Chemoenzymatic synthesis of the carbasugars carba-β-l-galactopyranose, carba-β-l-talopyranose and carba-α-l-talopyranose from methyl benzoate

Article abstract of DOI:10.1039/b921545j

The cis-dihydrodiol metabolite from methyl benzoate has been used as a synthetic precursor of carba-β-l-galactopyranose, carba-β-l- talopyranose and carba-α-l-talopyranose. The structures and absolute configurations of these carbasugars were determined by a combination of NMR spectroscopy, stereochemical correlation and X-ray crystallography.

Full text of DOI:10.1039/b921545j

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Chemoenzymatic synthesis of the carbasugars carba-b-L-galactopyranose,
carba-b-L-talopyranose and carba-a-L-talopyranose from methyl benzoate†‡
Derek R. Boyd,*a Narain D. Sharma,a Nigel I. Bowers,a Gerard B. Coen,a John F. Malone,a Colin R. O’Dowd,a
Paul J. Stevensona and Christopher C. R. Allenb
Received 15th October 2009, Accepted 14th December 2009
First published as an Advance Article on the web 21st January 2010
DOI: 10.1039/b921545j
The cis-dihydrodiol metabolite from methyl benzoate has been used as a synthetic precursor of
carba-b-L-galactopyranose, carba-b-L-talopyranose and carba-a-L-talopyranose. The structures and
absolute configurations of these carbasugars were determined by a combination of NMR spectroscopy,
stereochemical correlation and X-ray crystallography.
since it has the carbon skeleton, including the exocyclic hydrox-
ymethylene group. As it turned out, benzyl alcohol was found to be
Introduction
Replacement of the ring oxygen atom in monosaccharides, with
a very poor substrate for the soil bacterium Pseudomonas putida
a methylene group, leads to a series of carbohydrate mimetics,
UV4 – the source of toluene dioxygenase (TDO). Competitive
originally classified as pseudosugars but are now generally referred
enzyme-catalysed oxidation of the exocylic hydroxymethylene
to as carbasugars.1 The structural similarity and increased stability
of carbasugars, compared with natural sugars, and the possibility
group, to yield benzaldehyde and benzoic acid, was found to occur
in preference to the formation of the required cis-dihydrodiol 2 and
thus it was only obtained in very low yield (4%).4
of their recognition as enzyme substrates or inhibitors, have led to
extensive synthetic efforts.1 One approach to the synthesis of car-
basugars has utilized enantiopure cis-dihydrodiols, derived from
the bacterial metabolism of the corresponding monosubstituted
benzene substrate. While a wide range of cis-dihydrodiols (>400)
have been isolated from these and other laboratories,2a–i to date,
only a few have been employed in the synthesis of carbasugars.3a–h
The first arene cis-dihydrodiols used as precursors in carbasugar
synthesis were those derived from benzene (R = H) (Scheme 1).3a–c
Unfortunately the cis-dihydrodiol of benzene is achiral and the
synthetic routes to carbasugars generally involved a significant
number of steps (12–16).
Biotransformations of several other substrates using P. putida
UV4 also gave the cis-diol metabolite 2 as a minor product, e.g.
toluene (≤4%), benzaldehyde (8%) and benzyl cyanide (15%).4,5
The yield of cis-dihydrodiol 3 obtained using P. putida UV 4
and benzyl acetate as substrate was slightly higher (20%) but
was accompanied by a significant degree of hydrolysis to yield
benzyl alcohol. No evidence of ester hydrolysis was found by the
use of a recombinant strain (E. coli pKST7) containing TDO;
cis-dihydrodiol 3 was isolated in an improved yield (43%)4 and
was, therefore, deemed suitable for scale-up and further study
as a potential precursor of carbasugars. However, subsequent
attempts to introduce cis- or trans-diol groups, regioselectively, at
the unsubstituted 5,6-double bond through osmylation or epox-
idation/hydrolysis proved to be more difficult due to competing
oxidation at the alternative 3,4-double bond. cis-Dihydroxylation
occurred to a lesser degree (ca. 10%) and epoxidation to a
greater degree (ca. 50%), at the 3,4-double bond, generating
isomeric mixtures of oxidation products. In order to improve the
regioselectivity, and consequently reduce the problem of isomer
separation, we explored the possibility of regioselective chemical
oxidation occurring exclusively at the 5,6-double bond in cis-
dihydrodiol 4.
Fungal enzyme-catalysed oxidation of methyl benzoate, and
identification of the resulting microbial metabolites, have recently
been studied in our laboratories.6a,b Monooxygenase-catalysed
epoxidation occurred exclusively at the 1,2-bond of methyl ben-
zoate (and substituted methylbenzoates), in growing cultures of
the Phellinus family of wood-rotting fungi, to give isolable 1,2-
arene oxide/oxepine metabolites. These relatively stable arene ox-
ide/oxepines were found, in turn, to hydrolyse to trans-dihydrodiol
metabolites of methyl benzoates under weakly basic conditions.6a,b
These arene oxide/oxepine natural products, from methyl ben-
zoate (and derivatives) isolated in low yields (<5%), were found
Over the past fifteen years, four other cis-dihydrodiols (e.g. from
toluene,3d benzonitrile,3e iodobenzene3f ,g and methylbenzoate
)
3h
have been used in carbasugar synthesis, each being enantiopure
(e.g. R = I), with several having the required carbon skeleton (e.g.
R = Me, CN, CO2Me, Scheme 1).
Following on from our earlier approaches to the synthesis of
carbasugars from cis-dihydrodiol derivative 1 of iodobenzene, we
have recently examined the potential of other monosubstituted
cis-dihydrodiols (Scheme 2)3g. These include cis-dihydrodiols 2,
3 and 4, derived from benzyl alcohol, benzyl acetate and methyl
benzoate, respectively. In principle, the cis-dihydrodiol metabolite
2 of benzyl alcohol appears to be an ideal precursor of carbasugars,
aSchool of Chemistry and Chemical Engineering, The Queen’s Univer-
sity of Belfast, Belfast, UK BT9 5AG. E-mail: dr.boyd@qub.ac.uk;
Tel: +44(0)2890974421
bSchool of Biological Sciences, The Queen’s University of Belfast, Belfast,
UK BT9 5AG
† This paper is part of an Organic & Biomolecular Chemistry web theme
issue on biocatalysis
‡ Electronic supplementary information (ESI) available: 1H NMR spectra
of 11, 18 and 26. CCDC reference numbers 746877. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b921545j
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1415–1423 | 1415
©

View Article Online
Scheme 1 Synthesis of carbasugars from benzene- and monosubstituted-benzene cis-dihydrodiol metabolites.
to racemize spontaneously and were accompanied by enzymatic
reduction products (benzyl alcohols). As a result, the fungal
metabolites proved to be much less attractive synthetic precursors
compared with the cis-dihydrodiol bacterial metabolites formed
by dioxygenase-catalysed oxidation of methyl benzoate. Using
P. putida UV4, cis-dihydroxylation was reported to occur exclu-
sively at the 2,3-bond to give the relatively stable cis-dihydrodiol 4
as the sole bioproduct (53% yield),7 in enantiopure form without
any evidence of competing biotransformation pathways (e.g. ester
hydrolysis).
Since cis-dihydrodiol 4 contains the required carbon skeleton
of both shikimic acids and carbasugars (after reduction of the
carbomethoxy group), it had earlier been used as a precursor of
6b-hydroxyshikimic acid7 and an acetonide derivative of carba-a-
L-galactopyranose.3h The apparent advantages of utilizing enan-
tiopure (1S,2R)-arene cis-dihydrodiol 4 as a chiral precursor for
the three carbasugars, carba-b-L-galactopyranose 11, carba-b-L-
talopyranose 18 and carba-a-L-talopyranose 26, are discussed
herein.
Scheme 2 Reported (1 and 4) and potential (2 and 3) benzene
cis-dihydrodiol precursors of carbasugars.
1416 | Org. Biomol. Chem., 2010, 8, 1415–1423
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
t
Scheme 3 Reagents and conditions: i CO, Pd(OAc)2, NaOAc·3H2O, MeOH (62%); ii 2,2-DMP, PTSA (93%); iii MCPBA, CH2Cl2, (77%); iv BuOH,
H2O, pH 8 buffer (70%); v TBDMSOTf, Et3N, CH2Cl2 (82%); vi Rh–Al2O3, H2, EtOH (62%); vii LiAlH4, Et2O (84%); viii MeOH, HCl (84%)
synthesised earlier in twelve steps from myo-inositol,9 was found
to be similar to that of the sample of carba-b-L-galactopyranose
Results and discussion
11 (in D2O) derived from methyl benzoate (Scheme 3).
The supply of cis-dihydrodiol metabolite 4, produced during the
current study by TDO-catalysed biotransformations of methyl-
benzoate using whole cells of P. putida UV4 (35% yield), was
supplemented by an alternative chemoenzymatic synthesis from
iodobenzene cis-dihydrodiol 1 (Scheme 3). cis-Dihydrodiol 1
was available from the biotransformation (P. putida UV4) of
iodobenzene in higher isolated yields (ca. 80%).5 Carbonylation of
diol 1 [Pd(OAc)2, NaOAc·3H2O in MeOH], under an atmosphere
of carbon monoxide at room temperature, provided an alternative
chemoenzymatic route to the (1S,2R)-cis-dihydrodiol 4 derivative
of methylbenzoate (50% yield overall from iodobenzene).
Protection of cis-dihydrodiol 4 was carried out using 2,2-
dimethoxypropane (DMP), in the presence of an acid catalyst
(PTSA), to yield the known acetonide 5 (Scheme 3).7 Epoxidation
of compound 5 occurred in a regio- and stereo-selective manner,
with the new oxygen atom being added exclusively at the 5,6 bond
and trans to the acetonide group, to give the known epoxide 6
(77% yield).8 Regioselective ring-opening, at the allylic carbon,
was achieved using a mixture of tert-butanol and water buffered
at pH 8, to furnish trans-dihydrodiol 7 (70% yield).
Protection of trans-diol 7 as di-TBDMS derivative 8 (82% yield),
followed by hydrogenation using a Rh–Al2O3 catalyst, resulted
in hydrogen being preferentially added from the less sterically
hindered face, opposite to the acetonide group, yielding compound
9 (82% yield) after chromatography. The next step in the synthesis
involved reduction of the ester group with lithium aluminium
hydride to give the differentially protected form of carba-b-L-
galactopyranose 10 (84% yield). Deprotection of compound 10
under acidic conditions yielded the required carbasugar 11 (84%
yield) in seven steps from cis-dihydrodiol 4. The reported 1H- and
13C-NMR spectra of carba-b-DL-galactopyranose 11 (in CD3OD),
The chemoenzymatic synthesis of carba-b-L-talopyranose 18
from methyl benzoate cis-dihydrodiol 4 was achieved in five
steps by two alternative routes, (Scheme 4). Stereoselective
catalytic osmylation of cis-dihydrodiol 4 was performed by
using trimethylamine-N-oxide dihydrate (TMANO) as the co-
oxidant in CH2Cl2 solution.10 Purification by chromatography
(charcoal/Celite column) gave the key tetraol 12 (70% yield).
Catalytic hydrogenation (5% Rh–Al2O3) of the alkene group in
tetraol 12, in common with hydrogen addition to compound
8 (Scheme 3), occurred stereoselectively from the less hindered
face to give tetraol 13 as the major product. A competing side
reaction, i.e. chemoselective hydrogenolysis of the pseudoaxial
allylic hydroxyl group at C-6 in tetraol 12 and hydrogenation
leading to the formation of achiral meso-triol 14, was also
observed. The mixture of tetraol 13 and triol 14 (70 : 30) was
not separable by charcoal/Celite chromatography. The structure
of triol 14 was, however, readily assigned in the mixture, due to
its symmetry. Treatment with DMP–PTSA yielded a mixture of
mono- and bis-acetonides (16/15), which was readily separated by
flash column chromatography to give 15 (in 63% from tetraol 12).
A pure sample of racemic acetonide 16 was fully characterised,
confirming the structure of the precursor triol 14.
An alternative synthetic approach, to the synthesis of bis-
acetonide 15, involved protection of cis-tetraol 12 (as bis-acetonide
19) followed by catalytic hydrogenation (5% Rh–Al2O3). Although
the formation of bis-acetonide 19 was relatively slow, after leaving
for 24 h the resulting mixture of mono- and bis-acetonides (ca.
1 : 4) was readily separated by chromatography to furnish a pure
sample of bis-acetonide 19; the minor polar mono-acetonide was
recycled to give more of compound 19, resulting in an overall
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1415–1423 | 1417
©

View Article Online
Scheme 4 Reagents and conditions: i OsO4, TMANO, CH2Cl2 (70%); ii Rh–Al2O3, H2, EtOH (12 → 13, >70%; 12 → 14, <30%; 19 → 15, 91%):
compound 15, 92%; iii 2,2¢-DMP, PTSA (13 → 15, 59%; 12 → 16, 25%); 12 → 19, 80%; 15, 59%, compound 16, 25%: compound 19, 80%; iv LiAlH4,
Et2O (76%); v TFA, THF, H2O (86%); vi Ac2O, pyridine (85%).
yield of ca. 80%. A major advantage of this approach over the
hydrogenation of tetraol 12 was that the unwanted competing
hydrogenolysis reaction was completely suppressed, resulting in a
much higher yield (91%) of the desired compound 15.
trans-diol 22 (68% yield). Compound 22 was acetylated and
the resulting diacetate 23 (98% yield) subjected to catalytic
hydrogenation (H2, 5% Rh–Al2O3), which occurred from the
less hindered face to give the substituted cyclohexane derivative
24 (83% yield). The final steps in the synthesis of carba-a-L-
talopyranose 26 were similar to those used in Schemes 3 and 4
involving ester group reduction to give triol 25 (71% yield) and
deprotection to give carbasugar 26 (88% yield). The L-pentacetate
derivative 26Ac ([a]D -26, CHCl3) was found to be spectroscopically
indistinguishable from the reported sample of the opposite D-
enantiomer ([a]D +27.5) obtained in thirteen steps from the achiral
cis-dihydrodiol of benzene.3b
The final steps were similar to those used in Scheme 3 and in-
volved reduction of ester 15 to give alcohol 17 (76% yield), followed
by deprotection to afford carba-b-L-talopyranose 18 (86% yield).
Further characterisation and confirmation of the structure and
stereochemistry of carbasugar 18 was achieved by formation of
the corresponding crystalline pentaacetate 18Ac ([a]D +8.4, CHCl3;
85% yield). Pentaacetate 18Ac had identical characteristics to those
reported after its synthesis ([a]D +5.2, CHCl3) in twelve steps from
D-mannose,3b or from the meso-cis-dihydrodiol of benzene ([a]D
-8.7, CHCl3).3c X-Ray crystallographic analysis (Fig. 1) showed
compound 18Ac to exist in a chair conformation with an equatorial
CH2OAc group and the other OAc groups adopting alternating
axial and equatorial positions
The third carbasugar, carba-a-L-talopyranose 26, was syn-
thesised in seven steps from cis-dihydrodiol 4 (Scheme 5). The
directing effect of the hydroxyl groups in cis-dihydrodiol 4 was
utilized during its epoxidation using MCPBA; it resulted in the
regio- and stereo-selective formation of cis-diol epoxide 20 (82%
yield, Scheme 5). Acetonide 21 (98% yield), a stereoisomer of
epoxide 6, was similarly treated under mild alkaline conditions
(tert-BuOH–H2O, pH 8 buffer) (Scheme 3), to give cyclohexene
Conclusion
The synthesis of three carbasugars, carba-b-L-galactopyranose
11, carba-b-L-talopyranose 18 and carba-a-L-talopyranose 26
from (1S,2R)-cis-dihydrodiol metabolite 4 of methyl benzoate has
been achieved in significantly fewer steps (5–7), compared with the
earlier synthesis of these enantiopure carbasugars or their racemic
(D/L) analogues from alternative precursors. The relative and
absolute configurations have been established by a combination
of X-ray crystallography, NMR spectroscopy, stereochemical
correlation and comparison with literature data. The value of
the single enantiomer cis-dihydrodiol precursor 4 in the synthesis
1418 | Org. Biomol. Chem., 2010, 8, 1415–1423
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Scheme 5 Reagents and conditions: i MCPBA, CH2Cl2, (82%); ii 2,2-DMP, PTSA (98%); iii tBuOH, H2O, pH 8 buffer (68%); iv Ac2O, pyridine (98%); v
Rh–Al2O3, H2, EtOH (83%); vi LiAlH4, Et2O (71%); vii TFA, THF, H2O (88%); viii Ac2O, pyridine (82%).
of carbasugars 11, 18 and 26 complements our earlier synthesis
of four other isomeric carbasugars using cis-dihydrodiol 1 from
iodobenzene.3g
Experimental
NMR (1H and 13C) spectra were recorded on Bruker Avance DPX-
300, 3-400 and DRX-500 instruments. Coupling constants are
reported in Hz and mass spectra were run at 70 eV, on a VG Au-
tospec Mass Spectrometer, using a heated inlet system. Accurate
molecular weights were determined by the peak matching method,
with perfluorokerosene as the standard. Elemental microanalyses
were carried out on a PerkinElmer 2400 CHN microanalyser. A
Perkin-Elmer 341 polarimeter was used for optical rotation ([a]D)
measurements (ca. 20 ◦C, 10-1 deg cm2 g-1).
Flash column chromatography and preparative layer chro-
matography (PLC) were performed on Merck Kieselgel type 60
(250-400 mesh) and PF254/366 respectively. Merck Kieselgel type
60F254 analytical plates were used for TLC.
cis -(1S,2R)-Dihydrodiol 4 (35% yield) was obtained by bio-
transformation of methyl benzoate using P. putida UV4 and
conditions reported earlier.5,7
(i) Synthesis of carba-b-L-galactopyranose 11
Chemoenzymatic synthesis of methyl cis-(1S,2R)-1,2-dihydroxy-
cyclohexa-3,5-diene-3-carboxylate 4. A solution of cis-(1S,2S)-
1,2-dihydroxy-3-iodocyclohexa-3,5-diene 1 (0.5 g, 2.1 mmol,
[a]D +41 (MeOH, >98% e.e.) in MeOH (50 cm3), containing
NaOAc·3H2O (0.43 g, 3.2 mmol) and palladium(II) acetate
Fig. 1 X-Ray structure of pentaacetate 18Ac
.
(0.05 g), was stirred (20 h) at room temperature under carbon
This journal is The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1415–1423 | 1419
©

View Article Online
monoxide (1 atm). The palladium catalyst was filtered off, the
filtrate concentrated, and the residue purified by column chro-
matography (ethyl acetate–hexane) to yield cis-dihydrodiol 4 as a
colourless viscous liquid (0.22 g, 62%, [a]D +58, CH2Cl2), identical
with an authentic sample obtained from the biotransformation
(P. putida UV4) of methyl benzoate.
(3S,4S,5R,6R)-5,6-Isopropylidinedioxy-3,4-di-(tert-butyldime-
thylsilanoxy)cyclohex-1-ene-carboxylic acid methyl ester 8. tert-
Butyldimethylsilyltrifluoromethanesulfonate (0.33 g, 1.34 mmol)
was added to a stirred solution of (-)-diol 7 (0.15 g, 0.61 mmol) in
CH2Cl2 (10 cm3) containing Et3N (3 cm3) at 0 ◦C under nitrogen.
After allowing the reaction mixture to stir at room temperature
for a further 30 min, it was quenched by the addition of saturated
NaHCO3 solution (15 cm3). The mixture was extracted with
CH2Cl2 (2 ¥ 30 cm3), the solution dried (MgSO4) and the solvent
removed under reduced pressure to yield the crude product
8. Purification by PLC (20% Et2O in hexane, Rf 0.2) yielded
compound 8 as a colourless oil (0.24 g, 82%); [a]D +43 (c 0.7,
CHCl3); (Found: M+ 472.2601. C23H44O6Si2 requires 472.2676);
Methyl cis-(1S,2R)-1,2-isopropylidenedioxycyclohexa-3,5-diene-
3-carboxylate 5.
1,2-dihydroxycyclohexa-3,5-diene-3-carboxylate
A
solution of methyl (+)-cis-(1S,2R)-
(1.00 g,
4
5.88 mmol), and PTSA (0.005 g) in DMP (15 cm3) was stirred
(2 h) at room temperature. A few drops of NaHCO3 solution
were added to the mixture, excess DMP removed under reduced
pressure, the residue treated with water (20 cm3) and the mixture
extracted with EtOAc (2 ¥ 25 cm3). The organic layer was dried
(Na2SO4), the solvent removed in vacuo and the crude product
purified by column chromatography (Et2O–hexane). Acetonide 5
was obtained as a colourless oil (1.15 g, 93%); [a]D +134 (c 0.93,
CHCl3); dH (500 MHz, CDCl3) 1.40 (3 H, s, CMe), 1.42 (3 H, s,
CMe), 3.79 (3 H, s, CO2Me), 4.65 (1 H, d, J2,1 8.8, 2-H), 4.71 (1
H, dd, J1,2 8.8, J1,6 3.9, 1-H), 5.88 (1 H, dd, J6,1 3.9, J6,5 9.1, 6-H),
5.97 (1 H, d, J4,5 5.6, 4-H), 5.99 (1 H, d, J5,4 5.6, J5,6 9.1, 5-H). The
1H-NMR spectrum was consistent with the reported data.7
n
max/cm-1 1730 (C O), 1220 (C–O); dH (500 MHz, CDCl3) 0.09,
=
(6 H, s SiMe2), 0.12 (6 H, s, SiMe2), 0.90 (9 H, s, SiBut), 0.92 (9
H, s, SiBut) 1.40 (3 H, s, CMe), 1.46 (3 H, s, CMe), 3.73 (1 H, dd,
J
J
4,5 7.3, J4,3 6.8, 4-H), 3.80 (3 H, s, CO2Me), 4.11 (1 H, dd, J5,6 6.4,
5,4 7.3, 5-H), 4.14 (1 H, J3,2 2.6, J3,4 6.8, 3-H) 4.93 (1 H, d, J6,5 6.4,
6-H), 6.80 (1 H, d, J2,3 2.6, 2-H); m/z (EI) 472 (M+, 1%), 357 (30),
57 (100).
(1R,2R,3R,4S,5S)-4,5-Di(tert-butyldimethylsilanoxy)-2,3-iso-
propylidinedioxy-cyclohexane-carboxylic acid methyl ester 9. (+)-
Alkene 8 (0.17 g, 0.36 mmol) was hydrogenated, in absolute EtOH
(60 psi, 24 h), using 5% Rh–Al2O3 catalyst (0.08 g). The catalyst
was filtered off, the filtrate concentrated under reduced pressure,
and the crude product purified by column chromatography (30%
Et2O in hexane). The hydrogenated ester 9 was obtained as a
white solid (0.14 g, 82%); mp 108–109 ◦C (from Et2O–hexane);
(3R,4R,5R,6R)-3,4-Epoxy-5,6-isopropylidinedioxycyclohex-1-
enecarboxylic acid methyl ester 6. MCPBA (1.30 g, 7.6 mmol)
was added in small portions to a solution of (+)-acetonide 5
(1.45 g, 6.9 mmol) in CH2Cl2 (50 cm3) and the mixture stirred
at room temperature for 12 h. Excess MCPBA was converted into
m-chlorobenzoic acid by stirring with a solution of NaHSO3. The
acid was then removed by washing the organic layer thoroughly
with a saturated solution of NaHCO3. The CH2Cl2 solution was
dried (MgSO4), the solvent removed under reduced pressure, and
the crude product purified by column chromatography (CH2Cl2)
to yield epoxide 6 as a colourless oil (1.20 g, 77%); [a]D +94 (c
0.3, CHCl3), (lit. [a]D +101.8);8 (Found: M+ 226.0841. C11H14O5
[a]D +32 (c 0.6, CHCl3); (Found: C, 58.2; H, 10.0. C23H46O6Si2
-1
=
requires C, 58.2.9; H, 9.8%); nmax/cm 1741 (C O), 1218 (C–O);
d
H (500 MHz, CDCl3) 0.075 (6 H, s, SiMe2), 0.08 (6 H, s, Si Me2),
0.89 (9 H, s, SiBut), 0.90 (9 H, s, SiBut) 1.33 (3 H, s, CMe), 1.48 (3
H, s, CMe), 1.87 (1 H, m, 6-H), 1.97 (1 H, m, 6¢-H), 2.73 (1 H, m,
1-H), 3.51 (1 H, ddd, J5,6¢ 10.5, J5,4 6.4, J5,6 5.2, 5-H), 3.60 (1 H,
dd, J4,5 6.4, J4,3 5.6, 4-H), 3.73 (3 H, s, CO2Me), 4.01 (1 H, dd, J3,4
5.6, J3,2 6.0, 3-H), 4.53 (1 H, dd, J2,3 6.0, J2,1 2.7, J2,6 1.4, 2-H); dC
(125 MHz, CDCl3) -4.43, -4.34, -4.02 ¥ 2, -3.89 ¥ 2, 25.73, 26.02,
26.03, 27.41, 28.60, 40.27, 51.97, 72.79, 73.89, 77.54, 80.68; m/z
(EI) 474 (M+,1%), 359 (41), 73 (100).
requires 226.0841); nmax/cm-1 1725 (C O), 1223, 1256 (C–O); dH
=
(500 MHz, CDCl3) 1.40 (3 H, s, CMe), 1.43 (3 H, s, CMe), 3.45 (1
H, dd, J3,2 4.0, J3,4 1.1, 3-H), 3.57 (1 H, dd, J4,3 1.1, J4,5 3.7, 4-H),
3.81 (3 H, s, CO2Me), 4.78 (1 H, dd, J5,6 7.3, J5,4 3.7, 5-H), 4.80 (1
H, d, J6,5 7.3, 6-H), 7.11 (1 H, d, J2,3 4.0, 2-H); m/z (EI) 226 (M+,
3%), 211 (70).
[(1S,2R,3R,4S,5S)-4,5-bis-Di(tert-butyldimethylsilanoxy)-2,3-
isopropylidinedioxycyclohexyl]-methanol 10. LiAlH4 (0.036 g,
0.95 mmol) was added in portions to a solution of (+)-ester
9 (0.15 g, 0.32 mmol) in dry Et2O (10 cm3). The mixture was
stirred and refluxed (16 h) under anhydrous conditions. Excess of
reagent was destroyed by careful addition of moist Et2O, brine
(20 cm3) added, and the mixture extracted with Et2O (3 ¥ 20 cm3).
The extract was dried (MgSO4), the solvent evaporated and the
crude product purified by column chromatography (30% Et2O in
hexane). Compound 10 was obtained as a gum (0.12 g, 84%); [a]D
-1.0 (c 0.9, CHCl3); (Found: M+ 446.28836. C22H46O5Si2 requires
446.2880); nmax/cm-1 1218 (C–O), 3438 (O–H); dH (500 MHz,
CDCl3) 0.076 (3 H, s, SiMe), 0.080 (3 H, s, SiMe), 0.084 (3 H, s,
SiMe), 0.13 (3 H, s, SiMe), 0.89 (9 H, s, SitBu), 0.90 (9 H, s, SitBu),
1.34 (3 H, s, CMe), 1.49 (3 H, s, CMe), 1.67 (1 H, m, 1-H), 1.91
(1 H, m, 6-H), 2.13 (1 H, m, 6¢-H), 3.47 (1 H, m, 7-H), 3.52 (1 H,
m, 7¢-H), 3.70 (1 H, ddd, J4,3 11.0, J4,5 7.5, J4,2 6.5, 4-H), 3.80 (1
H, ddd, J5,4 7.5, J5,6¢ 3.5, J5,6 7.2, 5-H), 3.93 (1 H, dd, J3,4 11.0, J3,2
5.5, 3-H), 4.28 (1 H, m, 2-H); dC (125 MHz, CDCl3) -3.95, -3.76,
(3S,4R,5S,6R)-3,4-Dihydroxy-5,6-isopropylidinedioxycyclohex-
1-enecarboxylic acid methyl ester 7. A stirred mixture of (+)-
epoxide 6 (0.20 g, 0.88 mmol), t-BuOH (20 cm3) and phosphate
buffer (pH 8.0, 5 cm3) was refluxed (ca. 4 d) until all the epoxide
had reacted. The solvent was removed under reduced pressure,
saturated NaCl solution (10 cm3) was added, the mixture extracted
with EtOAc (2 ¥ 30 cm3), the organic extract dried (MgSO4) and
the EtOAc removed under reduced pressure. Purification of the
crude product by PLC (60% EtOAc in hexane, Rf 0.2) yielded
trans-diol 7 as a white solid (0.15 g, 70%); mp 130 ◦C (from CHCl3–
hexane); [a]D -6.0 (c 0.3, CHCl3); (Found: C 54.1; H 6.3. C11H16O6
requires C 54.1; H 6.6%); nmax/cm-1 3425 (OH), 1724 (C O), 1223
=
(C–O); dH (500 MHz, CDCl3) 1.45 (3 H, s, CMe), 1.51 (3 H, s,
CMe), 3.72 (1 H, dd, J4,5 8.6, J4,3 8.2, 4-H), 3.81 (3 H, s, CO2Me),
4.12 (1 H, dd, J5,6 6.0, J5,4 8.6, 5-H), 4.22 (1 H, d, J3,4 8.2, 3-H),
4.96 (1 H, d, J6,5 6.0, 6-H), 6.99 (1 H, s, 2-H); m/z (EI) 244 (M+,
15%), 229 (50).
1420 | Org. Biomol. Chem., 2010, 8, 1415–1423
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
-3.37 ¥ 2, -3.22 ¥ 2, 18.63 ¥ 2, 26.56, 26.69, 28.38, 30.92, 36.97,
65.16, 73.79, 76.34, 79.41, 82.48; m/z (EI) 446 (M+, 1%), 431 (6),
331 (55), 199 (100).
(20 cm3) and subjected to catalytic hydrogenation (H2, 5%
Rh–Al2O3, 55 psi, 18 h). The catalyst was removed by filtration,
and the filtrate concentrated under reduced pressure, to yield
a mixture (3 : 1) of two hydrogenated compounds 13 (major)
and 14 (minor). The mixture (0.53 g) was converted into the
corresponding mixture of acetonides 15 and 16 after treatment
with DMP in Me2CO solution. These acetonides were separated
by flash column chromatography (EtOAc–hexane) to gave bis-
acetonide 15 as a white solid (0.44 g, 63%); mp 83–85 ◦C; Rf 0.25
(50% EtOAc in hexane); [a]D +154 (c 0.44, CHCl3); (Found: M+,
286.1419. C14H22O6 requires 286.1416); dH (500 MHz, CDCl3)
1.33 (3 H, s, CMe), 1.36 (3 H, s, CMe), 1.49 (3 H, s, CMe), 1.54
(3 H, s, CMe), 2.13 (1 H, m, 6-H), 2.32 (2 H, m, 1-H, 6¢-H), 3.73
(3 H, s, OMe), 4.07 (1 H, dd, J4,5 7.6, J4,3 3.7, 4-H), 4.37 (1H,
ddd, J5,6 9.4, J5,6¢ = J5,4 7.6, 5-H), 4.56 (1 H, dd, J3,2 7.1, J3,4 3.7,
3-H), 4.67 (1 H, ddd, J2,3 7.1, J2,1 3.6, J2,6 1.8, 2-H); dH (125 MHz,
CDCl3) 23.85, 24.31, 25.32, 26.14, 26.30, 41.66, 52.04, 72.77,
73.17, 73.47, 73.90, 109.44, 110.02, 171.52; m/z (EI) 286 (M+,
24%), 271 (90), 171 (32), 153 (40), 139 (51), 125 (66), 111 (46), 73
(70), 59 (82), 43 (100).
Carba-b-L-galactopyranose
[(1S,2R,3R,4R,5S)-5-hydroxy-
methyl cyclohexane-1,2,3,4-tetraol] 11. A solution of (-)-di-
TBDMS 10 (0.076 g, 0.17 mmol) in MeOH (2 cm3), containing few
drops HCl (1 M), was stirred overnight at ambient temperature.
The solvent was distilled off and the residue purified by column
chromatography (1 : 1, activated charcoal : Celite, H2O → 20%
EtOH–H2O). The fractions obtained with 20% EtOH, upon
concentration, gave carbasugar 11 as a colourless oil (0.025 g,
85%); [a]D -75 (c 0.6, CHCl3); (Found 178.0841. C7H14O5 requires
178.0841); nmax/cm-1 3359 (OH); dH (500 MHz, D2O) 1.24 (1 H,
m, 6-H), 1.62 (2 H, m, 5-H, 6¢-H), 3.27 (1 H, dd, J2,3 2.9, J
3,4
9.5, 3-H), 3.37 (3 H, m, 1-H, 2-H, 7¢-H), 3.50 (1 H, dd, J7,1 2.9, J
11.0, 7-H), 3.87 (1 H, bs, 2-H); dC (125 MHz, CDCl3) 29.17,
7,7¢
38.75, 62.6, 69.81, 72.16, 74.49, 75.19; m/z (EI) 178 (M+, 5%),
160 (100).
(ii) Synthesis of carba-b-L-talopyranose 18
Catalytic hydrogenation of (-)-bis-acetonide 19, under similar
conditions to those used for tetraol 12, gave the hydrogenated
product, (+)-bis-acetonide 15, as the sole product (91% yield).
Methyl (3S,4S,5R,6R)-3,4,5,6-tetrahydroxy-1-cyclohexene-1-
carboxylate 12. To a solution of (+)-diol 4 (2.50 g, 0.015 mol)
and trimethylamine N-oxide dihydrate (3.25 g) in CH2Cl2
(100 cm3) was added a catalytic quantity of OsO4. After stirring
the mixture overnight at room temperature, the solvent was
distilled off and the product purified by column chromatography
(1 : 1, activated charcoal : Celite, H2O → 20% EtOH–H2O) to
yield syn-tetraol 12 as a colourless crystalline solid (2.10 g, 70%);
mp 104–106 ◦C; [a]D +55 (c 0.34, MeOH); [Found: (FAB) (MH)+
205.0712. C8H13O6 requires 205.0713]; dH (500 MHz, D2O) 3.84
(1 H, dd, J5,6 6.5, J5,4 4.5, 5-H), 3.87 (3 H, s, OMe), 4.21 (1 H, dd,
J4,5 4.5, J4,3 6.5, 4-H), 4.49 (1 H, dd, J3,2 2.3, J3,4 6.5, 3-H), 4.63 (1
H, dd, J6,5 6.5, J6,2 1.2, 6-H), 6.92 (1 H, dd, J2,3 2.3, J2,6 1.2, 2-H);
dC (125 MHz, D2O) 52.69, 65.16, 67.86, 68.29, 71.44, 131.01,
141.05, 168.02 (CO2Me); m/z 205 ([MH]+, 45%), 112 (100).
(3aR,5R,7S,7aS)-Methyl
7-hydroxy-2,2-dimethylhexahydro-
benzo[d][1,3]dioxole-5-carboxylate 16. The minor acetonide
16 was isolated as a colourless oil (0.14 g, 25%); Rf 0.5, (50%
EtOAc–hexane); (Found: M+, 230.1150. C11H18O5 requires
230.1154); dH (500 MHz, CDCl3) 1.36 (3 H, s, CMe), 1.52 (3 H, s,
CMe), 1.78 (1 H, q, J4,4 = J
= J4,5 8.9, 4-H ax), 1.86 (1 H, q,
4,3a
J6,6¢ = J6,7 =J6,5 11.3, 6-H ax), 2.04 (2 H, m, 4-H, 6-H both eq),
2.12 (1 H, d, J 9.1, OH), 2.33 (1 H, m, 5-H), 3.70 (3 H, s, OMe),
3.83 (1 H, m, 7-H), 4.23 (1 H, dd, J3a,4 8.9, J3a,7a 5.7, 3a-H), 4.28
(1 H, m, 7a-H); dC (75 MHz, CDCl3) 25.94, 27.81, 29.99, 30.36,
36.82, 52.01, 68.22, 74.02, 75.26, 109.32, 174.54; m/z (EI) 230
(M+, 4%), 215 (93), 155 (38), 123 (75), 95 (96), 67 (68), 59 (83), 43
(100).
Methyl (3S,4S,5R,6R)-3,4;5,6-diisopropylidenetetraoxycyclo-
hexene-1-carboxylate 19. To a solution of (+)-tetraol 12 (0.204 g,
1.00 mmol) in Me2CO (8 cm3) was added an excess of DMP
(4 cm3) and PTSA (0.015 g). After stirring the reaction mixture
overnight at room temperature, it was worked up by a procedure
similar to that of compound 5. The crude product was purified
by PLC (40% EtOAc in hexane) to give the less polar, major,
bis-acetoni◦de 19 as a white solid (0.230 g, 80% after recycling);
mp 86–88 C; [a]D -6.4 (c 0.36, CHCl3); (Found: M+, 284.1268.
C14H20O6 requires 284.1260); dH (500 MHz, CDCl3) 1.39 (3 H, s,
Me), 1.42 (3 H, s, Me), 1.45 (3 H, s, Me), 1.52 (3 H, s, Me), 3.82
(3 H, s, CO2Me), 4.43 (2 H, m, 4-H, 5-H), 4.66 (1 H, dd, J3,4 2.0,
(1S,2R,3R,4S,5S)-2,3,4,5-Diisopropylidenetetraoxycyclohexyl-
methanol 17. To a solution of (+)-bis-acetonide 15 (0.2 g,
0.7 mmol), in dry Et2O (10 cm3), LiAlH4 (0.080 g, 2.1 mmol)
was added and the mixture refluxed (18 h) under anhydrous
conditions. The reaction mixture was quenched with moist Et2O,
the solvent removed under reduced pressure, and the crude product
crystallized from ether–hexane to afford alcohol 17 as a white
crystalline solid (0.136 g, 76%); mp 90–92 ◦C (decomp.); [a]D
+117 (c 0.44, CHCl3); (Found: C, 60.2; H, 8.4. C13H22O5 requires
C, 60.5; H, 8.6%); dH (500 MHz, CDCl3) 1.35 (3 H, s, Me), 1.37
(3 H, s, Me), 1.51 (3 H, s, Me), 1.55 (3 H, s, Me), 1.88 (2 H, m,
6-H, 6¢-H), 2.14 (1 H, m, 1-H), 3.72 (2 H, m, 7-H, 7¢-H), 4.09 (1 H,
dd, J4,5 7.4, J4,3 3.8, 4-H), 4.42 (1 H, ddd, J5,4 7.4, J5,6 = J5,6¢, 7.8,
5-H), 4.48 (1 H, dd, J3,2 7.3, J3,4 3.8, 3-H), 4.54 (1 H, m, 2-H); dC
(75 MHz, CDCl3) 24.13, 24.83, 25.33, 26.11, 26.31, 36.88, 64.08,
73.25, 73.29, 73.92, 74.42, 108.99, 109.72.
J
3,2 3.1, 3-H), 4.91 (1 H, m, 6-H), 6.84 (1 H, dd, J 2,3, 3.1 J 2,6 0.70,
2-H); dC (125 MHz, CDCl3) 26.29, 26.33, 26.47, 27.66, 52.28,
68.94, 72.17, 72.24, 73.14, 110.71, 111.27 ¥ 2, 127.75, 137.83,
165.87; m/z (EI) 284 (M+, 2%), 269 (M+-CH3, 100), 211 (31), 169
(81), 137 (72), 109 (42), 59 (58). 43(100). The more polar PLC
band yielded the minor mono-acetonide, which was recycled.
Carba-b-L-talopyranose [(1S,2S,3R,4R,5S)-5-hydroxymethyl-
cyclohexane-1,2,3,4-tetraol)] 18. A solution of (+)-alcohol 17
(0.13 g, 0.5 mmol) in a mixture (2 cm3) of TFA–THF–H2O
(0.5 : 4 : 1) was kept (2 h) at 60 ◦C and then allowed to stir
overnight at room temperature. The solvents were removed under
Methyl
(1R,2R,3R,4S,5S)-2,3,4,5-diisopropylidenetetraoxy-
cyclohexane-1carboxylate 15 and (3aR,5R,7S,7aS)-methyl 7-
hydroxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate
16. (+)-Tetraol 12 (0.50 g, 2.45 mmol) was dissolved in EtOH
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1415–1423 | 1421
©

View Article Online
reduced pressure and the crude product purified by column
chromatography (1 : 1, activated charcoal : Celite, H2O → 5%
EtOH–H2O) to give carba-b-L-talopyranose 18 as a colourless
syrup; (0.080 g, 86%); [a]D +3.6 (c 0.56, H2O); (Found: M+–2H2O,
142.0625. C7H10O3 requires 142.0629); dH (500 MHz, D2O) 1.60
(2 H, m, 7-H, 7¢-H), 1.70 (1 H, m, 5-H), 3.59 (2 H, m, 4-H, 6-H),
3.73 (2 H, m, 1-H, 6¢-H), 4.02 (2 H, m, 2-H, 3-H); dC (75 MHz,
D2O) 24.38, 39.51, 62.87, 69.32, 70.06, 70.72, 74.72; m/z (EI) 142
(M+–2H2O, 8%), 124 (7), 116 (13), 111 (17), 100 (17), 86 (49), 72
(100), 69 (42), 57 (43) 31 (77).
48.71, 52.67, 57.98, 64.30, 67.54, 135.19, 138.61, 167.20; m/z: 186
(M+, 0.5%), 168 (8), 152 (33), 139 (47), 125(100).
Methyl(3aR,5aS,6aR,6bS)-2,2-dimethyl-3a,5a,6a,6b-tetrahy-
drooxireno[2¢,3¢:3,4]-benzo-[d][1,3]dioxole-4-carboxylate 21. (-)-
Epoxide 20 (1.60 g, 8.60 mmol) on reacting with DMP–PTSA gave
crude acetonide 21. Purification by PLC (50% Et2O in hexane, Rf
0.26) yielded acetonide 21 as a colourless oil (1.9 g, 98%); [a]D
-118 (c 0.73, CHCl3); (Found: M+, 226.0852. C8H10O5 requires
-1
=
226.0841); nmax/cm (neat): 1719 (C O); dH (500 MHz, CDCl3):
1.46 (3 H, s, CMe), 1.53 (3 H, s, CMe), 3.60 (1 H,dd, J5a,5 3.8,
J5a,6a 3.4, 5a-H), 3.70 (1 H, dd, J,6a,5a 3.8, J6a,6b 2.4, 6a-H), 3.81
(3 H, s, CO2Me), 4.46 (1H, dd, J6b,6a 2.4, J6b,3a 6.4, 6b-H), 5.04
(1H, d, J3a,6b 6.4, 3a-H), 7.45 (1H, d, J5,5a 3.8, 5-H); dC (125 MHz,
CDCl3): 25.51, 27.34, 48.98, 52.36, 56.66, 69.08, 73.01, 108.54,
132.29, 139.42, 165.38; m/z: 227 ([M + 1]+, 7%), 211 (100).
Carba-b-L-talopyranose pentaacetate 18Ac. (+)-Carbasugar 17
(0.030 g, 0.17 mmol) was treated with Ac2O (0.25 cm3) in pyridine
(0.5 cm3) and the mixture stirred overnight at room temperature.
Excess pyridine was removed under reduced pressure, the residue
taken up in EtOAc (15 cm3) and the solution washed successively
with 0.5 N HCl and water. The organic layer was dried (Na2SO4)
and concentrated in vacuo to yield pentaacetate 18Ac as a colourless
crystalline solid (0.055 g, 85%); mp 140–141 ◦C (EtOAc–hexane),
Methyl (3aR,6R,7S,7aS)-6,7-dihydroxy-2,2-dimethyl-3a,6,7,7a-
tetrahydro-1,3-benzodioxole-4-carboxylate 22. A solution of (-)-
acetonide 21 (1.85 g, 8.19 mmol), in a mixture of pH 8.0 buffer
(5 cm3) and tBuOH (20 cm3), was gently refluxed until the reaction
was complete (ca. 7 d). The solvent was removed in vacuo,
saturated NaCl solution (15 cm3) added to the concentrate, and
the mixture extracted with EtOAc (3 ¥ 20 cm3). The extract was
dried (Na2SO4), concentrated in vacuo, and the product purified by
PLC (Rf 0.11, 50% ethyl acetate–hexane) to yield trans-diol 22 as a
white crystalline solid (1.28 g, 64%); mp 145 ◦C (EtOAc–hexane);
◦
◦
(lit.11 135–138 C; lit3b 139–140 C); [a]D + 8.4 (c 0.82, CHCl3),
(lit.11 [a]D +5.2; litent -8.7); (Found: C, 52.4; H, 6.1. C17H24O10
3b
requires C, 52.6; H, 6.2%); dH (500 MHz, CDCl3) 1.70 (1 H, ddd,
J6,6¢ 12.6, J6,1 = J6,5 4.8, 6-H), 1.91 (1 H, q, J6¢,6 = J6¢,1 = J6¢,5
12.6, 6¢-H), 1.99 (3 H, s, OAc), 2.02 (3 H, s, OAc), 2.04 (3 H, s,
OAc), 2.09 (3 H, s, OAc), 2.13 (3 H, s, OAc), 3.94 (1 H, dd, J7,7
¢
11.0, J7,1 6.2, 7-H), 4.08 (1 H, dd, J7¢,7 11.0, J7¢,1 8.8, 7¢-H), 4.93 (2
H, m, 4-H, 1-H), 5.41 (1 H, dd, J2,1 = J2,3 3.0, 2-H), 5.51 (1 H,
t, J3,4 = J3,2 3.0, 3-H); dC (125 MHz, CDCl3) 20.56, 20.68, 20.74,
20.79, 20.83, 23.54, 35.40, 63.03, 66.24, 68.79, 68.99, 69.01, 169.60,
169.84, 169.97, 170.09, 170.78.
[a]D -13 (c 0.95, CHCl3); (Found: M–Me+, 229.0705. C10H13O6
-1
=
requires 229.0699); nmax/cm (neat): 3364 (O–H), 1725 (C O); dH
(500 MHz, CDCl3) 1.36 (3 H, s, CMe), 1.41 (3 H, s, CMe), 3.59
(1 H, dd, J7a,3a 5.6, J7a,7 7.4, 7a-H), 3.81 (3 H, s, CO2Me), 4.52 (1
H, d, J3a,7a 5.6, 3a-H), 4.61 (1 H, dd, J7,6 7.6, J7,7a 7.4, 7-H), 5.11
(1 H, dd, J6,5 1.7, J6,7 7.6, 6-H), 6.92 (1 H, d, J5,6 1.7, 5-H); dC
(125 MHz, CDCl3): 25.69, 27.14; 52.29, 68.66, 72.60, 74.29, 74.77,
110.11, 129.54, 141.42, 165.81; m/z: (EI) 244 (M+, 1%), 229 (33),
139 (100).
Crystal data for (+)-pentaacetate 18Ac. C17H24O10, M = 388.4,
˚
monoclinic, a = 8.860(2), b = 8.897(2), c = 13.022(3) A,
◦
3
˚
b = 109.05(3) , U = 970.3(4) A , T = 298(2) K, Mo-Ka
˚
radiation, l = 0.71073 A, space group P21 (no. 4), Z = 2,
F(000) = 412, Dx = 1.329 g cm-3, m = 0.110 mm-1, Bruker
SMART CCD diffractometer, f/w scans, 3.3◦ < 2q < 57.3◦,
measured/independent reflections: 11 280/4312, direct methods
solution, full-matrix least squares refinement on Fo2, anisotropic
displacement parameters for non-hydrogen atoms; all hydrogen
atoms were located in a difference Fourier synthesis but were
included in the final refinement at positions calculated from the
geometry of the molecules using the riding model, with isotropic
vibration parameters. Final R1 = 0.047 for 3163 data with Fo >
4s(Fo), 249 parameters, wR2 = 0.128 (all data), GoF = 0.97,
Methyl
(3aR,6R,7S,7aR)-6,7-di(acetyloxy)-2,2-dimethyl-
23. (-)-
3a,6,7,7a-tetrahydro-1,3-benzodioxole-4-carboxylate
trans-Diol 22 (1.30 g, 5.33 mmol) on reacting with Ac2O–pyridine
yielded crude diacetate product. Purification by PLC (Rf 0.3, 50%
Et2O–hexane) afforded diacetate 23 as a colourless oil (1.63 g,
+
98%); [a]D -118 (c. 0.62, CHCl3); (Found: M–CH3 , 313.0928.
-1
=
C14H17O8 requires 313.0923); nmax/cm (neat): 1729 (C O); dH
(500 MHz, CDCl3) 1.38 (3 H, s, CMe), 1.39 (3 H, s, CMe), 2.10
(3 H, s, OAc), 2.15 (3 H, s, OAc), 3.81 (3 H, s, CO2Me), 4.61 (1 H,
d, J3a,7a 5.3, 3a-H), 5.10 (1 H, dd, J7a,3a 5.3, J7a,7 7.2, 7a-H), 5.16 (1
H, dd, J7,6 9.3, J7,7a 7.2, 7-H), 5.84 (1 H, dd, J6,7 9.3, J6,5 1.8, 6-H),
6.71 (1 H, d, J5,6 1.8, 5-H); dC (125 MHz, CDCl3): 19.76, 19.89,
25.23, 26.45 ¥ 2, 51.43, 66.99, 70.49, 71.64, 72.83, 109.82, 130.61,
135.55, 164.38; m/z (EI) 328 (M+, 1%), 313 (47), 43 (100).
-3
˚
Drmin,max = -0.19/0.18 e A . CCDC 746877.
(iii) Synthesis of carba-a-L-talopyranose 26
Methyl (1aS,4R,5R,5aR)-4,5-dihydroxy-1a,4,5,5a-tetrahydro-1-
benzoxirene-3-carboxylate 20. Following the procedure given for
the synthesis of compound 6, methyl benzoate (+)-cis-dihydrodiol
4 (2.00 g, 11.8 mmol) was treated with MCPBA (2.21 g, 13.0 mmol)
in CH2Cl2 solution (50 cm3). Purification of the crude product, by
column chromatography (MeOH–CHCl3), yielded compound 20
as an oil (1.79 g, 82%); [a]D -125 (c 1.27, MeOH); (Found: M+,
186.0521. C8H10O5 requires 186.0528); nmax/cm-1(neat): 3421 (O–
Methyl (3aR,4R,6R,7S,7aR)-6,7-di(acetyloxy)-2,2-dimethyl-
perhydro-1,3-benzodioxole-4-carboxylate 24. Catalytic hydro-
genation (H2, 5% Rh–Al2O3, 35 psi, 20 h) of (-)-diacetate 23
(1.00 g, 3.05 mmol) in EtOH (30 cm3) gave, after purification
by column chromatography (MeOH–CHCl3), hydrogenated
triester 24 as a viscous gum (0.84 g, 83%); [a]D -39 (c 0.51,
CHCl3); (Found: M+, 330.1316. C15H22O8 requires 330.1315);
=
H), 1716 (C O); dH (400 MHz, D2O): 3.70 (2 H, m, 1a-H, 5a-H),
-1
=
3.77 (3 H, s, CO2Me), 4.08 (1 H, d J4,5 5.0, 4-H), 4.57 (1 H, dd, J5,4
n
max/cm (neat): 1741 (C O); dH (500 MHz, CDCl3) 1.32 (3 H, s,
5.0, J5,5a 2.0, 5-H), 7.28 (1 H, d, J2,1a 4.0, 2-H); dC (100 MHz, D2O):
CMe), 1.50 (3 H, s, CMe), 1.84 (1 H, m, 5-H), 2.03 (3 H, s, OAc),
1422 | Org. Biomol. Chem., 2010, 8, 1415–1423
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
2.13 (3 H, s, OAc), 2.52 (1 H, m, 5¢-H), 2.75 (1 H, m, 4-H), 3.73
(3 H, s, CO2Me), 4.54 (1 H, dd, J7a,3a 7.6, J7a,7 2.8, 7a-H), 4.82 (1
H, ddd, J3a,7a 7.6, J3a,4 3.1, J3a,7 1.6, 3a-H), 5.06 (1 H, m, 7-H), 5.23
(1 H, ddd, J6,7 8.2, J6,5¢ 1.3, J6,5 1.3, 6-H); dC (125 MHz, CDCl3):
20.94, 20.97, 23.90, 25.64, 25.70, 39.24, 51.89, 68.70, 71.55, 73.34,
74.02, 109.72, 170.33, 170.73, 171.36; m/z (EI) 330 (M+, 2%), 315
(68), 43 (100).
(1 H, m, H-4), 5.21 (1 H, t, J 3.4, H-3), 5.40 (1 H, t, J 3.1, H-2);
dC (125 MHz, CDCl3) 19.68, 19.71, 19.76, 19.77, 20.03, 22.95,
32.66, 61.96, 66.28, 67.35, 67.44, 67.52, 168.37, 168.47, 168.79,
168.93, 169.36; m/z (EI) 388 (M+, 8%), 329 (16), 268 (23), 243
(48), 226 (39), 166 (77), 124 (80).
Acknowledgements
[(1S,2R,3S,4S,5R)-4,5-Dihydroxy-2,3-isopropylidenedioxycy-
clohexyl]-methanol 25. A solution of (-)-triester 24 (0.200 g,
0.61 mmol) in dry Et2O (30 cm3) was treated with an excess
of LiAlH4 in a similar manner to compounds 9 and 15. Pu-
rification by column chromatography (MeOH–CHCl3) yielded
triol 25 as a colourless gum (0.094 g, 71%); [a]D -6.5 [c 1.3,
(CD3)2O]; (Found: M+–Me, 203.0917. C9H15O5 requires 203.0919);
dH (500 MHz, (CD3)2O) 1.26 (3 H, s, CMe), 1.36 (3 H, s, CMe),
1.45 (1 H, m, H-6), 1.8 (1H, ddd, J6¢,6 13.8, J6¢,1 = J6¢,5 8.0, 6¢-H),
1.86 (1 H, m, 1-H), 3.42 (1 H, m, 7-H), 3.53 (2 H, m, 4-H, 7¢-H),
4.39 (1 H, dd, J3,4 3.4, J3,2 7.6, 3-H), 4.49 (1 H, ddd, J2,3 7.6, J 2.69,
J 1.22, 2-H); dC (125 MHz, (CD3)2O) 22.26, 24.21, 34.11, 34.30,
61.95, 66.55, 71.60, 72.95, 74.73, 106.59; m/z (EI): 203 (M+-Me,
68%), 97 (37), 95 (50), 83 (57), 71 (49), 59 (79), 57 (69), 55 (66), 43
(100), 42 (74), 41 (80).
We gratefully acknowledge financial support from SFI (NDS,
Grant No. 04/IN3/B581), DENI (NIB), and The Queen’s Uni-
versity of Belfast (GBC, CRO’D).
References
1 O. Arjona, A. M. Gomez, J. C. Lopez and J. Plumet, Chem. Rev., 2007,
107, 1919.
2 (a) S. M. Resnick, K. Lee and D. T. Gibson, J. Ind. Microbiol.
Biotechnol., 1996, 17, 438; (b) D. R. Boyd and G. N. Sheldrake, Nat.
Prod. Rep., 1998, 15, 309; (c) T. Hudlicky, D. Gonzalez and D. T.
Gibson, Aldrichim. Acta., 1999, 32, 35; (d) D. T. Gibson and R. E.
Parales, Curr. Opin. Biotechnol., 2000, 11, 236; (e) D. R. Boyd, N. D.
Sharma and C. C. R. Allen, Curr. Opin. Biotechnol., 2001, 12, 564;
(f) R. A. Johnson, Org. Reactions, 2004, 63, 117; (g) D. R. Boyd and
T. Bugg, Org. Biomol. Chem., 2006, 4, 181; (h) K. A. B. Austin, M.
Matveenko, T. A. Reekie and M. G. Banwell, Chem. Aust., 2008, 75, 3;
(i) T. Hudlicky and J. W. Reed, Synlett, 2009, 685.
Carba-a-L-talopyranose[(1R,2S,3R,4R,5S)-5-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol] 26. (-)-Trihydroxyacetonide 25
(0.13 g, 0.6 mmol) was deprotected, following the procedure
given for the removal of the acetonide group in compound 17.
Purification of the crude product by a charcoal/Celite column
yielded carbasugar 26 as a gum (0.090 g, 85%); [a]D +11 (c 1.2,
MeOH); (Found: M+, 178.0835. C7H14O5 requires 178.0841); dH
(500 MHz, D2O) 1.57 (1 H, dt, J6e,1 = J6e,5 4.3, J6e,6a 14.31, 6-H),
1.88 (1 H, m, 6¢-H), 2.10 (1 H, m, 5-H), 3.66 (1 H, m, 7-H), 3.76
(1 H, m, 7¢-H), 3.85 (1 H, br s, 3-H), 3.90 (1 H, br s, 2-H), 4.12
(2 H, br d, J 7.52, 1-H, 4-H); dC (125 MHz, D2O) 25.21, 38.07,
62.63, 69.29 ¥ 2, 71.39, 74.12; m/z (EI) 178 (M+, 3%), 149 (30), 71
(25), 57 (35), 44 (82), 42 (91), 41 (100).
3 (a) S. Ley and L. L. Yeung, Synlett, 1992, 291; (b) L. Pingli and
M. Vandewalle, Synlett, 1994, 228; (c) L. Pingli and M. Vandewalle,
Tetrahedron, 1994, 50, 7061; (d) H. A. Carless and S. S. Malik, J. Chem.
Soc., Chem. Commun., 1995, 2447; (e) C. H. Tran and D. H. G. Crout,
Tetrahedron: Asymmetry, 1996, 7, 2403; (f) D. A. Entwistle and T.
Hudlicky, Tetrahedron Lett., 1995, 36, 2591; (g) D. R. Boyd, N. D.
Sharma, N. Llamas, J. F. Malone, C. R. O’Dowd and C. C. R. Allen,
Org. Biomol. Chem., 2005, 3, 1953; (h) F. Fabris, J. Collins, B. Sullivan,
H. Leisch and T. Hudlicky, Org. Biomol. Chem., 2009, 7, 2619.
4 D. R. Boyd, N. D. Sharma, N. I. Bowers, J. Duffy, J. S. Harrison and
H. Dalton, J. Chem. Soc., Perkin Trans. 1, 2000, 1345.
5 D. R. Boyd, N. D. Sharma, B. Byrne, M. V. Hand, J. F. Malone, G. N.
Sheldrake, J. Blacker and H. Dalton, J. Chem. Soc., Perkin Trans. 1,
1998, 1935.
6 (a) D. R. Boyd, J. T. G. Hamilton, N. D. Sharma, J. S. Harrison, W. C.
Mc Roberts and D. B. Harper, Chem. Commun., 2000, 1481; (b) D. R.
Boyd, N. D. Sharma, J. S. Harrison, J. F. Malone, W. C. McRoberts,
J. T. G. Hamilton and D. B. Harper, Org. Biomol. Chem., 2008, 6, 1251.
7 A. J. Blacker, R. J. Booth, G. M. Davies and J. K. Sutherland, J. Chem.
Soc., Perkin Trans. 1, 1995, 2861.
8 M. G. Banwell, L. Liu, C. R. Parish, and C. G. Freeman, International
Patent No. WO 03/004454 A1, 2003.
9 R. Verduyn, S. H. van Leeuwen, G. A. van der Marel and J. H. van
Boom, Recl. Trav. Chim. Pays-Bas, 1996, 115, 67.
10 T. J. Donohoe, P. R. Moore, M. J. Waring and N. J. Newcombe,
Tetrahedron Lett., 1998, 39, 8755.
11 A. M. Go´mez, E. Moreno, G. O. Danelon, S. Valverde and J. C. Lopez,
Tetrahedron: Asymmetry, 2003, 14, 2961.
Carba-a-L-talopyranose
pentaacetate
26Ac. Carba-a-L-
talopyranose 26 (0.030 g, 0.17 mmol) was acetylated using
Ac2O–pyridine. Pentaacetate 26Ac was obtained as a colourless
gum (0.054 g, 82%); [a]D -26.0 (c 1.2, CHCl3) (lit.8 + 27.5,
D-isomer); (Found: M+, 388.1372. C17H24O10 requires 388.1369);
dH (500 MHz, CDCl3) 1.65 (1 H, m, 6-H), 1.96 (1 H, m, 6¢-H),
2.01 (3 H, s, OCOMe), 2.04 (3 H, s, OCOMe), 2.07 (6H, s,
OCOMe), 2.10 (3 H, s, OCOMe), 2.42 (1 H, m, 1-H), 3.97 (1 H,
m, 1-H), 4.10 (1 H, m, J1B,1 11.1, H-1B), 5.13 (1 H, m, H-5), 5.16
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1415–1423 | 1423
©