Reactions of 2-hydroxy-6,8-dioxabicyclo[3.2.1]oct-3-ene with diethylaminosulfur trifluoride and with halogens. Facile synthesis of 1,6- anhydrohalohexopyranoses

Article abstract of DOI:10.1055/s-1998-4484

D-Galactal 1 reacts in THF in the presence of catalytic amounts of concentrated sulfuric acid to give (2R)-2-hydroxy-6,8-dioxabicyclo[3.2.1]oct- 3-ene (4) in a Ferrier-type rearrangement in 40% yield. When 4 is treated with diethylaminosulfur trifluoride

Full text of DOI:10.1055/s-1998-4484

201
February 1998
SYNTHESIS
Reactions of 2-Hydroxy-6,8-dioxabicyclo[3.2.1]oct-3-ene with Diethylaminosulfur
Trifluoride and with Halogens. Facile Synthesis of 1,6-Anhydrohalohexopyranoses
Franz Oberdorfer,* Roland Haeckel, Gilbert Lauer
Deutsches Krebsforschungszentrum, Abteilung Radiochemie, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
Phone +49(6221)422443; Fax +49(6221)422572; E mail: f.oberdorfer@dkfz-heidelberg.de
Received 31 July 1997
Abstract: D-Galactal 1 reacts in THF in the presence of catalytic parative route for building chiral centers at hexose carbon
amounts of concentrated sulfuric acid to give (2R)-2-hydroxy-6,8-
dioxabicyclo[3.2.1]oct-3-ene (4) in a Ferrier-type rearrangement in
40% yield. When 4 is treated with diethylaminosulfur trifluoride
(DAST) under certain reaction conditions, a novel intramolecular
second order allylic rearrangement follows leading to previously
unknown diastereomeric monofluoro derivatives 7 and 8. Direct a-
pyranoses. Usually this acid-catalyzed reaction delivers
substitution of 4 by DAST affords the 2-monofluoro derivative 6
under kinetic control. When DAST is used with dimethylformamide
as solvent an apparent [1,3] sigmatropic migration of the 2-hydroxy
positions 2–4, and to a wide variety of 1,6-anhydrohalo-
hexopyranoses, starting from glycals.
A Ferrier-type rearrangement of glycals14 was applied for
the introduction of the 1,6-anhydro bridge into the hexo-
2,3-unsaturated monocyclic pseudoglycals, but it can be
readily diverted to an intramolecular pathway. The strict
group of 4 gives (4S)-4-hydroxy-6,8-dioxabicyclo[3.2.1]oct-2-ene absence of a nucleophile, including water, and highly di-
(9). The corresponding 4-fluoro-substituted product was not obtained
from the reaction of 9 with DAST. Oxidation of 4 and repeated treat-
luted conditions are necessary. We previously reported on
this novel glycal rearrangement in the case of D-glucal.15
ment with DAST gives a novel 2,2-difluoro compound 11. Electro-
On treatment of D-galactal 1 in THF in the presence of a
philic addition of bromine to protected 4 afforded the 1,6-
anhydromonobromo- and -dibromohexopyranoses 15–17. Monohalo
and monopseudohalo derivatives (-F, -Cl, -Br, -N3) 22-25 were pre-
pared by nucleophilic oxirane ring opening of the easily available
endo-epoxides 18–20.
Key words: diethylaminosulfur trifluoride, glycal rearrangement, yl)furan17 (5) (Scheme 1). The presence of copper(II)
dioxabicyclooctenes, 1,6-anhydrohalohexopyranoses, hexose epoxides
small quantity of concentrated sulfuric acid and molecular
sieves, compound 4 was formed through the cyclic allylic
oxocarbenium ion 3 within 1 hour with 40% yield,16 to-
gether with the expected 2-(D-glycero-1,2-dihydroxyeth-
sulfate, as with D-glucal, or the presence of any other
Lewis acid, gave either no reaction at all, or led to the ex-
clusive formation of 5.
Various methods for preparation of 1,6-anhydrohexopy-
ranoses have been reported1 including thermal degrada-
tion of polysaccharides,2 cyclization and Lewis acid
mediated cyclization of hexopyranoses,3 and total synthe-
ses by the Diels–Alder reaction of acrolein derivatives4
following, in principle, the Lewis acid catalyzed diene al-
dehyde cyclocondensation.5 The resulting products are
generally useful starting materials for a variety of synthe-
ses.1–7 Locked in the 1C4 conformation, such 1,6-anhydro-
hexopyranoses are quite rigid structures which offer
special advantage for the stereoselective introduction of
functional groups at carbohydrate ring positions 2 to 4
while the 1- and 6-hydroxy functions are protected by the
anhydro bridge. The 1,6-anhydro bridge is stable in basic
Scheme 1
media, but is cleaved readily under acidic aqueous condi-
tions. Numerous halogenated dioxabicyclooctanes,8 as
well as dioxabicyclooctanones and -octenones,9 hiding
Compound 4 was then reacted with DAST in dichlo-
the carbohydrate configuration have been prepared, most-
ly by multistep procedures, for their use in stereoselective
synthesis and in the chiron approach of assembly of more
complex molecules.10 Among the halohexopyranoses es-
pecially attractive are fluoro-substituted sugars,11 with
one or more fluorine atoms at specific molecular sites, as
synthetic analogs of natural products with pharmacologi-
cal activity. In particular, 4-deoxy-4-fluoro-D-glucose is
expected to act as a chain terminating agent in glycogen
synthesis and has potential in the treatment of glycogen
storage diseases. The fluorinated analog of galactose, 2-
deoxy-2-fluoro-D-galactose, may be utilized in cancer di-
agnosis and treatment as a uridylate trapping chemothera-
peutic drug.12 It also impairs N-glycosylation of
membrane and secretory glycoproteins.13 We now dem-
onstrate within this work a relatively simple and short pre-
romethane at low temperature (–80 °C). The expected
fluorinated compound 6 was obtained together with the
novel diastereomeric fluoro-substituted dioxabicyclo-
octenes 7 and 8 (Scheme 2). Formation of 7 and 8 could
be suppressed successfully at room temperature giving
exclusively 6 in 50% yield. Although rearrangements in
carbohydrate ring systems in presence of DAST are well
known,18 it was a surprising observation to us that 4 rear-
ranged in the presence of DAST at a low temperature. It
seemed that, after an initial attack of DAST at the 2-hy-
droxy substituent, a second order allylic rearrangement
took place where the oxygen atom of the 6-membered ring
attacked the 3,4-double bond by the s-route. Fluoride fin-
ally entered the 5-position of 4 from the two possible sides
which delivered the diastereomeric compounds 7 with flu-
orine in the equatorial position and 8 with the fluorine in

202
Papers
SYNTHESIS
Scheme 4
Scheme 2
12 and 13 with acetyl hypobromite in CCl4 gave mono-
bromo derivatives 16 and 17 (Scheme 5). Compound 14
reacted analogously without significant difference. The
formation of a trans-diequatorial product was never ob-
served. Fluorine, chlorine and iodine either did not add to
the double bond or gave very complex product mixtures
which were not analyzed, No reaction occurred with
acetyl hypofluorite and acetyl hypochlorite. The bromi-
nated derivatives were obtained in 65–92% yield, typical-
ly within 12 hours at room temperature.
the axial position in a 2:1 ratio. The structures of 7 and 8
were identified by COSY and NOE experiments.
Addition of 2 equivalents of DAST to 4 in DMF as solvent
at –50 °C afforded the known compound 919 by a formally
suprafacial [1,3] sigmatropic migration of the hydroxy
group. This reaction should be a thermally forbidden pro-
cess and suggested a mechanism by which the solvent was
utilized as a support reactant. The reaction probably in-
volved initial quaternization of the amide by DAST. The
resulting ion-pair intermediate was then attacked at the
carbonyl group by the 2-hydroxy group of 4 yielding the
respective formate. A hetero-Cope rearrangement fol-
lowed and delivered 9 after hydrolysis in 50% yield
(Scheme 3). Formate intermediates may be isolated and
characterized.20 It is quite interesting in this case that
DAST may be used together with an acid amide as an acyl-
ating reagent.
SEM = 2-(trimethylsily)ethoxymethyl
a) BnBr, NaH, DMF, 20°C, 0.5 h. b) Ac2-O, pyridine, 20°C, 12 h. c)
SEMCl, i-Pr2NH, 20°C, 3 h.
Scheme 5
Scheme 3
Compounds 16 and 17 were transformed quantitatively
The reaction of an oxo group with DAST was expected to into the corresponding bromohydrins and subsequently
result in difluorination of the carbonyl carbon.21 We, into the endo-epoxides 18, 19 and 20 in 73–80% yield.16
therefore, readily oxidized 4 to 10 using MnO2 in CHCl3 The exo-epoxide 21 was prepared by a Prilezaev reaction
following a procedure described by Köll et al.22 Subse- of 12 with almost water-free m-chloroperoxybenzoic acid
quent treatment of 10 with DAST delivered the novel di- (mCPBA) in CH2Cl2.16 Epoxides 18 and 19, and the re-
fluoro derivative 11 (Scheme 4). It was identified by its spective epimers derived from glucal,15, 22 were used to
1H, 13C and 19F NMR spectra. The geminal coupling con- prepare 1,6-anhydrohalohexopyranoses (halo = fluoro,
stant for the CF2 group was 280 Hz.
chloro, bromo) by nucleophilic opening of the oxirane.1, 8
Compound 19 lost its acetyl group during the reaction
with KBr yielding immediately 25 (Scheme 6).
Protection of 4 with groups of different chemical proper-
ties allowed the study of subsequent electrophilic reac-
tions of the dioxabicyclooctene molecule. Following this Acidic cleavage of the 1,6-anhydro bridge of 25 with HCl
route we prepared the dibromo compound 15 in a stereo- afforded 2-bromo-2-deoxy-D-galactose which is expected
selective reaction of 13 with bromine in only ten minutes to act as a therapeutic and diagnostic uridylate trapping
and in very good yield (95%). Treatment of compounds tool in cancer treatment like its fluoro analog,12 also prob-

February 1998
SYNTHESIS
203
(2S)-2-Fluoro-6,8-dioxabicyclo[3.2.1]oct-3-ene (1,6-Anhydro-2,3-
dideoxy-4-fluoro-b-D-erythro-hex-2-enopyranose, 6):
4 (0.060 g, 0.47 mmol) was dissolved in CH2Cl2 (3 mL). KF (0.015 g,
0.26 mmol), K2CO3 (0.015 g, 0.11 mmol) and DAST (r = 1.222,
0.125 mL, 0.95 mmol) were added. The solution was stirred for 5 h
at 20°C. Sat. Na2CO3 (0.5 mL) was added. The organic layer was sep-
arated and evaporated. Purification by flash chromatography (hexane/
EtOAc 9:1) gave 6 (0.030 g, 50%) as a colorless oil; Rƒ = 0.27 (hex-
ane/EtOAc 4:1).
Anal. C6H7FO2 calcd: C 55.41, H 5.42, F 14.60; found: C 55.50, H
5.40, F 14.50.
HRMS: calcd 130.0430; found 130.044.
(1R,2S)-2-Fluoro-3,8-dioxabicyclo[3.2.1]oct-6-ene (7) and
(1R,2R)-2-Fluoro-3,8-dioxabicyclo[3.2.1]oct-6-ene (8):
DAST (0.4 mL, 3 mmol) was dissolved in CH2Cl2 (3 mL) and cooled
to –80°C. 4 (0.333 g, 2.6 mmol) was dissolved in CH2Cl2 (2 mL) and
added. After 10 min the solvents were evaporated and the crude prod-
ucts were purified by flash chromatography (hexane/EtOAc 9:1) giv-
ing 7 (0.107 g, 32%) and 8 (0.054 g, 16%) as colorless oils.
7: Rƒ = 0.21 (toluene/CH2Cl2/hexane 1:1:1).
Anal. C6H7FO2 calcd: C 55.41, H 5.42, F 14.60; found: C 55.75, H
5.50, F 14.55.
8: Rƒ = 0.26 (hexane/EtOAc 9:1).
Anal. C6H7FO2 calcd: C 55.41, H 5.42, F 14.60; found: C 55.64, H
5.31, F 14.72.
a) KHF2, ethylene glycol, reflux, 24 h. b) 1,1,2,2-tetrachloroethane,
reflux, 12 h. c) NaN3, EtOH, reflux, 48 h. d) KBr, MeCN, reflux, 3 h
Scheme 6
Table 1. 1H NMR Data (250 MHz, CDCl3)a
ably exhibiting radiosensitizing properties. We have pres-
ently used this method as a most suitable procedure for the
preparation of [80 mBr]-labeled 2-bromo-2-deoxy-D-galac-
tose (half life of 80 mBr 4.42 h, g, 80Br 17.6 min, ≈ 3% b+)
which is applied in tracer kinetic studies of liver galactose
metabolism. Pseudohalohexopyranoses may be obtained
as well by this procedures, yet only one example is present-
ed in this work by the azido derivative 24.
Com- H-1
pound
H-2
H-3
H-4
H-5
H-6ab H-6bb
4c
6
7
5.51 5.89 5.71
5.53 6.71 5.83
5.83 4.60 6.48
5.41 4.51 6.59
5.52 4.67 6.03
5.78 6.08 7.10
5.57 6.24 5.78
5.49 5.88 5.79
5.54 5.97 5.68
5.49 5.87 5.73
5.59 4.52 4.55
5.41 3.87 5.51
5.52 3.95 5.48
5.63 3.53 3.28
5.69 3.58 3.40
5.67 3.62 3.36
4.82
4.40
6.78
6.78
5.85
–
4.52
4.80
4.76
4.66
3.66
4.75
4.65
4.55
4.66
4.75
5.17
4.38
4.50
4.36
4.49
4.42
4.37
3.64
3.70
3.65
4.42
3.91
3.34
3.18
3.40
3.46
3.63
3.83
3.86
3.92
3.90
3.76
3.65
3.78
3.56
3.64
3.62
3.74
3.87
4.19
3.88
3.89
4.35
3.95
4.08
3.95
4.25
4.16
4.21
4.72
4.38
4.41
4.13
4.05
4.01
4.17
4.26
8
9c
10
11
12
13
14
15
16
17
Reactions were monitored by TLC with Polygram Sil G/UV 254 (Ma-
chery & Nagel). Silica gel (Merck, Kieselgel 60) was used for flash
column chromatography. Chemicals were purchased from AIdrich,
Sigma or Fluka. Mass spectra (MS) and high resolution mass spectra
(HRMS) were measured with a Varian MAT 711 device.
1H, 13C and 19F NMR were measured with Bruker AC-250 and AM-
500 spectrometers at the spectroscopy department of the German
Cancer Reserch Center; difluorotetrachloroethane and TFA were
used as reference for 19F NMR shifts. Spectroscopic data of carbohy-
drate ring positions are presented in Tables 1 to 4. Chemical shifts of
protecting groups are given with the respective preparation procedure
(compounds 12–25). Stereocenters involved in a configuration
change were marked by R or S. Carbohydrate-derived names of prod-
ucts are noted in parentheses.
–
4.55
5.75
4.65
4.91
4.06
5.48
3.99
5.52
4.26
3.96
4.46
18
19
20c
21
22c
23c
24c
25c
5.56 3.11
3.01
5.47 4.50 4.13
5.34 3.64 to 3.75 4.45
5.42 3.57 4.07
5.47 4.03 4.18
to 3.77 4.07
3.81
3.65
4.44
4.18
4.32
4.52
(2R)-2-Hydroxy-6,8-dioxabicyclo[3.2.1]oct-3-ene (1,6-Anhydro-
2,3-dideoxy-b-D-threo-hex-2-enopyranose, 4):4
a Signal assignments were made according to the original
carbohydrate notation. A carbohydrate-derived nomen-
clature of compounds is given in the experimental part.
Chemical shifts are relative to 2,2,3,3-tetradeuterio-3-(tri-
methylsilyl)propanonic acid (TSP). Only ring protons are
D-Galactal 1 (0.453 g, 3.1 mmol) was dissolved in THF (45 mL) in
the presence of molecular sieves (0.4 nm, 5 g). H2SO4(r = 1.84,
0.1 mL) was added and the mixture was refluxed for 1 h, then allowed
to reach r.t. It was treated with Et3N (1 mL) and filtered. The solvent
was evaporated and the brown residue purified by flash chromatogra-
phy (CH2Cl2/EtOAc 4:1). Compound 4 eluted first and was obtained
as a colorless oil (0.159 g, 40%). The second fraction contained 5 as
a colorless oil (0.079 g, 20%).
considered. Most of the spectra could be analyzed by simple inspec-
tion. Compounds which contain protecting groups often show over-
lapping protons and are strongly second order. These signals were not
completely analyzed and the chemical shift values are the midpoints
of nearly first order multiplets. For chemical shifts of protecting
groups, see experimental part (compounds 12-19, 21–24).
b Indices a and b denote exo- and endo-protons at C-6.
4: Rƒ = 0.73 (EtOAc).
Anal. C6H8O3 calcd: C 56.25, H 6.29; found: C 56.20, H 6.22.
HRMS: calcd 128.0473 ; found 128.047.
517: Rƒ = 0.64 (EtOAc).
c d = OH: 4: 1.81; 9: 2.48; 20: 2.43; 22: 2.72; 23: 2.22; 24: 2.81; 25:
2.73 (2 H).
Anal. C6H8O3 calcd: C 56.25, H 6.29; found: C 56.15, H 6.20.

204
Papers
SYNTHESIS
Table 4. 19F NMR (235 MHz) Chemical Shift and Coupling Constant
Table 2. Coupling Constants JHH (Hz)a
Dataa
Com- 3J1,2
pound
3J2,3
3J3,4
3J4,5
3J5,6a 3J5,6b 3J6,6
Com-
pound
6
7
8
11
22
4
6
7
8
9
3.0
3.4
3.0
1.5
3.4
1.3
2.9
3.1
3.0
1.1
2.0
1.4
2.9
2.9
0.6
1.7
1.8
1.3
1.5
9.7
9.6
5.4
5.5
3.8
9.8
9.7
9.6
9.7
2.6
1.3
1.4
4.0
4.0
4.0
1.7
m
2.0
4.5
8.2
8.1
9.6
–
1.8
4.7
3.0
3.4
5.0
5.1
3.0
3.0
1.0
5.2
4.7
1.5
5.6
5.1
4.3
–
m
3.4
≈ 3.8
4.9
3.9
5.0
6.0
6.1
5.2
5.2
≈ 5.2
5.3
6.0
6.7
0.7
1.1
6.5
6.3
≈ 4.5
5.9
5.6
5.0
5.2
5.0
6.0
6.1
6.2
3.7
5.0
3.8
4.8
2.0
1.8
2.7
2.2
2.1
1.5
≈ 1.7
2.0
1.3
1.0
1.1
0.7
1.6
1.6
2.0
0.5
≈ 0.5
≈ 0.3
≈ 0.4
8.1
8.0
8.1
8.8
7.9
8.2
7.7
8.0
7.7
7.9
7.3
7.5
7.2
7.3
8.1
7.4
7.8
7.7
7.8
dF
–92.99
–40.40
–54.48
–16.85
–39.25
–115.62
J (Hz) 2J = 47.20 2J = 69.91 2J = 68.72 2J = 280.0 2J = 44.60
3J = 2.57 3J = 2.23 3J = 1.55 3J = 1.40 3J = 14.22
10
12
13
14
15
16
17
18
19
21
22
23
24
25
3J = 1.61
3J = 0.80 3J = 3.60
4J = 0.60
4J = 1.80 4J = 4.83 4J = 3.31
4J = 0.91 4J = 1.40
4J = 0.32 4J = 0.83
5J = 0.70 5J = 0.30 5J = 1.10
5J = 0.54
a
Chemical shifts are relative to TFA = 0 ppm. Coupling constants
were obtained from the peak frequency listing of either 1H or 19F
NMR spectra.
≈ 3.8
5.3
2.9
6,8-Dioxabicyclo[3.2.1]oct-3-en-2-one (1,6-Anhydro-2,3-dideoxy-
4-oxo-b-D-glycero-hex-2-enopyranose, 10) and 2,2-Difluoro-6,8-
dioxabicyclo[3.2.1]oct-3-ene (1,6-Anhydro-2,3,4-trideoxy-4,4-di-
fluoro-b-D-glycero-hex-2-enopyranose, 11):
1.5
1.3
2.3
a
Couplings were obtained from the peak frequency listing and
rounded to one decimal or were estimated from nearly first order
multiplets in each case. Assignments are according to the
carbohydrate notation (note a in Table 1). JHF and long range JHF
couplings were observed; values are shown in Table 4.
Compound 10 was prepared according to Lit.22; Rf = 0.31 (hexane/ac-
etone 4:1). Analytical data agree. 10 (0.599 g, 4.75 mmol) was dis-
solved in CH2Cl2 (6 mL) and DAST (0.528 mL, 4 mmol) was added.
The solution was stirred for 12 h. Water (5 mL) was added. The or-
ganic layer was separated and evaporated. Flash chromatography
(hexane/acetone 4:1) gave 11 (0.211 g, 30%) as a colorless oil.
11: Rƒ = 0.45 (hexane/acetone 4:1).
Anal. C6H6F2O2 calcd: C 48.67, H 4.05, F 25.66; found: C 48.50, H
4.00, F 25.50.
Table 3. 13C NMR Data (62.89 MHz, CDCl3)a
HRMS: calcd 148.0336; found 148.058.
Compound C-1
C-2
C-3
C-4
C-5
C-6
Preparation of O-Protected Derivatives of 4. Compounds 12–14:
4
6
7
8
9
95.80 129.15 128.35
95.20 133.55 121.70
75.25 67.87 62.25
83.75 74.15 61.30
1,6-Anhydro-4-O-benzyl-2,3-dideoxy-b-D-threo-hex-2-enopyra-
nose (12):
104.27
107.48
95.47
64.29 129.44 134.02 66.95 64.66
65.87 131.27 134.49 66.64 65.89
76.81 126.29 130.10 67.17 62.56
Compound 4 (0.150 g, 1.17 mmol) was dissolved in DMF (5 mL).
NaH (0.031 g, 1.3 mmol) was added and the mixture was stirred for
10 min. Benzyl bromide (0.2 mL, 1.68 mmol) was added. After stir-
ring for 30 min at 20°C, H2O (10 mL) was added. The mixture was
extracted with CCl4 (4 ´ 25 mL). The combined organic layers were
washed, dried and evaporated. The residue was purified by flash chro-
matography (hexane/ EtOAc 4:1) giving 12 (0.219 g, 86%) as a col-
orless oil; Rƒ = 0.47 (hexane/acetone 4:1).
10
11
12
13
14
15
16
17
18
19
21
22
23
24
25
96.04 127.12 147.33 194.51 79.63 62.72
95.60 135.10 122.00 163.00 75.50 75.50
95.83 128.33 127.11
95.95 130.06 125.51
95.93 128.43 127.84
74.66 73.47 62.55
72.77 70.30 63.05
74.47 74.66 62.81
64.00 73.08 64.80
70.17 73.62 65.21
63.82 72.59 65.25
69.15 72.56 63.55
68.12 68.25 63.74
70.46 71.98 63.51
71.48 72.13 64.02
73.99 73.85 65.26
71.99 72.40 64.35
64.51 75.19 63.14
101.50
100.78
100.91
97.08
97.11
97.05
46.68
46.94
46.28
57.35
57.45
50.80
88.30
79.17
62.72
48.38
48.56
69.31
70.41
48.03
47.72
48.50
67.02
64.01
68.05
69.19
Anal. C13H14O3 calcd: C 71.54, H 6.45; found: C 71.06, H 6.30.
HRMS: calcd 218.0943 ; found 218.238.
1H NMR (250 MHz, CDCl3): d = 4.55 (m, 3H, H-aCH2, H-4, H-5),
1
4.66 (d, 1H, H-bCH2, Ja,b = 11.9 Hz), 7.33 (m, 5H, arom.).
13C NMR (62,89 MHz, CDCl3): d = 71.10 (-CH2Ph), 127.45, 127.76,
98.90
128.10 (arom.), 137.70 (arom.).
101.15
100.34
100.94
4-O-Acetyl-1,6-anhydro-2,3-dideoxy-b-D-threo-hex-2-enopyra-
nose (13):
Stirring of 4 (0.220 g, 1.72 mmol) in pyridine (3 mL) and Ac2O
(2.8 mL) for 12 h afforded the acetate 13 (0.278 g, 95%) as a colorless
oil, following standard workup and flash chromatography (CH2Cl2/
EtOAc 4:1); Rƒ = 0.66 (hexane/EtOAc 1:1).
a
For chemical shifts of protecting groups of compounds 12–19 and
21–24 see experimental part.
Anal. C8H10O4 calcd: C 56.44, H 5.87; found: C 56.35, H 5.75.
HRMS: calcd 170.0579; found 170.059.
(4S)-4-Hydroxy-6,8-dioxabicyclo[3.2.1]oct-2-ene (1,6-Anhydro-
3,4-dideoxy-b-D-threo-hex-3-enopyranose, 9):
1H NMR (250 MHz, CDCl3): d = 2.09 (s, 3H, H-CH3).
13C NMR (62.89 MHz, CDCl3): d = 20.91 (-CH3), 170.16 (C=O).
4 (0.120 g, 0.94 mmol) was dissolved in DMF (5 mL) and cooled to
–50 °C. DAST (0.265 mL, 2 mmol) was added and the mixture was
stirred for 20 min. H2O (5 mL) was added. The solvent was evaporat-
ed and the residue was purified by flash chromatography (CH2Cl2/
EtOAc 4:1) to give 9 (0.060 g white solid, 50%); Rƒ = 0.54 (EtOAc);
mp 66 °C (in agreement with Lit.19, 22).
1,6-Anhydro-2,3-dideoxy-4-O-[2-(trimethylsilyl)ethoxymethyl]-
b-D-threo-hex-2-enopyranose (14):
i-Pr2NH (r = 0.772, 0.525 mL, 4 mmol) and SEMCl (r = 0.942, 4 mL,
22.6 mmol) were added to a solution of 4 (0.210 g, 1.64 mmol) in

February 1998
SYNTHESIS
205
CH2Cl2 (2 mL). The mixture was stirred for 3 h, then water (20 mL) 19: Rƒ = 0.43 (hexane/acetone 3:2).
was added. The organic layer was separated and evaporated. Flash Anal. C8H10O5 calcd: C 51.63, H 5.37; found: C 51.40, H 5.20.
chromatography (hexane/EtOAc 4:1) delivered 14 (0.381 g, 90%) as 1H NMR (250 MHz, CDCl3): d = 2.15 (s, 3H, H-CH3).
a colorless oil; Rƒ = 0.46 (hexane/EtOAc 7:3).
13C NMR (62.89 MHz, CDCl3): d = 20.79 (-CH3), 170.15 (C=O).
Anal. C12H22O4Si calcd: C 55.84, H 8.52; found: C 55.80, H 8.50.
20: Rƒ = 0.33 (hexane/acetone 3:2).
1H NMR (500 MHz, CDCl3): d = 0.02 (s, 9H, -SiCH3), 0.92 (m, 2H, 1H NMR (250 MHz, CDCl3): d = 2.43 (s, 1H, OH).
H-C3¢), 3.61 (m, 2H, H-C2¢), 4.75 (m, 2H, H-C1¢, 3J = 11.9 Hz, 3J =
8.0 Hz).
1,6:2,3-Dianhydro-4-O-benzyl-b-D-gulo-pyranose (21):
13C NMR (62.89 MHz, CDCl3): d = –1.46 (-SiCH3), 18.14 (C-3¢), Derivative 12 (0.523 g, 2.4 mmol) was dissolved in CH2Cl2 (5 mL)
65.47 (C-2¢), 94.84 (C-1¢).
and stirred at r.t. for 24 h in presence of anhyd mCPBA. Then sat.
aq Na2CO3 was added. The mixture was evaporated nearly to dryness
and the residue was extracted several times with portions of hexane/
acetone (4:1, 50 mL in total). The combined extracts were concentrat-
ed. Flash chromatography (hexane/acetone 5:1) gave 21 (0.320 g,
57%) as a colorless oil; Rƒ = 0.39 (hexane/acetone 4:1). Analytical
data compare well with 18; C13H14O4 found: C 66.80, H 6.12.
4-O-Acetyl-1,6-anhydro-2,3-dibromo-2,3-dideoxy-b-D-galactopy-
ranose (15):
Derivative 13 (0.187 g, 1.1 mmol) was dissolved in CCl4 (2 mL). Br2
(0.176 g, 1.1 mmol) was added at 0 °C. The reaction was complete af-
ter 10 min and the solvent was evaporated. Flash chromatography
(hexane/EtOAc 9:1) delivered 15 (0.261 g, 95%) as a colorless oil; Rƒ
= 0.70 (hexane/EtOAc 1:1).
1,6-Anhydro-4-O-benzyl-2-deoxy-2-fluoro-b-D-galactopyranose
(22):
Anal. C8H10Br2O4 calcd: C 29.10, H 3.03, Br 48.44; found: C 29.00,
H 2.95, Br 48.30.
Compound 18 (0.0492 g, 0.21 mmol) was dissolved in ethylene gly-
col (2 mL). KHF2 (0.050 g, 0.64 mmol) was added and the mixture
was refluxed for 24 h.24 Aq 15% K2CO3 (15 mL) was added. It was
extracted with CHCl3 (3 ´ 10 mL). The combined organic layers were
washed with water (5 mL), dried and evaporated. Flash chromatogra-
phy (hexane/EtOAc 5:1) gave 22 (0.011 g, 20%) as a colorless oil; Rƒ
= 0.43 (hexane/acetone 4:1).
HRMS: calcd 327.8946; found 249.976 (M+-Br).
1H NMR (250 MHz, CDCl3): d = 2.15 (s, 3H, H-CH3).
13C NMR (62.89 MHz, CDCl3): d = 20.65 (-CH3), 167.20 (C=O).
Reaction with Acetyl Hypobromite. 3-O-Acetyl-1,6-anhydro-4-O-
benzyl-2-bromo-2-deoxy-b-D-galactopyranose (16) and 3,4-Di-O-
acetyl-1,6-anhydro-2-bromo-2-deoxy-b-D-galactopyranose (17):
Derivative 12 (0.109 g, 0.5 mmol) or 13 (0.357 g, 2.1 mmol) was dis-
solved in CCl4 (5 mL). Freshly prepared acetyl hypobromite23 was
added (about 0.5 mmol for 12; about 2.1 mmol for 13) and the mixture
was stirred for 12 h at 20°C. After addition of H2O (5 mL), the organ-
ic layer was separated, dried and evaporated. Flash chromatography
gave 16 (0.164 g, 92%, hexane/acetone 6:1) or 17 (0.422 g, 65%, hex-
ane/EtOAc 4:1) as colorless oils.
Anal. C13H15FO4 calcd: C 61.41, H 5.94, F 7.47; found: C 61.60, H
5.81, F 7.22.
HRMS: calcd 254.0954; found 254.094.
1H NMR (250 MHz, CDCl3): d =2.72 (dd, 1H, OH), 4.68 (d, 2H, H-
CH2, 2J = 11.9 Hz), 7.35 (m, 5H, arom.).
13C NMR (62.89 MHz, CDCl3): d = 72.17 (-CH2Ph), 127.91, 128.53,
128.80, 136.96 (arom.).
16: Rƒ = 0.35 (hexane/acetone 4:1).
1,6-Anhydro-4-O-benzyl-2-chloro-2-deoxy-b-D-galactopyranose
(23):
Anal. C15H17BrO5 calcd: C 50.44, H 4.79, Br 22.37; found: C 50.30,
H 4.61, Br 22.05.
A mixture of 18 (0.300 g, 1.28 mmol) and tetrabutylammonium chlo-
ride (2 mg) was refluxed in 1,1,2,2-tetrachloroethane (3 mL) for 12 h.
The mixture was cooled and the solvent was evaporated. Product 23
(0.121 g, 35%) was isolated after chromatography (hexane/EtOAc
gradient 7:1–4:1) as a waxy white solid; Rƒ = 0.35 (hexane/EtOAc
4:1).
HRMS: calcd 356.0259; found 356.025 (M+-H).
1H NMR (250 MHz, CDCl3): d = 2.04 (s, 3H, H-CH3), 4.38 (m, 3H,
2
H-aCH2, H-5), 4.54 (d, 1H, H-bCH2, Ja,b = 11.9 Hz), 7.25 (m, 5H,
arom.).
13C NMR (62.89 MHz, CDCl3): d = 20.90 (-CH3), 71.79 (-CH2PH),
127.71, 128.1, 128.54, 137.27 (arom.), 169.56 (C=O).
Anal. C13H15ClO4 calcd: C 57.68, H 5.57, Cl 13.09; found: C 57.77,
H 5.41, Cl 13.35.
17: Rƒ = 0.18 (hexane/EtOAc 3:1).
HRMS: calcd 235.0970; found 235.097 (M+-Cl).
1H NMR (250 MHz, CDCl3): d = 2.2 (s, 1H, OH), (d, 1H, H-aCH2,
2Ja,b = 11.7 Hz), 4.82 (d, 1H, H-bCH2), 7.35 (m, 5H, arom.).
13C NMR (62.89 MHz, CDCl3) : d = 76.35 (-CH2Ph), 127.95, 128.21,
128.58, 137.42 (arom.).
Anal. C10H13BrO6 calcd: C 38.86, H 4.20, Br 25.85; found: C 38.70,
H 4.10, Br 25.19.
1H NMR (250 MHz, CDCl3): d = 2.04, 2.08 (s, s, 6H, H-CH3).
13C NMR (62.89 MHz, CDCl3): d = 20.54 (-CH3), 20.73 (-CH3),
169.07 (C=O), 169.50 (C=O).
1,6:2,3-Dianhydro-b-D-talo-pyranose (20) and Its O-Protected
Analogs 18 and 19:
1,6-Anhydro-2-azido-4-O-benzyl-2-deoxy-b-D-galactopyranose
(24):
The bromo derivatives 16 (0.997 g, 2.8 mmol) and 17 (0.989 g,
3.2 mmol) were dissolved in MeOH/H2O (8:1) by volume (80 mL)
and K2CO3 (0.5 g) was added. The respective solutions were stirred
for 3 d at r.t. Evaporation of solvent and chromatography (hexane/
EtOAc 4:1) delivered 18 (1,6:2,3-dianhydro-4-O-benzyl-b-D-talo-
pyranose; 0.524 g, 80%, colorless wax) from substrate 16, and 20
(1,6:2,3-dianhydro-b-D-talo-pyranose; 0.364 g, 78%, colorless oil)
from substrate 17. Stirring of crude 20 for 12 h in pyridine (10 mL)
and Ac2O (9 mL) afforded after chromatography (hexane/EtOAc 4:1)
19 (4-O-acetyl-1,6:2,3-dianhydro-b-D-talo-pyranose; 0.440 g, 73%,
colorless oil). Analytical data of 18–20 agree with Lit.1, 16, 20. 22. 24
Substrate 18 (0.492 g, 2.1 mmol) was dissolved in EtOH (120 mL),
H2O (30 mL) and NH4Cl (0.749 g, 14 mmol) and a large excess of
NaN3 (0.748 g, 11.5 mmol) was added. The mixture was refluxed for
48 h. Solvents were evaporated and the product was separated by
flash chromatography (hexane/EtOAc 4:1) giving 24 (0.314 g, 54%)
as a thick white oil; Rƒ = 0.20 (hexane/EtOAc 4:1).
Anal. C13H15N3O4 calcd: C 56.31, H 5.44, N 15.21; found: C 56.17,
H 5.31, N 15.28.
1H NMR (250 MHz, CDCl3): d = 2.81 (d, 1H, OH), 4.65 (d, 1H, H-
2
aCH2, Ja,b = 11.7 Hz), 4.70 (d, 1H, H-bCH2), 7.25-7.38 (m, 5H,
arom.).
13C NMR (62.89 MHz, CDCl3): d = 72.19 (-CH2Ph), 127.89, 128.51,
18: Rƒ = 0.27 (hexane/acetone 4:1).
Anal. C13H14O4 calcd: C 66.66, H 6.01; found: C 65.50, H 5.95.
128.77, 136.92 (arom.).
HRMS : calcd 234.0892; found 234.088.
2
1H NMR (250 MHz, CDCl3): d = 4.67 (d, 1H, H-aCH2, Ja,b
=
1,6-Anhydro-2-bromo-2-deoxy-b-D-galactopyranose (25):
Acetate 19 (0.201 g, 1.08 mmol) was dissolved in MeCN (0.5 mL)
and KBr (0.357 g, 3 mmol) was added. The mixture was refluxed for
3 h. Evaporation of the solvent followed by chromatography (hexane/
11.9 Hz), 4.82 (d, 1H, H-bCH2), 7.35 (m, 5H, arom.).
13C NMR (62.89 MHz, CDCl3): d = 71.22 (-CH2Ph), 127.70, 128.09,
128.57, 137.65 (arom.).

206
Papers
SYNTHESIS
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