(d, 1H, J1,2ˆ3.4 Hz, H-2), 4.93 (d, 1H, H-3), 5.71 (d, 1H,
H-1), 7.41±7.86 (m, 23H, CPh3 and 2£MeC6H4SO2); 13C
NMR (CDCl3): d 21.75 and 21.82 (2£MeC6H4SO2), 26.33
and 26.55 (CMe2), 62.26 (C-6), 77.11 (C-5), 77.89 (C-4),
81.22 (C-3), 82.38 (C-2), 86.75 (CPh3), 104.39 (C-1), 112.7
(CMe2), 127.06±145.5 (CPh3 and 2£MeC6H4SO2). A
mixture of crude 7 (26.0 g) and toluene-4-sulfonic acid
(1.5 g, 7.89 mmol) in ethylene glycol (150 mL) was stirred
at 808C for 2 h. After the usual workup (see preparation of
8), crude 9 remained as a crystalline solid. Recrystallization
of the residue from toluene gave pure 9 (5.95 g) as white
needles, mp 144±1468C. An additional amount of pure 9
(0.7 g) was obtained after puri®cation of the mother liquor
by ¯ash column chromatography (2:1 EtOAc±light petro-
leum). Total yield of 9 was 6.65 g (54% from 5). Recrys-
tallization from toluene afforded an analytical sample 9: mp
1468C; [a]Dˆ120.7 (c, 0.68 in CHCl3); Rf 0.17 (2:1
EtOAc±light petroleum), Rf 0.13 (3:1 toluene±Me2CO);
nmax (KBr): 3450±3260 (broad), 2970, 2920, 1610, 1360,
2,5-Anhydro-3-O-methanesulfonyl-l-idose ethylene acetal
(8). To a solution of 5 (5.0 g, 27.22 mmol) in dry pyridine
(50 mL) was added trietyl chloride (10.12 g, 36.32 mmol)
and the mixture was kept at room temperature for 3 days.
After cooling to 08C, mesyl chloride (4.5 mL, 57.75 mmol)
was added dropwise to the stirred and cooled solution. The
mixture was left at 148C for 24 h, then poured onto ice
(80 g) and acidi®ed with 6 M HCl (120 mL). The separated
precipitate was dissolved in CH2Cl2 (200 mL) and the
solution was washed successively with cold 10% HCl
(200 mL) and water (3£100 mL). Organic layer was dried
and evaporated to give chromatographically homogenous 6
(14.04 g, ,100%) as a white amorphous powder: mp 170±
1718C (decomp.); Rf 0.35 (CH2Cl2), Rf 0.46 (9;1 toluene±
EtOAc); 1H NMR (CDCl3): d 1.34 and 1.51 (2£s, 3H each,
CMe2), 2.90 and 3.19 (2£s, 3H each, 2£MeSO2), 3.47 (dd,
1H, J6a,6bˆ11.3 Hz, J5,6aˆ4.7 Hz, H-6a), 3.65 (dd, 1H,
J5,6bˆ2.1 Hz, H-6b), 3.70 (dd, 1H, J3,4ˆ2.7 Hz, J4,5ˆ
9.4 Hz, H-4), 5.02 (d, 1H, H-3), 5.97 (d, 1H, H-1), 7.21±
7.51 (m, 15H, CPh3). 13C NMR (CDCl3): d 26.16 and 26.43
(CMe2), 38.62 and 39.26 (2£MeSO2), 62.36 (C-6), 75.82
(C-4), 76.35 (C-5), 80.26 (C-3), 82.80 (C-2), 87.66
(CPh3), 104.75 (C-1), 112.74 (CMe2), 127.23, 127.90,
128.59 and 143.02 (CPh3). To a suspension of crude 6
(3.79 g, 6.12 mmol) in ethylene glycol (22 mL) was added
toluene-4-sulfonic acid (0.379 g, 1.99 mmol) and the
mixture was stirred at 808C for 5 h. The reaction mixture
1
1190, 1100, 1060, 920 cm21; H NMR (CDCl3): d 2.46 (s,
3H, MeC5H4SO2), 2.73 (t, 1H, exchangeable with D2O,
J6,OHˆ4.0 Hz, OH-6), 3.82±3.97 (m, 5H, 2£CH2-dioxlane
and H-6a), 4.03 (dd, 1H, J6a,6bˆ12.7 Hz, J5,6bˆ3.8 Hz,

V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
5935
H-6b), 4.14 (dd, 1H, J1,2ˆ6.1 Hz, J2,3ˆ4.2 Hz, H-2), 4.22
(m, 1H, J4,5ˆ4.2 Hz, J5,6aˆ2.7 Hz, H-5), 4.30 (d, 1H,
exchangeable with D2O, J4,OHˆ4.3 Hz, OH-4), 4.55 (dd,
1H, J3,4ˆ2.0 Hz, H-4), 4.91 (dd, 1H, H-3), 4.95 (d, 1H,
H-1), 7.31±7.87 (m, 4H, MeC6H4SO2). 13C NMR
(CDCl3): d 21.76 (MeC6H4SO2), 61.66 (C-6), 65.21 and
65.35 (2£CH2-dioxolane), 77.09 (C-4), 79.44 (C-2), 79.52
(C-5), 84.98 (C-3), 101.62 (C-1), 128.23, 129.81, 130.01
and 145.24 (MeC6H4SO2); EI-MS: m/z 359 (M121).
Anal. Calcd for C15H20O8S: C 49.99, H 5.59, S 8.90.
Found: C 50.06, H 5.74, S 8.77.
C18H24O8S: C 53.99, H 6.04, S 8.01. Found: C 54.34, H
6.30, S 8.36.
2,5-Anhydro-3-deoxy-4,6-O-isopropylidene-l-threo-hex-
2-enose (12). (Procedure A) To a solution of 10 (0.418 g,
1.29 mmol) in dry acetonitrile (5 mL) was added Bu4NF
(1.69 g, 6.45 mmol) and the mixture was re¯uxed in an
atmosphere of N2 for 48 h. The mixture was evaporated
and the residue (1.626 g) puri®ed by ¯ash chromatography
(19:1 toluene±Me2CO), to afford pure 12 (0.224 g, 76%) as
colorless syrup.
2,5-Anhydro-4,6-O-isopropylindene-3-O-methanesulfonyl-
l-idose ethylene acetal (10). A mixture of 8 (0.42 g,
1.51 mmol), toluene-4-sulfonic acid (0.0056 g, 0.03 mmol)
and 2,20-dimethoxypropane (7 mL) was stirred at room
temperature for 24 h. The solution was poured into 10%
NaCl solution (14 mL), neutralized with NaHCO3 (0.01 g)
and extracted with CH2Cl2 (3£10 mL). The extracts were
combined, dried and evaporated. Flash chromatography (9:1
CH2Cl2±EtOAc) of the residue (0.52 g) yielded pure 10
(0.426 g, 87%) as a colorless syrup: [a]Dˆ172.4 (c, 0.64
in CHCl3); Rf 0.28 (9:1 CH2Cl2±EtOAc), Rf 0.36 (1:1
EtOAc±light petroleum); nmax (KBr): 3000, 2930, 1360,
Procedure B: a mixture of 11 (0.82 g, 2.05 mmol), Bu4NF
(2.85 g, 10.9 mmol) in acetonitrile (15 mL) was re¯uxed in
an atmosphere of N2 for 48 h. The workup followed by
chromatographic puri®cation according to procedure A,
gave pure 12 (0.358 g, 82%) as a colorless syrup:
[a]Dˆ186.3 (c, 1.1 in CHCl3); Rf 0.25 (19:1 toluene±
Me2CO), Rf 0.6 (2:1 toluene±Me2CO); nmax (®lm): 3100,
3010, 2950, 2900, 1690, 1380, 1210, 1120, 1040, 970 cm21
;
1H NMR (CDCl3): d 1.37 and 1.38 (2£s, 3H each, CMe2),
3.87 (dd, 1H, J6a,6bˆ11.9 Hz, J5,6aˆ6.8 Hz, H-6a), 3.90±
4.09 (m, 5H, 2£CH2-dioxolane and H-6b), 4.50 (m, 1H,
J4,5ˆ6.6 Hz, H-5), 4.94 (dd, 1H, J3,4ˆ2.8 Hz, H-4), 5.24
(d, 1H, H-3), 5.52 (s, 1H, H-1); 13C NMR (CDCl3): d
22.96 and 26.51 (CMe2), 58.97 (C-6), 65.29 and 65.33
(2£CH2-dioxolane), 72.66 (C-4), 78.81 (C-5), 97.56 (C-1),
98.85 (CMe2), 99.47 (C-3), 160.87 (C-2). HR-MS: Calcd for
C11H16O5: 228.0998. Found: m/z 228.0992.
1
1190, 1100, 930 cm21; H NMR (CDCl3): d 1.33 and 1.41
(2£s, 3H each, CMe2), 3.09 (s, 3H, MeSO2), 3.80±4.11 (m,
6H, 2£CH2-dioxolane and 2£H-6), 4.15 (m, 1H, J5,6ˆ
2.3 Hz, J4,5ˆ2.5 Hz, H-5), 4.28 (dd, 1H, J2,3ˆ3.6 Hz,
J1,2ˆ7.2 Hz, H-2), 4.50 (dd, 1H, J3,4ˆ1.1 Hz, H-4), 4.88
(dd, 1H, H-3), 5.10 (d, 1H, H-1); 13C NMR (CDCl3) d
19.20 and 28.42 (CMe2), 37.94 (MeSO2), 60.36 (C-6),
64.99 and 65.26 (2£CH2-dioxolane), 72.66 (C-5), 74.08
(C-4), 80.19 (C-2), 84.55 (C-3), 97.53 (CMe2), 101.85
(C-1). Attempted crystallization from MeOH gave small
amount of the crystalline sample 10, mp 112±1148C
(decomp.), along with variety decomposition products that
remained in the mother liquor. Due to instability of the
product 10, a correct microanalysis of HR-MS could not
be obtained.
2,5-Anhydro-4,6-O-benzylidene-3-O-methanesulfonyl-l-
idose (13). To a solution of 8 (0.55 g, 1.93 mmol) in dry
DMF (5.5 mL) was added toluene-4-sulfonic acid (0.06 g,
0.32 mmol)
and
a,a0-dimethoxytoluene
(1.2 mL,
7.99 mmol). The mixture was stirred at 708C for 20 h,
then neutralized with NaHCO3 (0.2 g), evaporated and the
residue was extracted with CH2Cl2 (2£10 mL). The extracts
were combined, dried and evaporated to yellow oil (0.5 g).
Flash column chromatography (1:1 EtOAc±light petro-
leum) gave pure 13 (0.43 g, 60%) as a colorless syrup:
[a]Dˆ147.4 (c, 0.23 in CHCl3); Rf 0.76 (EtOAc). nmax
(®lm): 3040, 3000, 2960, 2910, 1620, 1400, 1370, 1200,
2,5-Anhydro-4,6-O-isopropylidene-3-O-p-toluenesulfonyl-
l-idose ethylene acetal (11). Diol 9 (1.0 g, 2.78 mmol),
toluene-4-sulfonic acid (0.01 g, 0.05 mmol) and 2,20-
dimethoxypropane (10 mL) were stirred at room tempera-
ture for 24 h. The usual workup gave crude 11, which was
puri®ed by ¯ash chromatography (2:1 light petroleum±
EtOAc), to give colorless needles of pure 11 (0.86 g,
77%). Recrystallization from MeOH yielded an analytical
sample 11: mp 142±1448C; [a]Dˆ179.1 (c, 0.23 in
CHCl3); Rf 0.68 (2:1 EtOAc±light petroleum); nmax
(KBr): 3080, 3020, 2980, 2920, 2900, 1600, 1390, 1200,
1
1160, 1100, 1020, 980, 920 cm21; H NMR (CDCl3): d
3.13 (s, 3H, MeSO2), 3.82±4.05 (m, 4H, 2£CH2-dioxolane),
4.1 (dd, 1H, J6a,6bˆ13.1 Hz, J5,6aˆ1.8 Hz, H-6a), 4.24 (m,
1H, J4,5ˆ2.4 Hz, H-5), 4.38 (dd, 1H, J1,2ˆ7.1 Hz, J2,3ˆ
3.7 Hz, H-2), 4.50 (d, 1H, H-6b), 4.74 (dd, 1H, J3,4ˆ
1.0 Hz, H-4), 5.08 (d, 1H, H-3), 5.17 (d, 1H, H-1), 5.48 (s,
1H, PhCH), 7.31±7.52 (m, 5H, Ph); 13C NMR (CDCl3): d
37.98 (MeSO2), 65.06 and 65.34 (2£CH2-dioxolane), 67.29
(C-6), 73.15 (C-5), 79.26 (C-4), 80.79 (C-2), 83.72 (C-3),
99.05 (PhCH), 101.88 (C-1), 126.11, 128.24, 129.2 and
137.24 (Ph). CI-MS: m/z 373 (M111). HR-MS: Calcd for
C11H20O8S: 372.0879. Found: m/z 372.0888.
1
1100, 930 cm21; H NMR (CDCl3): d 1.29 and 1.35 (2£s,
3H each, CMe2), 2.42 (s, 3H, MeC6H4SO2), 3.53±4.92 (m,
4H, CH2-dioxolane), 3.96 (m, 2H, J5,6aˆ2.8 Hz, J5,6b
ˆ
2.1 Hz, 2£H-6), 4.06 (m, 1H, J4,5ˆ2.8 Hz, H-5), 4.10 (dd,
1H, J2,3ˆ3.7 Hz, J1,2ˆ7.0 Hz, H-2), 4.44 (m, 1H,
J3,4ˆ1.1 Hz, J2,4ˆ1.8 Hz, H-4), 4.81±4.91 (m, 2H, H-1
and H-3), 7.31±7.75 (m, 1H, MeC6H4SO2); 13C NMR
(CDCl3): d 19.45 and 28.42 (CMe2), 21.71 (MeC6H4SO2),
60.52 (C-6), 65.03 and 65.16 (2£CH2-dioxolane), 72.88
(C-5), 73.67 (C-4), 80.52 (C-2), 84.05 (C-3), 97.68
(CMe2), 101.51 (C-1), 128.34, 129.66, 132.90 and 145.18
(MeC6H4SO2); EI-MS: m/z 385 (M12Me). Anal. Calcd for
2,5-Anhydro-4,6-O-benzylidene-3-O-p-toluenesulfonyl-
l-idose ethylene acetal (14). A mixture of 9 (5.5 g,
15.26 mmol), a,a0-dimethoxytoluene (9.7 mL, 64.62
mmol) and toluene-4-sulfonic acid (0.15 g, 0.79 mmol) in
dry DMF (40 mL) was stirred at 708C for 24 h. After neutra-
lization with NaHCO3 (0.8 g) the solvent was evaporated
and the remaining crude residue was extracted with CH2Cl2
(2£20 mL). The combined extracts were dried and

5936
V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
evaporated to pale yellow syrup. Direct crystallization from
MeOH yielded pure 14 (5.4 g) as colorless needles, mp
139±1408C. Flash chromatography (49:1, toluene±
Me2CO) of the mother liquor afforded an additional amount
of pure 14 (0.50 g). Total yield 5.9 g (86%). An analytical
sample 14 was obtained by recrystallization from MeOH:
mp 139±1408C; [a]Dˆ164.5 (c, 0.34 in CHCl3); Rf 0.73
(2:1 EtOAc±light petroleum); Rf 0.50 (4:1 toluene±
Me2CO). nmax (KBr): 3080, 3020, 2900, 1600, 1370,
toluene±Me2CO). Pure 16 (0.827 g, 94%) was obtained as a
colorless syrup: [a]Dˆ119.7 (c, 1.16 in CHCl3); Rf 0.4 (2:1
toluene±Me2CO). nmax (®lm): 3000, 2970, 2920, 1390,
1
1290, 1120, 970 cm21; H NMR (CDCl3): d 1.36 and 1.40
(2£s, 3H, each, CMe2), 2.07 (dd, 1H, J2,3aˆ3.6 Hz, J3a,3b
ˆ
14.3 Hz, H-3a), 2.28 (ddd, 1H, J2,3bˆ9.2 Hz, J3b,4ˆ5.3 Hz,
H-3b), 3.72 (m, 1H, J5,6ˆ3.0 Hz, J4,5ˆ2.8 Hz, H-5), 3.81±
4.08 (m, 6H, 2£CH2-dioxolane and 2£H-6), 4.35 (m, 1H,
H-4), 5.03 (d, 1H, J1,2ˆ7.1 Hz, H-1); 13C NMR (CDCl3): d
19.56 and 28.38 (CMe2), 35.38 (C-3), 60.65 (C-6), 65.09
and 65.14 (2£CH2-dioxolane), 70.01 (C-4), 75.22 (C-5),
79.16 (C-2), 97.61 (CMe2), 104.86 (C-1). CI-MS: m/z 231
(M111). HR-MS: Calcd for C11H18O5: 230.1154. Found: m/
z 230.1161.
1
1190, 1100, 920 cm21; H NMR (CDCl3): d 2.45 (s, 3H,
MeC6H4SO2), 3.58±3.97 (m, 4H, 2£CH2-dioxolane), 4.07
(dd, 1H, J6a,6bˆ12.8 Hz, J5,6aˆ1.8 Hz, H-6a), 4.20 (m, 1H,
J4,5ˆ2.2 Hz, H-5), 4.27 (dd, 1H, J1,2ˆ7.3 Hz, J2,3ˆ3.4 Hz,
H-2), 4.47 (d, 1H, H-6b), 4.74 (m, 1H, H-4), 4.95 (m, 2H,
H-1 and H-3), 5.45 (s, 1H, PhCH), 7.3±7.8 (m, 9H, Ph and
MeC6H4SO2); 13C NMR (CDCl3): d 21.75 (MeC6H4SO2),
65.05 and 65.17 (2£CH2-dioxolane), 67.45 (C-6), 73.18
(C-5), 78.98 (C-4), 81.10 (C-2), 83.17 (C-3), 99.23
(PhCH), 101.52 (C-1), 126.25±145.97 (Ph and
MeC6H4SO2). EI-MS: m/z 447 (M121); CI-MS: m/z 449
(M111). Anal. Calcd for C22H24O8S: C 58.92, H 5.39, S
7.15. Found: C 59.13, H 5.17, S 7.36.
2,5-Anhydro-4,6-O-benzylidene-3-deoxy-l-xylo-hexose
ethylene acetal (17). Compound 15 (1.3 g, 4.7 mmol) in
EtOH (15 mL) was hydrogenated over PtO2 (0.13 g,
0.57 mmol) for 24 h. After workup as described above
(preparation of 16), crude 17 was obtained which was
puri®ed on a column of silica gel (100 g, 5:1 toluene±
Me2CO). Pure 17 (1.19 g, 91%) was isolated in the form
of a colorless syrup: [a]Dˆ114.2 (c, 1.42 in CHCl3); Rf
0.55 (2:1 toluene±Me2CO). nmax (®lm): 3090, 3010, 2950,
2,5-Anhydro-4,6-O-benzylidene-3-deoxy-l-threo-hex-2-
enose ethylene acetal (15). (Procedure A) A mixture of 13
(0.104 g, 0.28 mmol) and Bu4NF (0.235 g, 0.9 mmol) in dry
MeCN (2 mL) was re¯uxed in an atmosphere of N2 for 48 h.
The reaction mixture was diluted with CH2Cl2 (15 mL) and
washed with water (3£10 mL). Organic solution was dried
and evaporated to brown syrup (0.08 g). Chromatographic
puri®cation on a column of ¯ash silica (7:3 light petroleum±
Me2CO) afforded pure 15 (0.052 g, 67%) as a white crystal-
line solid.
2930, 2900, 1620, 1410, 1220, 1130, 1110, 1000, 960 cm21
;
1H NMR (CDCl3): d 2.27 (m, 1H, J3a,3bˆ14.6 Hz, J2,3a
ˆ
3.7 Hz, H-3a), 2.35 (ddd, 1H, J2,3bˆ9.2 Hz, J3b,4ˆ4.9 Hz,
H-3b), 3.76 (m, 1H, J5,6aˆ2.1 Hz, J5a,6bˆ1.0 Hz, H-5),
3.82±4.08 (m, 5H, 2£CH2-dioxolane, and H-2), 4.13 (dd,
1H, J6a,6bˆ13.1 Hz, H-6a), 4.48 (m, 2H, H-4 and H-6b), 5.12
(d, 1H, J1,2ˆ7.0 Hz, H-1), 5.45 (PhCH), 7.25±7.45 (m, 5H,
Ph); 13C NMR (CDCl3): d 35.46 (C-3), 65.22 and 65.29
(2£CH2-dioxolane), 67.17 (C-6), 75.36 (C-5), 76.44 (C-4),
79.57 (C-2), 99.81 (PhCH), 104.97 (C-1), 126.34, 128.31,
129.01 and 138.24 (Ph). CI-MS: m/z 279 (M111). HR-MS:
Calcd for C15H18O5: 278.1154. Found: m/z 278.1149.
Procedure B: to a solution of 3-O-tosyl derivative 14
(1.67 g, 3.72 mmol) in dry acetonitrile (20 mL) was added
Bu4NF (4.0 g, 15.29 mmol) and the mixture was re¯uxed in
an atmosphere of N2 for 24 h. The solvent was evaporated
off; the residue was puri®ed by ¯ash chromatography (49:1
toluene±Me2CO) to yield pure 15 (0.888 g, 86%) as color-
less needless. Recrystallization from MeOH gave an ana-
lytical sample 15: mp 918C; [a]Dˆ1130.2 (c, 0.42 in
CHCl3); Rf 0.68 (2:1 toluene±Me2CO). nmax (KBr): 3080,
3010, 2920, 1670, 1600, 1470, 1400, 1330, 1250, 1210,
2,5-Anhydro-6-O-benzoyl-4-bromo-3,4-dideoxy-l-ribo-
hexose ethylene acetal (18). A mixture of 17 (0.097 g,
0.35 mmol), NBS (0.073 g, 0.41 mmol) and BaCO3
(0.073 g, 0.41 mmol) in dry CCl4 (5 mL) was re¯uxed in
an atmosphere of N2 for 1.5 h. The solvents were evaporated
and the residue puri®ed by column chromatography (17 g;
5:1 light petroleum±EtOAc) to yield pure 18 (0.079 g, 63%)
as a colorless syrup: [a]Dˆ226.8 (c, 0.7 in CHCl3); Rf 0.79
(9:1 light petroleum±EtOAc). nmax (®lm): 3080, 2960,
1
1130, 1040, 950 cm21; H NMR (CDCl3); d 3.96±4.10
(m, 4H, 2£CH2-dioxolane), 4.13 (m, 1H, J4,5ˆ4.6 Hz,
1
J5,6aˆ3.0 Hz, J5,6bˆ1.0 Hz, H-5), 4.29 (dd, 1H, J6a,6b
ˆ
2900, 1725, 1600, 1460, 1275, 1100, 950 cm21; H NMR
13.7 Hz, H-6a), 4.65 (d, 1H, H-6b), 4.94 (dd, 1H,
J3,4ˆ2.9 Hz, H-4), 5.47 (m, 2H, H-1 and H-3), 5.61 (s,
1H, PhCH), 7.25±7.45 (m, 5H, Ph); 13C NMR (CDCl3): d
65.12 and 65.23 (2£CH2-dioxolane), 66.27 (C-6), 76.32
(C-4), 77.2 (C-5), 97.58 (PhCH), 98.08 (C-3), 101.14
(C-1) 126.17, 128. 21, 128.9 and 137.94 (Ph), 162.08
(C-2). EI-MS: m/z 276 (M1). Anal. Calcd for C15H16O5: C
65.21, H 5.84; Found: C 65.40, H 5.92.
(CDCl3): d 2.36 (ddd, 1H, J3a,3bˆ13.4 Hz, J2,3aˆ7.4 Hz,
J3a,4ˆ5.9 Hz, H-3a), 2.55 (ddd, 1H, J3b,4ˆ6.9 Hz, J2,3b
ˆ
6.7 Hz, H-3b), 3.28±4.04 (m, 4H, 2£CH2-dioxolane),
4.28±4.55 (m, 5H, H-2, H-4, H-5 and 2£H-6), 4.93 (d,
1H, J1,2ˆ3.4 Hz, H-1), 7.39±8.10 (m, 5H, Ph); 13C NMR
(CDCl3): d 37.16 (C-3), 45.09 (C-4), 63.94 (C-6), 65.42 and
65.51 (2£CH2-dioxolane), 78.81 (C-2), 85.38 (C-5), 103.76
(C-5), 103.76 (C-1), 128.36, 129.73 and 133.13 (Ph), 166.2
(CvO). CI-MS: m/z 357 (M111). HR-MS: Calcd for
C15H17BrO5: 356.0259. Found: m/z 356.0266.
2,5-Anhydro-3-deoxy-4,6-O-isopropylidene-l-xylo-hexose
ethylene acetal (16). A solution of 12 (0.87 g, 3.81 mmol)
in EtOH (20 mL) was hydrogenated over PtO2 (0.08 g,
0.35 mmol) for 24 h at room temperature. The mixture
was ®ltered and the catalyst washed with EtOAc. The ®ltrate
and washings were combined and evaporated to give crude
16 that was puri®ed by ¯ash column chromatography (9:1
2,5-Anhydro-4-O-benzoyl-6-bromo-6-deoxy-l-idose ethyl-
ene acetal (19). A mixture of 13a (0.10 g, 0.34 mmol) and
BaCO3 (0.04 g, 0.2 mmol) in dry CCl4 (5 mL) was treated
with NBS (0.073 g, 0.41 mmol) as described above. After
0.5 h the mixture was evaporated and the residue puri®ed by

V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
5937
¯ash chromatography (49:1 CH2Cl2±Me2±CO) to give pure
19 (0.084 g, 66%) as a solid. Recrystallization from
CH2Cl2±hexane gave an analytical sample 19: mp 142±
1438C; [a]Dˆ144.6 (c, 0.24 in CHCl3); Rf 0.74 (1:1 cyclo-
hexane±Me2CO). nmax (KBr): 3430 (broad), 2980, 2920,
The extracts were combined, washed with water, dried and
evaporated to yellow oil. Flash column chromatography
(9:1 toluene2Me2CO) yielded pure 21 (1.26 g, 80%) as a
colorless syrup: [a]Dˆ115.4 (c, 0.78 in CHCl3); Rf 0.47
(EtOAc). nmax (®lm): 3520±3400 (broad), 2930, 2900,
1
1730, 1610, 1290, 1130, 1090, 910 cm21
;
1H NMR
1600, 1360, 1200, 1120, 980 cm21, H NMR (CDCl3): d
(CDCl3): d 3.48±3.63 (m, 2H, J6a,6bˆ10.2 Hz, J5.6a
ˆ
1.93 (d, 1H, J3a,3bˆ14.0 Hz, H-3a), 2.27 (ddd, 1H, J2,3bˆ
8.5 Hz, J5,6bˆ6.3 Hz, H-6a and H-6b), 3.85±4.11 (m, 4H,
2£CH2-dioxolane), 4.18 (dd, 1H, J1,2ˆ5.2 Hz, J2,3ˆ3.8 Hz,
H-2), 4.54 (dd, 1H, J3,4ˆ1.2 Hz, H-3), 4.78 (ddd, 1H,
J4,5ˆ3.4 Hz, H-5), 5.23 (d, 1H, H-1), 5.54 (dd, 1H, H-4),
7.41±8.06 (m, 5H, Ph); 13C NMR (CDCl3): d 27.34 (C-6),
65.26 and 65.38 (2£CH2-dioxolane), 75.54 (C-3), 78.51
(C-4), 79.87 (C-5), 81.57 (C-2), 102.4 (C-1), 128.56,
129.1, 129.64 and 133.59 (Ph), 165.25 (CvO). CI-MS:
m/z 373 (M111). Anal. Calcd for C16H19BrO8: C 48.28, H
4.59. Found: C 48.00, H 4.32.
8.8 Hz, J3b,4ˆ5.0 Hz, H-3b), 2.44 (s, 3H, MeC6H4SO2),
3.73 (d, 1H, exchangeable with D2O, J4,OHˆ10.7 Hz, OH),
3.83±4.07 (m, 5H, 2£CH2-dioxolane, and H-5), 4.15 (m,
2H, J6a,6bˆ9.2 Hz, H-4 and H-6a), 4.31 (m, 2H, H-2 and
H-6b), 4.95 (s, 1H, H-1), 7.33±7.8 (m, 4H, MeC6H4SO2);
13C NMR (CDCl3): d 21.67 (MeC6H4SO2), 34.75 (C-3),
65.58 and 65.66 (2£CH2-dioxolane), 68.94 (C-6), 70.93
(C-4), 78.13 (C-2), 81.56 (C-5), 103.45 (C-1), 128.1,
129.82, 132.98 and 144.79 (MeC6H4SO2). CI-MS: m/z 345
(M111). HR-MS: Calcd for C15H20O7S: 344.0930. Found:
m/z 344.0939.
2,5-Anhydro-3-deoxy-l-xylo-hexose ethylene acetal (20).
(Procedure A) A solution of 16 (0.77 g, 3.95 mmol) and
CF3CO2H (0.8 mL) in MeOH (7.2 mL) was stirred at
room temperature for 0.5 h, and then evaporated by co-
distillation with toluene. Flash chromatography (2:1 tolu-
ene±Me2CO) of the residue gave pure 20 (0.505 g, 79%)
as a colorless syrup.
2,5-Anhydro-3,6-dideoxy-l-xylo-hexose ethylene acetal
(22). A mixture of 21 (1.26 g, 3.66 mmol) and LiAlH4
(0.7 g, 18.44 mmol) in dry THF (20 mL) was re¯uxed in
an atmosphere of N2 for 4 h. Excess of the reagent was
decomposed by addition of EtOAc (1 mL), the mixture
was ®ltered and the precipitate washed with EtOAc. The
combined ®ltrate and washings were evaporated and the
remaining crude 22 puri®ed by ¯ash chromatography (5:1
toluene±Me2CO). Pure 22 (0.575 g, 90%) was thus obtained
as a colorless syrup: [a]Dˆ143.4 (c, 1.03 in CHCl3); Rf
0.23 (5:1 toluene±Me2CO). nmax (®lm): 3460 (broad),
Procedure B: a solution of 4,6-O-benzylidene derivative 17
(1.1 g, 3.95 mmol) in glacial acetic acid (6 mL) and water
(1 mL) was stirred at re¯ux temperature for 7 h. The mixture
was evaporated by co-distillation with toluene and the
remaining crude 20 was puri®ed by ¯ash chromatography
(EtOAc), to afford pure 20 (0.606 g, 81%) as a colorless
syrup.
;
3000±2900, 1450, 1110, 1090, 980 cm21 1H NMR
(CDCl3): d 1.25 (d, 3H, J5,6ˆ6.4 Hz, 3£H-6), 1.90 (d, 1H,
J3a,3bˆ14.0 Hz, H-3a), 2.26 (ddd, 1H, J2,3bˆ9.2 Hz, J3b,4
ˆ
5.2 Hz, H-3b), 3.43 (d, 1H, exchangeable with D2O,
J4,OHˆ11.0 Hz, OH), 3.76±4.11 (m, 6H, 2£CH2-dioxolane,
H-4, and H-5), 4.19 (d, 1H, H-2), 4.95 (s, 1H, H-1); 13C
NMR (CDCl3): d 14.09 (C-6), 35.41 (C-3), 65.58 and
65.68 (2£CH2-dioxolane), 72.31 (C-4), 77.04 (C-2), 80.19
(C-5), 103.78 (C-1). CI-MS: m/z 175 (M111). HR-MS:
Calcd for C8H14O4: 174.0892. Found: m/z 174.0885.
Procedure C: a solution of 15 (0.8 g, 2.9 mmol) in EtOH
(20 mL) was hydrogenated over 10% Pd/C (0.3 g) for 4 h at
room temperature. To the reaction mixture was then added
glacial acetic acid (4 mL) and hydrogenation was continued
for an additional 12 h. The mixture was ®ltered, the catalyst
washed with EtOAc, and the combined ®ltrate and washings
were evaporated by co-distillation with toluene. Flash
column chromatography (EtOAc) of the residue afforded
pure 20 (0.445 g, 83%) as a colorless syrup: [a]Dˆ110.9
(c, 1.34 in CHCl3); Rf 0.19 (EtOAc). nmax (®lm): 3420
2,5-Anhydro-3,6-dideoxy-4-O-p-toluenesulfonyl-l-xylo-
hexose ethylene acetal (23). To a solution of 22 (0.77 g,
4.42 mmol) in dry pyridine (10 mL) was added TsCl (2.5 g,
13.11 mmol) and the mixture was kept at room temperature
for 48 h. The reaction mixture was poured into 6 M HCl
(30 mL) and extracted with CH2Cl2 (4£15 mL). The
combined extracts were washed with water, dried and
evaporated to pale yellow oil. Flash chromatography (99:1
CH2Cl2±Me2CO) of the residue gave pure 23 (1.165 g,
80%) as a colorless syrup: [a]Dˆ116.8 (c, 1.04 in
CHCl3); Rf 0.72 (EtOAc), Rf 0.55 (1:1 toluene±EtOAc).
nmax (®lm): 3010±2910, 1610, 1370, 1200, 1120,
(broad), 2940, 2900, 1110±1050, 950 cm21
;
1H NMR
(CDCl3): d 1.94 (ddd, 1H, J3a,3bˆ14.0 Hz, J2,3aˆ3.7 Hz,
J3a,4ˆ1.8 Hz, H-3a), 2.32 (ddd, 1H, J2,3bˆ9.5 Hz, J3b,4
ˆ
5.5 Hz, H-3b), 2.85 (bs, 1H, exchangeable with D2O, OH),
3.78±4.11 (m, 8H, 2£CH2-dioxolane, H-4, H-5 and 2£H-6),
4.24 (m, 1H, H-2), 5.0 (d, 1H, J1,2ˆ2.1 Hz, H-1), 5.30 (bs,
1H, exchangeable with D2O, OH); 13C NMR (CDCl3): d
35.51 (C-3), 61.84 (C-6), 65.54 and 65.67 (2£CH2-dioxo-
lane), 71.98 (C-2), 77.6 (C-4), 83.29 (C-5), 103.84 (C-1).
CI-MS: m/z 191 (M111). HR-MS: Calcd for C8H14O5:
190.0841. Found: m/z 19.0838.
1
950 cm21; H NMR (CDCl3): d 1.23 (d, 3H, J5,6ˆ6.3 Hz,
3£H-6), 2.1 (ddd, 1H, J3a,3bˆ15.0 Hz, J2,3aˆ5.8 Hz, J3a,4
ˆ
2.0 Hz, H-3a) 2.33 (ddd, 1H, J2,3bˆ8.6 Hz, J3b,4ˆ6 Hz,
H-3b), 2.45 (s, 3H, MeC6H4SO2), 3.79 (m, 1H, J1,2ˆ
6.2 Hz, H-2), 3.8±4.02 (m, 5H, 2£CH2-dioxolane and H-
5), 4.84 (d, 1H, H-1), 4.9 (m, 1H, J4,5ˆ3.7 Hz, H-4), 7.3±
7.83 (m, 4H, MeC6H4SO2); 13C NMR (CDCl3): d 14.47
(C-6), 21.73 (MeC6H4SO2), 34.92 (C-3), 65.36 (2£CH2-
dioxolane), 78.16 (C-2), 78.39 (C-5), 82.16 (C-4), 104.45
(C-1), 127.81, 129.93, 133.9 and 144.94 (MeC6H4SO2).
2,5-Anhydro-3-deoxy-6-O-p-toluenesulfonyl-l-xylo-hexose
ethylene acetal (21). To a cooled (2288C) solution of 20
(0.87 g, 4.57 mmol) in dry pyridine (8 mL) was added a cold
(2288C) solution of tosyl chloride (1.4 g, 7.34 mmol) in dry
pyridine (8 mL). The reaction mixture was left at 2288C for
6 days, then poured into 6 M HCl (30 mL) and the resulting
emulsion was extracted with dichloromethane (3£20 mL).

5938
V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
CI-MS: m/z 329 (M111). HR-MS: Calcd for C15H20O6S:
328.0981. Found: m/z 328.0995.
Me2CO). nmax (®lm): 3460 (broad), 2990, 2940, 2890,
1
1730, 1610, 1290, 1130 cm21; H NMR (CDCl3): d 1.35
(d, 3H, J5,6ˆ6.5 Hz, 3£H-6), 2.04 (ddd, 1H, J3a,3b
ˆ
2,5-Anhydro-4-O-benzoyl-3,6-dideoxy-l-ribo-hexose ethyl-
ene acetal (24). A mixture of 23 (1.15 g, 3.5 mmol) and
KOBz (2.5 g, 15.65 mmol) in DMF (30 mL) was stirred at
1008C for 24 h. The solvent was removed by high vacuum
distillation, the residue was treated with CH2Cl2 (2£20 mL),
and the combined extracts were ®ltered and evaporated to
yellow oil. Chromatographic puri®cation on a column of
¯ash silica (CH2Cl2) afforded pure 24 (0.64 g, 66%) as a
colorless syrup: [a]Dˆ10.5 (c, 1.7 in CHCl3); Rf 0.7
(19:1 CH2Cl2±Me2CO), Rf 0.72 (1:1 toluene±EtOAc).
nmax (®lm): 3000, 2950, 2900, 1730, 1610, 1460, 1390,
13.7 Hz, J2,3aˆ5.6 Hz, J3a,4ˆ1.9 Hz, H-3a), 2.24 (m, 2H,
J2,3bˆ10.2 Hz, J3b,4ˆ6.3 Hz, H-3b and OH), 3.59 (ddd,
1H, J1a,1bˆ11.9 Hz, J1a,2ˆ4.6 Hz, H-1a), 3.87 (ddd, 1H,
J1b,2ˆ2.9 Hz, H-1b), 4.22 (dq, 1H, J4,5ˆ2.6 Hz, H-5), 4.32
(m, 1H, H-2), 5.14 (dd, 1H, H-4), 7.4±8.08 (m, 5H, Ph); 13C
NMR (CDCl3): d 19.80 (C-6), 33.04 (C-3), 63.80 (C-1),
79.06 (C-5), 80.36 (C-2), 80.64 (C-4), 128.37, 129.55,
129.87 and 133.16 (Ph), 166.11 (CvO). CI-MS: m/z 237
(M111). HR-MS: Calcd for C13H16O4: 236.1049. Found:
m/z 236.1041.
1
1290, 1130, 950 cm21; H NMR (CDCl3): d 1.34 (d, 3H,
2,5-Anhydro-4-O-benzoyl-1-iodo-1,3,6-trideoxy-l-ribo-
hexitol (27). To a solution of 26 (0.29 g, 1.23 mmol) in dry
toluene (25 mL) were added successively imidazole
(0.198 g, 2.24 mmol), Ph3P (0.742 g, 2.83 mmol) and iodine
(0.568 g, 2.24 mmol). The mixture was re¯uxed while stir-
ring in an atmosphere of N2 for 3 h, and then evaporated.
Flash column chromatography (toluene) of the residue
(1.8 g) yielded pure 27 (0.355 g, 84%) which was crystal-
lized from hexane to give colorless needless: mp 688C,
[a]Dˆ27.6 (c, 0.37 in CHCl3); lit.7 mp 688C, [a]Dˆ
211.67 (c, 0.93 in CHCl3); Rf 0.88 (4:1 toluene±Me2CO).
1H NMR (CDCl3): d 1.38 (d, 3H, J5,6ˆ6.5 Hz, 3£H-6), 2.06
(ddd, 1H, J3a,3bˆ13.8 Hz, J2,3aˆ9.8 Hz, J3a,4ˆ6.3 Hz, H-3a),
2.30 (ddd, 1H, J2,3bˆ5.4 Hz, J3b,4ˆ1.7 Hz, H-3b), 3.3 (dd,
1H, J1a,bˆ10.2 Hz, J1a,2ˆ6.2 Hz, H-1a), 3.37 (dd, 1H,
J1b,2ˆ4.9 Hz, H-1b), 4.19 (m, 1H, H-2), 4.3 (dq, 1H,
J4,5ˆ2.5 Hz, H-5), 5.16 (dt, 1H, H-4), 7.42±8.1 (m, 5H,
Ph); 13C NMR (CDCl3): d 9.36 (C-1), 20.15 (C-6), 38.62
(C-3), 77.83 (C-2), 80.36 (C-4), 81.46 (C-5), 128.5, 129.68,
129.87 and 133.32 (Ph), 166.11 (CvO). CI-MS: m/z 347
(M111).
J5,6ˆ6.6 Hz, 3£H-6), 2.15 (ddd, 1H, J3a,3bˆ13.8 Hz,
J2,3aˆ6.3 Hz, J3a,4ˆ2.4 Hz, H-3a), 2.25 (ddd, 1H, J3b,4
ˆ
5.9 Hz, J2,3bˆ9.4 Hz, H-3b), 3.82±4.07 (m, 4H, 2£CH2-
dioxolane), 4.14±4.29 (m, 2H, J1,2ˆ5.5 Hz, J4,5ˆ2.7 Hz,
H-2 and H-5), 4.93 (d, 1H, H-1), 5.15 (m, 1H, H-4), 7.4±
8.06 (m, 5H, Ph); 13C NMR (CDCl3): d 19.78 (C-6), 32.97
(C-3), 65.43 and 65.56 (2£CH2-dioxolane), 79.07 (C-2),
79.88 (C-4), 81.01 (C-5), 104.73 (C-1), 128.45, 129.65,
129.97 and 133.22 (Ph), 166.14 (CvO). CI-MS: m/z 279
(M111). HR-MS: Calcd for C15H18O5: 278.1154. Found:
m/z 278.1149.
2,5-Anhydro-4-O-benzoyl-3,6-dideoxy-l-ribo-hexitol (26).
(Procedure A) A solution of 24 (0.64 g, 2.3 mmol) in a
mixture of tri¯uoroacetic acid (7 mL) and 6 M HCl
(1.75 mL) was kept at 148C for 24 h. The reaction mixture
was evaporated by co-distillation with toluene to unstable
oil. Thus obtained crude 25 (0.7 g) was immediately
dissolved in MeOH (15 mL) and reduced with NaBH4
(0.2 g, 5.29 mmol) at room temperature for 2 h. The mixture
was poured into saturated NaCl solution (15 mL) and
extracted with CH2Cl2 (4£10 mL). The combined extracts
were dried and evaporated to give crude 26. Flash chroma-
tography (4:1 toluene±EtOAc) of the residue afforded pure
26 (0.328 g, 60%) as a colorless syrup.
2,5-Anhydro-1-iodo-1,3,6-trideoxy-l-ribo-hexitol (28).
To a solution of 27 (0.355 g, 1.02 mmol) in dry THF
(5 mL) was added saturated methanolic K2CO3 solution
(1 mL) and the suspension was stirred at room temperature
for 1.5 h. The mixture was poured into saturated NaCl solu-
tion (15 mL), acidi®ed with 6 M HCl, and extracted with
CH2Cl2 (4£10 mL). The combined extracts were washed
with brine, dried and evaporated. Column chromatography
(50 g; 9:1 toluene±Me2CO) of the residue (0.31 g) gave
pure 28 (0.205 g, 83%) as a colorless syrup: [a]Dˆ233.3
(c, 0.88 in CHCl3); lit.7 [a]Dˆ230.7 (c, 0.87 in CHCl3); Rf
Procedure B: to a stirred and ice-cooled solution of alcohol
22 (0.7 g, 4.02 mmol), benzoic acid (0.95 g, 7.79 mmol) and
triphenylphosphine (3.0 g, 11.44 mmol) in dry THF
(40 mL) was added dropwise a solution of diethyl azodicar-
boxylate (3.5 mL, 22.22 mmol) in dry THF (15 mL). The
mixture was stirred at 08C for 15 min and then at room
temperature for 20 h. The mixture was poured into saturated
NaHCO3 solution (100 mL) and extracted with CH2Cl2
(4£50 mL). The extract was dried and evaporated, and the
residue was puri®ed by ¯ash chromatography (CH2Cl2), to
give 24 (1.5 g) contaminated with a small amount of
aromatic impurities. The impure sample 24 was dissolved
in a mixture of tri¯uoroacetic acid (8 mL) and 6 M HCl
(2 mL) and the solution was kept at 148C for 24 h. After
workup as described above (procedure A), the remaining
crude aldehyde 25 was dissolved in MeOH (15 mL) and
treated with NaBH4 (0.25 g, 6.61 mmol) at room tempera-
ture for 2 h. After the workup according to procedure A,
crude 26 was obtained and puri®ed by column chroma-
tography (50 g; 9:1 toluene±Me2CO). Pure 26 (0.26 g,
27% from 22) was obtained as a colorless syrup:
[a]Dˆ27.8 (c, 1.09 in CHCl3); Rf 0.27 (4:1 toluene±
1
0.38 (4:1 toluene±Me2CO). H NMR (CDCl3): d 1.23 (d,
3H, J5,6ˆ6.4 Hz, 3£H-6), 1.87 (ddd, 1H, J3a,3bˆ13.3 Hz,
J2,3aˆ8.7 Hz, J3a,4ˆ6.1 Hz, H-3a), 2.03 (ddd, 1H,
J2,3bˆ2.9 Hz, J3b,4ˆ6.2 Hz, H-3b), 3.04 (bs, 1H, exchange-
able with D2O, OH), 3.21 (dd, 1H, J1a,1bˆ10.2 Hz, J1a,2
ˆ
6.1 Hz, H-1a), 3.28 (dd, 1H, J1b,2ˆ4.8 Hz, H-1b), 3.95 (dq,
1H, J4,5ˆ3.3 Hz, H-5), 4.02 (dt, 1H, H-4), 4.11 (m, 1H,
H-2); 13C NMR (CDCl3): d 10.63 (C-1), 19.95 (C-6),
40.87 (C-3), 77.22 (C-2 and C-4), 83.31 (C-5). CI-MS:
m/z 243 (M111).
(1)-Muscarine iodide (1). A sealed tube containing 28
(0.19 g, 0.78 mmol) and ethanolic 40% Me3N (8 mL) was
heated at 808C for 3 h. The volatiles were evaporated and
the syrupy residue partitioned between distilled water
(4 mL) and EtOAc (3 mL). After removal of the aqueous

V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
5939
phase, the organic layer was washed with water (2 mL). The
combined aqueous solutions were evaporated by co-distil-
lation with toluene, to yield pure alkaloid 1 (0.22 g, 93%) as
a pale yellow solid. (For 1H and 13C NMR spectral data see
Table 1). Recrystallization from 2-propanol afforded
needles: mp 147±1498C, [a]Dˆ17.6 (c, 0.4 in EtOH);
lit.7 mp 1498C, [a]Dˆ16.36 (c, 0.35 in EtOH).
1H, H-4), 7.4±8.09 (m, 5H, Ph); 13C NMR (CDCl3): d 14.48
(C-6), 35.08 (C-3), 64.94 (C-1), 75.92 (C-4), 78.01 (C-2),
78.24 (C-5), 128.53, 129.62, 130.01, and 133.24 (Ph),
165.98 (CvO). CI-MS: m/z 237 (M111). HR-MS: Calcd
for C13H16O4: 236.1049. Found: m/z 236.1045.
2,5-Anhydro-4-O-benzoyl-1-iodo-1,3,6-trideoxy-l-xylo-
hexitol (32). Treatment of 31 (0.359 g, 1.52 mmol) with
imidazole (0.237 g, 3.48 mmol), Ph3P (0.888 g, 3.38
mmol) and iodine (0.68 g, 2.68 mmol) in dry toluene
(25 mL), according to the procedure described above for
27, yielded crude 32. Column chromatography on silica
gel (150 g; 49:1 toluene±Me2CO) afforded pure 32
(0.475 g, 90%) as a colorless syrup: [a]Dˆ131.2 (c, 0.96
in CHCl3); Rf 0.74 (4:1 toluene±Me2CO). nmax (®lm): 3000,
2,5-Anhydro-4-O-benzoyl-3,6-dideoxy-l-xylo-hexose ethyl-
ene acetal (29). To a solution of 22 (0.162 g, 0.93) in dry
pyridine (4 mL) was added benzoyl chloride (0.5 mL,
4.3 mmol). The mixture was kept at room temperature for
24 h, then acidi®ed with 6 M HCl (12 mL) and extracted
with CH2Cl2 (4£8 mL). The extracts were combined,
washed successively with water and saturated NaHCO3
solution, dried, and concentrated to an oil. Column chroma-
tography on silica gel (40 g; 7:1 toluene±Me2CO) afforded
pure 29 (0.222 g, 86%) as a colorless syrup: [a]Dˆ26.7 (c,
0.86 in CHCl3); Rf 0.51 (4:1 toluene±Me2CO). nmax (®lm):
1
2950, 2870, 1730, 1610, 1290, 1120, 1190 cm21; H NMR
(CDCl3): d 1.34 (d, 3H, J5,6ˆ6.1 Hz, 3£H-6), 2.02 (ddd, 1H,
J3a,3bˆ14.6 Hz, J2,3aˆ5.8 Hz, J3a,4ˆ1.8 Hz, H-3a), 2.64
(ddd, 1H, J2,3bˆ8.2 Hz, J3b,4ˆ6.4 Hz, H-3b), 3.31 (dd, 1H,
J1a,1b 9.8 J1a,2ˆ7.2 Hz, H-1a), 3.39 (dd, 1H, J1b,2ˆ5.4 Hz,
H-1b), 4.08±4.22 (m, 2H, J4,5ˆ4.0 Hz, H-2 and H-5), 5.51
(ddd, 1H, H-4), 7.42±8.11 (m, 5H, Ph); 13C NMR (CDCl3):
d 9.18 (C-1), 14.75 (C-6), 39.34 (C-3), 75.68 (C-4), 77.51
(C-2), 78.92 (C-5), 128.5, 129.61, 129.89 and 133.22 (Ph),
165.87 (CvO). CI-MS: m/z 347 (M111). HR-MS: Calcd
for C13H15IO3: 346.0066. Found: m/z 346.0072.
1
3000±2900, 1720, 1600, 1270, 1120, 940 cm21; H NMR
(CDCl3): d 1.34 (d, 3H, J5,6ˆ6.4 Hz, 3£H-6), 2.14 (ddd, 1H,
J3a,3bˆ14.6 Hz, J3a,4ˆ1.8 Hz, J2,3aˆ5.5 Hz, H-3a), 2.56
(ddd, 1H, J2,3bˆ8.2 Hz, J3b,4ˆ6.4 Hz, H-3b), 3.84±4.06
(m, 5H, 2£CH2-dioxolane and H-2), 4.12 (m, 1H, J4,5
3.7H-5), 4.98 (d, 1H, J1,2ˆ5.8 Hz, H-1), 5.48 (m, 1H,
H-4), 7.4±8.14 (Ph); 13C NMR (CDCl3): d 14.47 (C-6),
34.91 (C-3), 65.37 and 65.39 (2£CH2-dioxolane), 75.54
(C-4), 78.60 (C-2), 78.59 (C-5), 104.95 (C-1), 128.48,
129.69, 130.07 and 133.18 (Ph), 166.0 (CvO). CI-MS:
m/z 557 (2M111), 279 (M111). HR-MS: Calcd for
C15H18O5: 278.1154. Found: m/z 278.1151.
2,5-Anhydro-1-iodo-1,3,6-trideoxy-l-xylo-hexitol (33). A
solution of 32 (0.44 g, 1.27 mmol) in dry THF (5 mL) was
treated with saturated methanolic K2CO3 solution (1 mL), as
described above (procedure for 28), to afford crude 33. Flash
chromatography (9:1 toluene±Me2CO) yielded pure 33
(0.201 g, 65%) as an oil. Crystallization from hexane gave
colorless needless: mp 63.58C, [a]Dˆ21.5 (c, 1.13 in
CHCl3); lit.8 mp 628C, [a]Dˆ20.34 (c, 0.16 in CHCl3); Rf
0.4 (4:1 toluene±Me2CO). 1H NMR (CDCl3): d 1.28 (d, 3H,
J5,6ˆ6.4 Hz, 3£H-6), 1.77 (ddd, 1H, J3a,3b 14.3 J2,3aˆ5.2 Hz,
J3a,4ˆ1.3 Hz, H-3a), 1.97 (bs, 1H, exchangeable with D2O,
OH), 2.4 (ddd, 1H, J2,3bˆ8.4 Hz, J3b,4ˆ6.0 Hz, H-3b), 3.31
(dd, 1H, J1a,1b 10.0 J1a,2ˆ4.7 Hz, H-1a), 3.4 (dd, 1H,
J1b,2ˆ6.3 Hz, H-1b), 3.86 (m, 1H, J4,5ˆ3.4 Hz, H-5), 3.94
(m, 1H, H-2), 4.17 (bs, 1H, H-4); 13C NMR (CDCl3): d
11.69 (C-1), 14.07 (C-6), 41.34 (C-3), 73.27 (C-4), 76.69
(C-2), 79.82 (C-5), CI-MS: m/z 243 (M111).
2,5-Anhydro-4-O-benzoyl-3,6-dideoxy-l-xylo-hexitol (31).
(Procedure A) A solution of 29 (0.193 g, 0.69 mmol) in
tri¯uoroacetic acid (2 mL) and 6 M HCl (0.5 mL) was
stored at 148C for 24 h. The mixture was evaporated by
co-distillation with toluene, and the remaining crude
aldehyde 30 (0.2 g) was reduced with NaBH4 (0.06 g,
1.59 mmol) in MeOH (5 mL) following the procedure for
preparation of 26. Column chromatography (20 g; 4:1
toluene±Me2CO) afforded pure 31 (0.097 g, 59%) as color-
less syrup.
Procedure B: treatment of 22 (0.54 g, 3.1 mmol) with
benzoyl chloride (1.5 mL, 12.91 mmol) in dry pyridine
(6 mL) under the same reaction conditions as described
above (preparation of 29) afforded crude 29 (1.6 g). Hydro-
lysis of the crude 29 with a mixture of tri¯uoroacetic acid
(8 mL) and 6 M HCl (1 mL) at 148C for 24 h gave the
unstable aldehyde 30, which was subsequently reduced
with NaBH4 (0.5 g, 13.22 mmol) in MeOH (15 mL). After
workup as described in the procedure for preparation of 26,
followed by ¯ash column chromatography (4:1 toluene±
Me2CO), pure 31 (0.385 g, 53%) was obtained as a colorless
syrup: [a]Dˆ125.2 (c, 0.92 in CHCl3); Rf 0.16 (4:1
toluene±Me2CO). nmax (®lm): 3450 (broad), 3000, 2960,
(1)-epi-Muscarine iodide (2). Iodo alcohol 33 (0.16 g,
0.66 mmol) was treated with a 40% ethanolic solution of
Me3N (15 mL) according to the same procedure as
described for 1. The usual workup gave pure alkaloid 2
1
(0.19 g, 95%) as a yellow syrup. (For H and 13C spectral
data see Table 1). Crystallization from 2-propanol gave pale
yellow needles: mp 172±1738C, [a]Dˆ131.7 (c, 0.4 in
H2O); lit.8 mp 1758C, [a]Dˆ132 (c, 0.55 in H2O).
Acknowledgements
2890, 1740, 1610, 1460, 1300, 1130 cm21 1H NMR
;
(CDCl3): d 1.33 (d, 3H, J5,6ˆ6.7 Hz, 3£H-6), 1.98 (ddd,
1H, J3a,3bˆ14.6 Hz, J2,3aˆ6.1 Hz, J3a,4ˆ1.8 Hz, H-3a),
2.17 (bs, 1H, exchangeable with D2O, OH), 2.52 (ddd,
1H, J2,3bˆ8.5 Hz, J3b,4ˆ6.5 Hz, H-3b), 3.65 (dd, 1H, J1a,1b
11.3 J1a,2ˆ5.6 Hz, H-1a), 3.8 (dd, 1H, J1b,2ˆ2.8 Hz, H-1b),
4.09 (m, 1H, J4,5ˆ3.9 Hz, H-5), 4.15 (m, 1H, H-2), 5.49 (m,
This work was supported by a research grant from the
Ministry of Science and Technology of the Republic of
Ï
Serbia. The authors thank Dr P. Radivojsa (Centre of
Chemistry, ICTM, Belgrade, YU), for the measurements
of optical rotation, as well as to Mrs T. Marinko-Covell
Â
(University of Leeds, UK) and to Mr D. Djokovic (Faculty

5940
V. Popsavin et al. / Tetrahedron 56 (2000) 5929±5940
8. Hatekeyama, S.; Sakurai, K.; Takano, S. Heterocycles 1986, 24,
633±636.
of Chemistry, University of Belgrade, YU), for recording
the mass spectra.
9. Knight, D. W.; Shaw, D.; Fenton, G. Synlett 1994, 295±296.
10. Synthesis of enantiomerically pure muscarine analogs from
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