Highly functionalised cyclopentanes by radical cyclisation of unsaturated bromolactones III. Preparation of carbaaldohexofuranoses. Determination of the relative configuration at C-4/C-5 of 2,3-unsaturated heptono-1,4-lactones by means of 1H NMR spectroscopy

Article abstract of DOI:10.1055/s-1999-3384

Two new carbaaldohexofuranoses, carba-β-D-glucofuranose and carba-α- L-mannofuranose, have been prepared using 5,6-O-isopropylidene-D-glycero-L- galacto-heptono-1,4-lactone (6) as the starting material. The key step was a highly stereoselective intramolecular 5-exo-trig radical cyclisation of C-2 substituted 2,3-unsaturated 7-bromo-7-deoxyheptono-1,4-lactones promoted by tributyltin hydride. Assignment of the configuration of the unsaturated lactones was based upon NMR data of related compounds. The starting material, compound 6, was obtained by chain elongation of D-gulose, and a facile method for separation of the epimers from the chain elongation has been developed. Thus 5,6-O-isopropylidene-D-glycero-L-galacto-heptono-1,4-lactone (6) and D- glycero-L-taloheptono-1,4-lactone (5) were isolated crystalline in ca. 30% and 10% yield, respectively.

Full text of DOI:10.1055/s-1999-3384

PAPER
317
Highly Functionalised Cyclopentanes by Radical Cyclisation of Unsaturated
Bromolactones III. Preparation of Carbaaldohexofuranoses.
Determination of the Relative Configuration at C-4/C-5 of 2,3-Unsaturated
1
Heptono-1,4-lactones by Means of H NMR Spectroscopy
Anne Marie Horneman, Inge Lundt*
Department of Organic Chemistry, Technical University of Denmark, Building 201, DK-2800 Lyngby, Denmark
Fax +45(4593)3968; E-mail: okil@pop.dtu.dk
Received 7 May 1998
D-Gulono-1,4-lactone (1) was reduced with sodium boro-
Abstract: Two new carbaaldohexofuranoses, carba-b-D-glucofura-
hydride to give D-gulose (2), which after treatment with
nose and carba-a-L-mannofuranose, have been prepared using 5,6-
aqueous sodium cyanide gave a mixture of D-glycero-L-
O-isopropylidene-D-glycero-L-galacto-heptono-1,4-lactone (6) as
galacto- and D-glycero-L-talo-heptonic acid 3 (Scheme 1).
the starting material. The key step was a highly stereoselective in-
tramolecular 5-exo-trig radical cyclisation of C-2 substituted 2,3-
unsaturated 7-bromo-7-deoxyheptono-1,4-lactones promoted by
tributyltin hydride. Assignment of the configuration of the unsatur-
ated lactones was based upon NMR data of related compounds. The
starting material, compound 6, was obtained by chain elongation of
D-gulose, and a facile method for separation of the epimers from the
chain elongation has been developed. Thus 5,6-O-isopropylidene-
D-glycero-L-galacto-heptono-1,4-lactone (6) and D-glycero-L-talo-
heptono-1,4-lactone (5) were isolated crystalline in ca. 30% and
The separation of these isomers has already been reported
10
by other groups. As early as 1920, La Forge described the
purification of D-glycero-L-galacto-heptonic acid via crys-
11
tallisation of the barium salt. Isbell obtained both D-glyc-
ero-L-galacto-heptonic acid and D-glycero-L-talo-heptonic
acid in low yields by repeated crystallisation of the lead
12
salts. Hudson et al. separated the isomers by fractional
crystallisation of the corresponding phenylhydrazides, ob-
taining D-glycero-L-galacto- and D-glycero-L-talo-hepton-
ic phenylhydrazide in 36% and 34% yield, respectively.
1
0% yield, respectively.
Key words: carbasugars, radical cyclisation, bromoaldonolactones,
13
2
,3-unsaturated 1,4-aldonolactones, heptonolactones
Recently Fleet and co-workers obtained the protected de-
rivatives 3,4:6,7-di-O-isopropylidene-D-glycero-L-galac-
1
Polyoxygenated cyclopentanes have attracted attention
2
as structural elements of carbocyclic nucleosides and
3
glycosidase inhibitors and as carbocyclic analogues of
carbohydrates,4 often referred to as carbasugars. The car-
bocyclic analogues are resistant to hydrolysis due to the
lack of an acetal moiety, making them interesting com-
pounds from a biological point of view.
,5
We have recently reported the preparation of the first car-
baaldohexofuranoses starting from 7-bromo-7-deoxy-
6
heptono-1,4-lactones. The bromolactones were convert-
ed into C-2 substituted 2,3-unsaturated 7-bromo-7-deoxy-
heptono-1,4-lactones, which upon treatment with tributyl-
tin hydride underwent a highly stereoselective intramo-
7
lecular 5-exo-trig radical cyclisation to give cyclopentane
derivatives. These, in turn, could be converted to carbaal-
dohexofuranoses and carbapentofuranoses. This synthesis
of carbasugars is short and high yielding, and the carba-
sugars are obtained optically pure, as the starting com-
pounds are obtained from the chiral pool. However,
access to other isomers of carbahexofuranoses by this
strategy is limited by the availability of bromodeoxyhep-
tono-1,4-lactones.8 Our next aim was, therefore, the
preparation of new isomers of bromodeoxyheptono-1,4-
lactones and their subsequent conversion to new carba-
hexofuranoses. Retrosynthesis showed that chain elonga-
tion of D-gulose to give the epimers D-glycero-L-galacto-
heptono-1,4-lactone and D-glycero-L-talo-heptono-1,4-
lactone would finally lead to new carbahexofuranoses.
,9
+
+
+
(
a) NaBH , H ; (b) NaCN; (c) acetone, H ; (d) H O ; (e) PhNHNH .
4
3
2
Scheme 1
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart á New York

3
18
A. M. Horneman, I. Lundt
PAPER
to-heptono-1,5-lactone and 2,3:6,7-di-O-isopropylidene-D-
glycero-L-talo-heptono-1,5-lactone in 11% and 16% yield,
respectively, by cyanohydrin chain elongation of 2,3:5,6-
di-O-isopropylidene-D-gulofuranose followed by chro-
matographic separation of the isomers.
HudsonÕs procedure12 for the separation of isomers
seemed the most rewarding, and, thus, the heptonic acids
were converted to the corresponding phenylhydrazides,
but repeated attempts to separate the isomers by fractional
crystallisation were unsuccessful since only 2Ð4% D-glyc-
ero-L-galacto-heptonic phenylhydrazide (9) was ob-
tained. HudsonÕs procedure describing the reaction of
aldonic acids and phenylhydrazine to give the hydrazides
was, therefore, modified slightly, since it seemed more ef-
ficient to prepare hydrazides from a lactone rather than
from an acid. The two isomeric heptonic acids were lacto-
nised by concentration from acidic solution prior to reac-
tion with phenylhydrazine. Crystallisation gave in this
case 27% D-glycero-L-galacto-heptonic phenylhydrazide
Scheme 2
(9), which by acidic hydrolysis gave D-glycero-L-galacto-
heptono-1,4-lactone (7) (Scheme 1). Crystallisation of the
second isomer, D-glycero-L-talo-heptonic phenylhy-
drazide (8), could not be reproduced. Yields in the modi-
fied Hudson procedure were modest and only one isomer
was isolated, and a search for a better separation strategy
was therefore undertaken. Isopropylidenation of the mix-
ture of epimeric heptono-1,4-lactones 3 was expected to
give mono- and diprotected lactones which presumably
could be separated by a simple extraction procedure. This
strategy was inspired by the work of Fleet et al. on
acetonides of octonolactones in which the separation of
acetals of the epimeric octonolactones relied on chro-
matographic methods. In our case, 3 was refluxed in acid-
ic acetone to give isopropylidene-protected heptonol-
actones which were partitioned between the aqueous and
organic phases. From the aqueous phase 5,6-O-isopropy-
lidene-D-glycero-L-galacto-heptono-1,4-lactone (6) was
obtained in 36% yield from 1 which could be used directly
for further synthesis. After chromatography 6 was ob-
tained crystalline in 30% yield. Crude di-O-isopropy-
lidene-protected D-glycero-L-talo-heptono-1,4-lactone 4
was found in the organic phase. In order to remove some
lipophilic byproducts the organic phase was extracted
with aqueous sodium hydroxide and the alkaline water
phase was acidified. Deionisation with acidic ion ex-
change resin gave crystalline D-glycero-L-talo-heptono-
mediate acetoxonium ion occurs with inversion of config-
uration. The bromolactone 10 could also be prepared by
treatment of 5,6-O-isopropylidene-D-glycero-L-galacto-
heptono-1,4-lactone (6) with HBr in HOAc for 40 min-
utes. In this case, the yield of the monobrominated lactone
1
0 was 71%, while the dibrominated lactone 11 was ob-
tained in 24% yield.
2
1
-Substituted 2,3-unsaturated 7-bromo-7-deoxyheptono-
1
4
,4-lactones were the starting materials for intramolecular
6
radical cyclisations as in previous related work. For the
introduction of the double bond b-elimination of acetic
acid was considered. Compound 10 was protected at the
exocyclic hydroxy groups with an isopropylidene group
to afford compound 12, and the hydroxy groups at C-2
and C-3 were acetylated using acetic anhydride and tri-
ethylamine (Scheme 3). b-Elimination of acetic acid and
isomerisation at C-4 occurred in the same step to give a
mixture of the unsaturated lactones having D-xylo- (13)
and D-lyxo-configuration (14), which were isolated by
chromatography in 31% and 21% yield, respectively. Pre-
vious experience has shown that the base induced isomer-
6
,16
isation at C-4 is difficult to avoid. The assignment of
the configuration at C-4 of the unsaturated heptonolac-
tones will be discussed below. Attempts to cyclise 13 and
1
4 by reaction with tributyltin hydride gave only the 7-
deoxy analogues of the starting material. The radical cy-
clisations were hindered by the trans-oriented isopropyl-
idene groups, so the isopropylidene groups were removed
using aqueous trifluoroacetic acid to give the correspond-
ing lactones 15 and 18. When the unsaturated lactone 15
was reacted with tributyltin hydride cyclisation took place
to give 16 (89%) and 17 (4%), which were separated by
1
,4-lactone (5) in 10% yield from 1.
Bromodeoxyaldonolactones can be prepared from al-
donolactones by treatment with HBr in HOAc as de-
9
,15
scribed previously.
heptono-1,4-lactone (7) was stirred with HBr in HOAc for
0 minutes 7-bromo-7-deoxy-D-glycero-L-galacto-hep-
When D-glycero-L-galacto-
2
tono-1,4-lactone (10) was isolated in 70% yield together
with 4% of a dibromoheptonolactone, tentatively assigned
1
flash chromatography. H NMR spectroscopy showed 16
and 17 to be C-4 epimers, and the configurations at C-4
were determined by the coupling constants between H-4
and H-5; the larger coupling constant, J4,5 = 10 Hz (16),
indicating cis-oriented protons, and the smaller coupling
constant, J4,5 = 4.5 Hz (17), indicating trans-oriented pro-
as
6,7-dibromo-6,7-dideoxy-L-glycero-L-galacto-hep-
tono-1,4-lactone (11) (Scheme 2). Assignment of the con-
figuration at C-6 of the latter was based on the
experience9 that substitution with bromide of the inter-
,15
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of Carbaaldohexofuranoses
319
tons. Similarly, the reaction of 18 with tributyltin hydride
gave a major cyclisation product 19 (81%), and the C-4
epimer 20 (10%) as a minor product. The assignment of
configuration was again based on coupling constants be-
tween H-4 and H-5, J4,5 = 9.5 Hz (19) indicating cis-ori-
ented protons and J4,5 = 6.5 Hz (20) indicating trans-
oriented protons. The high stereoselectivity in the ring-
closure reactions can be explained by steric shielding of
6
,17a
the enolate radical by the cyclopentane ring.
+
(
a) BH •SMe ; (b) Ac O, H .
3
2
2
Scheme 4
tem.17a The carbahexofuranoses 21 and 23 were acetylated
for characterisation to give 22 and 24 respectively. Thus,
two new carbaaldohexofuranoses have been prepared,
new types of compounds which we have recently de-
6
scribed.
The b-elimination step described above was accompanied
by isomerisation at C-4 to give two 2-acetoxy-2,3-un-
saturated heptono-1,4-lactones 13 and 14. In order to elu-
cidate the configuration at C-4 of 13 and 14, two
configurationally related unsaturated heptonolactones
were prepared from the known 2,3-unsaturated hep-
1
7a
tonolactone (25)
(Scheme 5). Compound 25 was
deacetylated by reaction with acidic methanol to give 26
and the exocyclic hydroxy groups were protected with an
isopropylidene group to give 7-bromo-7-deoxy-5,6-di-
O-isopropylidene-D-lyxo-hept-2-enono-1,4-lactone (27)
(Scheme 5). Treatment of 27 with triethylamine in di-
chloromethane caused epimerisation at C-4 to give 7-
bromo-2,3,7-trideoxy-5,6-di-O-isopropylidene-D-xylo-hept-
Scheme 3
2-enono-1,4-lactone (28). The configuration at C-4 of the
related compounds 13 and 14 was established by compar-
The yields in the flash chromatographic separation of 13
and 14 were low because the compounds were close run-
ning and repeated chromatographic separations were nec-
essary. It was found that the total yield of 16 and 19 was
raised if 13 and 14 were not separated, but used directly in
the hydrolysis step followed by flash chromatographic
separation of 16 and 19 after the cyclisation step. In this
way 16 was isolated in 24% yield and 19 in 22% yield
based on the starting material 12.
The bicyclic compounds 16 and 19 were both converted to
carbaaldohexofuranoses by reduction of the lactone moi-
ety and the acetoxy group (Scheme 4). Thus reduction of
16 using boraneÐdimethyl sulfide complex gave carba-b-
D-glucofuranose (21) and similar reduction of 19 gave
carba-a-L-mannofuranose (23). It should be noted that the
boraneÐdimethyl sulfide reductions of 16 and 19 were
considerably slower than reduction of similar compounds
without an oxy-substituent at C-4 in the bicyclic sys-
Scheme 5
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

3
20
A. M. Horneman, I. Lundt
PAPER
Table 1 1 H NMR Data for Determination of the Relative Configura-
tion of C-4 and C-5 in 2,3-Unsaturated Aldonolactones
ison with the coupling constants between H-4 and H-5 in
7 (J4,5 = 8.0 Hz) and 28 (J4,5 = 2.0 Hz). Compound 13
J4,5 = 2.0 Hz) was thereby established to be 2-O-acetyl-7-
bromo-3,7-dideoxy-5,6-O-isopropylidene-D-xylo-hept-2-
enono-1,4-lactone, and compound 14 (J4,5 = 7.0 Hz) was
established to be 2-O-acetyl-7-bromo-3,7-dideoxy-5,6-O-
isopropylidene-D-lyxo-hept-2-enono-1,4-lactone.
2
(
Compound
R'
R''
J4,5
H-4
Ref
(Hz)
d
H
OAc
H
Ac
1.5
1.2
2.5
2.5
2.5
5.30
5.36
5.38
5.24
5.49
17
6
17
6
C(CH3)2
C(CH3)2
Ac
In the course of our program of preparing carbasugars via
radical cyclisations of unsaturated lactones we have pre-
pared a series of 2,3-unsaturated heptono-1,4-lactones,
and occasionally assignment of the configuration at C-4
has demanded more detailed studies as exemplified
above. Structure determination by comparison with NMR
data of 2,3-unsaturated aldono-1,4-lactones known from
the literature did not always allow a definite assign-
ment.1 Furthermore, the empirical rule set up by Casir-
N3
NHCOCF3 Ac
6
4
,5-threo
,5-threo
a
OAc
OAc
H
C(CH3)2
H
C(CH3)2
2.0
5.5
2.0
5.17
5.20
5.25
(13)
(15)
(28)
a
a
8,19
19
aghi et al. stating that 2,3-unsaturated g-lactones having
the ÔtailÕ group ÔupÕ in the conventional HaworthÕs depic-
tion display levorotation, while those bearing this group
ÔdownÕ show dextrorotations has in our case not been use-
ful, as the compounds in question have displayed optical
4
H
Ac
C(CH3)2
H
6.0
7.0
7.0
8.0
5.15
5.02
5.09
5.01
17
a
OAc
OAc
H
(14)
a
a
6
(18)
(27)
rotations of the same sign, e.g. compound 15 and 18. For
C(CH3)2
this reason we have confirmed the structures via chemical
6
proofs. We have, however, observed some general trends
in the NMR spectra of 2,3-unsaturated heptono-1,4-lac-
tones which may be helpful in the structure determination
of related compounds (Table 1). The coupling constant
between H-4 and H-5 indicates whether the configuration
is 4,5-erythro or 4,5-threo. Thus J4,5 of the 4,5-threo con-
figurated hept-2-enono-1,4-lactones was generally found
in the range of 1Ð2.5 Hz, with the exception of compound
4,5-erythro
OAc
H
C(CH3)2
C(CH3)2
9.0
9.5
5.03
5.05
6
17
1
5 (J4,5 = 5.5 Hz), whereas J4,5 of 4,5-erythro configurated
hept-2-enono-1,4-lactones was larger, between 6 and
.5 Hz. The chemical shift of H-4 was generally found at
higher field for 4,5-erythro configurated hept-2-enono-
,4-lactones as compared to the corresponding 4,5-threo
configurated hept-2-enono-1,4-lactones.
4,5-erythro
a
9
This work.
1
reproducible method in contrast to the classical crystalli-
sations of various derivatives of D-glycero-L-galacto-hep-
Further evidence for the assignment of the relative config- tonic acid and D-glycero-L-talo-heptonic acid. D-glycero-
uration at C-4/C-5 of the 2,3-unsaturated-1,4-lactones L-galacto-Heptono-1,4-lactone was used as the starting
was obtained from chemical shifts of the bicyclic lac- material for the preparation of two new carbahexofura-
tones, which were formed by radical cyclisation of the un- noses, carba-b-D-glucofuranose and carba-a-L-manno-
1
3
saturated heptonolactones. The C chemical shift of C-1 furanose, via an intramolecular 5-exo-trig radical
in the bicyclic lactones indicates whether the relative con- cyclisation of 2,3-unsaturated 7-bromo-7-deoxyheptono-
figuration at C-1/C-8 (corresponding to C-4/C-5 in the un- 1,4-lactones. The relative configuration at C-4/C-5 of the
saturated lactones) is erythro or threo (Table 2). In the 2,3-unsaturated heptono-1,4-lactones was determined by
1
1
,8-erythro-configurated compounds C-1 is more shield- comparison with H NMR data of related compounds.
ed and therefore an absorption at higher field was ob-
served as compared to the corresponding 1,8-threo-
configurated compounds. Thus, for the 1,8-erythro-con-
figurated bicyclic lactones C-1 was observed at ca. d =
Mps are uncorrected. Optical rotations were determined on a Per-
kinÐElmer 241 polarimeter. NMR were recorded on Bruker AC-
250 and AM-500 instruments. For spectra in D O, either dioxane (d
2
8
0Ð82 (CDCl ) and d = 84Ð85 (D O) while C-1 of the 1,8- = 67.4), acetone (d = 29.8) or MeCN (d = 1.3) were used as the in-
3 2
13
ternal reference for C NMR, and the solvent peak (d = 4.63) for
threo-configurated bicyclic lactones was observed at ca. d
1
H NMR. For spectra in CDCl d = 76.9 was used as internal refer-
3
=
84Ð87 (CDCl ) and d = 88Ð89 (D O). These observa-
3
2
13
1
ence for C NMR and CHCl (d = 7.27) for H NMR.Column chro-
1
3
3
tions are supported by a previous C NMR study of cis/
trans substituted cyclopentanols.
matography was performed on silica gel 60, Merck (mesh 230Ð400,
particle size 0.040Ð0.63 mm) using the flash technique. D-Gulono-
2
0,21
1
,4-lactone was prepared from D-xylose.22 Bu SnH was prepared
In summary, we have reported a new strategy for the sep-
aration of isomers from cyanohydrin chain elongation of
D-gulose which relies on extraction. This is an easy and
3
23
from bis(tributyltin)oxide and polymethylhydrosiloxane. Reac-
tions involving Bu SnH or BH •SMe were performed under N .
3
3
2
2
All concentrations were performed in vacuo. Anhydrous solvents
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of Carbaaldohexofuranoses
321
Table 2 13C Chemical Shifts for Determination of the Relative Con-
figuration at C-1 and C-8 in cis-Fused 2-Oxabicyclo[3.3.0]oct-3-ones
13
C NMR (D O/dioxane, 62.9 MHz): d = 61.8 (C-6), 69.9, 70.2,
2
72.1, 74.6 (C-2, C-3, C-4, C-5), 94.7 (C-1).
The crude D-gulose (2) was stirred with basic ion exchange resin
Compound
R'
H
R''
C-1
d
Ref
17
(IRA-67, 100 mL). Filtration and concentration gave 2 (29.9 g,
1
66 mmol) which was dissolved in water (300 mL), and NaCN (9 g,
84.9b
183 mmol, 1 equiv) was added to the solution. The mixture was left
Ac
+
at r.t. overnight. Ion exchange resin (IR 120 H , 150 mL) was added
and stirred for 0.5 h. The aqueous solution was poured onto a col-
umn of ion exchange resin (IR 120 H , 200 mL) which was washed
with water until pH 6Ð7. The solvent was evaporated and the res-
idue was concentrated from toluene to give a mixture of the two
C-2 epimeric heptonolactones 3 as a syrup (31 g, 90%).
85.5b
84.3b
6
6
C(CH3)
2
+
Ac
1
,8-threo
1
3
C NMR (D O/dioxane, 62.9 MHz): d = 62.0, 62.1, (2 × C-7), 68.3,
2
6
8.7, 69.9, 70.0, 71.5, 72.9, 73.3 (C-2, C-3, C-5, C-6), 80.1, 86.2, (2
Ac
Ac
83.9b
6
×
C-4), 175.6, 178, (2 × C-1).
D-glycero-L-talo-Heptono-1,4-lactone (5) and 5,6-O-Isopro-
pylidene-D-glycero-L-galacto-heptono-1,4-lactone (6)
A mixture of the two epimeric heptono-1,4-lactones 3 (31 g,
149 mmol) was dissolved in anhyd acetone (300 mL) and TsOH
83.0b
17
88.3c
89.2c
H
H
6
(3 g) was added. The reaction flask was equipped with a Soxhlet ap-
paratus containing molecular sieves (3 •) and the solution was re-
fluxed for 22 h. The mixture was neutralised with ion exchange
resin (IR 67 OH washed in acetone), filtered and concentrated to
H
17
Ð
give a syrup. The residue was suspended in water (150 mL) and
H
86.7b
a(16)
washed with CH Cl (3 × 150 mL) and the combined organic phases
2
2
were extracted with water (50 mL).
Preparation of 5 from the Organic Phase: The combined organic
phases were extracted with 2 N NaOH (3 × 75 mL) and the com-
1
1
,8-threo
bined basic aqueous phases were acidified with ion exchange resin
H
H
Ac
H
79.8b
17
+
(
IR 120, H ) until pH 1, and stirring maintained for 1 h. The ion ex-
84.1c
change resin was filtered off and washed with water until neutral.
The filtrate was stirred with activated charcoal, filtered and concen-
trated to give the title compound as a syrup (5.39 g, 17%), which
crystallised upon standing. Recrystallisation from EtOH gave com-
17
H
80.5b
a(19)
,8-erythro
11
20
pound 5 (3.2 g, 10%); mp 139Ð141¡C (Lit. mp 145¡C); [a]D
11
20
+
25.4 (c = 4, H O) [Lit. [a]D +25.5].
H
H
C(CH3)2
H
82.2b
84.5c
79.8b
17
17
6
2
1
3
C NMR (D O/dioxane, 62.9 MHz): d = 63.1 (C-7), 69.4, 70.9,
2
71.1, 72.7, (C-2, C-3, C-5, C-6), 87.4 (C-4), 179.2 (C-1).
C(CH3)2
Preparation of 6 from the Aqueous Phase
1
,8-erythro
The combined aqueous phases were concentrated to give compound
6
as a syrup (13.3 g, 36% from 1) which was pure enough for further
a
This work. b CDCl . D O.
c
13
synthesis as seen from its C NMR spectrum. Purification by flash
chromatography (EtOAc) gave pure 6 (11.1 g, 30% from 1) which
crystallised upon standing at Ð18¡C. Recrystallisation from EtOAc/
hexane gave a
colourless crystalline compound; mp 98Ð100¡C; [a]D +59 (c = 1.0,
EtOH).
3
2
were obtained by storing over molecular sieves. Microanalysis were
carried out by Research Institute for Pharmacy and Biochemistry,
Prague, Czech Republic and Microanalytical Laboratory, Institute
for Physical Chemistry, University of Vienna, Austria. MS were ob-
tained on a VG TRIO-2 instrument by chemical ionisation mass
20
1
H NMR (CD OD, 500 MHz): d = 1.37, 1.41, (2 × CH ), 3.72 (d,
3
3
2
H, H-7, H-7'), 4.14 (m, 3H, H-4, H-5, H-6), 4.25 (dd, 1H, J3,4 = 7
spectrometry with NH as reagent gas.
3
Hz, H-3), 4.36 (d, 1H, J2,3 = 7.5 Hz, H-2).
1
3
D-glycero-L-galacto-Heptono-1,4-lactone and D-glycero-L-talo-
Heptono-1,4-lactone (3)
C NMR (CD OD, 62.9 MHz): d = 26.9, 27.5, (2 × CH ), 62.7 (C-
3 3
7), 75.4, 75.5, 77.0, 78.2, 79.7 (C-2, C-3, C-4, C-5, C-6), 111 (acetal
C), 176 (C-1).
D-Gulono-1,4-lactone (1) (30 g, 168 mmol) was dissolved in water
+
(
300 mL) and ion exchange resin (IR 120 H , 120 mL) was added.
+
+
CI-MS: m/z = 266 (M + NH ), 249 (M + H ).
4
The flask was cooled in an ice bath and NaBH (7.85 g, 207 mmol)
4
Anal. C H O (248.23): calcd C, 48.39; H, 6.50. Found C, 48.58;
H, 6.27.
was added slowly with stirring keeping pH 3Ð5. Stirring was main-
10 16
7
+
tained for 0.5 h after which time ion exchange resin (IR 120 H ,
1
50 mL) was added and the mixture was stirred for another 0.5 h.
The ion exchange resin was filtered off and the filtrate concentrated.
D-glycero-L-galacto-Heptonic Acid Phenylhydrazide (9)
The residue was concentrated from MeOH (5 × 100 mL) to give D-
A mixture of the two epimeric heptono-1,4-lactones 3 (33.5 g,
161 mmol) was dissolved in 50% EtOH (250 mL) and phenylhydra-
zine (19 mL, 193 mmol) was added. After refluxing for 3.5 h the mix-
ture was cooled to r.t. and EtOH was evaporated. The aqueous phase
2
0
24
gulose (2) as a syrup (ca. 30 g); [a] Ð18.3 (c = 1.1, H O) [Lit.
D
2
20
[
a] Ð20.4 (H O)].
D 2
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

3
22
A. M. Horneman, I. Lundt
PAPER
was washed with CH Cl (4 × 100 mL) and concentrated. The residue
7-Bromo-7-deoxy-5,6-O-isopropylidene-D-glycero-L-galacto-
2
2
was dissolved in warm 80% EtOH (30 mL) and the solution was left
at r.t. overnight during which time a precipitate formed. The precipi-
tate was suspended in 80% EtOH (20 mL), filtered and washed with
heptono-1,4-lactone (12)
Camphorsulfonic acid (0.65 g, 2.8 mmol) was added to a solution
of 10 (11.40 g, 42.1 mmol) in anhyd acetone (250 mL). The flask
was equipped with a Soxhlet apparatus containing molecular sieves
(3•) and the mixture was refluxed for 21 h. The solution was then
neutralised with excess NaHCO (5 g), filtered and concentrated.
The residue was dissolved in water (25 mL), extracted with EtOAc
80% EtOH to give the title compound 9 (13.70 g, 27%) as slightly
coloured crystals, mp 174Ð179¡C. Recrystallisation from 80% EtOH
1
2
raised the melting point; mp 190Ð192¡C (Lit. mp 193Ð194¡C);
3
2
0
12
20
[
a] Ð12.0 (c = 1.0, H O) [Lit. [a]D Ð11.2 (c = 1.0, H O)].
D
2
2
13
(4 × 25 mL) and the organic phases dried (Na
2 4
SO ) and concentrat-
C NMR (D O/acetone, 62.9 MHz): d = 62.0 (C-7), 68.9, 69.3,
2
ed. The crude product was purified by flash chromatography
7
1
0.4, 70.6, 72.8, (C-2, C-3, C-4, C-5, C-6), 113.1, 120.7, 129.0,
46.8 (phenyl), 175 (C-1).
EtOAc/hexane 1:1) to give 12 as a syrup (10.92 g, 83%); [a]2
0
(
D
+
50.5 (c = 0.3, EtOH).
1H NMR (CDCl
, 500 MHz): d = 1.42, 1.47 (2 × CH
OH), 3.50 (dd, 1H, J6,7'
D-glycero-L-galacto-Heptono-1,4-lactone (7)
3
3
), 3.21 (bd,
=
7 Hz, H-7), 3.59 (dd, 1H, J6,7' = 4.5, J7,7'
=
Phenylhydrazide 9 (10.0 g, 31.6 mmol) was dissolved in warm wa-
+
ter (100 mL), ion exchange resin (IR 120 H , 300 mL) was added
1
0.5 Hz, H-7'), 3.63 (bd, OH), 4.48 (bd, 1H, H-2), 4.21 (dd, 1H, J5,6
=
7.6 Hz, H-5), 4.37 (dd, 1H, J3,4 = 7.5, J4,5 = 2.5 Hz, H-4), 4.40
and the mixture refluxed for 5 h. Filtration and evaporation gave
compound 7 as a coloured foam (7.0 g, quant). The crude product
was used without further purification.
(ddd, 1H, H-6), 4.52 (bdd, 1H, J2,3 = 7 Hz, H-3).
13
C NMR (CDCl , 62.9 MHz): d = 27.2, 26.6 (2 × CH ), 31.7 (C-7),
3
3
1
3
C NMR (D O, 62.9 MHz): d = 62.1 (C-7), 68.7, 71.4, 72.9, 73.3
74.1, 74.6, 75.1, 77.6, 78.9 (C-2, C-3, C-4, C-5, C-6), 110.9 (acetal
C), 174.5 (C-1).
2
(
C-2, C-3, C-5, C-6), 80.0 (C-4), 175.5 (C-1).
CI-MS: m/z = 328, 330 ( Br, Br, M + NH ), 311, 313 ( Br, 81Br,
79
81
+
79
4
+
7
-Bromo-7-deoxy-D-glycero-L-galacto-heptono-1,4-lactone (10)
M + H )
Procedure A: From 7: Heptonolactone 7 (7.0 g, 31.6 mmol) was
dissolved in glacial HOAc (7 mL) at ca. 80¡C. The solution was
cooled to r.t. and then 37% HBr in HOAc (45 mL) was added. The
mixture was stirred vigorously for 20 min to obtain a homogeneous
solution. MeOH (70 mL) was added and the mixture was left at r.t.
overnight. The solvent was evaporated and the residue was concen-
trated from water (3 × 50 mL) and toluene (50 mL). The syrup was
purified by flash chromatography (EtOAc) to give the title com-
pound 10 as colourless crystals (6.01 g, 70%), mp 119Ð122¡C; Rf
Anal. C H BrO (311.13): calcd C, 38.60; H, 4.86. Found C,
10
15
6
3
8.73; H, 4.94.
2
-O-Acetyl-7-bromo-3,7-dideoxy-5,6-O-isopropylidene-D-xylo-
hept-2-enono-1,4-lactone (13) and 2-O-Acetyl-7-bromo-3,7-
dideoxy-5,6-O-isopropylidene-D-lyxo-hept-2-enono-1,4-lactone
(14)
Bromolactone 12 (1.00 g, 3.2 mmol) was dissolved in Ac O
2
(
2.43 mL, 25.7 mmol) and Et N (1.79 mL, 12.8 mmol) and left at r.t.
3
0
1
.30 (EtOAc). Repeated crystallisations from EtOAc gave mp 125Ð
2
0
for 0.5 h after which the solvents were evaporated. The residue was
26¡C; [a] +52 (c = 0.4, MeOH).
D
dissolved in CH Cl (20 mL), washed with water (4 × 20 mL), dried
2
2
A dibromoheptonolactone, tentatively assigned as 6,7-dibromo-
,7-dideoxy-L-glycero-L-galacto-heptono-1,4-lactone (11), was
(
MgSO ) and concentrated. The two isomers were separated by re-
4
6
peated flash chromatography (EtOAc/CH Cl2 1:100) to give 2-
2
isolated as a solid (0.4 g, 4%); R 0.65 (EtOAc).
f
O-acetyl-7-bromo-3,7-dideoxy-5,6-O-isopropylidene-D-lyxo-hept-2-
enono-1,4-lactone (14) (0.23 g, 21%); R 0.48 (CH Cl /EtOAc 40:1);
f
2
2
20
Procedure B: From 6
Protected heptonolactone 6 (0.50 g, 2.0 mmol) was suspended in
[a] +39 (c = 1.2, CHCl ) and 2-O-acetyl-7-bromo-3,7-dideoxy-5,6-
D 3
O-isopropylidene-D-xylo-hept-2-enono-1,4-lactone (13) (0.33 g,
2
0
3
7% HBr in HOAc (4 mL) and the suspension was stirred vigorous-
31%); R 0.42 (CH Cl /EtOAc 40:1); [a] Ð1.2 (c = 2 CHCl ) as co-
f
2
2
D
3
ly for 40 min. MeOH (10 mL) was added and the solution was left
at r.t. overnight. The solvents were evaporated and the residue was
concentrated from water (3 × 30 mL) and toluene (30 mL). Flash
chromatography (EtOAc) gave 10 (0.39 g, 71%) and 11 (0.16 g,
lourless syrups.
Compound 13
1
H NMR (CDCl , 500 MHz): d = 1.30, 1.35, (2s, 6H, 2 × CH ), 2.24
3
3
2
4%).
(
s, OAc), 3.39 (dd, 1H, H-7), 3.52 (dd, 1H, J7,7' = 10.5 Hz, H-7'),
4
.09 (dd, 1H, J5,6 = 7 Hz, H-5), 4.36 (ddd,1H, J6,7' = 4.5, J6,7
=
=
Compound 10
7.5 Hz, H-6), 5.17 (dd, 1H, J4,5 = 2.0 Hz, H-4), 6.99 (d, 1H, J3,4
2 Hz, H-3).
1
H NMR (D O, 500 MHz): d = 3.46 (dd, 1H, J = 6 Hz, H-7), 3.57
2
6,7
(
dd, 1H, J6,7' = 4, J7.7' = 11 Hz, H-7'), 3.88 (dd, 1H, J5,6 = 5 Hz, H-
13
C NMR (CDCl , 62.9 MHz): d = 20.8 (OAc), 26.3, 27.2, (2 ×
3
5
), 3.92 (m, 1H, H-6), 4.25 (dd, 1H, J3,4 = 9 Hz, H-3), 4.31 (dd, 1H,
CH ), 31.7 (C-7), 75.3, 77.2, 78.9 (C-4, C-5, C-6), 111.2 (acetal C),
1
3
J4,5 = 3.5 Hz, H-4), 4.50 (d, 1H, J2,3 = 9 Hz, H-2).
29.9 (C-3), 138.1 (C-2), 166.8, 166.6 (C-1, OAc).
1
3
C NMR (D O/dioxane, 62.9 MHz): d = 35.2 (C-7), 70.8, 71.2,
2
Anal. C H BrO (335.15): calcd C, 43.01; H, 4.51; Br, 23.84.
Found C, 42.97; H, 4.46; Br, 23.76.
12
15
6
7
4.0, 74.3, (C-2, C-3, C-5, C-6), 80.8 (C-4), 176.6 (C-1).
7
9
+
81
+
CI-MS: m/z = 288 ( Br, M + NH ), 290 ( Br, M + NH ).
4
4
Anal. C H BrO (271.06): calcd C, 31.02; H, 4.09; Br, 29.48.
Found C, 31.22; H, 4.05; Br, 29.59.
Compound 14
7
11
6
1
H NMR (CDCl , 500 MHz): d = 1.44, 1.47 (2s, 6H, 2 × CH ), 2.32
(
3
3
2s, OAc), 3.50 (dd, 1H, H-7), 3.63 (dd, 1H, J7,7' = 11 Hz, H-7'), 3.85
(
dd, 1H, J5,6 = 7 Hz, H-5), 4.29 (ddd, 1H, J6,7 = 5, J6,7' = 4.5 Hz, H-
Compound 11
1
6), 5.02 (dd, 1H, J4,5 = 7.0 Hz, H-4), 7.38 (d, 1H, J3,4 = 2.0 Hz, H-3).
H NMR (CD COCD , 500 MHz): d = 4.07 (m, 2H, H-5, H-7), 4.18
3
3
13
(
dd, 1H, J7,7' = 11.5 Hz, H-7), 4.39 (ddd, 1H, J5,6 = 2.5, J6,7' = 5 Hz,
C NMR (CDCl , 62.9 MHz): d = 20.7 (OAc), 27.0, 27.2 (2 ×
3
3
H-6), 4.41 (dd, 1H, H-3), 4.49 (d, 1H, J2,3 = 8.5 Hz, H-2), 4.62 (dd,
CH ), 32.2 (C-7), 78.2, 78.8, 79.5, (C-4, C-5, C-6), 111.3 (acetal),
131.3 (C-3), 138.4 (C-2), 165.8, 166.7 (C-1, OAc).
1
H, J3,4 = 8, J4,5 = 1.5 Hz, H-4).
1
3
C NMR (CD COCD , 62.9 MHz): d = 38.5 (C-7), 53.2 (C-6),
Anal. C H BrO (335.15): calcd C, 43.01; H, 4.51; Br, 23.84.
Found C, 43.23; H, 4.47; Br, 24.02.
3
3
12 15
6
7
0.5, 74.3, 75.2 (C-2, C-3, C-5), 80.0 (C-4), 174.5 (C-1).
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of Carbaaldohexofuranoses
323
1
2
-O-Acetyl-7-bromo-3,7-dideoxy-D-xylo-hept-2-enono-1,4-lac-
H NMR (CDCl , 500 MHz): d = 2.32 (s, 3H, OAc), 2.78, 2.85, (2
3
tone (15)
× OH), 3.55 (m, 2H, 2 × H-7), 3.83 (m, 1H, H-5), 4.14 (m, 1H, H-
Protected lactone 13 (0.27 g, 0.8 mmol) was dissolved in 80% TFA
6), 5.09 (dd, 1H, J4,5 = 7.0 Hz, H-4), 7.48 (d, 1H, J3,4 = 2 Hz, H-3).
(
1.3 mL) and left at r.t. for 0.5 h. Water (3 mL) was added and the
13
C NMR (CD OD, 62.9 MHz): d = 20.5 (OAc), 33.7 (C-7), 72.2,
3
aqueous phase was extracted with CH Cl (10 × 5 mL). The com-
bined organic phases were neutralised with excess NaHCO , fil-
tered, dried (MgSO ), stirred with activated charcoal, filtered and
concentrated to give 15, a slightly coloured crystalline solid (0.15 g,
2
2
7
2.6 (C-5, C-6), 81.1 (C-4), 135.6 (C-3), 139.3 (C-2), 168.6, 177.5
3
(C-1, OAc).
4
CI-MS: m/z = 295, 297 ( Br, Br M + H ), 312, 314 ( Br, 81Br M
+
79
81
+
79
+
NH ).
6
1
1
3%) which could be recrystallised from EtOAc/Et O; mp 131Ð
4
2
2
0
33¡C; [a] +0.8 (c = 0.5, EtOH).
D
Anal. C H BrO (295.09): calcd C, 36.63; H, 3.76; Br, 27.08.
9 11 6
Found C, 37.08; H, 3.60; Br, 26.51.
H NMR (CDCl , 500 MHz): d = 2.34 (s, 3H, OAc), 2.68 (m, 2 ×
3
OH), 3.54 (dd, 1H, J7,7' = 10.5 Hz, H-7), 3.57 (dd, 1H, H-7'), 3.97
(
1
m, 1H, J6,7 = 6.5, J6,7' = 5.5 Hz, H-6), 4.01 (m, 1H, H-5), 5.20 (dd,
H, J4,5 = 5.5 Hz, H-4), 7.31 (d, 1H, J3,4 = 1.5 Hz, H-3).
(1R,4R,5S,7R,8S)-4-O-Acetyl-7,8-dihydroxy-2-oxabicyclo-
[3.3.0]octan-3-one (19)
Unsaturated lactone 18 (85 mg, 0.29 mmol) was dissolved in EtOAc
13
C NMR (CD OD, 62.9 MHz): d = 20.5 (OAc), 34.4 (C-7), 72.9,
3
(
2 mL) and heated to reflux. A solution of Bu SnH (0.12 mL,
3
7
(
3.5 (C-5, C-6), 82.1 (C-4), 134.0 (C-3), 139.4 (C-2), 168.5, 168.6
0.43 mmol) and AIBN (4 mg, 0.02 mmol) in EtOAc (1 mL) was added
C-1, OAc).
over 1 h. The solvent was evaporated and the residue was dissolved
in MeCN (10 mL), washed with hexane (4 × 10 mL) and concen-
trated. The product mixture was separated by flash chromatography
MS: m/z = 295, 297 ( Br, Br M + H ), 312, 314 ( Br, 81Br M +
NH ).
7
9
81
+
79
+
4
(
CH Cl /acetone 2:1). The title compound 19 was isolated as slight-
Anal. C H BrO (295.09): calcd C, 36.63; H, 3.76. Found C, 36.66;
H, 3.75.
2 2
9
11
6
ly coloured crystals (50 mg, 81%); R 0.23 (CH Cl /acetone 2:1);
f
2
2
mp 121Ð123¡C (EtOAc); [a]2 Ð136 (c = 0.5, EtOH). The C-4 iso-
0
D
mer of the title compound, (1R,4S,5S,7R,8S)-4-O-acetyl-7,8-dihy-
droxy-2-oxabicyclo[3.3.0]octan-3-one (20), was isolated as a
crystalline compound (6 mg, 10%); R 0.42 (CH Cl /acetone 2:1).
(
1S,4S,5R,7R,8S)-4-O-Acetyl-7,8-dihydroxy-2-oxabicyclo-
[3.3.0]octan-3-one (16)
f
2
2
Unsaturated lactone 15 (0.10 g, 0.34 mmol) was dissolved in anhyd
EtOAc (2 mL) and heated to reflux. A solution of Bu SnH
3
Compound 19
(
(
0.18 mL, 0.67 mmol) and AIBN (5 mg, 0.03 mmol) in EtOAc
2 mL) was added over the course of 1 h. The solvent was evaporat-
1
H NMR (CD OD, 500 MHz): d = 1.56 (ddd, 1H, J = 10.5, J6,7
=
3
5,6
8.5 Hz, H-6), 2.08 (ddd, 1H, J6,6' = 14, J6',7 = 7.5, J5,6' = 4 Hz, H-6'),
2.17 (s, 3H, OAc), 3.28 (m,1H, H-5), 3.86 (dd, 1H, H-8), 3.95 (dd,
1H, J7,8 = 7.5 Hz, H-7), 4.84 (dd, 1H, J1,5 = 6.5, J1,8 = 4.5 Hz, H-1),
5.65 (d, 1H, J4,5 = 9.5 Hz, H-4).
ed and the residue was suspended in MeCN (10 mL) and washed
with hexane (4 × 10 mL). The MeCN was concentrated to give a
residue which was purified by flash chromatography (CH Cl /ace-
2
2
tone 2:1). The title compound 16 was isolated as a syrup (65 mg,
2
0
13
8
9%); R 0.34 (CH Cl /acetone 2:1); [a] +78 (c = 0.7, CHCl ). The
C NMR (CDCl , 125.8 MHz): d = 20.3 (OAc), 27.5 (C-6), 35.8
3
f
2
2
D
3
C-4 isomer of the title compound, (1S,4R,5R,7R,8S))-4-O-acetyl-
,8-dihydroxy-2-oxabicyclo[3.3.0]octan-3-one (17), was isolated
as a syrup (3 mg, 4%); R 0.45 (CH Cl /acetone 2:1).
(C-5), 68.6 (C-4), 75.0 (C-7), 78.9 (C-8), 80.5 (C-1).
7
+
+
CI-MS: m/z = 234 (M + NH ), 217 (M + H ).
4
f
2
2
Anal. C H O (216.19): calcd C 50.00; H, 5.59. Found C, 50.21; H,
9
12
6
5
.44.
Compound 16
1
H NMR (CDCl , 500 MHz): d = 1.87 (ddd, 1H, J = 5 Hz, H-6),
3
6,7
2
(
1
.10 (ddd, 1H, J6,6' = 14.5, J6',7 = 5 Hz, H-6'), 2.22 (s, 3H, OAc), 3.40
dddd, 1H, J5,6' = 9, J5,6 = 5 Hz, H-5), 4.17 (m, 1H, H-7), 4.24 (m,
H, H-8), 4.79 (dd, 1H, J1,8 = 1, J1,5 = 7 Hz, H-1), 5.54 (d, 1H, J4,5
Compound 20
1
H NMR (CD OD, 500 MHz): d = 2.03 (ddd, 1H, J6,7 = 2 Hz, H-6),
3
2.12 (s, 3H, OAc), 2.22 (ddd, 1H, J6,6' = 14.5, J6',7 = 5 Hz, H-6'), 2.94
(dddd, 1H, J5,6 = 10, J5,6' = 5 Hz, H-5), 3.96 (dd, 1H, H-8), 4.10 (ddd,
=
10 Hz, H-4).
1
5
H, J7,8 = 2.5 Hz, H-7), 5.05 (dd, 1H, J1,5 = 9.5, J1,8 = 4 Hz, H-1),
1
3
C NMR (CDCl , 125.8 MHz): d = 20.3 (OAc), 30.9 (C-6), 37.8
3
.11 (d, 1H, J4,5 = 6.5 Hz, H-4).
(
(
C-5), 69.4 (C-4), 76.9 (C-7), 80.9 (C-8), 86.7 (C-1), 169.9, 173.3,
C-1, OAc).
13C NMR (CDCl
5.9, 76.9, (C-4, C-7, C-8), 82.3 (C-1).
, 125.8 MHz): d = 36.6 (C-6), 41.3 (C-5), 75.4,
3
7
+
+
CI-MS: m/z = 234 (M + NH ), 217 (M + H ).
4
Anal. C H O (216.19): calcd C, 50.00; H, 5.59. Found C, 50.22;
H, 5.36.
9
12
6
(1S,4S,5R,7R,8S)-4-O-Acetyl-7,8-dihydroxy-2-oxabicyclo-
3.3.0]octan-3-one (16) and (1R,4R,5S,7R,8S)-4-O-Acetyl-7,8-
[
dihydroxy-2-oxabicyclo[3.3.0]octan-3-one (19)
The syntheses of 16 and 19 could be performed on a mixture of
products in analogy with the synthesis of each isomer. Bromolac-
tone 12 (3.68 g, 11.8 mmol) was treated with Ac2O (8.9 mL,
94.7 mmol) and Et3N (6.6 mL, 47.3 mmol) as described above to
give a mixture of unsaturated lactones 13 and 14 (4.02 g,) as a co-
Compound 17
1
H NMR (CDCl , 500 MHz): d = 2.16 (m, 1H, H-6), 2.38 (m, 1H,
H-6'), 2.96 (m, 1H, H-5), 4.09 (m, 2H, H-7, H-8), 4.86 (dd, 1H, J1,8
3
=
1, J1,5 = 9 Hz, H-1), 5.16 (d, 1H, J4,5 = 4.5 Hz, H-4).
1
3
C NMR (CDCl , 125.8 MHz): d = 20.4 (OAc), 36.5 (C-6), 43.3
3
loured syrup. The isopropylidene groups were hydrolysed using
(
C-5), 67.0, 75.9, 81.5, (C-4, C-7, C-8), 87.7 (C-1).
8
0% TFA (15 mL) to give a mixture of 15 and 18 (2.20 g) as a
slightly coloured crystalline residue. A quantity of this residue
1.85 g, ca. 6.3 mmol) was treated with Bu SnH (4.3 mL,
2
-O-Acetyl-7-bromo-3,7-dideoxy-D-lyxo-hept-2-enono-1,4-lac-
(
3
tone (18)
1
5.6 mmol) and AIBN in the usual manner to give after workup a
mixture of 16 and 19 (1.78 g, syrup). The isomers were separated
by repeated flash chromatography (CH Cl /acetone 5:2) to give 16
0.51 g, 24%), and 19 (0.47 g, 22%). NMR spectra were identical
with those described above.
Protected lactone 14 (0.20 g, 0.6 mmol) was dissolved in 80% TFA
(1 mL) and treated as described above for compound 13 to give 18
20
2
2
as a crystalline compound (0.12 g, 67%); mp 113Ð115¡C; [a]D +48
(
(c = 0.7, EtOH).
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

3
24
A. M. Horneman, I. Lundt
PAPER
Carba-b-D-glucofuranose (21)
crystals (0.052 mg, 80%), which were recrystallised from Et O; mp
2
121Ð122¡C; [a]2 Ð59 (c = 0.5, CHCl3).
0
Compound 16 (0.195 g, 0.9 mmol) was dissolved in anhyd THF
D
(5 mL), BH3
•
SMe (0.9 mL, 9.0 mmol) was added at r.t. and the so-
1
2
H NMR (CDCl , 500 MHz): d = 1.73 (ddd, 1H, J = 3.5, J = 9.5, J
3
lution was refluxed for 6 h. The reaction was quenched by addition
of water (10 mL), the solvents were evaporated and the residue was
concentrated from MeOH (3 × 30 mL). The crude product was pu-
rified by flash chromatography (acetone/MeOH 9:1). The isolated
product was dissolved in water filtered through activated charcoal
=
14 Hz, H-4a'), 2.0, 2.02, 2.06, 2.07, 2.08 (5s, 15 H, 5 × CH ), 2.28
3
(ddd, 1H, J = 9.5, J = 10, J = 14 Hz, H-4a), 2.66 (dq, 1H, J = 3.5, J
=
10 Hz, H-4), 3.94 (dd, 1H, J = 5.5, J = 12.5 Hz, H-6'), 4.33 (dd,
1
8
H, J = 2.5, J = 12.5 Hz, H-6), 5.09 (ddd, 1H, J = 2.5, J = 5.5, J =
Hz), 5.22 (dd, 1H, J = 3.5, J = 7.5 Hz), 5.27 (m, 1H), 5.46 (tr, 1H,
2
0
to give 21 as a colourless syrup (0.11g, 77%); [a] Ð39 (c = 0.4,
MeOH).
D
J = 3.5 Hz).
1
3
C NMR (CDCl , 125.7 MHz): d = 20.4, 20.5, 20.6, 20.61, 20.8 (5
1
3
H NMR (D O, 500 MHz): d = 1.38 (ddd, 1H, J = 8.5 Hz, H-4a),
2
×
CH ), 30.6 (C-4a), 38.8 (C-4), 63.4 (C-6), 69.6, 71.9, 75.4, 77.0
3
1
4
1
.98 (ddd, 1H, J4a',4a = 12, J = 7, J = 6 Hz, H-4a'), 2.06 (m, 1H, H-
(C-1, C-2, C-3, C-5), 169.8, 169.9, 170.0, 170.4, 170.5 (5 × OAc).
), 3.41 (dd, 1H, J5,6 = 6.5 Hz, H-6), 3.60 (dd, 1H, J5,6' = 3, J6,6'
2 Hz, H-6'), 3.74 (m, 2 H, H-2, H-5), 3.88 (m, 1H, J1,2 = 2.5 Hz,
=
Anal. C H O (388.37): calcd C, 52.57; H, 6.23. Found C, 52.84;
17 24 10
H, 6.13.
H-1), 3.96 (dd, 1H, J2,3 = 6, J3,4 = 2.5 Hz, H-3).
1
3
C NMR (CD OD, 62.9 MHz): d = 33.9 (C-4a), 42.3 (C-4), 72.5,
3
7
-Bromo-2,3,7-trideoxy-D-lyxo-hept-2-enono-1,4-lactone (26)
7
7.6, 77.8, 85.1, (C-1, C-2, C-3, C-5), 65.3 (C-6).
6
Acetylated lactone 25 (3.0 g, 9.3 mmol) was suspended in HCl/
+
+
CI-MS: m/z = 196 (M + NH ), 179 (M + H ). C H O (178.19).
4
7
14
5
MeOH (30 mL, 1% AcCl in MeOH) and stirring was maintained for
7
2 h. The solvent was evaporated and the crude product was crys-
1
,2,3,5,6-Penta-O-acetyl-carba-b-D-glucofuranose (22)
tallised from Et O affording 26 as colourless crystals (1.57 g, 72%);
mp 109Ð111¡C; [a]D + 133 (c = 1.6, EtOH).
2
20
Carba-b-D-glucofuranose (21) (0.082 g, 0.46 mmol) was dissolved
in Ac O (1.1 mL, 1.2 mmol) and HClO (1 drop) was added. The
1
2
4
H NMR (D O, 500 MHz): d = 3.43 (dd, 1H, J = 7.5 Hz, H-7),
2
6,7
solution was left for 3 h after which water (2 mL) was added. The
3
5
7
.49 (dd, 1H, J6,7' = 5.5, J7,7' = 11 Hz, H-7'), 3.96 (m, 2H, H-5, H-6),
.23 (ddd, 1H, J4,5 = 5.5 Hz, H-4), 6.18 (dd, 1H, J3,4 = 1.5 Hz, H-3),
.81 (dd, 1H, J2,3 = 5.5, J2,4 = 1 Hz, H-2).
solution was extracted with CH Cl (3 × 5 mL), the combined or-
2
2
ganic phases were washed with water (3 × 5 mL) and aq NaHCO3
10 mL), dried (MgSO ), filtered and concentrated. The residue was
(
4
13
C NMR (D O/acetone, 62.9 MHz): d = 35.8 (C-7), 73.1, 73.5 (C-
purified by flash chromatography (EtOAc/hexane 2:3) to give the
2
2
0
5, C-6), 87.1 (C-4), 123.8 (C-3), 160.0 (C-2), 178.5 (C-1).
title compound as a syrup (0.159 g. 89%); [a] Ð23 (c = 1.2,
D
CHCl3).
Anal. C H BrO (237.05): calcd C, 35.45; H, 3.83; Br, 33.71. Found
C, 35.50; H, 3.75; Br, 33.19.
7
9
4
1
H NMR (CDCl , 500 MHz): d = 1.72 (dtr, 1H, J = 8.5, J = 13 Hz,
3
H-4a), 2.01, 2.06, 2.07, 2.08, 2.09 (5s, 5 × 3H, 5 × CH ), 2.39 (ddd,
3
1
H, J = 6, J = 7, J = 13 Hz, H4a'), 2.57 (m, 1H, H-4), 3.93 (dd, 1H,
J5,6' = 5, J6,6' = 12 Hz, H-6'), 4.40 (dd, 1H, J5,6 = 2.5 Hz, H-6), 5.01
d, 1H, J = 3 Hz), 5.09 (dtr, 1H, J = 3, J = 8.5 Hz), 5.15 (m, 1H),
7-Bromo-2,3,7-trideoxy-5,6-O-isopropylidene-D-lyxo-hept-2-
enono-1,4-lactone (27)
Camphorsulfonic acid (68 mg, 0.3 mmol) was added to a solution
of lactone 26 (1.40 g, 5.9 mmol) in anhyd acetone (20 mL) and 2,2-
dimethoxypropane (10 mL). The solution was left at r.t. for 35 h af-
(
5
.18 (m, 1H).
13
C NMR (CDCl , 125.7 MHz): d = 20.63, 20.67, 20.72, 20.75 (5 ×
3
ter which excess solid NaHCO was added and stirred until neutral.
3
CH ), 32.2 (C-4), 41.0 (C-4a), 63.9 (C-6), 69.2, 75.0, 77.6, 81.6 (C-
1
3
The suspension was filtered, the filtrate was concentrated and the
, C-2, C-3, C-5), 169.2, 169.4, 170.0, 170.1, 170.5 (5 × OAc).
syrup was suspended in Et O, filtered, concentrated and purified by
2
Anal. C H O (388.37): calcd C, 52.57; H, 6.23. Found C, 52.35;
H, 6.05.
1
7
24 10
flash chromatography (EtOAc/hexane 1:2) to give 27 as a colour-
less oil (1.46 g, 90%); [a]2
0
+124 (c = 1.0, CHCl3)
D
1
H NMR (CDCl , 500 MHz): d = 1.46, 1.48 (2s, 6H, 2 × CH ), 3.52
3
3
Carba-a-L-mannofuranose (23)
(
dd, 1H, H-7), 3.67 (dd, 1H, J7,7' = 11.5 Hz, H-7'), 3.76 (dd, 1H, J5,6
Compound 19 (0.20 g, 0.92 mmol) was dissolved in anhyd THF
=
(
1
6.5 Hz, H-5), 4.32 (ddd, 1H, J6,7 = 5.5, J6,7' = 4 Hz, H-6), 5.01
ddd, 1H, J4,5 = 8 Hz, H-4), 6.24 (dd, 1H, J3,4 = 2 Hz, H-3), 7.64 (dd,
H, J2,3 = 5.5, J2,4 = 1.5 Hz, H-2).
(
5 mL). BH •SMe (0.92 mL, 9.2 mmol) was added at r.t. and the
3 2
solution was refluxed overnight during which time a colourless pre-
cipitate was formed. Workup was conducted as described for the
preparation of 21 to give the title compound 23 as a colourless syrup
13
C NMR (CDCl , 62.9 MHz): d = 26.6, 26.8 (2 × CH ), 32.1 (C-7),
3
3
2
0
77.9, 78.8, 82.4 (C-4, C-5, C-6), 110.6 (acetal), 122.0 (C-3), 154.0
C-2), 171.5 (C-1).
(
0.10 g, 68%); [a] Ð24 (c = 0.98, MeOH).
D
(
1
H NMR (D O, 500 MHz): d = 1.46 (dd, 1H, J = 4.5, J = 10 Hz, H-
2
Anal. C H BrO (277.11): calcd C, 43.34; H, 4.73; Br, 28.83.
Found C, 43.21; H, 4.47; Br, 28.90.
4
4
5
3
a), 1.83 (ddd, 1H, J4a',4a = 14, J = 10 Hz, H-4a'), 2.12 (ddd, 1H, H-
10 13
4
), 3.36 (dd, 1H, J5,6 = 6.5 Hz, H-6), 3.60 (ddd, 1H, J4,5 = 10 Hz, H-
), 3.79 (dd, 1H, J1,2 = 7.5 Hz, H-2), 4.04 (dd, 1H, J2,3 = 4, J3,4
=
.5 Hz, H-3), 4.08 (ddd, 1H, H-1).
7-Bromo-2,3,7-trideoxy-5,6-O-isopropylidene-D-xylo-hept-2-
enono-1,4-lactone (28)
1
3
C NMR (D O/MeCN, 62.9 MHz): d = 32.0 (C-4a), 40.9 (C-4),
2
7-Bromo-2,3,7-trideoxy-5,6-O-isopropylidene-D-lyxo-hept-2-enono-
6
4.5 (C-6), 71.7, 73.4, 75.9, 80.9, (C-1, C-2, C-3, C-5).
1
,4-lactone (27) (0.32 g, 1.2 mmol) was dissolved in CH Cl (3 mL)
2
2
+
+
CI-MS: m/z = 196 (M + NH ), 179 (M + H ). C H O (178.19).
4
7
14
5
and Et N (0.18 mL, 1.3 mmol). The solvent was evaporated after
3
1
h and the products were separated by flash chromatography
1
,2,3,5,6-Penta-O-acetyl-carba-a-L-mannofuranose (24)
(EtOAc/hexane 1:3). Starting material 27 was recovered (0.10 g,
Compound 23 (0.030 g, 0.17 mmol) was dissolved in Ac O
31%); R 0.36 (EtOAc/hexane 1:2). The compound 28 was obtained
2
f
(
0.4 mL, 4.2 mmol) and HClO (1 drop) was added. The reaction,
as a solid (0.10 g, 31%); R 0.29 (EtOAc/hexane 1:2); mp 89Ð
4
f
20
workup and purification were done as described for the preparation
of compound 22. The title compound 24 was obtained as colourless
90¡C(Et O); [a] Ð70.3 (c = 0.5, CHCl3).
2 D
1
H NMR (CDCl , 500 MHz): d = 1.38, 1.42, (2s, 6H, 2 × CH ), 3.47
3
3
(
dd, 1H, H-7), 3.59 (dd, 1H, J7,7' = 10.5 Hz, H-7'), 4.17 (dd, 1H, J5,6
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of Carbaaldohexofuranoses
325
=
7.5 Hz, H-5), 4.45 (ddd, 1H, J6,7' = 4.5, J6,7 = 7.5 Hz, H-6), 5.25
(10) La Forge, F. B. J. Biol. Chem. 1920, 41, 251.
(ddd, 1H, J4,5 = 2 Hz, H-4), 6.21 (dd, 1H, J3,4 = 2 Hz, H-3), 7.47 (dd,
(11) Isbell, H. S. J. Res. Nat. Bur. Stand. 1937, 19, 639.
1
H, J2,3 = 5.5, J2,4 = 1.5 Hz, H-2).
(12) Merril, A. T.; Haskins, W. T.; Hann, R. M.; Hudson, C. S.
1
3
J. Am. Chem. Soc. 1947, 69, 70.
C NMR (CDCl , 62.9 MHz): d = 26.3, 27.2, (2 × CH ), 31.7 (C-
3
3
(
13) Beacham, A. R.; Bruce, I.; Choi, S.; Doherty, O.; Fairbanks,
A. J.; Fleet, G. W. J.; Skead, B. M.; Peach, J. M.; Saunders, J.;
Watkin, D. J. Tetrahedron: Asymmetry 1991, 2, 883.
7
1
), 75.5, 78.6, 81.1 (C-4, C-5, C-6), 111.0 (acetal C), 122.6 (C-3),
52.6 (C-2), 172.3 (C-1).
Anal. C H BrO (277.11): calcd C, 43.34; H, 4.73; Br, 28.83.
Found C, 43.81; H, 4.65; Br, 31.64.
1
0
13
4
(14) Bell, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymme-
try 1996, 7, 595.
(15) Bock, K.; Lundt, I.; Pedersen, C. Carbohydr. Res. 1979, 68,
3
13.
Acknowledgement
Lundt, I.; Pedersen, C. Synthesis 1992, 669.
16) Lederkremer, R. M.; Varela, O. Adv. Carbohydr. Chem. Bio-
chem. 1994, 50, 125.
(
(
(
We thank Jytte Grove-Rasmussen for technical assistance, Mr.
Henrik Kragh for preparation of the two heptonolactones 5 and 6.
We also thank Dr. J¿rgen ¯gaard Madsen for recording the mass
spectra.
17) (a) Horneman, A. M.; Lundt, I. Tetrahedron 1997, 53, 6879.
(b) Horneman, A. M.; Lundt, I.; Soetofte, I. Synlett 1995, 918.
18) Vekemans, J. A. J. M.; Dapperens, C. W. M.; Claessen, R.;
Koeten, A. M. J.; Godefrei, E. F.; Chittenden, G. J. F. J. Org.
Chem. 1990, 55, 5336.
References
Vekemans, J. A. J. M.; De Bruyn, R. G. M.; Caris, R. C. H.
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Chittenden, G. J. F. J. Org. Chem. 1987, 52, 1093.
Vekemans, J. A. J. M.; Franken, G. A. M.; Dapperens, C. W.
M.; Godefrei, E. F.; Chittenden, G. J. F. J. Org. Chem. 1988,
(
(
1) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779.
2) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
Agrofolio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.
3) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993,
5
3, 627.
(
(
(
(
(
(
19) Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P.; Fava, G. G.;
1
15, 444.
4) Marschner, C.; Baumgartner, J.; Griengl, H. J. Org. Chem.
995, 60, 5224.
5) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem. 1990,
8, 21.
Belicchi, M. F. Tetrahedron 1990, 46, 5807
20) Ritchie, R. G. S.; Cyr, N.; Korsch, B.; Koch, H. J.; Perlin, A.
S. Can. J. Chem. 1975, 53, 1424.
1
21) Damtoft, S.; Jensen, S. R.; Nielsen, B. J. Phytochemistry
4
1
981, 2717.
(
(
6) Horneman, A. M.; Lundt, I. J. Org. Chem. 1998, 63, 1919.
7) For literature on radical cyclisations see:
Giese, B. Org. React. 1996, 48, 301.
(
(
22) Karabinos, J. V. Org. Synth. Coll. Vol. 4 1963, 506.
23) Hayashi, K.; Iyoda, J.; Shiihara, I. J. Organometal. Chem.
1
967, 10, 81.
24) Blanksema, J. J,; Van Ekenstein, W.A. Chem. Zentralbl.
908, 1583.
(
8) Lundt, I.; Madsen, R. Synthesis 1995, 787.
Bock, K.; Lundt, I.; Pedersen, C.; Sonnichsen, R. Carbohydr.
Res. 1988, 174, 331.
(
1
(9) For a review on aldonolactones see:
Lundt, I. Top. Curr. Chem. 1997, 187, 117.
Synthesis 1999, No. 2, 317–325 ISSN 0039-7881 © Thieme Stuttgart · New York