Stereodivergent synthesis of diastereoisomeric carba analogs of glycal-derived vinyl epoxides: A new access to carbasugars

Article abstract of DOI:10.1002/chir.21003

A convenient method for the stereoselective synthesis of diasteroisomeric vinyl epoxides (-)-2α and (-)-2β, the carba analogs of D-galactal and D-allal-derived vinyl epoxides 1αand 1β, has been elaborated starting from tri-O-acetyl-D-glucal. The key step of this synthesis is an application of the known Claisen thermal rearrangement of a glucal derivative, the vinyl allyl ether (+)-3b, which allows to switch the glycal structure into the corresponding carba analog scaffold. Epoxides (-)-2α and (-)-2β derive from the same synthetic intermediate, the trans diol (+)-5. Chirality, 2011. 2011 Wiley-Liss, Inc. Copyright

Full text of DOI:10.1002/chir.21003

CHIRALITY 23:820–826 (2011)
Stereodivergent Synthesis of Diastereoisomeric Carba Analogs of
Glycal-Derived Vinyl Epoxides: A New Access to Carbasugars
*
ILEANA FRAU, VALERIA DI BUSSOLO, LUCILLA FAVERO, MAURO PINESCHI, AND PAOLO CROTTI
Dipartimento di Scienze Farmaceutiche, Universita` di Pisa, Pisa, Italy
Contribution to the Carlo Rosini Special Issue
ABSTRACT
A convenient method for the stereoselective synthesis of diasteroisomeric vinyl
epoxides (2)-2a and (2)-2b, the carba analogs of D-galactal and D-allal-derived vinyl epoxides
1aand 1b, has been elaborated starting from tri-O-acetyl-D-glucal. The key step of this synthesis
is an application of the known Claisen thermal rearrangement of a glucal derivative, the vinyl
allyl ether (1)-3b, which allows to switch the glycal structure into the corresponding carba ana-
log scaffold. Epoxides (2)-2a and (2)-2b derive from the same synthetic intermediate, the
C
VV
trans diol (1)-5. Chirality 23:820–826, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: carbasugars; stereoselective synthesis; Claisen thermal rearrangement
were transferred via a syringe. Organic solutions were dried on Na2SO4
INTRODUCTION
and concentrated by a rotary evaporator below 408C at ca. 25 Torr. Flash
column chromatography was performed using 230–400 mesh silica gel.
Analytical thin layer chromatography (TLC) was performed on Alugram
SIL G/UV254 silica gel sheets with detection by 0.5% phosphomolybdic
acid solution in 95% ethanol (EtOH). Preparative TLC was performed
using glass plates precoated to a depth of 0.25 or 0.50 mm with 230–400
mesh silica gel impregnated with a fluorescent indicator (254 nm). Et3N,
Ac2O, and CH2Cl2 were distilled from CaH2, tetrahydrofuran (THF) was
distilled from Na/benzophenone. Anhydrous N,N-dimethylformamide
(DMF), CH3CN, and Pyridine were purchased from Aldrich. PMBCl,
Ph3PMe1I2, potassium hexamethyldisilazide (KHMDS), NaBH4, BnBr,
NaH, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), MsCl, Ms2O, t-
BuOK, 1,2;3,4-di-O-isopropyliden galactopyranose, and 3-cyclohexene-1-
methanol were purchased from Aldrich and used without purification. 2-
Iodoxybezoic acid (IBX) was synthesized according to the literature
methods,12 glucal diol (1)-6 was prepared as previously described.13
Proton and carbon-13 nuclear magnetic resonance (1H NMR and 13C
NMR) spectra were recorded on a Bruker AC 250 NMR spectrometer
(300 and 62.5 MHz for 1H and 13C, respectively); chemical shifts are
expressed in parts per million (d scale) downfield from tetramethylsilane
and refer to residual protium in the NMR solvent (CHCl3: d 7.26). Data
are presented as follows: chemical shift, multiplicity (s 5 singlet, d 5
doublet, t 5 triplet, m 5 multiplet, and/or multiple resonances), integra-
tion, and coupling constant in Hertz (Hz). Optical rotations were
acquired on a Perkin Elmer-341 Digital Polarimeter. Melting points were
recorded with a Kofler melting point apparatus and were uncorrected.
High-performance liquid chromatography with Daicel Chiracel OD-H
chiral column was used for the measurements (97:3 hexane/i-Pr2O).
Carbasugars are carbocyclic analogs of carbohydrates that
play a crucial role within the broad field of carbohydrate mim-
etics.1 Natural carbasugars as well as synthetic carbasugars
have shown to possess interesting biological activities.2,3
They are particularly attractive, because their structural re-
semblance to the parent sugars would facilitate their recogni-
tion by biological systems in place of the related natural sug-
ars. Moreover, the structural substitution of the endocyclic ox-
ygen atom with a methylene group leads to compounds that
are more stable toward endogenous degradative enzymes.
The synthetic strategies adopted to obtain carbapyranoses
can be broadly classified as: (i) synthetic methods that use
non carbohydrates as starting materials4–6 and (ii) protocols
that utilize carbohydrates as the precursors.7,8 In this frame-
work, the use of carbohydrates provides important advan-
tages, over the other methods, in the preparation of their car-
bocyclic analogs mostly because the enantiomeric purity of
the target carbasugars is generally guaranteed.
Recently, we have developed a new uncatalyzed, substrate-
dependent, stereospecific glycosylation process using the dia-
stereoisomeric D-allal and D-galactal-derived vinyl epoxides
1a and 1b, as unprecedented glycosyl donors (Scheme 1).9,10
On this basis, we herein focus our attention on the synthe-
sis of enantiopure carba analogs of glycosyl donors 1a and
1b, the diastereoisomeric vinyl epoxides 2a and 2b, to
check their suitability as pseudoglycosyl donors, with the
aim to realize a new approach to the stereoselective synthe-
sis of carbasugars.
EXPERIMENTAL
3,4-Di-O-(p-Methoxybenzyl)-6-O-(2-Tetrahydropyranyl)-
D-Glucal (2)-(7)
A solution of trans diol (1)-613 (1.18 g, 5.13 mmol) in anhydrous
DMF (15 mL) was added dropwise at 08C to a suspension of 60% NaH in
The most significant features of our stereoselective synthetic
strategy are (i) the construction of the carbocyclic system 4 by
way of an application of the known Claisen rearrangement
developed by Sudha and Nagarajan11 to the glycal substrate
3b and (ii) the synthesis of an efficient carba-type precursor,
the trans diol 5, which is easily transformed into diastereoiso-
meric vinyl epoxides 2a and 2b (Scheme 2).
Contract grant sponsor: Universita` di Pisa.
Contract grant sponsor: Ministero dell’Istruzione, della Universita` e della
Ricerca, Roma.
Contract grant sponsor: Merck Research Laboratories (2005 ADP Chemistry
Award).
*Correspondence to: Valeria Di Bussolo, Universita` di Pisa, Via Bonanno 33,
I-56126 Pisa, Italy. E-mail: valeriadb@farm.unipi.it
Received for publication 16 March 2011; Accepted 21 June 2011
DOI: 10.1002/chir.21003
Published online 17 August 2011 in Wiley Online Library
(wileyonlinelibrary.com).
MATERIALS AND METHODS
All reactions were performed in flame-dried modified Schlenk (Kjel-
dahl shape) flasks fitted with a glass stopper or rubber septa under a pos-
itive pressure of argon. Air- and moisture-sensitive liquids and solutions
C
VV
2011 Wiley-Liss, Inc.

CARBA-ANALOGS OF GLYCAL-DERIVED VINYL EPOXIDES
821
Scheme 1. Stereospecific glycosylation of alcohols by vinyl epoxides 1a and 1b.
paraffin (1.03 g, 25.6 mmol, 5.0 equiv) in anhydrous DMF (15 mL). After
stirring at r.t. for 30 min, the suspension was cooled at 08C and p-
methoxybenzylchloride PMBCl (1.7 mL, 12.8 mmol, 2.5 equiv.) was
added dropwise. The reaction mixture was allowed to warm to r.t. and
stirred for 12 h. Dilution with Et2O and evaporation of the washed (satu-
rated aqueous NaCl) and dried (MgSO4) organic solution afforded 3,4-
di-O-para-methoxybenzyl (PMB)-derivative (2)-7 (2.02 g, 84% yield),
practically pure as a yellow oil, which was used in the next step without
any further purification: Rf 5 0.20 (8:2 hexane/ethyl acetate (AcOEt));
[a]2D0 20.3 (CHCl3, c 1.5). 1H NMR (250 MHz, CDCl3) d 7.17–7.36 (m,
4H), 6.78–6.97 (m, 4H), 6.40 (ddd, 1H, J 5 6.2, 3.1, and 1.3 Hz), 4.84
(ddd, 1H, J 5 6.2, 2.7, 0.9 Hz), 4.55–4.82 (m, 2H), 4.77 (d, 1H, J 5 10.8
Hz), 4.68 (d, 1H, J 5 10.8 Hz), 4.49 (dd, 1H, J 5 11.3 and 1.9 Hz), 4.13–
4.22 (m, 1H), 3.95–4.12 (m, 2H), 3.65–3.93 (m, 3H), 3.80 (s, 6H), 3.42–
3.55 (m, 1H), 1.41–1.92 (m, 6H). 13C NMR (62.5 MHz, CDCl3) (2 diaster-
eoisomers) d 159.4, 144.8, 130.6, 129.7, 129.6, 113.9, 100.2, 100.0, 99.4,
99.2, 75.8, 75.6, 74.3, 73.6, 73.5, 70.4, 62.5, 62.2, 55.5, 30.7, 25.6, 19.7,
19.5. Anal. Calcd for C27H34O7: C, 68.92; H, 7.29. Found: C, 69.24; H,
7.55.
reaction mixture was filtered on a pad of Celite1 that was further eluted
with AcOEt. Evaporation of the solvent afforded aldehyde 9 (0.93 g, 94%
yield), pure as an oil, which was used in the next step without any fur-
ther purification: Rf 5 0.22 (7:3 hexane/AcOEt); 1H NMR (250 MHz,
CDCl3) d 9.53 (d, 1H, J 5 0.6 Hz), 7.20–7.34 (m, 2H), 7.09–7.17 (m, 2H),
6.79–6.93 (m, 4H), 6.65 (d, 1H, J 5 6.2 Hz), 5.00–5.09 (m, 1H), 4.62 (d,
1H, J 5 11.7 Hz), 4.55 (d, 1H, J 5 11.7 Hz), 4.51–4.59 (m, 1H), 4.29 (s,
2H), 4.01–4.06 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72–3.78 (m, 1H). 13
C
NMR (62.5 MHz, CDCl3) d 198.9, 159.6, 159.5, 145.0, 129.7, 129.6, 129.4,
114.2, 114.0, 100.5, 79.4, 72.2, 71.6, 69.4, 66.9, 55.5. Anal. Calcd for
C22H24O6: C, 68.74; H, 6.29. Found: C, 69.02; H, 6.11.
1,5-Anhydro-Di-O-(p-Methoxybenzyl)-2,6,7-Trideoxy-D-
arabino-Hept-1,6-Dienitol (1)-(3b)
A solution 0.5M of KHMDS in THF (6.8 mL, 3.40 mmol, 1.4 equiv)
was added dropwise to a solution of Ph3PMe1I2 (1.47 g, 3.65 mmol, 1.5
equiv) in anhydrous THF (15 mL) at 2788C, and the mixture was stirred
at the same temperature for 30 min and at 08C for 1 h. After cooling at –
788C, a solution of aldehyde 9 (0.93 g, 2.43 mmol) in anhydrous THF
(15 mL) was added dropwise, and the reaction mixture was stirred at r.t.
for 5 h. Dilution with Et2O and filtration on Fluorisil1-silica gel pad
afforded an organic solution, which was washed (saturated aqueous
NH4Cl, saturated aqueous NaHCO3, and saturated aqueous NaCl) and
dried. Evaporation of the organic solution afforded a crude product con-
sisting of olefin (1)-3b, practically pure as a solid, m.p. 35–378C (0.845
g, 91% yield): Rf 5 0.43 (7:3 hexane/AcOEt); [a]2D0 11.1 (CHCl3, c 0.10).
1H NMR (250 MHz, CDCl3) d 7.17–7.37 (m, 4H), 6.79–6.97 (m, 4H), 6.41
(d, 1H, J 5 6.2 Hz), 6.03 (ddd, 1H, J 5 17.2, 10.5 and 6.5 Hz), 5.41 (d,
1H, J 5 17.2 Hz), 5.30 (d, 1H, J 5 10.5 Hz), 4.85 (dd,1H, J 5 6.2 and 2.7
Hz), 4.70 (d, 1H, J 5 10.7 Hz), 4.60 (d, 1H, J 5 10.7), 4.57 (d, 1H, J 5
11.3 Hz), 4.51 (d, 1H, J 5 11.3 Hz), 4.29 (t, 1H, J 5 7.7 Hz), 4.12–4.20
(m, 1H), 3.80 (s, 6H), 3.56 (dd, 1H, J 5 8.5 and 6.2 Hz). 13C NMR (62.5
MHz, CDCl3) d 159.5, 159.4, 144.6, 134.6, 130.7, 130.4, 129.8, 129.5,
118.4, 113.9, 100.7, 78.2, 78.1, 75.3, 73.6, 70.6, 55.4. Anal. Calcd for
C23H26O5: C, 72.23; H, 6.85. Found: C, 72.82; H, 6.73.
3,4-Di-O-(p-Methoxybenzyl)-D-Glucal (2)-(8)
3,4-Di-O-PMB-derivative (2)-7 (2.0 g, 4.26 mmol) was dissolved in a
(1.5:2:1) AcOH/THF/H2O mixture (70 mL), and the reaction solution
was stirred for 12 h at 508C. After dilution with Et2O and neutralization
with solid NaHCO3, evaporation of the washed (saturated aqueous
NaHCO3 and saturated aqueous NaCl) and dried organic solution
afforded a crude solid product (2.35 g) consisting of primary alcohol
(2)-8, which was purified by recrystallization from hexane/AcOEt (1.28
g, 78% yield), m.p. 67–698C: Rf 5 0.14 (7:3 hexane/AcOEt); [a]2D0 221.7
(CHCl3, c 0.6). 1H NMR (250 MHz, CDCl3) d 7.21–7.32 (m, 4H), 6.84–
6.92 (m, 4H), 6.39 (dd, 1H, J 5 6.2, 1.2 Hz), 4.87 (dd, 1H, J 5 6.2, 2.7
Hz), 4.78 (d, 1H, J 5 11.1 Hz), 4.64 (d, 1H, J 5 11.1), 4.60 (d, 1H, J 5
11.1 Hz), 4.50 (d, 1H, J 5 11.1 Hz), 4.16–4.22 (m, 1H), 3.87–3.96 (m,
1H), 3.82–3.86 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.76 (dd, 1H, J 5 8.4,
6.5 Hz); 13C NMR (62.5 MHz, CDCl3) d 159.5, 159.4, 144.6, 130.3, 130.2,
129.9, 129.6, 114.0, 100.4, 77.4, 75.3, 74.3, 73.5, 70.5, 62.0, 55.4. Anal.
Calcd for C22H26O6: C, 68.38; H, 6.78. Found: C, 68.82; H, 6.53.
3,4-Di-O-(p-Methoxybenzyl)-5a-Carba-D-Glucal (2)-(4)
Olefin (1)-3 (0.50 g, 1.31 mmol) was dissolved in 1,3-dichlorobenzene
(5 mL), and the mixture was stirred at 2408C for 20 min in AP 100 Sili-
cone oil (Aldrich) warming bath. After cooling, the reaction mixture was
added to a solution of NaBH4 (0.075 g, 1.96 mmol, 6 equiv) in anhydrous
2:1 THF/EtOH (5 mL) and stirred at r.t. for 20 min. After dilution with
CH2Cl2, evaporation of the washed (saturated aqueous NaCl) and dried
2-Formyl-3,4-Di-(p-Methoxybenzyloxy)-3,4-Dihydro-2H-
Pyrane (9)
IBX (2.18 g, 7.77 mmol, 3.0 equiv)12 was added to a solution of pri-
mary alcohol (2)-8 (1.0 g, 2.59 mmol) in anhydrous CH3CN (60 mL),
and the reaction mixture was stirred at 458C for 5 h. After cooling, the
Scheme 2. Carba trans diol 5 as common synthetic intermediate of carba vinyl epoxide 2a and 2b.
Chirality DOI 10.1002/chir

822
DI BUSSOLO ET AL.
Scheme 3. Synthesis of primary alcohol (2)-4.
organic solution, afforded primary alcohol (2)-4 (0.483 g, 96% yield),
pure as a solid, m.p. 46–488C: Rf 5 0.28 (1:1 hexane/AcOEt); [a]D20
214.6 (CHCl3, c 0.52). H NMR (250 MHz, CDCl3) d 7.19–7.39 (m, 4H),
6.80–6.95 (m, 4H), 5.62–5.81 (m, 2H), 4.91 (d, 1H, J 5 11.0 Hz), 4.67 (d,
1H, J 5 11.0 Hz), 4.66 (d, 1H, J 5 11.2 Hz), 4.58 (d, 1H, J 5 11.2 Hz),
4.15–4.25 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.49–3.67 (m, 3H),
1.57–2.22 (m, 3H). 13C NMR (62.5 MHz, CDCl3) d 159.5, 159.4, 130.6,
130.1, 129.7, 128.9, 128.2, 127.0, 126.2, 114.1, 114.0, 82.1, 81.1, 74.1, 71.2,
66.0, 55.4, 40.7, 28.2. Anal. Calcd for C23H28O5: C, 71.85; H, 7.34. Found:
C, 72.02; H, 7.43.
6-O-Benzyl-5a-Carba-D-Glucal (1)-(5)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.405 g, 1.79 mmol, 1.5
equiv) was added at r.t. to a solution of benzyl derivative (1)-11 (0.567
g, 1.19 mmol) in 18:1 CH2Cl2/H2O mixture (34 mL) and the reaction so-
lution was stirred at the same temperature for 3 h. After dilution with
CH2Cl2, evaporation of the washed (saturated aqueous NaHCO3 and sat-
urated aqueous NaCl) and dried organic layer, afforded a crude product
(0.35 g), which was subjected to flash chromatography. Elution with 1:1
hexane/AcOEt mixture afforded trans diol (1)-5, pure as a liquid (0.22
g, 79% yield): Rf 5 0.18 (1:1 hexane/AcOEt); [a]2D0 140.8 (CHCl3, c
0.13). 1H NMR (250 MHz, CDCl3) d 7.19–7.49 (m, 5H), 5.42–5.71 (m,
2H), 4.55 (s, 2H), 4.12–4.24 (m, 1H), 3.49–3.76 (m, 3H), 1.85–2.24 (m,
3H). 13C NMR (62.5 MHz, CDCl3) d 137.8, 128.7, 128.5, 128.1, 127.9,
127.0, 77.4, 74.0, 73.7, 73.5, 38.4, 28.4. Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 72.02; H, 7.43.
1
6-O-Benzyl-3,4-Di-O-(p-Methoxybenzyl)-5a-Carba-D-Glucal
(1)-(11)
Primary alcohol (2)-4 (0.483 g, 1.26 mmol) in anhydrous DMF (4
mL) was added dropwise at 08C to a suspension of 60% NaH in mineral
oil (0.15 g, 3.78 mmol, 3.0 equiv) in anhydrous DMF (4 mL), and the
resulting reaction mixture was stirred at r.t. for 40 min. After cooling at
08C, BnBr (0.37 mL, 3.15 mmol, 2.5 equiv) was added dropwise, and the
mixture was stirred at r.t. for 2 h. Evaporation of the washed (saturated
aqueous NaCl) and dried organic layer, afforded a crude mixture (0.631
g), which was subjected to flash chromatography. Elution with an 8:2
hexane/AcOEt mixture afforded monobenzyl-derivative (1)-11, pure as
a liquid (0.567 g, 95% yield): Rf 5 0.36 (8:2 hexane/AcOEt); [a]2D0 12.9
(CHCl3, c 0.83). 1H NMR (250 MHz, CDCl3) d 7.15–7.40 (m, 9H), 6.80–
6.92 (m, 4H), 5.61–5.81 (m, 2H), 4.81 (d, 1H, J 5 10.5 Hz), 4.62 (s, 2H);
4.55 (d, 1H, J 5 10.5 Hz), 4.50 (s, 2H), 4.10–4.21 (m, 1H), 3.81 (s, 3H),
3.80 (s, 3H), 3.53–3.71 (m, 3H), 2.20–2.31 (m, 2H), 1.99–2.15 (m, 1H).
13C NMR (62.5 MHz, CDCl3) d 159.3, 138.8, 138.4, 132.4, 132.2, 129.8,
129.6, 129.2, 128.9, 128.6, 127.9, 127.8, 127.6, 113.9, 81.0, 79.4, 74.2, 73.2,
71.3, 70.7, 55.5, 39.5, 29.0. Anal. Calcd for C30H34O5: C, 75.92; H, 7.22.
Found: C, 76.04; H, 7.53.
6-O-Benzyl-3-O-(t-Butyldimethylsilyl)-5a-Carba-D-Glucal
(2)-(12)
A solution of trans diol (1)-5 (3.35 g, 14.4 mmol) in anhydrous DMF
(38 mL) containing imidazole (1.97 g, 28.88 mmol, 2.0 equiv) was treated
at 08C with TBSCl (2.60 g, 17.33 mmol, 1.2 equiv), and the reaction mix-
ture was stirred at r.t. for 48 h. Dilution with Et2O and evaporation of the
washed (saturated aqueous NaCl) and dried organic solution afforded a
crude product (4.93 g, 98% yield) consisting of O-tert-butyl-dimethylsilyl
(TBS)-derivative (2)-12, practically pure as a liquid, which was used in
the next step without any further purification: Rf 5 0.69 (1:1 hexane/
1
AcOEt); [a]2D0 28.6 (CHCl3, c 0.43). H NMR (250 MHz, CDCl3) d 7.23–
7.40 (m, 5H), 5.58–5.68 (m, 1H), 5.43–5.51 (m, 1H), 4.57 (d, 1H, J 5 12.3
Hz) 4.51 (d, 1H, J 5 12.3 Hz), 4.12–4.20 (m, 1H), 3.50–3.68 (m, 3H),
1.88–2.35 (m, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.07 (s, 3H). 13C NMR
(62.5 MHz, CDCl3) d 138.4, 129.7, 128.5, 127.7, 126.9, 75.6, 75.1, 73.5,
Scheme 4. Claisen rearrangement of glucal (1)-3 into carba system 10.
Chirality DOI 10.1002/chir

CARBA-ANALOGS OF GLYCAL-DERIVED VINYL EPOXIDES
823
Scheme 5. Stereodivergent synthesis of vinyl epoxides (2)-2a and (2)-2b from trans diol (1)-5.
72.4, 38.8, 28.8, 26.0, 18.3, 24.2, 24.3. Anal. Calcd for C20H32O3Si: C,
71.77; H, 7.74. Found: C, 72.02; H, 7.43.
same temperature, dilution with Et2O and evaporation of the washed
(saturated aqueous NaCl) and dried organic solution afforded a crude
product consisting of trans hydroxy mesylate (1)-14 which was sub-
jected to flash chromatography. Elution with a 6:4 hexane/AcOEt mix-
ture afforded trans hydroxy mesylate (1)-14 (2.12 g, 71% yield), pure as
6-O-Benzyl-3-O-(t-Butyldimethylsilyl)-4-O-Mesyl-5a-Carba-
D-Glucal (1)-(13)
1
a liquid: Rf 5 0.22 (6:4 hexane/AcOEt); [a]2D0 119.3 (CHCl3, c 0.53). H
A solution of alcohol (2)-12 (2.46 g, 7.08 mmol) in an 1:1 anhydrous
pyridine/CH2Cl2 mixture (16 mL) was treated at 08C with MsCl (1.1 mL,
14.16 mmol, 2 equiv), and the reaction mixture was stirred 12 h at the
same temperature. Dilution with Et2O and evaporation of the washed
(10% aqueous HCl, saturated aqueous NaHCO3, and saturated aqueous
NaCl) and dried organic solution afforded a crude product (2.89 g, 96%
yield) consisting of mesylate (1)-13, practically pure, as a solid, which
was used in the next step without any further purification, m.p. 144–
NMR (250 MHz, CDCl3) d 7.27–7.40 (m, 5H), 5.67–5.78 (m, 1H), 5.52–
5.60 (m, 1H), 4.70 (dd, 1H, J 5 10.7 and 7.6 Hz), 4.54 (d, 1H, J 5 11.8
Hz), 4.47 (d, 1H, J 5 11.8 Hz), 4.37–4.45 (m, 1H), 3.63 (dd, 1H J 5 9.5
and 4.7 Hz), 3.57 (dd, 1H J 5 9.5 and 3.2 Hz), 3.11 (s, 3H), 2.14–2.38 (m,
3H). 13C NMR (62.5 MHz, CDCl3) d 138.2, 128.5, 127.8, 127.7, 127.6,
127.4, 85.7, 73.4, 71.5, 69.8, 38.5, 38.1, 29.0. Anal. Calcd for C15H20O5S:
C, 57.67; H, 6.45. Found: C, 58.01; H, 6.09.
1468C: Rf 5 0.14 (9:1 hexane/AcOEt); [a]20 116.8 (CHCl3, c 0.44). 1H
D
6-O-Benzyl-3,4-Anhydro-5a-Carba-D-Galactal (2)-(2b)
NMR (250 MHz, CDCl3) d 7.28–7.40 (m, 5H), 5.64–5.82 (m, 1H), 5.51
(dd, 1H, J 5 10.0 and 1.7 Hz), 4.64 (dd, 1H, J 5 8.7 and 6.5 Hz), 4.51 (s,
2H), 4.32–4.44 (m, 1H), 3.66 (dd, 1H, J 5 9.4 and 3.7 Hz), 3.55 (dd, 1H, J
5 9.4 and 6.4 Hz), 3.04 (s, 3H), 2.04–2.49 (m, 3H), 0.91 (s, 9H), 0.12 (s,
3H) 0.07 (s, 3H). 13C NMR (62.5 MHz, CDCl3) d 137.5, 129.7, 128.7,
127.9, 127.4, 126.0, 75.2, 73.6, 72.9, 72.0, 38.2, 33.6, 25.8, 24.0, 18.5, 25.1,
25.2. Anal. Calcd for C21H34O5SSi: C, 59.12; H, 8.03. Found: C, 59.50; H,
7.81.
A solution of trans hydroxy mesylate (1)-14 (1.06 g, 3.40 mmol) in
anhydrous benzene (65 mL) was treated with t-BuOK (0.381 g, 3.40
mmol, 1.0 equiv), and the resulting reaction mixture was stirred 4 h at
room temperature. Dilution with Et2O and evaporation of the filtered or-
ganic solution afforded a crude product consisting of epoxide (2)-2b
(0.631 g, 99% yield) practically pure, as a liquid: Rf 5 0.40 (8:2 hexane/
1
AcOEt); [a]2D0 23.9 (CHCl3, c 0.13). H NMR (250 MHz, CDCl3) d 7.28–
7.41 (m, 5H), 5.87–6.02 (m, 2H), 4.62 (d, 1H, J 5 12.0 Hz), 4.55 (d, 1H,
J 5 12.0 Hz), 3.52–3.70 (m, 3H), 3.28–3.33 (m, 1H), 2.02–2.27 (m, 2H),
1.70–1.84 (m, 1H). 13C NMR (62.5 MHz, CDCl3) d 138.4, 132.7, 128.5,
127.7, 123.2, 73.4, 73.0, 56.5, 47.8, 33.7, 24.7. Enantiomeric excess (ee)
>99%. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.86;
H, 7.31.
6-O-Benzyl-4-O-Mesyl-5a-Carba-D-Glucal (1)-(14)
A solution of mesylate (2)-13 (4.20 g, 9.56 mmol) in anhydrous THF
(315 mL) was treated at 08C with 1M tetrabutylammonium fluoride
(TBAF) in THF (9.56 mL, 9.56 mmol, 1.0 equiv). After 2 h stirring at the
6-O-Benzyl-3,4-Anhydro-5a-Carba-D-Allal (2)-(2a)
Et3N (70.0 lL, 0.553 mmol, 6.5 equiv), Py (1.0 lL, 0.01 mmol), and a
solution of Ms2O (0.015 g, 0.085 mmol, 1.0 equiv) in anhydrous THF
(0.5 mL) were successively added to a solution of trans diol (1)-5 (0.020
g, 0.085 mmol) in anhydrous THF (0.5 mL) at 08C, and the reaction mix-
ture was stirred at the same temperature for 30 min. The completeness
of the mesylation was monitored by TLC analysis and after that, the mix-
ture was treated in situ with t-BuOK (0.019 g, 0.170 mmol, 2.0 equiv)
and stirred at r.t. for 2 h. Dilution with CH2Cl2 and evaporation of the fil-
Scheme 6. Reaction of epoxide (2)-2b with1,2;3,4-di-O-isopropyliden-a-D-
galoctopyranose.
Chirality DOI 10.1002/chir

824
DI BUSSOLO ET AL.
Scheme 7. Reaction of epoxide (2)-2a with 3-cyclohexene-1-methanol.
tered organic solution afforded a crude reaction product (0.020 g) con-
sisting of epoxide (2)-2a together with a small amount (3%) of the di-O-
mesyl derivative of the starting diol 5 (1H NMR). The crude product
was subjected to flash chromatography. Elution with an 8:2 hexane/
AcOEt mixture afforded epoxide (2)-2a (0.15 g, 82% yield), pure as a liq-
1H, J 5 10.6, 3.9 Hz), 5.68–5.78 (m, 1H), 5.52 (d, 1H, J 5 5.1 Hz), 4.62 (dd,
1H, J 5 5.9, 2.4 Hz), 4.53 (s, 2H), 4.34 (dd, 1H, J 5 5.4 and 2.4 Hz), 4.18–
4.28 (m, 1H), 4.03–4.10 (m, 1H), 3.58–3.38 (m, 6H), 1.90–2.28 (m, 3H),
1.50 (s, 3H), 1.43 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H). 13C NMR (62.5 MHz,
CDCl3) d 138.2, 130.5, 128.6, 127.9, 127.8, 124.6, 109.4, 108.8, 96.5, 73.6,
72.2, 71.8, 71.2, 70.9, 70.8, 68.2, 68.1, 66.1, 35.4, 29.9, 26.2, 26.0, 25.4, 24.7.
Anal. Calcd for C26H36O8: C, 65.53; H, 7.61. Found: C, 65.71; H, 7.25.
uid: Rf5 0.39 (8:2 hexane/AcOEt); [a]20 21.5 (CHCl3, c 0.11). 1H NMR
D
(250 MHz, CDCl3) d 7.28–7.40 (m, 5H), 5.84–5.97 (m, 1H), 5.71–5.82 (m,
1H), 4.52 (s, 2H), 3.42–3.51 (m, 1H), 3.45 (dd, 1H, J 5 9.0 and 7.1 Hz),
3.35 (dd, 1H, J 5 9.0 and 7.6 Hz), 3.19 (td, 1H, J 5 4.0 and 1.7 Hz), 2.61–
2.78 (m, 1H), 2.13–2.29 (m, 1H), 1.95–2.11 (m, 1H). 13C NMR (62.5
MHz, CDCl3) d 138.3, 131.1, 128.5, 127.8, 127.7, 123.2, 73.3, 70.3, 56.3,
46.8, 31.9, 23.9. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C,
77.71; H, 7.23.
Reaction of Epoxide (2)-2a with 3-Cyclohexene-1-
Methanol Under 0.005 N TsOHꢀH2O/CH2Cl2 Protocol
Epoxide (2)-2a (0.030 g, 0.139 mmol) was added to a solution of 3-
cyclohexene-1-methanol (0.050 mL, 0.417 mmol, 3.0 equiv) in CH2Cl2
(1.4 mL) containing TsOHꢀH2O (1.3 mg, 0.007 mmol, 0.05 equiv)
(epoxide:3-cyclohexene-1-methanol:TsOHꢀH2O
5 1:3:0.05), and the
Reaction of Epoxide (2)-2b with 1,2;3,4-Di-O-
(Isopropyliden)-D-Galactal Under 0.005 N TsOHꢀH2O/
CH2Cl2 Protocol
reaction mixture was stirred at r.t. for 20 h. After dilution with CH2Cl2,
solid NaHCO3 was added, and stirring was prolonged for 15 min. Evap-
oration of the washed (saturated aqueous NaCl) and filtered organic
solution afforded a crude reaction product (0.069 g) consisting of a
30:28:42 mixture of corresponding anti-1,2-addition product 16, anti-
1,4-addition product 18, and syn-1,4-addition product 17 (Scheme 7) in
the presence of an excess of 3-cyclohexene-1-methanol. The reaction
mixture was dissolved in anhydrous pyridine (1.5 mL) and treated at
08C with Ac2O (0.5 mL), and the resulting reaction mixture was stirred
at r.t. for 16 h. Dilution with toluene and evaporation of the organic sol-
vent afforded a crude reaction product (0.086 g), which was subjected
to preparative TLC (an 8:2 hexane/i-Pr2O mixture was used as the
eluant). Extraction of the two more intense bands (the slower moving
band contained 17-Ac) afforded an unseparable mixture of anti-1,2-
addition product 16-Ac and anti-1,4-addition product 18-Ac (0.011 g)
and 3-cyclohexenemethyl 6-O-benzyl-4-O-acetyl-5a-carba-a-D-threo-hex-2-
enopyranoside (17-Ac; syn-1,4-addition product; 0.010 g, 19% yield), as
a liquid: Rf 5 0.17 (8:2 hexane/i-Pr2O); 1H NMR (250 MHz, CDCl3) d
Epoxide (2)-2b (0.014 g, 0.065 mmol) was added to a solution of 1,2;3,4-
di-O-(isopropyliden)-D-galactal (0.101 g, 0.39 mmol, 6.0 equiv), TsOHꢀH2O
(0.0012 g, 0.006 mmol, 0.1 equiv) in anhydrous CH2Cl2 (0.44 mL)
[epoxide:1,2;3,4-di-(O-isopropyliden)-D-galactal:TsOHꢀH2O 5 1:6:0.05), and
the reaction mixture was stirred at r.t. for 2 h. After dilution with CH2Cl2,
solid NaHCO3 was added and stirring was prolonged for 15 min. Evapora-
tion of the washed (saturated aqueous NaCl) and filtered organic solution
afforded a crude reaction product (0.069 g), consisting of corresponding
anti-1,2-addition product 15 (Scheme 6) and the excess of 1,2;3,4-di-O-(iso-
propyliden)-D-galactal, which was subjected to preparative TLC (an 8:2 hex-
ane/i-Pr2O mixture was used as the eluant). Extraction of the more intense
band afforded (1)-3-O-[6-(1,2:3,4-di-O-isopropyliden-a-D-galactopyranosyl)]-
6-O-benzyl-5a-carba-D-gulal (15) (anti-1,2-addition product) (0.030 g, 87%
yield), pure as a yellow oil: Rf5 0.16 (8:2 hexane/i-Pr2O); [a]2D0 14.4
(CHCl3, c 0.52). 1H NMR (250 MHz, CDCl3) d 7.27–7.40 (m, 5H), 5.89 (dt,
Scheme 8. Rationalization of 1,2-regioselectivity observed with epoxide (2)-2b.
Chirality DOI 10.1002/chir

CARBA-ANALOGS OF GLYCAL-DERIVED VINYL EPOXIDES
825
Scheme 9. Rationalization of regioselective result in nucleophilic addition reaction with epoxide (2)-2a.
7.35–7.27 (m, 5H), 5.99–5.88 (m, 1H), 5.76 (dd, 1H, J 5 9.8, 2.0 Hz),
5.66 (br s, 2H), 5.30–5.20 (m, 1H), 4.53 (d, 1H, J 5 12.0 Hz), 4.44 (d,
1H, J 5 12.0 Hz), 3.83–3.73 (m, 1H), 3.52–3.25 (m, 4H), 2.36–2.19 (m,
1H), 2.10–2.00 (m, 4H), 1.99 (s, 3H), 1.53–1.92 (m, 3H), 1.11–1.36 (m,
2H). 13C NMR (62.5 MHz, CDCl3) d 171.1, 138.6, 130.1, 128.5, 127.9,
127.8, 127.3, 126.2, 74.3, 74.2, 73.5, 73.2, 70.8, 70.7, 70.5, 35.2, 34.3,
29.1, 28.7, 25.9, 24.8, 21.4. Anal. Calcd for C23H30O4: C, 74.56; H, 8.16.
Found: C, 74.94; H, 7.89.
Alcohol (2)-8 was oxidized to aldehyde 9 by a very clean
reaction with freshly prepared IBX12 in CH3CN at 458C. It is
worth noting that performing the oxidation reaction at a tem-
perature higher than 458C, the easy oxidation of the benzylic
carbon of the p-methoxybenzyl group determined the forma-
tion of consisting amounts (more than 30%) of the corre-
sponding p-methoxybenzaldehyde. Application of the previ-
ously described Wittig C1-extension protocol (Ph3P1CH3I2/
KHMDS/THF) to aldehyde 911 afforded glycal-derived olefin
(1)-3b in a high yield (91%).
Glycal (1)-3b, differing from 3a only for the type of pro-
tecting groups, was subjected with success to the known
thermal Claisen rearrangement (2508C)11 to give g,d-unsatu-
rated aldehyde 10. In accordance with the seminal paper,11
in this process, depicted in Scheme 4, the aldehydic C(1)-car-
bon of compound 10 derives from vinyl C(1)-carbon of the
endocyclic double bond of glycal 3. Aldehyde 10 turned out
to be unstable, and therefore, it was immediately subjected
to NaBH4 reduction to alcohol (2)-4 without any further pu-
rification (Scheme 3).
Alcohol (2)-4 was easily benzylated by BnBr/NaH proto-
col to give the completely protected carbaglucal derivative
(1)-11 (Scheme 5). Due to the presence of orthogonal O-Bn
and O-PMB protecting groups on the primary and secondary
hydroxy groups, respectively, compound (1)-11 appears to
be a very useful substrate for further selective functionaliza-
tion of the carba glucal skeleton.
As expected, the removal of the C(3)- and C(4)-O-PMB
groups of (1)-11 with DDQ did not affect the double bond
of the carba glycal system and afforded C(6)-O-Bn protected
trans diol (1)-5, a useful precursor of both chiral vinyl epox-
ides (2)-2a and (2)-2b (Scheme 5).
RESULTS AND DISCUSSION
The first part of the synthesis of epoxides 2a and 2b is
centered on the previously described Claisen rearrangement
of a suitable allyl-vinyl ether to transform a glycal system
into a corresponding carbaglycal system.11 The 3,4-di-O-ben-
zyl-protected glycal 3a, originally used by Sudha and Nagara-
jan to effect this transformation,11 was not appropriate to our
synthetic approach which needed the presence of a 3,4-di-O-
protection easily removable without affecting the double
bond. Our choice fell on the p-methoxybenzyl protective
group, whose removal (DDQ/CH2Cl2/H2O) is notoriously
compatible with the presence of an unsaturation. As a conse-
quence, the new allyl-vinyl ether (1)-3b was synthesized
starting from tri-O-acetyl-D-glucal (Scheme 3). Following a
previously described procedure,13 tri-O-acetyl-D-glucal was
transformed into O-tetrahydropyran (THP)-protected trans
diol (1)-6, which was subsequently alkylated (PMBCl/
NaH/DMF, room temperature protocol) to the correspond-
ing 3,4-di-O-(p-methoxybenzyl)-glucal (2)-7.
Deprotection of acetal (2)-7 with 1.5:2:1 AcOH/THF/H2O
mixture at 508C afforded the 3,4-di-O-(PMB)-protected pri-
mary alcohol (2)-8 in good yield (78%) after recrystallization
from hexane/AcOEt. Attempts made to prepare alcohol (2)-
8 by (i) regioselective monosilylation of the primary hydroxy
group of D-glucal, followed by O-PMB alkylation of the resid-
ual secondary hydroxy functionalities and C(6) deprotec-
tion14 or (ii) a regioselective C(6)-O-PMB deprotection (tri-
methylsilyl iodide (TMSI)/Et3N)15 of the fully O-PMB pro-
tected D-glucal were unfortunately unsuccessful.
The elaboration of trans diol (1)-5 into enantiopure epox-
ide (2)-2b was carried out by a stereoselective application of
our recently described racemic protocol.16 Following this
procedure, trans diol (1)-5 was selectively protected at the
secondary allyl hydroxy group by TBSCl (1 equiv) with for-
mation of the corresponding O-TBS derivative (2)-12, subse-
quently mesylated (MsCl/Py) at the residual secondary
Chirality DOI 10.1002/chir

826
DI BUSSOLO ET AL.
hydroxyl group with the formation of mesylate (1)-13.
Deprotection of (1)-13 with TBAF/THF provided trans
hydroxy mesylate (1)-14 that, under basic conditions (t-
BuOK), gave the desired epoxide (2)-2b [62% overall yield
from trans diol (1)-5, four steps]. On the other hand, due to
the known high reactivity and instability of the secondary ali-
phatic allylic mesylates,17 trans diol (1)-5 was transformed
into allylic mesylate 15 with 1 equiv of Ms2O at 08C, and
then, directly cyclized in situ, upon addition of t-BuOK, to
give enantiopure epoxide (2)-2a, accompained by only a
small amount (3%) of the di-O-mesylate of the starting trans
diol (1)-5. Easy separation by flash chromatography
(hexane/EtOAc 8:2 as the eluant) afforded epoxide (2)-2a
as a pure enantiomer [82% yield from trans diol (1)-5].
glucal as the starting material and trans diol (1)-5 as the piv-
otal synthetic intermediate. The key step of the synthesis is
constituted by the well-known Claisen thermal rearrange-
ment of a sugar to a pseudosugars11 applied, in the present
case, to 3,4-di-O-PMB-D-glucal derivative (1)-3b, the allyl
vinyl ether which turned out to be appropriate for this trans-
formation and the prosecution of the synthetic protocol. The
reaction of epoxide (2)-2a with a model O-nucleophile,
under acidic conditions, gives consistent amounts of the cor-
responding syn- and anti-1,4-addition products, having an a-
and b-O-linked-1,6-carba disaccharide structure. This result
makes epoxide (2)-2a a useful candidate for the construc-
tion of O-linked carba oligosaccharides and represents a
potentially new synthetic tool to carbasugars synthesis.
Enantiopure vinyl epoxides (2)-2a and (2)-2b were then
tested as pseudoglycosyl donors in nucleophilic addition
reactions with two nucleophiles such as 1,2;3,4-di-O-isopropy-
liden-a-D-galoctopyranose and 3-cyclohexene-1-methanol,
which were used as O-nucleophile models for the possible
synthesis of mixed or homogenous carba disaccharides.
In accordance with the results obtained with racemic
ACKNOWLEDGMENTS
Professor Renato Noto of the University of Palermo is
kindly acknowledged for helpful discussions.
LITERATURE CITED
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16
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Chirality DOI 10.1002/chir