Synthesis of L- and D-4,6-dideoxyhexoses and 4,6-dideoxy-C-phenylglycosides from enzyme-generated products

Article abstract of DOI:10.1002/ejoc.200800662

Optically active 1,3-diols 1 were prepared by biocatalysed routes. The synthetic versatility of compounds 1 as chiral building blocks was shown. The oxidative cleavage of the double bond afforded a carbonyl moiety, which allowed for elongation by Grignard addition and further derivatisation to make deoxy sugars readily available. The epoxidation of the same double bond allowed the direct intramolecular opening of the epoxide ring to generate deoxy C-phenylglycosides. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800662

FULL PAPER
DOI: 10.1002/ejoc.200800662
Synthesis of
L
- and
D
-4,6-Dideoxyhexoses and 4,6-Dideoxy-C-phenylglycosides
from Enzyme-Generated Products
Daniela Acetti,[a] Elisabetta Brenna,*[a] Claudio Fuganti,[a] Francesco G. Gatti,[a]
Luciana Malpezzi,[a] and Stefano Serra[b]
Keywords: Enzymes / Lipase / Baker’s yeast / Deoxyhexose / C-Glycosides / Carbohydrates
Optically active 1,3-diols 1 were prepared by biocatalysed
routes. The synthetic versatility of compounds 1 as chiral
building blocks was shown. The oxidative cleavage of the
double bond afforded a carbonyl moiety, which allowed for
elongation by Grignard addition and further derivatisation to
make deoxy sugars readily available. The epoxidation of the
same double bond allowed the direct intramolecular opening
of the epoxide ring to generate deoxy C-phenylglycosides.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
several stereogenic centres. We have recently optimized[11]
an enzymatic method for the kinetic resolution of 1,3-diols
of type I (Scheme 1), to be converted into chiral synthons
II, showing two or three stereogenic centres with controlled
stereochemistry and one carbonyl group suitable of further
functionalisation.
Introduction
A growing trend in pharmaceutical research is the devel-
opment of step-economical syntheses of novel structures
with improved or new activities. This target is achieved by
optimizing new reactions and synthetic strategies, which al-
lows for a shorter route to a target molecule, or by
designing less complex molecules with comparable or supe-
rior function, which can be prepared in practical and novel
manners.[1] Both approaches have stimulated the develop-
ment of synthetic building blocks whose synthesis is well
optimized and that can be assembled to afford the desired
compound.
The 1,3-diol structural motif, for example, occurs as an
important subunit in a number of biologically active prod-
ucts and intermediates used for the synthesis of complex
molecules.[2] Several synthetic procedures even to complex
1,3-polyol arrays have been developed with great success.[3]
The total synthesis of palytoxin represents one of the most
outstanding examples.[4]
Scheme 1.
We wish herein to report on the synthesis of the single
The strategies for the creation of 1,3-dioxygenated stereo- stereoisomers of new 1,3-diols 1 with defined stereochemis-
centres have been recently reviewed[5] and include (i) re- try at three adjacent stereogenic centres and on their use as
duction of β-hydroxy ketones,[6] (ii) Tishchenko reaction,[7] chiral synthons to prepare biologically active molecules
(iii) stereoselective reduction of 1,3-diketones,[8] (iv) Prins such as 4,6-dideoxyhexoses 2 and 4,6-dideoxy-C-phenylgly-
reaction,[9] and other miscellaneous reactions.[10]
cosides 3, which contain non-oxygenated carbon atoms in
It seems desirable to develop synthetic procedures to pro- positions 4 and 6 in the sugar ring. Deoxy sugars and C-
cure 1,3-diol chiral synthons in all their possible configura- glycosides are integral components of several therapeuti-
tions, which can be assembled into chiral molecules with cally relevant products, and their presence is often critical
in conferring bioactivity.[12] These derivatives have recently
received great attention, and their synthesis is a rather chal-
lenging task.[13] The preparation of modified carbohydrate
moieties can also be exploited for the development of novel
sugar mimics able to antagonize oligosaccharides at the
protein receptor level and to interfere with the recognition
events, on which the transmission or the onset of a disease
is based. The design of glycomimetic structures is aimed
[a] Politecnico di Milano, Dipartimento di Chimica, Materiali ed
Ingegneria Chimica; Istituto di Chimica del Riconoscimento
Molecolare – CNR,
Via Mancinelli 7, 20131 Milano, Italy
Fax: +39-02-23993180
E-mail: elisabetta.brenna@polimi.it
[b] Istituto di Chimica del Riconoscimento Molecolare – CNR,
Dipartimento di Chimica, Materiali ed Ingegneria Chimica,
Via Mancinelli 7, 20131 Milano, Italy
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at reducing the carbohydrate-likeness of the mimics and to
Enzymatic acetylation of rac-syn,syn-1 gave diacetate
increase their drug-like properties.[14] Ganglioside GM1, for (+)-syn,syn-6 and unreacted alcohol (–)-syn,syn-1. The ab-
example, interacts with cholera toxin using galactose and solute stereochemistry was established by analogy with that
N-acetylneuraminic acid residues at the oligosaccharide determined for anti derivatives (see Configuration Assign-
non-reducing end.[15] It was discovered that the terminal ment below). The enantiomeric excess of both diacetate (+)-
galactose could potentially serve as an “anchor” point for syn,syn-6 and unreacted diol (–)-syn,syn-1 was found to be
antagonist design,[16] and aryl galactosides[17] and galactose Ͼ99% by GC analysis of the corresponding acetonides (+)-
dendrimers[18] were developed as effective cholera toxin an- and (–)-syn,syn-5 on a chiral column.
tagonists. The interest in this field encouraged us to investi-
gate the synthetic versatility of our chiral building blocks
by preparing a modified carbohydrate related to galactose.
Lipase-catalysed acetylation of the mixture of the other
three diols afforded monoacetates (–)-anti,syn-7, (+)-anti,
anti-7, and (+)-syn,anti-7, which could be separated by col-
umn chromatography, and a mixture of the unreacted start-
ing diols. The absolute configuration (see Configuration As-
signment below) was assigned by degradation of a mixture
of (–)-anti,syn-7 and (+)-anti,anti-7. The enantiomeric ex-
cess of anti,anti-7 was 98% by GC analysis of the corre-
sponding acetonide on a chiral column.
Results and Discussion
Synthesis of Optically Active Diols 1
We also experimented with the Baker’s yeast reduction
of syn- and anti-4, which afforded a 1:1 mixture of diols
anti,anti-1 and syn,anti-1 (Scheme 4), which were converted
into the corresponding acetonides and separated by column
chromatography. The anti,anti-acetonide thus recovered was
enantiomerically pure (GC) and of opposite configuration
to that of the acetonide prepared from monoacetate (+)-
anti,anti-7.
The aldol condensation of cyclopentanone and cinnam-
aldehyde gave a mixture of the two diastereomeric hydroxy
ketones syn- and anti-4[19] (Scheme 2), which were submit-
ted to NaBH4 reaction to afford the four racemic dia-
stereomeric diols 1.
We could draw the conclusion that Baker’s yeast pro-
moted the stereoselective reduction of anti-4. To the best of
our knowledge, this reduction of compound 4 represents
the first example of a Baker’s yeast reduction of a β-hy-
droxy ketone to an optically active 1,3-diol. Literature in
this field reports only several examples of Baker’s yeast re-
duction of β-diketones to β-hydroxy ketones.[20]
When the mixture of the four racemic diols was treated
with dimethoxypropane in acetone in the presence of pyr-
Scheme 2.
Diol syn,syn-1 could be isolated from this reduction mix- idinium p-toluenesulfonate, only three diastereomeric aceto-
ture by column chromatography, and its relative stereo- nides were recovered, anti,anti-, syn,anti-, and syn,syn-5, be-
chemistry was assigned on the basis of the NMR spectra of sides two degradation products, (1E,3Z)- and (1E,3E)-8
the corresponding acetonide syn,syn-5. Diol syn,syn-1 and (Scheme 5). These products could be explained by admit-
the mixture of the other three diastereomers were submitted ting an acid-catalysed Grob fragmentation mainly of the
separately to lipase PS mediated transesterification in tert- missing acetonide anti,syn-5 via an allylic carbocationic in-
butyl methyl ether in the presence of vinyl acetate as an acyl termediate through a non-synchronous mechanism, as has
donor (Scheme 3).
been recently highlighted by Barluenga et al.[21]
Scheme 3. (i) Lipase PS, tert -butyl methyl ether, vinyl acetate; column chromatography.
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- and -4,6-Dideoxyhexoses and 4,6-Dideoxy-C-phenylglycosides
Scheme 4. (i) Baker’s yeast, H2O/ethanol, glucose; column chromatography.
Scheme 5. Acid-catalysed Grob fragmentation.
In order to show the synthetic potential of diols 1 as diastereomer syn,anti,syn-10 with total control of the con-
chiral building blocks, we employed them to prepare two figuration of the new stereogenic centre, probably through
important sets of compounds, 4,6-dideoxyhexoses 2 (in par- a chelation-controlled nucleophilic addition similar to those
ticular galactose) and 4,6-dideoxy-C-phenylglycosides 3. A described by Still et al.[23] for α-alkoxy ketones. Ozonolysis
complete preliminary investigation of the synthetic route with PPh3 quenching followed by treatment with Ac2O in
was performed on racemic materials.
pyridine, allowed us to isolate a 6:4 mixture of the two ano-
mers of 4,6-dideoxygalactopyranose triacetate 11. This
compound is structurally related to galactose; the OH
groups at C(4) and C(6) of galactose are substituted by CH2
moieties, connected by a C–C bond to form a five-mem-
bered fused ring.
Synthesis of Dideoxy Sugars
The three acetonides 5 were submitted, separately, to
ozonolysis and PPh3 treatment to afford aldehydes syn,syn-,
syn,anti-, and anti,anti-9, which contain three adjacent
stereocentres with controlled configuration and a carbonyl
moiety,[22] which could be employed to further functionalise
the molecule. Aldehyde syn,anti-9, for example (Scheme 6),
Synthesis of C-Glycosides
A mixture of diols anti,anti- and anti,syn-1 was epox-
was treated with vinylmagnesium bromide to afford only idised with m-chloroperbenzoic acid in CH2Cl2 to afford,
Scheme 6. (i) Vinylmagnesium bromide, THF; (ii) O3, MeOH/CH2Cl2, then PPh3; (iii) THF, H2O, 10% HCl.
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Scheme 7. (i) mCPBA, CH2Cl2; (ii) THF/H2O, HClO4; (iii) Ac2O, pyridine; (iv) 2,2-dimethoxypropane, acetone, pyridinium p-toluenesul-
fonate; (v) H2, Pd/C, EtOH, HClO4.
after workup and purification by column chromatography, tion, derived from the opening of the same epoxide giving
compound 12a and a mixture containing compound 13a rise to compound 12b.
and the two epoxide derivatives 14 and 15 (Scheme 7). This
latter mixture was dissolved in THF/H2O, treated with
HClO4 and acetic acid, and the products were separated
by column chromatography. Compound 13a was recovered
unreacted; the two epoxides were converted into com-
pounds 12b and 13b and recovered as their corresponding
diacetates, and tetraol 16 was recovered as the last eluted
fraction. The structures of C-phenylglycosides 12a,b and
13a,b were established by means of 1H and 13C NMR
analysis and by their conversion into their corresponding
acetate and acetonide derivatives, 17–20.
Tetraol 16 was submitted to hydrogenolysis and then
treated with dimethoxypropane in acetone, to afford, unex-
Figure 1. X-ray crystal structure of 21.
pectedly, the seven-membered ring 21. The structure was
established by X-ray crystallography (Figure 1).[24]
Compounds 12a and 13a, which are, respectively, a β-C-
phenyl-4,6-dideoxyalloside and -glucoside, were readily
formed during the epoxidation reaction (Scheme 8). The in-
tramolecular opening of the two diastereomeric epoxides
was highly favoured, leading to an all-equatorial arrange-
ment of the substituents in 13a and to the presence of only
one axial OH group in 12a. The other two diastereomers
12b and 13b, which are, respectively, a β-C-phenyl-4,6-dide-
oxyaltroside and an α-C-phenyl-4,6-dideoxymannoside,
could be obtained by acid-catalysed opening of derivatives
14 and 15. Tetraol 16, recovered from the hydrolysis reac- Scheme 8.
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- and -4,6-Dideoxyhexoses and 4,6-Dideoxy-C-phenylglycosides
Configuration Assignment
Some topics that arose during the development of this
work deserve future investigations, such as the bias towards
Grob fragmentation of the anti,syn-acetonide 5 and the ste-
ric requirements leading to the unexpected preference for
the dioxepinol derivative 21, rather than for a five- or six-
membered acetonide, in the reaction of tetraol 16 with di-
methoxypropane in acetone under acid catalysis.
A 1:1 mixture of monoacetates (+)-anti,anti-7 and (–)-
anti,syn-7 was submitted to ozonolysis followed by NaBH4
quenching to afford, after reaction with dimethoxypropane
in acetone and pyridinium p-toluenesulfonate, compound
(–)-22 (Scheme 9). This latter was saponified and treated
with PhCH2Br, after treatment with NaH in THF, to give
derivative 23, which was then deprotected, affording diol
24. Oxidative cleavage of the 1,2-diol with periodic acid in
THF, followed by NaBH4 reduction of the intermediate al-
dehyde, allowed us to obtain compound 25, which was de-
benzylated to afford compound (1R,2S)-(–)-26, whose abso-
lute configuration was known in the literature.[25] Thus, the
absolute configuration of the cyclopentane ring of (+)-anti,
anti- and (–)-anti,syn-7 was determined. The absolute con-
figuration of the syn derivatives was assigned on the basis
of analogy with that determined for the anti derivatives.
Experimental Section
General Methods: Lipase PS Burkholderia cepacia was employed in
this work. GC-MS analyses were performed by using an HP-5MS
column (30mϫ0.25mmϫ0.25µm). The following temperature pro-
gram was employed: 60 °C (1 min) / 6 °C/min / 150° (1 min) / 12 °/
1
min / 280° (5 min). H and 13C NMR spectra were recorded with
a 400 MHz spectrometer. The chemical shift scale was based on
internal tetramethylsilane. The enantiomeric excess of acetonides 5
was determined by GC analysis using a Chirasil DEX CB,
25 mϫ0.25 mm (Chrompack) column, installed on a DANI HT
86.10 gas chromatograph with the following temperature program:
60 °C (3 min) / 3 °C/min / 180 °C (10 min). The following retention
times were observed: (4S,4aR,7aR,E)-anti,anti-5 tR = 36.17 min,
(4R,4aS,7aS,E)-anti,anti-5 tR = 36.32 min, (4R,4aR,7aS,E)-syn,syn-
5 tR = 35.71 min, and (4S,4aS,7aR,E)-syn,syn-5 tR = 36.12 min.
Optical rotations were measured with a Dr. Kernchen Propol digi-
tal automatic polarimeter at 589 nm and are given in
10–1 degcm2 g–1. TLC analyses were performed with Merck Kiesel-
gel 60 F254 plates. All the chromatographic separations were car-
ried out with silica gel columns.
Preparation of Diols 1, Acetonides 5 and Aldehydes 9
Scheme 9. (i) O3, CH2Cl2/MeOH (1:1), then NaBH4; (ii) 2,2-di-
methoxypropane, acetone, pyridinium p-toluenesulfonate, reflux;
(iii) 25% aqueous KOH, MeOH; (iv) NaH, PhCH2Cl, THF; (v)
AcOH, a few drops HCl, THF/H2O (2:1); (vi) HClO4, THF, then
a few drops of ethylene glycol, MeOH and NaBH4 at –10 °C; (vii)
H2, 50 psi, Pd/C, ethyl acetate.
(RS)-2-[(SR,E)-1-Hydroxy-3-phenylallyl]cyclopentanone (syn-4) and
(RS)-2-[(RS,E)-1-Hydroxy-3-phenylallyl]cyclopentanone (anti-4): A
stirred solution of cyclopentanone (42 g, 0.5 mol) and cinnamal-
dehyde (66 g, 0.5 mol) in methanol (300 mL) at –10 °C was treated
with aqueous sodium hydroxide (40%, 1 mL). After 5 min, the
slightly yellow solution was poured into excess iced H2O, contain-
ing acetic acid (3 mL). The reaction mixture was extracted with a
2:1 mixture of ethyl acetate/hexane. The organic phase was washed
with saturated NaHCO3 solution and dried with sodium sulfate.
The oil obtained upon evaporation of the solvent was chromato-
graphed (SiO2) with increasing amounts of ethyl acetate in hexane,
providing oily 4 (63 g, 58%) as a 1:1 mixture of syn and anti dia-
The relative configuration of diols 1 was assigned by
analysis of the NMR spectra of the corresponding aceto-
nides 5.
Conclusions
1
stereomers. H NMR[19] (400 MHz, CDCl3): δ = 7.20–7.42 (m, 10
The work shows the synthetic versatility of diols of type
1. The lipase-mediated resolution and the enantiospecific
generation of a stereogenic centre by Baker’s yeast are use-
ful methods for the preparation of optically active starting
diols 1. The oxidative cleavage of the double bond affords
a carbonyl moiety, which allows elongation by Grignard ad-
dition and further derivatisation, to make deoxy sugars
readily available. The epoxidation of the same double bond
allows the direct intramolecular opening of the epoxide
ring, to generate deoxy C-phenylglycosides.
This work shows the accessibility of hydroxylated six-
membered rings starting from an aldol condensation by me-
ans of simple reactions employing biocatalysis to produce
optically pure products. The combination of our procedure
with known techniques for the diastereoselective reduction
of the starting aldol to syn- or anti-1,3-diols[26] can be em-
ployed to synthesize target diastereomers selectively.
H, aromatic hydrogen atoms of both diastereomers), 6.64 (d, J =
15.8 Hz, 2 H, 2 CH= of both diastereomers), 6.20 (dd, J = 6.3,
15.8 Hz, 1 H, C=CCH of one diastereomer), 6.15 (dd, J = 7.1,
15.8 Hz, 1 H, C=CCH of the other diastereomer), 4.76 (m, 1 H,
CHOH of one diastereomer), 4.38 (dt, J = 0.9, 7.1 Hz, 1 H, CHOH
of the other diastereomer), 1.59–2.46 (m, 14 H, hydrogen atoms
of the cyclopentane ring of both diastereomers) ppm. 13C NMR
(100.61 MHz, CDCl3): δ = 222.4, 222.3, 136.6, 136.5, 129.5, 129.0,
128.9, 128.6, 128.5, 128.3, 127.8, 127.7, 126.6, 126.5, 73.5, 71.1,
54.1, 53.9, 39.1, 38.6, 26.6, 23.6, 20.7, 20.5 ppm.
2-[(2E)-1-Hydroxy-3-phenylallyl]cyclopentan-1-ol (syn,syn-, syn,
anti-, anti,syn-, anti,anti-1): To a stirred solution of the 1:1 mixture
of syn- and anti-4 (22 g, 0.1 mol) in ethanol (150 mL) at 0 °C was
added sodium borohydride (3.7 g, 0.1 mol) portionwise over
30 min. After 10 h, the mixture was poured into iced H2O and ex-
tracted with ethyl acetate/hexane (4:1). The oily residue (18 g) ob-
tained upon concentration of the washed and dried organic phase
was chromatographed with ethyl acetate/hexane (4:6 Ǟ 6:4), pro-
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viding, in order, syn,syn-1 (3.92 g, 18%) and a mixture of the other
three diols 1 (14.8 g, 68%).
syn,syn-1: 1H NMR (400 MHz, CDCl3): δ = 7.19–7.41 (m, 5 H,
aromatic hydrogen atoms), 6.62 (d, J = 15.9 Hz, 1 H, CH=), 6.27
CH3) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 136.9, 130.9,
129.2, 128.4, 127.5, 126.4, 99.7, 73.2, 72.3, 47.1, 34.1, 28.8, 25.8,
24.2, 24.1 ppm. GC/MS: tR = 23.57 min; m/z (%) = 258 (5) [M]+,
243 (1), 200 (21), 183 (5), 133 (76), 104 (100).
1
(1E,3E)-8 and (1E,3Z)-8: H NMR (400 MHz, CDCl3): δ = 7.15–
(dd, J = 6.2, 15.9 Hz, 1 H, =CHCHOH), 4.76 (m,
1 H,
7.42 (m, 10 H, aromatic hydrogen atoms of both stereoisomers),
7.03 [dd, J = 11.0, 15.8 Hz, 1 H, H-2 of (3Z)-8], 6.73 [dd, J = 10.5,
15.8 Hz, 1 H, H-2 or H-3 of (3E)-8], 6.51 [d, J = 15.8 Hz, 1 H, H-
1 of (3Z)-8], 6.43 [d, J = 15.8 Hz, 1 H, H-1 of (3E)-8], 6.20 [m, 2
H, H-3 or H-2 of (3E)-8 and H-3 of (3Z)-8], 5.79 [dt, J = 15.8,
7.0 Hz, 1 H, H-4 of (3E)-8], 5.48 [dt, J = 10.0, 7.0 Hz, 1 H, H-4 of
(3Z)-8], 4.36 [m, 2 H, CH(OCH3)2 of both diastereomers], 3.31 (s,
12 H, 2 OCH3 of both diastereomers), 2.27 [q, J = 7.0 Hz, 2 H,
CH2C=C of (3Z)-8], 2.17 (q, J = 7.0 Hz, 2 H, CH2C=C of (3E)-
8], 1.63 (m, 4 H, CH2 of both diastereomers), 1.50 (m, 4 H, CH2
of both diastereomers) ppm. GC/MS: (1E,3E)-8: tR = 24.38 min;
m/z (%) = 246 (7) [M]+, 214 (10), 183 (12), 156 (100); (1E,3Z)-8:
tR = 23.87 min; m/z (%) = 246 (8) [M]+, 214 (10), 183 (15), 156
(100).
anti,anti-5: 1H NMR (400 MHz, CDCl3): δ = 7.18–7.38 (m, 5 H,
aromatic hydrogen atoms), 6.60 (d, J = 15.8 Hz, 1 H, CH=), 6.17
(dd, J = 15.8, 6.6 Hz, 1 H, =CHCHO), 4.29 (dd, J = 6.6, 9.5 Hz,
1 H, =CHCHO), 3.63 (dt, J = 6.9, 10.4 Hz, 1 H, CH2CHO), 1.96
(m, 1 H, CH of the cyclopentane ring), 1.53 (s, 3 H, CH3), 1.51 (s,
3 H, CH3), 1.12–1.79 (m, 6 H, hydrogen atoms of the cyclopentane
ring) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 136.7, 131.0,
128.8, 128.3, 127.5, 126.4, 100.0, 77.5, 75.2, 47.5, 30.0, 29.1, 22.4,
20.3, 18.1 ppm. GC/MS: tR = 24.00 min; m/z (%) = 258 (1) [M]+,
240 (1), 200 (38), 183 (32), 133 (19), 104 (100).
=CHCHOH), 4.40 (m, 1 H, CH2CHOH), 1.53–2.02 (m, 7 H, hy-
drogen atoms of cyclopentane ring) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 136.9, 131.6, 129.7, 128.5, 127.4, 126.4, 76.4, 72.6,
49.6, 36.0, 22.4, 21.9 ppm.
anti,syn-1: 1H NMR (400 MHz, CDCl3): δ = 7.19–7.42 (m, 5 H,
aromatic hydrogen atoms), 6.62 (d, J = 15.8 Hz, 1 H, CH=), 6.29
(dd, J = 6.5, 15.8 Hz, 1 H, =CHCHOH), 4.37 (t, J = 6.5 Hz, 1 H,
=CHCHOH), 4.14 (q, J = 6.4 Hz, 1 H, CH2CHOH), 1.37–2.10 (m,
7 H, hydrogen atoms of the cyclopentane ring) ppm. 13C NMR
(100.61 MHz, CDCl3): δ = 136.6, 131.3, 130.3, 128.5, 127.6, 126.4,
74.9, 74.1, 53.3, 34.7, 25.5, 21.8 ppm.
syn,anti-1: 1H NMR (400 MHz, CDCl3): δ = 7.20–7.41 (m, 5 H,
aromatic hydrogen atoms), 6.63 (d, J = 15.9 Hz, 1 H, CH=), 6.30
(dd, J = 7.0, 15.9 Hz, 1 H, =CHCHOH), 4.49 (dt, J = 2.2, 4.8 Hz,
1 H, CH2CHOH), 4.42 (t, J = 7.0 Hz, 1 H, =CHCHOH), 1.52–
2.02 (m, 7 H, hydrogen atoms of the cyclopentane ring) ppm. 13C
NMR (100.61 MHz, CDCl3): δ = 136.9, 131.8, 130.5, 128.5, 127.6,
126.5, 74.3, 73.9, 50.5, 35.2, 26.4, 22.4 ppm.
anti,anti-1: 1H NMR (400 MHz, CDCl3): δ = 7.20–7.41 (m, 5 H,
aromatic hydrogen atoms), 6.54 (d, J = 15.9 Hz, 1 H, CH=), 6.17
(dd, J = 7.1, 15.9 Hz, 1 H, =CHCHOH), 4.08–4.20 (m, 2 H,
=CHCHOH, CH2CHOH), 1.49–2.02 (m, 7 H, hydrogen atoms of
the cyclopentane ring) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
136.6, 131.2, 130.9, 128.5, 127.7, 126.4, 78.2, 78.1, 52.8, 33.9, 26.6,
21.1 ppm.
Baker’s Yeast Reduction of syn and anti-4: To a stirred mixture of
Baker’s yeast (500 g) and -glucose (200 g) in tap H2O (2 L) at
30 °C was added dropwise over 30 min a solution of syn- and anti-
4 (21.6 g, 0.1 mol) in ethanol (40 mL). After 2 d, under these condi-
tions, acetone (1 L) was added followed by ethyl acetate/hexane
(4:1, 1 L). After 1 d of stirring, the mixture was filtered through a
large Buchner funnel with a thick Celite pad previously washed
with acetone. The two phases were then separated, and the aqueous
phase was extracted twice with the ethyl acetate/hexane mixture.
The oily residue obtained upon evaporation of the washed and
dried organic phase was chromatographed with increasing amounts
of ethyl acetate in hexane, obtaining ketone 4 (13.2 g, 61%) and a
diol fraction (4.3 g, 20%). The latter mixture, on treatment with
2,2-dimethoxypropane (as was described above), afforded products
syn,anti-5 {[α]2D0 = +4.72 (c = 0.98, CHCl3)} and anti,anti-5 {[α]2D0
= –1.19 (c = 1.01, CHCl3)}, in a 1:1 ratio after separation by col-
umn chromatography. The enantiomeric excess of anti,anti-5 was
determined by GC analysis on a chiral column to be Ͼ99%.
2,2-Dimethyl-4-styrylhexahydrocyclopenta[d][1,3]dioxine (syn,syn-,
syn,anti-, anti,syn-, anti,anti-5), (1E,3Z)- and (1E,3E)-(8,8-Dimeth-
oxyocta-1,3-dienyl)benzene [(1E,3Z)-8, (1E,3E)-8]: To a mixture of
diols syn,syn-, syn,anti-, anti,syn-, and anti,anti-1 (4.6 g, 0.02 mol),
dissolved in acetone (30 mL) and 2,2-dimethoxypropane (15 mL) at
50–60 °C, pyridinium p-toluenesulfonate (50 mg, 0.198 mmol) was
added. Once the reaction was completed (Ͻ 10 min), the mixture
was diluted with ethyl acetate/hexane (1:1) and washed with satu-
rated NaHCO3 solution. The residue obtained upon concentration
was chromatographed (SiO2) with hexane/ethyl acetate (98:2 Ǟ
95:5), eluting in order, syn,syn-5 (0.77 g, 15%), syn,anti-5 (0.67 g,
13%), a 6:4 mixture of (1E,3E)-8 and (1E,3Z)-8 (0.54 g, 11%), and
anti,anti-5 (1.0 g, 19%).
syn,syn-5: 1H NMR (400 MHz, CDCl3): δ = 7.19–7.38 (m, 5 H,
aromatic hydrogen atoms), 6.61 (d, J = 15.9 Hz, 1 H, CH=), 6.17
(dd, J = 15.9, 6.2 Hz, 1 H, =CHCHO), 4.80 (m, 1 H, =CHCHO),
4.35 (m, 1 H, CH2CHO), 1.54–2.01 (m, 7 H, hydrogen atoms of
the cyclopentane ring), 1.53 (s, 3 H, CH3), 1.44 (s, 3 H, CH3) ppm.
13C NMR (100.61 MHz, CDCl3): δ = 137.0, 130.2, 129.4, 128.4,
127.4, 126.4, 98.1, 73.2, 69.9, 43.4, 33.0, 30.1, 21.9, 21.7, 19.5 ppm.
GC/MS: tR = 23.90 min; m/z (%) = 258 (6) [M]+, 243 (7), 200 (17),
183 (16), 133 (21), 104 (100). Enantiopure (+)- and (–)-syn,syn-5,
obtained from (+)-syn,syn-6 and (–)-syn,syn-1, showed, respec-
tively: [α]2D0 = +53.3 (c = 0.96, CHCl3) and [α]2D0 = –50.1 (c = 1.01,
CHCl3).
Acetylation of Diols syn,syn-, syn,anti-, anti,syn-, and anti,anti-1,
Mediated by Lipase Amano PS: In a typical experiment, a solution
of syn,syn-1 (3.0 g, 0.014 mol) in vinyl acetate/tert-butyl methyl
ether (1:1, 40 mL), was stirred with lipase Amano PS (3.0 g) at
room temperature for 2 d. The filtered solution was concentrated,
and the residue was chromatographed with increasing amounts of
ethyl acetate in hexane. Under these conditions, syn,syn-1 afforded
diacetyl derivative (+)-syn,syn-6 (0.42 g, 10%), followed by an in-
separable mixture of isomeric monoacetates and, finally, by the un-
converted starting diol (–)-syn,syn-1 (1.06 g, 36%).
syn,anti-5: 1H NMR (400 MHz, CDCl3): δ = 7.19–7.39 (m, 5 H,
aromatic hydrogen atoms), 6.59 (d, J = 15.8 Hz, 1 H, CH=), 6.20
(dd, J = 15.8, 6.6 Hz, 1 H, =CHCHO), 4.30 (dt, J = 2.5, 6.6 Hz, 1
(+)-syn,syn-6: [α]2D0 = +8.84 (c = 0.95, CHCl3); ee Ͼ 99%, deter-
mined by GC analysis on a chiral column of the corresponding
H, CH2CHO), 4.04 (dd, J = 7.3, 9.8 Hz, 1 H, =CHCHO), 2.18 (m, acetonide, prepared by saponification of the diacetate and subse-
1
1 H, CH of the cyclopentane ring), 1.44–1.92 (m, 6 H, hydrogen
quent treatment with 2,2-dimethoxypropane. H NMR (400 MHz,
atoms of the cyclopentane ring), 1.42 (s, 3 H, CH3), 1.39 (s, 3 H,
CDCl3): δ = 7.20–7.36 (m, 5 H, aromatic hydrogen atoms), 6.57 (d,
5130
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5125–5134

- and -4,6-Dideoxyhexoses and 4,6-Dideoxy-C-phenylglycosides
J = 16.0 Hz, 1 H, CH=), 6.12 (dd, J = 7.7, 16.0 Hz, 1 H,
C=CHCHOAc), 5.52 (t, J = 8.6 Hz, 1 H, C=CHCHOAc), 5.17
(dt, J = 2.2, 5.1 Hz, 1 H, CH2CHOAc), 2.25 (m, 1 H, CH of the
cyclopentane ring), 2.07 (s, 3 H, OAc), 2.03 (s, 3 H, OAc), 1.58–
2.01 (m, 6 H, hydrogen atoms of the cyclopentane ring) ppm. 13C
NMR (100.61 MHz, CDCl3): δ = 170.3 170.0, 136.3, 132.9, 128.5,
127.9, 126.7, 126.5, 76.4, 74.8, 47.9, 32.9, 27.1, 21.9, 21.2,
21.1 ppm.
(–)-syn,syn-1: [α]2D0 = –5.47 (c = 0.50, CHCl3); ee Ͼ 99%, deter-
mined by GC analysis of the corresponding acetonide on a chiral
column. NMR spectra are in agreement with those of the racemic
sample.
22.1, 21.7, 19.0 ppm. GC/MS: tR = 12.57 min; m/z (%) = 184 (1)
[M]+, 169 (22), 155 (45), 97 (38), 79 (34), 59 (100). Optically active
(–)-syn,syn-9 was prepared from the acetonide of (–)-syn,syn-1:
[α]2D0 = –38.5 (c = 0.94, CHCl3).
1
syn,anti-9: H NMR (400 MHz, CDCl3): δ = 9.71 (s, 1 H, CHO),
4.26 (dt, J = 2.5, 6.5 Hz, 1 H, CH2CH–O), 3.87 (d, J = 9.9 Hz, 1
H, CHCH–O), 2.27 (m, 1 H, CH of cyclopentane ring), 1.44–1.89
(m, 6 H, hydrogen atoms of cyclopentane ring), 1.42 (s, 3 H, CH3),
1.36 (s, 3 H, CH3) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
201.0, 99.9, 77.0, 72.2, 42.0, 33.4, 28.6, 25.7, 23.9, 23.5 ppm. GC/
MS: tR = 11.69 min; m/z (%) = 184 (1) [M]+, 169 (19), 155 (42), 97
(37), 79 (31), 59 (100).
1
anti,anti-9: H NMR (400 MHz, CDCl3): δ = 9.58 (d, J = 1.1 Hz,
The mixture of diols syn,anti-, anti,syn-, and anti,anti-1 provided,
under the above conditions, the following products in order of elu-
tion: anti,syn-7 (0.40 g, 11%), anti,anti-7 (0.55 g, 15%), syn,anti-
7 (0.22 g, 6%), and a mixture of unreacted starting diols (0.67 g,
22%).
(–)-anti,syn-7: [α]2D0 = –1.76 (c = 0.90, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.18–7.39 (m, 5 H, aromatic hydrogen atoms), 6.61 (d,
J = 16.1 Hz, 1 H, CH=), 6.20 (dd, J = 6.4, 16.1 Hz, 1 H,
C=CHCHOH), 5.05 (m, 1 H, CH2CHOAc), 4.34 (m, 1 H,
C=CHCHOH), 2.21 (m, 1 H, CH of the cyclopentane ring), 1.99
(s, 3 H, OAc), 1.48–1.95 (m, 6 H, hydrogen atoms of the cyclopen-
tane ring) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 171.5, 136.8,
130.8, 130.3, 128.5, 127.5, 126.4, 77.8, 73.0, 51.9, 32.6, 25.9, 23.1,
21.2 ppm.
(+)-anti,anti-7: [α]2D0 = +6.06 (c = 1.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.13–7.37 (m, 5 H, aromatic hydrogen atoms), 6.56
(d, J = 16.0 Hz, 1 H, CH=C), 6.17 (dd, J = 7.1, 15.7 Hz, 1 H,
C=CHCHOH), 5.14 (m, 1 H, CH2CHOAc), 4.09 (m, 1 H,
C=CHCHOH), 2.14 (m, 1 H, CH of the cyclopentane ring), 1.94
(s, 3 H, OAc), 1.50–1.88 (m, 6 H, hydrogen atoms of the cyclopen-
tane ring) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 171.1, 136.5,
130.4, 130.3, 128.0, 126.9, 125.9, 78.1, 73.8, 51.9, 32.4, 27.4, 23.3,
20.7 ppm.
1 H, CHO), 4.09 (dd, J = 1.1, 10.5 Hz, 1 H, CHCH–O), 3.63 (dt,
J = 6.8, 10.3 Hz, 1 H, CH2CH–O), 1.41–2.01 (m, 7 H, hydrogen
atoms of cyclopentane ring), 1.52 (s, 3 H, CH3), 1.50 (s, 3 H, CH3)
ppm. 13C NMR (100.61 MHz, CDCl3): δ = 200.6, 100.3, 80.8, 75.2,
42.5, 29.6, 28.4, 22.0, 20.0, 18.4 ppm. GC/MS: tR = 12.51 min; m/z
(%) = 183 (1) [M – 1]+, 169 (33), 155 (53), 97 (86), 79 (44), 59 (100).
Conversion of syn,anti-Aldehyde 9 into Deoxyhexose Derivatives 2
(RS)-1-[(4RS,4aRS,7aSR)-2,2-Dimethylhexahydrocyclopenta[d](1,3)-
dioxin-4-yl]prop-2-en-1-ol (syn,anti,syn-10): To the Grignard rea-
gent prepared in THF (150 mL) under nitrogen from Mg turnings
(2.3 g, 100 mmol) and vinyl bromide (22 g, 20 mmol) was added at
0 °C syn,anti-9 (2.0 g, 11.6 mmol) in THF (50 mL). After one night
at room temperature, a saturated solution of ammonium chloride
was added with caution at 0 °C. Dilution with iced H2O and sol-
vent extraction provided, after chromatographic purification, syn,-
anti,syn-10 (2.0 g, 78%). 1H NMR (400 MHz, CDCl3): δ = 5.86
(ddd, J = 6.3, 10.5, 17.1 Hz, CH=), 5.37 (m, 1 H,C=CHH), 5.21
(m, 1 H, C=CHH), 4.21 (dt, J = 2.5, 6.0 Hz, 1 H, CH2CHO), 3.99
(m, 1 H, CHOH), 3.33 (dd, J = 5.4, 9.5 Hz, 1 H, CHCHO), 2.17
(m, 1 H, CH of the cyclopentane ring), 1.33–1.88 (m, 6 H, hydrogen
atoms of the cyclopentane ring), 1.37 (s, 3 H, CH3), 1.32 (s, 3 H,
CH3) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 133.6, 116.8, 99.9,
75.9, 74.9, 72.7, 43.6, 33.3, 29.7, 25.0, 24.4, 24.1 ppm. GC/MS: tR
= 15.39 min; m/z (%) = 197 (20) [M –15]+, 155 (34), 97 (38), 59
(100).
(+)-syn,anti-7: [α]2D0
=
+29.3 (c = 0.69, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 7.19–7.41 (m, 5 H, aromatic hydrogen
atoms), 6.64 (d, J = 15.9 Hz, 1 H, CH=), 6.21 (dd, J = 6.6, 15.9 Hz,
1 H, C=CHCHOH), 5.39 (m, 1 H, CH2CHOAc), 4.07 (m, 1 H,
C=CHCHOH), 2.11 (s, 3 H, OAc), 1.40–1.97 (m, 7 H, hydrogen
atoms of the cyclopentane ring) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 171.7, 136.8, 130.7, 130.3, 128.3, 127.3, 126.3, 77.1,
71.8, 51.9, 32.2, 25.9, 21.7, 21.0 ppm.
(2RS,3SR,4RS,4aRS,7aSR)-Octahydrocyclopenta[b]pyran-2,3,4-
triyl Triacetate (11): Compound syn,anti,syn-10 (1.8g, 9.0 mmol),
dissolved in methanol/H2O (8:2, 20 mL), was treated in a H2O bath
with 4 drops of concentrated HCl. After 3 h, the hydrolysis was
complete. Most of the methanol was evaporated under vacuum,
and the residue was neutralised upon addition of NaHCO3 solu-
tion. Five extractions of the salted solution with ethyl acetate pro-
vided, after concentration and chromatography of the residue
through a short path of SiO2 of the residue using ethyl acetate as
eluent, a triol derivative (1.2 g, 77%). This material was dissolved
in CH2Cl2 (15 mL) and ozonised, as described above. The addition
of 1 mol-equiv. of triphenylphosphane and concentration of the re-
action mixture provided a semi-solid residue. This was treated with
Ac2O (10 mL) and pyridine (10 mL) overnight, providing, after
evaporation of the reagents under vacuum, an oil, which was chro-
matographed on SiO2 eluting with 35% ethyl acetate in hexane to
yield a triacetyl derivative (0.9 g, 67%) as a 6:4 mixture of β and α
2,2-Dimethylhexahydrocyclopenta[d][1,3]dioxine-4-carbaldehyde (syn,
syn-, syn,anti-, and anti,anti-9): Ozonised oxygen was passed
through a solution of acetonide 5 (2.6 g, 10 mmol) in CH2Cl2
(30 mL) at –78 °C until the appearance of a blue colour. A solution
of triphenylphosphane (2.6 g, 10 mmol) in CH2Cl2 (15 mL) was
then added dropwise at the same temperature. After standing at
room temp. for 1 h, the reaction mixture was concentrated to dry-
ness, and the oily residue was treated with a small amount of di-
ethyl ether. The phosphane oxide, which precipitated upon scratch-
ing the side of the flask, was removed by filtration. The liquid phase
was concentrated, and the residue was chromatographed on SiO2
eluting with ethyl acetate in hexane, yielding benzaldehyde and al-
dehyde 9 (1.1 g, 60%).
1
anomers. H NMR (400 MHz, CDCl3): δ = 6.25 (d, J = 3.5 Hz, 1
H, H-2 of the α anomer), 5.58 (d, J = 7.9 Hz, 1 H, H-2 of the β
1
syn,syn-9: H NMR (400 MHz, CDCl3): δ = 9.59 (s, 1 H, CHO), anomer), 5.49 (dd, J = 6.0, 10.5 Hz, 1 H, H-3 or H-4 of the α
4.52 (d, J = 3.4 Hz, 1 H, CHCH–O), 4.35 (q, J = 2.5 Hz, 1 H, anomer), 5.16–5.27 (m, 3 H, H-3 and H-4 of the β anomer + H-4
CH2CH–O), 1.52–2.05 (m, 7 H, hydrogen atoms of cyclopentane or H-3 of the α anomer), 4.40 (t, J = 4.1 Hz, 1 H, H-7a of the α
ring), 1.48 (s, 3 H, CH3), 1.46 (s, 3 H, CH3) ppm. 13C NMR anomer), 4.18 (t, J = 3.5 Hz, 1 H, H-7a of the β anomer), 2.55 (m,
(100.61 MHz, CDCl3): δ = 202.0, 98.4, 74.3, 73.3, 39.1, 32.4, 29.6, 1 H, CH of the cyclopentane ring α anomer), 2.44 (m, 1 H, CH of
Eur. J. Org. Chem. 2008, 5125–5134
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5131

D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, L. Malpezzi, S. Serra
FULL PAPER
the cyclopentane ring β anomer), 2.02, 2.05, 2.14 (3 s, 9 H, 3 OAc
of the α anomer), 2.03, 2.04, 2.09 (3 s, 9 H, 3 OAc of the β anomer),
1.55–1.96 (m, 12 H, hydrogen atoms of the cyclopentane ring of
both anomers) ppm. 13C NMR (100.61 MHz, CDCl3): β anomer:
δ = 170.3, 169.7, 169.2, 92.2, 78.1, 72.6, 68.7, 44.4, 31.8, 23.8, 21.4,
20.8, 20.7 ppm; α anomer: δ = 170.5, 170.1, 169.3, 90.8, 75.4, 68.9,
67.0, 44.1, 32.0, 23.6, 21.8, 20.6, 20.5 ppm. GC/MS: tR = 22.57,
22.63 min; m/z (%) = 241 (1) [M – 59]+, 198 (18), 156 (15), 110
(100).
13C NMR (100.61 MHz, CDCl3): δ = 138.8, 128.7, 127.5, 126.3,
80.7, 75.9, 72.7, 69.8, 45.6, 28.4, 24.2, 18.7 ppm.
1
16: H NMR (400 MHz, CDCl3): δ = 7.47–7.20 (m, 5 H, aromatic
hydrogen atoms), 4.98 (d, J = 4.3 Hz, 1 H, PhCHOH), 4.02 (q, J
= 7.4 Hz, 1 H, cyclopentane-CHOH), 3.70 (m, 1 H, CHOH), 3.60
(m, 1 H, CHOH), 2.00–1.00 (m, 7 H, hydrogen atoms of the cyclo-
pentane ring) ppm.
The structures of compounds 12a,b and 13a,b were confirmed by
observing the downfield shift only of protons H-3 and H-4 of the
sugar ring upon acetylation with Ac2O in pyridine. The structure
of compound 16 was confirmed by observing the downfield shift
of all four protons linked to oxygen atoms upon acetylation with
Ac2O in pyridine.
(2RS,3SR,4SR,4aRS,7aSR)-2-Phenyloctahydrocyclopenta[b]pyran-
3,4-diol (12a), (2RS,3SR,4RS,4aRS,7aSR)-2-Phenyloctahydrocyclo-
penta[b]pyran-3,4-diol (13a), (2SR,3RS,4SR,4aRS,7aSR)-2-Phenyl-
octahydrocyclopenta[b]pyran-3,4-diol (12b), (2SR,3RS,4RS,
4aRS,7aSR)-2-Phenyloctahydrocyclopenta[b]pyran-3,4-diol (13b),
and (1RS,2SR)-1-[(1RS,2RS)-2-Hydroxycyclopentyl]-3-phenylpro-
pane-1,2,3-triol (16): A mixture of racemic anti,anti- and anti,syn-
1 (4.36 g, 0.02 mol) was treated with m-chloroperbenzoic acid
(4.31 g, 0.025 mol) in CH2Cl2 (100 mL) at 0 °C. After 2 h at room
temperature, the reaction mixture was poured into H2O, washed
with a 10% solution of sodium bisulfite and a saturated solution
of NaHCO3, and extracted with CH2Cl2. The organic phase was
dried (Na2SO4) and concentrated under reduced pressure to give a
residue, which was chromatographed with increasing amounts of
ethyl acetate in hexane, to afford compound 12a (0.70 g, 12%) and
a 1:1:0.5 mixture of compounds 13a, 14, and 15 (2.01 g). 1H NMR
signals of epoxide rings: 14: δ = 3.97 (d, J = 1.9 Hz), 3.09 (dd, J =
1.9, 3.1 Hz) ppm; 15: δ = 3.83 (d, J = 1.9 Hz), 3.02 (dd, J = 1.9,
5.4 Hz) ppm.
(2RS,3SR,4SR,4aRS,7aSR)-2-Phenyloctahydrocyclopenta[b]pyran-
3,4-diol Acetonide (19): Compound 12a was converted into the cor-
responding acetonide according to the procedure already described
1
for the preparation of acetonides 5. H NMR (400 MHz, CDCl3):
δ = 7.45–7.27 (m, 5 H, aromatic hydrogen atoms), 4.49 (dd, J =
3.5, 4.5 Hz, 1 H, H-4), 4.44 (d, J = 8.7 Hz, 1 H, H-2), 3.97 (dd, J
= 4.5, 8.4 Hz, 1 H, H-3), 3.80 (dt, J = 7.1, 10.6 Hz, 1 H, H-7a),
2.06–1.55 and 1.65 (m + s, 10 H, 7 hydrogen atoms of the cyclopen-
tane ring + CH3), 1.40 (s, 3 H, CH3) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 140.8, 128.3, 127.6, 126.6, 110.3, 81.4, 78.1, 77.5, 74.4,
44.8, 28.4, 28.2, 26.4, 21.8, 19.6 ppm.
(2RS,3SR,4RS,4aRS,7aSR)-2-Phenyloctahydrocyclopenta[b]pyran-
3,4-diol Acetonide (20): Compound 13a was converted into its cor-
responding acetonide according to the procedure already described
1
for the preparation of acetonides 5. H NMR (400 MHz, CDCl3):
This latter mixture was dissolved in THF/H2O and treated with
CH3COOH (1 mL) and a few drops of HClO4. After 30 min, the
reaction mixture was diluted with H2O and extracted with diethyl
ether. The organic phase was washed with a saturated NaHCO3
solution, dried (Na2SO4) and concentrated under reduced pressure.
The residue was chromatographed, eluting with increasing amounts
of ethyl acetate in hexane. In order of elution, the following prod-
ucts were obtained: 13a (0.76 g, 13 %), 12b (0.35 g, 6 %), 13b
(0.29 g, 5%), and 16 (0.50 g, 8%).
δ = 7.55–7.23 (m, 5 H, aromatic hydrogen atoms), 4.52 (d, J =
9.2 Hz, 1 H, H-2), 3.54 (dd, J = 8.3, 10.2 Hz, 1 H, H-3 or H-4),
3.47–3.38 (t + dt, t J = 9.2 Hz, dt J = 7.3, 9.5 Hz, 2 H, H-4 or H-
3 + H-7a), 3.38 (t, J = 9.0 Hz, 1 H, H-4 or H-3), 2.20–1.50 (m, 7
H, hydrogen atoms of the cyclopentane ring), 1.46 (s, 3 H, CH3),
1.40 (s, 3 H, CH3) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
138.4, 128.4, 128.2, 126.7, 110.1, 83.7, 83.0, 81.4, 80.9, 48.7, 27.6,
26.8, 26.6, 24.1, 20.2 ppm.
(4RS,5RS,5aSR,8aRS)-4-Benzyl-2,2-dimethylhexahydro-4H-cyclo-
penta[d][1,3]dioxepin-5-ol (21): Tetraol 16 (0.30 g, 1.19 mmol) in
ethyl acetate (20 mL) was hydrogenated at 80 psi in the presence of
10% Pd/C (30 mg) at room temp. for 24 h. The reaction mixture
was filtered through a short column of SiO2, containing an upper
layer of Celite, obtaining, upon concentration of the organic phase,
a crude reaction product, which was treated with 2,2-dimeth-
oxypropane. Column chromatography (hexane/ethyl acetate, 7:3)
afforded derivative 21 (0.18 g, 55%). 1H NMR (400 MHz, CDCl3):
δ = 7.35–7.10 (m, 5 H, aromatic hydrogen atoms), 3.97 (m, 2 H, 2
CHO), 3.60 (dd, J = 1.14, 10.3 Hz, 1 H, CHOH), 2.91 (dd, J = 8.6,
13.4 Hz, 1 H, PhCHH), 2.83 (dd, J = 6.3, 13.4 Hz, 1 H, PhCHH),
2.18 (d, J = 10.3 Hz, 1 H, OH), 1.91–1.31 (m, 7 H, hydrogen atoms
of the cyclopentane ring), 1.51 (s, 3 H, CH3), 1.31 (s, 3 H, CH3)
ppm. 13C NMR (100.61 MHz, CDCl3): δ = 138.9, 129.7, 128.2,
126.2, 101.4, 74.8, 71.5, 68.8, 52.4, 39.3, 30.4, 25.0, 24.4, 22.6,
19.9 ppm.
12a: 1H NMR (400 MHz, CDCl3): δ = 7.45–7.27 (m, 5 H, aromatic
hydrogen atoms), 4.51 (d, J = 9.5 Hz, 1 H, H-2), 4.22 (m, 1 H, H-
4), 3.94 (dt, J = 7.3, 10.4 Hz, 1 H, H-7a), 3.59 (dd, J = 3.1, 9.5 Hz,
1 H, H-3), 2.00–1.50 (m, 7 H, hydrogen atoms of the cyclopentane
ring) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 139.4, 128.6,
128.4, 127.7, 79.3, 76.6, 73.9, 68.5, 47.9, 28.2, 21.1, 19.8 ppm.
13a: 1H NMR (400 MHz, CDCl3): δ = 7.45–7.27 (m, 5 H, aromatic
hydrogen atoms), 4.19 (d, J = 9.3 Hz, 1 H, H-2), 3.51 (dd, J = 8.3,
10.0 Hz, 1 H, H-3 or H-4), 3.48 (dt, J = 7.1, 10.3 Hz, 1 H, H-7a),
3.38 (t, J = 9.0 Hz, 1 H, H-4 or H-3), 2.00–1.20 (m, 7 H, hydrogen
atoms of the cyclopentane ring) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 138.7, 128.7, 128.5, 127.7, 83.9, 82.5, 78.0, 77.5, 49.5,
28.4, 24.3, 20.1 ppm.
12b: 1H NMR (400 MHz, CDCl3): δ = 7.50–7.25 (m, 5 H, aromatic
hydrogen atoms), 4.15 (t, J = 3.2 Hz, 1 H, H-7a), 4.06 (dd, J = 6.4,
9.3 Hz, 1 H, H-4), 4.02 (t, J = 9.3 Hz, 1 H, H-2), 3.61 (t, J =
9.3 Hz, 1 H, H-3), 2.40–1.20 (m, 7 H, hydrogen atoms of the cyclo-
pentane ring) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 138.8,
128.6, 128.3, 127.3, 81.6, 80.8, 73.7, 73.6, 47.0, 29.6, 23.4,
22.1 ppm.
Configuration Assignment of Optically Active Monoacetates anti,
anti- and anti,syn-7
(1R,2R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)cyclopentyl Acetate (22):
Ozonised oxygen was passed through a solution of a 1:1 mixture
of optically active anti,anti- and anti,syn-7 at –78 °C, produced in
the enzymatic incubation of a 1:1 mixture of diols 1 with PS (5.2 g,
20 mmol) in MeOH/CH2Cl2 (1:1, 80 mL). At the end of the reac-
tion, solid sodium borohydride was added in small portions under
13b: 1H NMR (400 MHz, CDCl3): δ = 7.50–7.25 (m, 5 H, aromatic
hydrogen atoms), 5.24 (br. s, H-2), 4.51 (br. s, 1 H, H-3), 3.61 (br.
d, J = 9.0 Hz, 1 H, H-4), 3.23 (dt, J = 7.4, 10.3 Hz, 1 H, H-7a),
2.50–1.00 (m, 7 H, hydrogen atoms of the cyclopentane ring) ppm.
5132
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Eur. J. Org. Chem. 2008, 5125–5134

- and -4,6-Dideoxyhexoses and 4,6-Dideoxy-C-phenylglycosides
nitrogen at the same temperature over 1 h until the decomposition
(1R,2S)-2-(Hydroxymethyl)cyclopentanol [(R,S)-(–)-26]: The O-ben-
of the ozonide was complete (TLC). The reaction mixture was zyl ether 25 (0.75 g, 3.6 mmol), dissolved in ethyl acetate (20 mL),
brought to room temperature, diluted with cold H2O and extracted
with CH2Cl2. The washed and dried organic phase was treated with
2,2-dimethoxypropane (30 mL), acetone (20 mL) and a few crystals
of pyridinium 4-toluenesulfonate and kept at a gentle reflux for
3 h. The cooled mixture was washed with a saturated solution of
NaHCO3, dried, and the solvents were evaporated to dryness to
leave a residue (ca. 5 g), which was purified by column chromatog-
raphy with increasing amounts of ethyl acetate in hexane, to give
compound 22 as a 1:1 mixture of two diastereomers (2.65 g, 58%).
was hydrogenated at 50 psi in the presence of 10% Pd/C (200 mg)
at room temp. for 24 h. The reaction mixture was filtered through
a short column of SiO2 containing an upper layer of Celite, provid-
ing, upon concentration of the organic phase, diol (–)-26 (0.35 g,
83%). [α]2D0 = –13.9 (c = 1.0, CHCl3) {ref.[25a] (1R,2S)-(–)-26: [α]2D0
= –22.7 (c = 0.75, CHCl3); ref.[25b] [α]2D0 = –13.7 (c = 1.0, CHCl3);
ref.[25c] (1S,2R)-(+)-26: [α]2D0 = +13.4 (c = 1.0, CHCl3); ref.[25d]
1
[α]2D0 = +38.7 (c = 1.0, MeOH)}. H NMR (400 MHz, CDCl3): δ
= 4.0 (q, J = 6.1 Hz, 1 H, CHOH), 3.67 (dd, J = 5.5, 10.6 Hz, 1
1H NMR (400 MHz, CDCl3): δ = 5.12 (m, 1 H, CHOAc of one H, CHHOH), 3.50 (dd, J = 8.7, 10.6 Hz, 1 H, CHHOH), 1.13–
diastereomer), 4.90 (m, 1 H, CHOAc of the other diastereomer), 2.05 (m, 7 H, CH2CH2CH2CH) ppm. 13C NMR (100.61 MHz,
4.10 (m, 1 H, CH–O), 3.99 (m, 3 H, CH–O), 3.63 (m, 2 H, CH– CDCl3): δ = 77.2, 65.6, 49.7, 34.4, 26.4, 21.8 ppm.
O), 1.47–2.15 (m + 2 s at δ = 2.01 and 2.00 ppm, 26 H, 14 hydrogen
atoms of cyclopentane ring and 2 OAc of both diastereomers),
1.49, 1.39, 1.33, and 1.32 (4 s, 12 H, 4 OCH3) ppm. 13C NMR
[1]
[2]
[3]
P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40–49.
a) S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021–2040; b) L.
Yet, Chem. Rev. 2003, 103, 4283–4306.
(100.61 MHz, CDCl3): δ = 170.6, 170.4, 108.9, 108.6, 78.4, 77.8,
77.2, 67.9, 67.6, 62.9, 48.2, 47.9, 32.7, 32.6, 27.1, 26.6, 26.2, 26.5,
25.4, 24.5, 23.1, 21.2, 21.1 ppm. GC/MS: tR = 16.66 min; m/z (%)
= 213 (59) [M – 15]+, 170 (1), 153 (15), 111 (100).
a) B. Schetter, R. Mahrwald, Angew. Chem. Int. Ed. 2006, 45,
7506–7525; b) K. C. Nicolaou, A. L. Nold, R. R. Milburn,
C. S. Chindler, Angew. Chem. Int. Ed. 2006, 45, 6527–6532; c)
M. J. Mitton-Fry, A. J. Cullen, T. Sammakia, Angew. Chem.
Int. Ed. 2007, 46, 1066–1070; d) C. Schenider, Angew. Chem.
Int. Ed. 1998, 37, 1375–1378; e) W. H. Hoffmann, Angew.
Chem. Int. Ed. 2003, 42, 1096–1109; f) J. T. Binder, S. F. Kirsch,
Chem. Commun. 2007, 4164–4166; g) J. D. Umarye, T. Leßm-
ann, A. B. Garcia, V. Mamane, S. Sommer, H. Waldmann,
Chem. Eur. J. 2007, 13, 3305–3319; h) S. Tosaki, Y. Horiuchi,
T. Nemoto, T. Ohshima, M. Shibasaki, Chem. Eur. J. 2004, 10,
1527–1544, and references cited herein.
4-[(1R,2R)-2-(Benzyloxy)cyclopentyl]-2,2-dimethyl-1,3-dioxolane
(23) and 1-[(1S,2R)-2-(Benzyloxy)cyclopentyl]ethane-1,2-diol (24):
Compound 22 (2.28 g, 10 mmol) in MeOH (20 mL) was treated in
an H2O bath with aqueous KOH (25%, 2 mL) for 2 h. The mixture
was diluted with iced H2O, brought to pH = 7 with dilute acetic
acid, and extracted twice with Et2O. The crude oily residue ob-
tained upon concentration of the solution was dissolved in dry
THF (50 mL) and treated whilst stirring under nitrogen at room
temp. with NaH (60% suspension in oil, 0.48 g, 12 mmol). After
6 h, a solution of benzyl bromide (2.65 g, 15 mmol) in THF
(10 mL) was added dropwise. After 24 h of stirring, the reaction
mixture was diluted with a few drops of MeOH and then with iced
H2O. The oily residue obtained upon concentration of the ethereal
extract of the latter reaction mixture was chromatographed to pro-
vide the O-benzyl ether 23 (1.9 g, 68%). Compound 23 (1.7 g,
6.15 mmol), dissolved in THF/MeOH (2:1, 30 mL), was treated in
an H2O bath for 1 h with acetic acid (1 mL) and 3 drops of concen-
trated HCl. The reaction mixture was concentrated to dryness, and
the residue was chromatographed on SiO2 eluting with ethyl acetate
[4]
[5]
[6]
Y. Kishi, Tetrahedron 2002, 58, 6239–6258.
S. E. Bode, M. Wolberg, M. Müller, Synthesis 2006, 557–588.
a) K. Narasaka, F. C. Pai, Tetrahedron 1984, 40, 2233–2238; b)
F. G. Kathawala, B. Prager, K. Prasad, O. Repic, M. S. Shapiro,
R. S. Stabler, L. Widler, Helv. Chim. Acta 1986, 69, 803–805;
c) Y. Umekawa, S. Sakaguchi, Y. Nishiyama, Y. Ishii, J. Org.
Chem. 1997, 62, 3407–3408; d) A. H. Hoveyda, D. A. Evans, J.
Am. Chem. Soc. 1990, 112, 6447–6449; e) S. Anwar, A. P. Davis,
Tetrahedron 1988, 44, 3761–3770.
a) J. Mlynarski, Eur. J. Org. Chem. 2006, 4779–4786; b) P. M.
Bodnar, J. T. Shaw, K. A. Woerpel, J. Org. Chem. 1997, 62,
5674–5675; c) Y. Umekawa, S. Sakaguchi, Y. Nishiyama, Y.
Ishii, J. Org. Chem. 1997, 62, 3409–3412.
a) D. Kalaitzakis, J. D. Rozzell, I. Smonou, S. Kambourakisb,
Adv. Synth. Catal. 2006, 348, 1958–1969; b) G. Bartoli, M.
Bosco, M. C. Bellocci, R. Dal pozzo, E. Marcantoni, L. Sam-
bri, Org. Lett. 2000, 2, 45–47; c) A. S. C. Chan, Tetrahedron:
Asymmetry 1997, 8, 4041–4045; d) H. Brunner, A. Terfort, Tet-
rahedron: Asymmetry 1995, 6, 919–922; e) Ikeda, E. Sato, T.
Sugai, H. Ohta, Tetrahedron 1996, 52, 8113–8122; f) M. Take-
shita, M. Miura, Y. Unuma, J. Chem. Soc. Perkin Trans. 1 1993,
2901–2905; g) R. Chenevert, S. Thiboutot, Can. J. Chem. 1986,
64, 1599–1601; h) C. Bonini, G. Righi, L. Rossi, Tetrahedron
1992, 48, 9801–9803; i) J. Barluenga, J. Resa, B. Olano, J. Org.
Chem. 1987, 52, 1425–1428; j) F. Yamada, T. Horie, M. Kawai,
H. Yamamura, S. Araki, Tetrahedron 1997, 53, 15685–15690.
a) J. S. Yadav, P. P. Rao, M. S. Reddy, N. V. Rao, A. R. Prasad,
Tetrahedron Lett. 2007, 48, 1469–1471; b) J. S. Yadav, M. S.
Reddy, P. P. Rao, A. R. Prasad, Tetrahedron Lett. 2006, 47,
4397–4401; c) J. S. Yadav, M. S. Reddy, A. R. Prasad, Tetrahe-
dron Lett. 2006, 47, 4937–4941.
[7]
[8]
1
diol 24 (1.12 g, 77%). H NMR (400 MHz, CDCl3): δ = 4.62–4.41
(m, 4 H, CH2OPh of both diastereomers), 4.01 (m, 1 H, CH–O),
3.83 (m, 1 H, CH–O), 3.73–3.48 (m, 6 H, CH–O and CH2OH of
both diastereomers), 1.48–2.00 (m, 14 H, hydrogen atoms of cyclo-
pentane ring of both diastereomers) ppm.
[(1S,2R)-2-(Benzyloxy)cyclopentyl]methanol (25): Compound 24
(1.12 g, 4.7 mmol), dissolved in THF (10 mL), was added at once
at room temp. to a stirred mixture of THF (80 mL) and periodic
acid (1.25 g, 5.5 mmol). After 5 min, a few drops of ethylene glycol
(0.2 mL) were added to the cloudy reaction mixture. After cooling
to –10 °C and dilution with MeOH (20 mL), sodium borohydride
was then added in small portions until the reduction of the interme-
diate aldehyde (TLC) was complete. The mixture was poured with
caution into iced H2O and extracted twice with Et2O. Concentra-
tion of the washed and dried organic extract yielded 25 (0.82 g,
81%). [α]2D0 = –48.8 (c = 0.95, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.21–7.35 (m, 5 H, Ar), 4.54 (d, J = 11.9 Hz, 1 H,
CHHAr), 4.45 (d, J = 11.6 Hz, 1 H, CHHAr), 3.72–3.78 (q, J =
5.4 Hz, 2 H, CHO), 3.54 (m, 2 H, CH2OH), 1.16–1.21 (m, 7 H,
CH2CH2CH2CH) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
138.6, 128.2, 127.5, 127.4, 83.8, 71.1, 65.5, 47.7, 31.4, 26.5,
22.3 ppm.
[9]
[10]
a) S. D. Rychnovsky, N. A. Powell, J. Org. Chem. 1997, 62,
6460–6461; b) M. Obringer, F. Colobert, B. Neugnot, G. Solla-
die, Org. Lett. 2003, 5, 629–633; c) S. BouzBouz, J. Cossy, Org.
Lett. 2000, 2, 501–504; d) M. J. Zacuto, S. J. O’Malley, J. L.
Leighton, Tetrahedron 2003, 59, 8889–8890; e) T. J. Hunter, G.
Eur. J. Org. Chem. 2008, 5125–5134
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5133

D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, L. Malpezzi, S. Serra
FULL PAPER
O’Doherty, Org. Lett. 2001, 3, 1049–1052; f) S. T. Sarraf, J. L. [21]
Leighton, Org. Lett. 2000, 2, 403–405.
J. Barluenga, M. Alvarez-Pérez, K. Wuerth, F. Rodriguez, F. J.
Fañanas, Org. Lett. 2003, 5, 905–908.
[11] A. Abate, E. Brenna, A. Costantini, C. Fuganti, F. G. Gatti,
L. Malpezzi, S. Serra, J. Org. Chem. 2006, 71, 5228–5240.
[12] a) T. Bililign, B. R. Griffith, J. S. Thorson, Nat. Prod. Rep.
2005, 22, 742–760; b) S. C. Timmons, D. L. Jakeman, Car-
bohydr. Res. 2007, 342, 2695–2704; c) M. R. Hansen, L. H.
Hurley, Acc. Chem. Res. 1996, 29, 249–258.
[13] a) A. Kirschning, M. Jesberger, K. U. Schoning, Synthesis
2001, 507–540; b) D. Y. W. Lee, M. He, Curr. Top. Med. Chem.
2005, 5, 1333–1350.
[22]
As for the optically active series, aldehyde (–)-syn,syn-9 was
prepared from the acetonide of (–)-syn,syn-1.
W. C. Still, J. H. McDonald, Tetrahedron Lett. 1980, 21, 1031–
1034.
[23]
[24] CCDC-679034contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[25] For (1R,2S)-(–)-26: a) S. Harada, N. Kowase, N. Tabuchi, T.
Taguchi, Y. Dobashi, A. Dobashi, Y. Hanzawa, Tetrahedron
1998, 54, 753–766; b) C. Fang, T. Ogawa, H. Suemune, K.
Sakai, Tetrahedron: Asymmetry 1991, 2, 389–398; for (1S,2R)-
(+)-26: c) J. Weidner, F. Theil, H. Schick, Tetrahedron: Asym-
metry 1994, 5, 751–754; d) K. Inoguchi, N. Fujie, K. Yoshi-
kawa, K. Achiwa, Chem. Pharm. Bull. 1992, 40, 2921–2926.
[26] For syn 1,3-diols: K.-H. Chen, G. E. Hardtmann, K. Prasad,
O. Repic, M. J. Shapiro, Tetrahedron Lett. 1987, 28, 155–158;
D. A. Evans, A. H. Hoveyda, J. Org. Chem. 1990, 55, 5190–
5192; H. Hamashita, K. Narasaka, Chem. Lett. 1996, 39, 540;
G. Bartoli, M. Bosco, E. Marcantoni, M. Massaccesi, S. Rin-
aldi, L. Sambri, Eur. J. Org. Chem. 2001, 4679–4684; for anti
1,3-diols: D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am.
Chem. Soc. 1988, 110, 3560–3578; S. Anwar, A. P. Davis, Tetra-
hedron 1988, 44, 3761–3770.
[14] A. Bernardi, D. Arosio, L. Manzoni, D. Monti, H. Posteri, D.
Potenza, S. Mari, J. Jimenez-Barbero, Org. Biomol. Chem.
2003, 1, 785–792.
[15] C.-L. Schengrund, N. J. Ringler, J. Biol. Chem. 1989, 264,
13233–13237.
[16] a) T. K. Sixma, S. E. Pronk, K. H. Kalk, B. A. M. van Zanten,
A. M. Berghius, W. G. Hol, Nature 1992, 355, 561–564; b)
W. E. Minke, F. Hong, C. L. M. J. Verlinde, W. G. J. Hol, E.
Fan, J. Biol. Chem. 1999, 274, 33469–33473.
[17] D. D. Mitchell, J. C. Pickens, J. Korotkov, E. Fan, W. G. J. Hol,
Bioorg. Med. Chem. 2004, 12, 907–920.
[18] H. M. Branderhost, R. M. J. Liskamp, G. M. Visser, R. J. Piet-
ers, Chem. Commun. 2007, 5043–5045.
[19] a) S. Sankararaman, R. Sudha, J. Org. Chem. 1999, 64, 2155–
2157; b) M. Nakajiama, T. Yokota, M. Saito, S. Hashimoto,
Tetrahedron Lett. 2004, 45, 61–64.
[20] a) J. C. Moore, D. J. Pollard, B. Kosjek, P. N. Devine, Acc.
Chem. Res. 2007, 40, 1412–1419; b) S. Servi, Synthesis 1990, 1.
Received: July 3, 2008
Published Online: September 16, 2008
5134
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Eur. J. Org. Chem. 2008, 5125–5134