Facile synthesis of 6a-carba-β-d-fructopyranose through an RCM approach

Article abstract of DOI:10.1016/j.tet.2008.02.046

A new synthetic approach toward 6a-carba-β-d-fructopyranose, a non-nutritive sweetener related to topiramate, is described. This scheme uses 2-C-hydroxymethyl-l-erythrose acetonide as starting material and efficiently delivers the target compound applying an RCM protocol for the construction of the carbocycle ring.

Full text of DOI:10.1016/j.tet.2008.02.046

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3998e4003
www.elsevier.com/locate/tet
Facile synthesis of 6a-carba-b-D-fructopyranose
through an RCM approach
*
Sotirios M. Totokotsopoulos, Alexandros E. Koumbis, John K. Gallos
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
Received 27 November 2007; received in revised form 23 January 2008; accepted 14 February 2008
Available online 5 March 2008
Abstract
A new synthetic approach toward 6a-carba-b-D-fructopyranose, a non-nutritive sweetener related to topiramate, is described. This scheme
uses 2-C-hydroxymethyl-L-erythrose acetonide as starting material and efficiently delivers the target compound applying an RCM protocol
for the construction of the carbocycle ring.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
cyclohexene.18 Additionally, the enantiomer of 1, 6a-carba-
b-L-fructopyranose (4), has been targeted by two different
groups.16,19
Carbocyclic analogs of monosaccharides, in which a methyl-
ene group has replaced the endocyclic oxygen, were initially
coined as pseudo-sugars,1 whereas later the term carbasugars2
prevailed. Carbasugars and some of their derivatives display
a wide range of biological properties owing to their close
structural resemblance to carbohydrates.3e5 Carbahexopyrano-
ses have been thoroughly studied during the past three decades,
after their derivatives were found to occur naturally,6e8 as
components, for example, of antibiotics9 and a-glycosidase
inhibitors.3,10 Consequently, extensive research work has been
devoted to the preparation of a variety of carbasugars and related
analogs.11,12 These compounds were evaluated in depth for their
biological action as enzyme inhibitors and regulators,12,13 and
for their potential use as artificial non-nutritive sweeteners.8,14
6a-Carba-b-D-fructopyranose (1, Fig. 1) could be used as
a non-nutritive sweetener since it has a sweet taste.14b In addition,
1 can easily provide access to compound 2, which is an active
carba-isostere of topiramate (3), a useful antiepileptic drug.15
Enantiomerically pure 1 has been synthesized previously
from a chemically resolved DielseAlder adduct of furan and
acrylic acid,16 from (ꢀ)-quinic acid,17 and from an enzymati-
cally resolved homochiral building block derived from
Carbasugar 1 and a plethora of natural products and com-
pounds with pharmaceutical and biological interest contain
a chiral tertiary alcohol moiety. Stereoselective construction
of this quaternary carbon center usually represents a major
challenge in the planned synthetic route.20 A part of our recent
research work focuses on the synthesis of such compounds
starting from inexpensive commercially available asymmetric
materials like carbohydrates.21 Among the different general
approaches22 for the construction of carbocycles from carbo-
hydrates, RCM represents a very attractive synthetic tool.23
In continuation of our previous work, we wish to report here
a new and very efficient approach for the synthesis of enantio-
pure 1 through an RCM approach.
O
OH
OH
O
O
HO
HO
HO
HO
X
O
HO
HO
OH
OH
OH
2 X = CH2
3 X = O
1
4
* Corresponding author. Tel.: þ30 2310 997714; fax: þ30 2310 997679.
E-mail address: igallos@chem.auth.gr (J.K. Gallos).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.046

S.M. Totokotsopoulos et al. / Tetrahedron 64 (2008) 3998e4003
3999
2. Results and discussion
etherification of the hemiacetal functionality and, preferentially,
a group belonging to the same acetonide orthogonal set. To
address this issue, 9 reacted initially with trityl chloride21c to
produce trityl-ether 10a. However, subsequent Wittig olefination
of 10a proved troublesome. None of the desired ester was
observed even upon prolonged application of forceful condi-
tions.25 This result can be solely attributed to the steric hindrance
induced by the bulky trityl group. Therefore, we decided to turn
our attention to the corresponding silyl-ether, 10b. After some
experimentation, we managed to prepare 10b in good yield.
The best results were obtained using pyridine as base and adding
gradually the silyl chloride to prevent formation of the corre-
sponding bis-silylated derivative. To our delight Wittig olefina-
tion worked uneventfully for 10b avoiding the formation of
tetrahydrofuran by-products by the addition of a catalytic
amount of acid. Moreover, it is worthy mentioning that only
the E-unsaturated ester 11 was formed, in contrast to the previ-
ously described results regarding reactions of stabilized ylides
with g-lactols of the same configuration.26 Substitution at C-2
seems to play a crucial role in this stereochemical outcome.
Nevertheless, the stereochemistry of the newly formed dou-
ble bond in 11 was of no importance since we intended to reduce
it in the next step. A one-step procedure involving conjugate
reduction of both double bond and ester moieties in 11 could
be considered as an attractive option to directly prepare 13. In-
deed, this was tested using NaBH4 but, instead of diol 13, the un-
wanted furan derivative 14 was formed. Obviously, this could be
accredited to the tendency of 11 to undergo an intramolecular
1,4-conjugate addition of the free hydroxyl group27 in a slightly
basic medium. Structural assignment of 14, which was obtained
as the sole product, was based on NOE studies (see Scheme 2).
An indirect route was then adopted involving initially the
selective reduction of the double bond under mild conditions
(Ra-Ni) to reach hydroxy-ester 12. A second reduction, using
LiBH4, followed in order to obtain the desired diol, 13.
Next, diol 13 was oxidized under classic Swern reaction
conditions. The 1,6-bisaldehyde intermediate, being highly
For the synthesis of 1, we envisaged the retrosynthesis
depicted in Scheme 1. According to this plan the desired target
could be derived from deprotection (DP) of the cis-dihydroxy-
lation (DH) product of cyclohexene derivative 5, which in
turn is disconnected to diene 6 via an RCM reaction. The latter
leads back to the unsaturated hydroxy-ester 7 through standard
functional group transformations (FGT), and 7 could be
reached from 8 employing a Wittig olefination.
RCM
DH
1
OP'
DP
PO
PO
OP
PO
OP'
5
6
FGT
Wittig olefination
O
CO2R
OP'
OH
HO
PO
OP'
PO
OP
OP
7
8
Scheme 1. Retrosynthetic analysis (P, P0¼protecting groups).
Practically, hydroxymethyl erythrose 9 (Scheme 2) is easily
accessible in high yields and multigram quantities from
L-arabinose.21c,24 In addition, it was clear that by choosing 9
(an equivalent of 8) as the starting material, two key points in
our planned synthesis were going to be resolved in a straightfor-
ward manner: unambiguous establishment of the correct stereo-
chemistry at the quartenary center and protection of the cis diol
system. Bearing in mind the inevitable masking of the primary
hydroxyl group, we realized that a substantially bulky protecting
group would be required in order to exclude a concurrent
CO2Me
CO2Me
OTBS
O
O
O
HO
OH
OH
OH
OR
H
see text
i or ii
iii
vi
H
L-arabinose
H
(from 10b)
O
O
O
O
O
O
O
O
OTBS
10a R = Tr
10b R = TBS
14
9
11
iv
OH
O
N
N
R
Mes
Mes
HO
O
HO
Cl
xi
x
ix
vii-viii
1
Ru
O
OTBS
OTBS
O
Ph
O
O
O
Cl
O
P(Cy)3
17
OTBS
OTBS
18
12 R = CO2Me
13 R = CH2OH
16
15
v
Scheme 2. Synthesis of 1. Reagents and conditions: (i) see Ref. 21c; (ii) TBSCl, pyridine, 70 ꢁC, 81%; (iii) Ph3P]CHCO2Me, PhCO2H, toluene, 80 ꢁC, 77%; (iv)
H2, Ra-Ni, MeOH, 25 ꢁC, 93%; (v) LiBH4, Et2O, 25 ꢁC, 94%; (vi) NaBH4, MeOH, 25 ꢁC, 70%; (vii) (COCl)2, DMSO, CH2Cl2, ꢀ60 to ꢀ40 ꢁC, then Et3N, ꢀ78 to
25 ꢁC; (viii) Ph3PþCH3Brꢀ, 12-crown-4-ether, n-BuLi, THF, ꢀ78 to 25 ꢁC, 50% overall from 13; (ix) Grubbs’ catalyst 17, CH2Cl2, 25 ꢁC, 82%; (x) OsO4, NMO,
Me2CO, H2O, 25 ꢁC, 99%; (xi) TFA, H2O, 25 ꢁC, 95%.

4000
S.M. Totokotsopoulos et al. / Tetrahedron 64 (2008) 3998e4003
unstable, was used directly in the next step after a short
workup. Thus, double olefination was followed and the desired
diene 15 was obtained in an overall good yield.
IR spectra were recorded on an FTIR instrument as indicated.
Mass spectra were obtained by electro spray technique, positive
mode (ES-MS) or MALDI-FTMS.
Having in place the two terminal alkene moieties in 15, we
then investigated conditions to reach cyclohexene derivative
16 through a ring closure olefin metathesis.28 To the best of
our knowledge, there is no precedent for an RCM reaction
of a 3,4,4-trisubstituted diene but in fact, we were glad to
realize that this metathesis worked smoothly at room temper-
ature using the commercially available Grubbs’ second gener-
ation catalyst 17.29
Dihydroxylation of the RCM product 16 was best
performed using OsO4 in a mixture of acetone and water,30
yielding almost quantitatively diol 18, whereas reaction in
MeOH was very sluggish. As expected this reaction occurred
with exclusive facial selectivity, influenced by the stereochem-
istry of the neighboring C-2.31 The trans disposition of C-2
and C-3 protons was clearly deduced based on their small
coupling constant.
4.1.1. 2-C-(tert-Butyldimethylsilyloxy)-2,3-O-isopropylidene-
L-erythrofuranose (10b)
Alcohol 921c,24 (2 g, 10.5 mmol) was dissolved in dry pyridine
(100 mL) and TBSCl (1.9 g, 12.6 mmol) was added in portions
over a period of 30 min. The mixture was stirred for 20 h at
70 ꢁC under an Ar atmosphere and then poured into a mixture
of CH2Cl2 (100 mL) and H2O (100 mL). The aqueous phase
was extracted with CH2Cl2 (3ꢂ100 mL), and the combined or-
ganic phases were washed with saturated brine (3ꢂ100 mL)
and dried (Na2SO4). After removal of the solvents under reduced
pressure, theresidualoil was purified bycolumnchromatography
on silica gel with a mixture of hexane/EtOAc (5:1 v/v) to give
2.59 g of lactols 10b (81%) as a thick oil (mixture of a and
b anomers in a ratio of ca. 1:1). Rf (hexane/EtOAc 4:1 v/v)
0.55; FTIR (neat film) 3445, 2977, 2932, 2858, 1472, 1372,
1252, 1107, 1006, 839, 779 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 5.31 (d, J¼7.1 Hz, 1H), 4.95 (d, J¼11.6 Hz, 1H), 4.66 (br d,
J¼3.2 Hz, 2H), 4.65 (s, 1H), 4.39 (d, J¼7.1 Hz, 1H), 4.08e
4.00 (m, 3H), 3.95 (d, J¼10.9 Hz, 1H), 3.84 (d, J¼10.9 Hz,
1H), 3.78 (d, J¼11.6 Hz, 1H), 3.74 (s, 2H), 3.53 (dd, J¼10.9,
3.2 Hz, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.41 (s, 3H), 1.38 (s,
3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.13 (s, 6H), 0.08 (s, 6H); 13C
NMR (75 MHz, CDCl3) d 113.5 (CMe2), 104.7 (C-1b), 97.7
(C-1a), 92.2 (C-2), 88.3 (C-2), 83.3 (C-4), 82.8 (C-4), 72.1
(C-5), 68.0 (C-5), 64.1 (C-20), 63.1 (C-20), 27.5 (2ꢂCMe2), 27.0
(CMe2), 26.8 (CMe2), 25.7 (CMe3), 25.6 (CMe2), 18.1 (CMe3),
18.0 (CMe3), ꢀ5.6 (SiMe2), ꢀ5.7 (SiMe2); HRMS m/z
327.1600 [C14H28O5SiNa (MþNa)þ requires 327.1598].
Finally, exposure of partially protected pentaol 18 to aque-
ous TFA caused the removal of both silyl and acetonide groups
and furnished crystalline 6a-carba-b-D-fructopyranose (1), in
one step and in an excellent yield.
3. Conclusions
In this article, a convenient alternative synthesis of enantio-
pure 6a-carba-b-D-fructopyranose (1) is described. Practically,
it embodies facile functional group interconversions starting
from 2-C-hydroxymethyl-L-erythrose acetonide (9), an easily
accessible L-arabinose chiron, and relies on an RCM reaction
for the construction of the carbocycle ring. It delivers 1 in nine
steps and in an overall yield higher than 21%.32 Moreover, it is
important to note that the same synthetic sequence could be
also applied for the preparation of enantiopure 6a-carba-b-L-
fructopyranose (4) using the equally easy available enantiomer
of 9, 2-C-hydroxymethyl-D-erythrose acetonide (a D-arabinose
derived chiron).21e,24
4.1.2. (4S,5S,E)-Methyl 4-(tert-butyldimethylsilyloxy-
methyl)-4,5-O-isopropylidene-4,5,6-trihydroxyhex-2-enoate
(11)
Lactol 10b (2.44 g, 8 mmol) and benzoic acid (250 mg,
2 mmol) were dissolved in dry toluene (75 mL). Methyl (triphe-
nylphosphoranylidene)acetate (3.2 g, 9.6 mmol) was added and
the mixture was heated for 2 days at 70 ꢁC under an Ar atmo-
sphere. Then, the solvent was removed under reduced pressure
and the residue was purified by column chromatography on sil-
ica gel with a mixture of hexane/EtOAc (8:1 v/v) to give 2.22 g
of unsaturated ester 11 (77%) as a thick oil. Rf (hexane/EtOAc
4:1 v/v) 0.45; [a]2D5 ꢀ26.0 (c 2.7, CHCl3); FTIR (neat film)
3480, 2980, 2932, 2853, 1733, 1653, 1472, 1436, 1383, 1298,
4. Experimental
4.1. General
All commercially available grade quality reagents were used
without further purification. All solvents were purified by
standard procedures before use. Dry solvents were obtained
by literature methods and stored over molecular sieves. All reac-
tions were conducted under nitrogen atmosphere. All reactions
were monitored on commercially available pre-coated TLC
plates (layer thickness 0.25 mm) of Kieselgel 60 F254. Com-
pounds were visualized by use of a UV lamp or/and p-anisalde-
hyde ethanolic solution and warming. Column chromatography
was performed in the usual way using Merck 60 (40e60 mm)
silica gel. NMR spectra were recorded on a 300 MHz spectrom-
eter (1H: 300 MHz, 13C: 75 MHz) in CDCl3, unless otherwise
stated. Chemical shifts are given in parts per million and J in
hertz using solvent or tetramethylsilane as an internal reference.
1159, 1090, 989, 839, 780 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 7.00 (d, J¼15.8 Hz, 1H, H-3), 6.21 (d, J¼15.8 Hz,
1H, H-2), 4.35 (t, J¼5.8 Hz, 1H, H-5), 3.75 (s, 3H, OMe),
3.74e3.68 (m, 2H, H-6), 3.67 (s, 2H, H-40), 2.24 (br s, 1H,
OH), 1.53 (s, 3H, CMe2), 1.44 (s, 3H, CMe2), 0.91 (s, 9H,
CMe3), 0.09 (s, 6H, SiMe2); 13C NMR (75 MHz, CDCl3)
d 166.4 (C-1), 146.2 (C-3), 122.0 (C-2), 109.3 (CMe2), 83.6
(C-4), 81.8 (C-5), 67.8 (C-40), 61.8 (C-6), 51.5 (OMe), 27.7
(CMe2), 26.3 (CMe2), 25.7 (CMe3), 18.1 (CMe3), ꢀ5.6
(SiMe2), ꢀ5.8 (SiMe2); HRMS m/z 383.1861 [C17H32O6SiNa
(MþNa)þ requires 383.1860].

S.M. Totokotsopoulos et al. / Tetrahedron 64 (2008) 3998e4003
4001
4.1.3. (4S,5S)-Methyl 4-(tert-butyldimethylsilyloxy-methyl)-
4,5-O-isopropylidene-4,5,6-trihydroxyhexanoate (12)
dropwise until pH 7 was reached. EtOAc (10 mL) was added
and the resulting solution was stirred for 30 min at room tem-
perature. Then, it was washed with saturated aqueous sodium
bicarbonate solution (25 mL) and saturated brine (25 mL). Af-
ter drying (Na2SO4), the solvents were removed under reduced
pressure and the obtained residue was purified by column
chromatography on silica gel with a mixture of hexane/EtOAc
(4:1 v/v) to give 51 mg of ester 14 (70%) as an oil. Rf (hexane/
EtOAc 4:1 v/v) 0.64; [a]D25 þ11.6 (c 0.8, CHCl3); FTIR (neat
film) 2986, 2954, 2931, 2858, 1744, 1472, 1463, 1371, 1252,
Unsaturated ester 11 (1.98 g, 5.5 mmol) was dissolved in
MeOH (100 mL). A catalytic amount of Ra-Ni was added and
the mixture was vigorously stirred under H2 (1 atm) for 24 h
at room temperature. Then, the reaction mixture was filtered
through CeliteÒ, the solvent was removed under reduced pres-
sure and the residue was purified by column chromatography
on silica gel with a mixture of hexane/EtOAc (8:1 v/v) to give
1.85 g of ester 12 (93%) as a thick oil: Rf (hexane/EtOAc 4:1
v/v) 0.31; [a]2D5 þ9.3 (c 15.9, CHCl3); FTIR (neat film) 3472,
2987, 2954, 2933, 2859, 1742, 1463, 1372, 1254, 1177, 1089,
1
1101, 839, 779 cmꢀ1; H NMR (300 MHz, CDCl3) d 4.62 (d,
J¼3.2 Hz, 1H, H-4), 4.08 (dd, J¼7.7, 5.1 Hz, 1H, H-2), 3.98
(d, J¼10.9 Hz, 1H, H-5a), 3.74 (br d, J¼1.3 Hz, 2H, H-30),
3.71 (s, 3H, OMe), 3.55 (dd, J¼10.9, 3.2 Hz, 1H, H-5b),
2.68e2.64 (m, 2H, CH2CO), 1.49 (s, 3H, CMe2), 1.39 (s,
3H, CMe2), 0.90 (s, 9H, CMe3), 0.09 (s, 6H, SiMe2); 13C
NMR (75 MHz, CDCl3) d 171.9 (CO), 112.8 (CMe2), 91.4
(C-3a), 84.5 (C-2), 78.5 (C-4), 72.4 (C-5), 64.4 (C-30a), 51.7
(OMe), 34.8 (CH2CO), 27.1 (CMe2), 27.0 (CMe2), 25.8
(CMe3), 18.2 (CMe3), ꢀ5.6 (SiMe2); HRMS m/z 383.1859
[C17H32O6SiNa (MþNa)þ requires 383.1860].
839, 779 cmꢀ1 1H NMR (300 MHz, CDCl3) d 4.02 (t,
;
J¼6.4 Hz, 1H, H-5), 3.70e3.64 (m, 2H, H-6), 3.61 (d,
J¼9.8 Hz, 1H, H-40a), 3.58 (s, 3H, OMe), 3.34 (d, J¼9.0 Hz,
1H, H-40b), 2.53 (br s, 1H, OH), 2.45e2.34 (m, 1H, H-2a),
2.25e2.15 (m, 1H, H-2b), 1.82e1.72 (m, 2H, H-3), 1.34 (s,
3H, CMe2), 1.26 (s, 3H, CMe2), 0.81 (s, 9H, CMe3), 0.05 (s,
6H, SiMe2); 13C NMR (75 MHz, CDCl3) d 173.9 (C-1), 108.3
(CMe2), 83.1 (C-4), 82.0 (C-5), 65.7 (C-40), 60.6 (C-6), 51.4
(OMe), 28.0 (C-3), 27.9 (CMe2), 26.5 (CMe2), 25.6 (CMe3),
25.5 (C-2), 18.0 (CMe3), ꢀ5.8 (SiMe2), ꢀ5.9 (SiMe2); HRMS
m/z 385.2020 [C17H34O6SiNa (MþNa)þ requires 385.2017].
4.1.6. (3S,4S)-4-(tert-Butyldimethylsilyloxymethyl)-3,4-O-
isopropylidene-octa-1,7-diene-3,4-diol (15)
4.1.4. (2S,3S)-3-(tert-Butyldimethylsilyloxymethyl)-2,3-O-
isopropylidene-1,2,3,6-tetraol (13)
Dry DMSO (1.4 mL, 20 mmol) was slowly added to a solu-
tion of (COCl)2 (0.9 mL, 10.8 mmol) in dry CH2Cl2 (15 mL)
at ꢀ60 ꢁC under an Ar atmosphere. The mixture was stirred
at this temperature for 10 min at which time a solution of
diol 13 (1.2 g, 3.6 mmol) in dry CH2Cl2 (6 mL) was added
dropwise. The resulting mixture was stirred for 15 min while
the temperature was kept at ꢀ40 ꢁC. Then, it was cooled at
ꢀ78 ꢁC and Et3N (6 mL, 43 mmol) was added slowly. Stirring
was continued for 30 min, the cooling bath was removed, and
the mixture was left for an additional period of 2 h at room
temperature. After the addition of CH2Cl2 (50 mL), the reac-
tion mixture was washed with saturated brine (2ꢂ50 mL)
and the combined organic phases were dried (Na2SO4). Re-
moval of the solvents under reduced pressure (below 45 ꢁC)
gave crude dialdehyde as a yellow oil. This was used without
any further purification in the next step. Thus, a solution of
Ph3PþCH3Brꢀ (7.67 g, 21.5 mmol) and 12-crown-4-ether
(0.7 mL, 4.3 mmol) in dry THF (20 mL) was cooled to
ꢀ78 ꢁC under an Ar atmosphere. A 1.6 M solution of
n-BuLi in hexanes (13.1 mL, 30 mmol) was added dropwise
and the mixture was stirred for 1 h at 0 ꢁC. Then, it was
re-cooled to ꢀ60 ꢁC and a solution of the crude dialdehyde
in dry THF (10 mL) was slowly added. The temperature was
kept at ꢀ20 ꢁC for 3 h and then the mixture was left at
room temperature overnight. After quenching with a saturated
aqueous ammonium chloride solution (20 mL) and the addi-
tion of H2O (30 mL), the resulting slurry was extracted with
CH2Cl2 (3ꢂ30 mL). The combined organic phases were dried
(Na2SO4) and the solvents were removed under reduced pres-
sure. The obtained residue was purified by column chromatog-
raphy on silica gel with a mixture of hexane/EtOAc (20:1 v/v)
to give 0.59 g of diene 15 (50% overall from 13) as an oil. Rf
(hexane/EtOAc 5:1 v/v) 0.48; [a]2D5 þ4.0 (c 2.6, CHCl3); FTIR
A solution of ester 12 (1.6 g, 4.4 mmol) in dry diethylether
(25 mL) was cooled to 0 ꢁC under an Ar atmosphere. Then,
LiBH4 (210 mg, 9.7 mmol) was added in portions and the mix-
ture was stirred vigorously for 2 h at the same temperature. The
reaction was quenched by the addition of a few drops of EtOAc
and left stirring until it reached room temperature. Saturated
brine (70 mL) was added and the mixture was extracted with
EtOAc (2ꢂ50 mL). The combined organic phases were dried
(Na2SO4) and the solvents were removed under reduced pres-
sure. Column chromatography of the obtained residue on silica
gel with a mixture of hexane/EtOAc (3:1 v/v) gave 1.41 g of diol
13 (96%) as a thick oil. Rf (hexane/EtOAc 1:1 v/v) 0.37; [a]D25
þ21.8 (c 7.6, CHCl3); FTIR (neat film) 3434, 2954, 2932,
2859, 1473, 1370, 1254, 1217, 1098, 1056, 839 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 4.13 (t, J¼6.2 Hz, 1H, H-2), 3.75
(d, J¼9.9 Hz, 1H, H-30a), 3.74e3.70 (m, 2H, H-1), 3.62e3.58
(m, 2H, H-6), 3.46 (d, J¼9.9 Hz, 1H, H-30b), 3.36 (br s, 1H,
OH), 3.15 (br s, 1H, OH), 1.76e1.52 (m, 4H, H-4 and H-5),
1.44 (s, 3H, CMe2), 1.36 (s, 3H, CMe2), 0.89 (s, 9H, CMe3),
0.08 (s, 6H, SiMe2); 13C NMR (75 MHz, CDCl3) d 107.9
(CMe2), 82.8 (C-3), 82.6 (C-2), 65.5 (C-30), 62.6 (C-6), 60.5
(C-1), 28.0 (C-4), 26.7 (CMe2), 26.4 (CMe2), 25.8 (C-5), 25.6
(CMe3), 17.9 (CMe3), ꢀ5.8 (SiMe2), ꢀ5.9 (CMe2); HRMS m/z
357.2070 [C16H34O5SiNa (MþNa)þ requires 357.2068].
4.1.5. Methyl 2-((2S,3R,4S)-3-(tert-butyldimethylsilyloxy-
methyl)-3,4-isopropylidene-dihydroxytetrahydrofuran-2-yl)-
acetate (14)
NaBH4 (38 mg, 1 mmol) was added to a solution of unsat-
urated ester 11 (73 mg, 0.2 mmol). The mixture was stirred for
48 h at room temperature. Then, glacial acetic acid was added

4002
S.M. Totokotsopoulos et al. / Tetrahedron 64 (2008) 3998e4003
(neat film) 3074, 2986, 2954, 2931, 2858, 1642, 1472, 1370,
1251, 1096, 839, 777 cmꢀ1 1H NMR (300 MHz, CDCl3)
(2:1 v/v) to give 428 mg of diol 18 (99%) as a thick oil. Rf
(hexane/EtOAc 1:1 v/v) 0.53; [a]2D5 þ26.1 (c 0.5, CHCl3);
FTIR (neat film) 3428, 2949, 2928, 2855, 1462, 1368, 1248,
;
d 5.91e5.72 (m, 2H, H-2 and H-7), 5.37 (d, J¼17.0 Hz, 1H,
H-1t), 5.23 (d, J¼10.3 Hz, 1H, H-1c), 5.01 (d, J¼17.0 Hz,
1H, H-8t), 4.92 (d, J¼10.3 Hz, 1H, H-8c), 4.59 (d,
J¼6.4 Hz, 1H, H-3), 3.61 and 3.57 (ABq, J¼10.9 Hz, 2H,
H-40), 2.27e2.15 (m, 1H, H-6a), 2.08e1.95 (m, 1H, H-6b),
1.54e1.49 (m, 2H, H-5), 1.46 (s, 3H, CMe2), 1.38 (s, 3H,
CMe2), 0.88 (s, 9H, CMe3), 0.06 (s, 6H, SiMe2); 13C NMR
(75 MHz, CDCl3) d 139.0 (C-7), 137.3 (C-2), 117.5 (C-1),
114.1 (C-8), 107.9 (CMe2), 83.8 (C-4), 82.1 (C-3), 65.2
(C-40), 31.4 (C-5), 28.3 (C-6), 27.5 (CMe2), 26.9 (CMe2),
25.9 (CMe3), 18.0 (CMe3), ꢀ5.4 (SiMe2), ꢀ5.7 (SiMe2);
HRMS m/z 349.2171 [C18H34O3SiNa (MþNa)þ requires
349.2169].
1
1089, 837, 775 cmꢀ1; H NMR (300 MHz, CDCl3) d 4.17
(d, J¼2.4 Hz, 1H, H-2), 4.11e4.07 (m, 1H, H-4), 3.91e3.85
(m, 1H, H-3), 3.75 (d, J¼9.8 Hz, 1H, H-10a), 3.68 (br d,
J¼8.0 Hz, 1H, OH), 3.62 (d, J¼9.8 Hz, 1H H-10b), 2.48 (br
s, 1H, OH), 1.89e1.67 (m, 4H, H-5 and H-6), 1.46 (s, 3H,
CMe2), 1.33 (s, 3H, CMe2), 0.92 (s, 9H, CMe3), 0.12 (s, 6H,
SiMe2); 13C NMR (75 MHz, CDCl3) d 108.4 (CMe2), 81.0
(C-2), 79.3 (C-1), 69.7 (C-3), 69.2 (C-4), 67.8 (C-60), 31.7
(C-6), 28.1 (CMe2), 26.5 (C-5), 26.3 (CMe2), 25.9 (CMe3), 18.4
(CMe3), ꢀ5.6 (SiMe2); HRMS m/z 355.1909 [C16H32O5SiNa
(MþNa)þ requires 355.1911].
4.1.9. 6a-Carba-b-D-fructopyranose (1)
4.1.7. (1S,2S)-1-(tert-Butyldimethylsilyloxymethyl)-1,2-O-
isopropylidene-cyclohex-3-ene-1,2-diol (16)
A cold mixture of TFA and H2O (1:1, 40 mL) was added in
a flask containing diol 17 (400 mg, 1.2 mmol). The mixture
was stirred for 3 h at room temperature. Then, the volatiles
were removed under reduced pressure and the mixture was
co-evaporated with EtOH (3ꢂ20 mL). The obtained residue
was re-dissolved in H2O (20 mL) and this solution was washed
with CH2Cl2 (3ꢂ20 mL). The aqueous phase was co-evapo-
rated with EtOH (3ꢂ15 mL) to give 203 mg of 6a-carba-b-
D-fructopyranose (1) (95%) as a white amorphous solid. Mp
96e98 ꢁC (lit.17b mp 96e97 ꢁC); [a]2D5 ꢀ53.5 (c 0.5, MeOH)
Grubbs’ second generation catalyst {benzylidene[1,3-
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-
(tricyclohexylphosphine)ruthenium (17), a total of 68 mg,
0.08 mmol} was periodically added to a stirring solution of di-
ene 15 (555 mg, 1.7 mmol) in dry CH2Cl2 (80 mL) at room
temperature and under an Ar atmosphere. After 2 days, the
solvent was removed under reduced pressure and the residue
was purified by column chromatography on silica gel with
a mixture of hexane/EtOAc (20:1 v/v) to give 415 mg of cy-
clohexene derivative 16 (82%) as an oil. Rf (hexane/EtOAc
5:1 v/v) 0.59; [a]2D5 þ16.1 (c 0.3, CHCl3); FTIR (neat film)
3031, 2985, 2954, 2930, 2858, 1472, 1367, 1252, 1214,
[lit.17b [a]D25 ꢀ53.0 (c 0.46, MeOH)]; H and 13C NMR were
1
identical with those reported in the literature;18 HRMS m/z
201.0734 [C7H14O5Na (MþNa)þ requires 201.0733].
1099, 1084, 1042, 839, 777 cmꢀ1 1H NMR (300 MHz,
;
References and notes
CDCl3) d 5.95 (dt, J¼9.6, 3.6 Hz, 1H, H-3), 5.83e5.78 (m,
1H, H-4), 4.39 (d, J¼3.6 Hz, 1H, H-2), 3.63 and 3.47 (ABq,
J¼10.2 Hz, 2H, H-10), 2.20e2.13 (m, 1H, H-5a), 2.00e1.92
(m, 1H, H-5b), 1.85 (dt, J¼12.9, 5.8 Hz, 1H, H-6a); 1.68
(ddd, J¼13.5, 7.7, 5.8 Hz, 1H, H-6b), 1.42 (s, 3H, CMe2),
1.39 (s, 3H CMe2), 0.86 (s, 9H, CMe3), 0.04 (s, 6H, SiMe2);
13C NMR (75 MHz, CDCl3) d 131.9 (C-4), 125.4 (C-3),
108.6 (CMe2), 81.3 (C-1), 72.2 (C-2), 67.8 (C-10), 28.5 (C-6),
28.1 (CMe2), 28.0 (CMe3), 25.9 (CMe2), 22.7 (C-5), 18.3
(CMe3), ꢀ5.4 (SiMe2), ꢀ5.5 (SiMe2); HRMS m/z 321.1855
[C16H30O3SiNa (MþNa)þ requires 321.1856].
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¨
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Weinheim, 2005.