Facile separation of chiral 1,3-dihydrobenzo[c]furan derivatives using a D-xylose moiety as a protecting group

Article abstract of DOI:10.1016/S0957-4166(00)00488-2

1,2-O-Isopropylidene-α-D-xylofuranose has been used to protect one aldehyde group of o-phthalaldehyde. This chiral protecting group acts as a resolving agent and this leads to separable diastereoisomers when a new stereogenic centre is created by the conversion of the second aldehyde group to a benzyloxyhydroxyethyl chain. These separated diastereoisomers were cyclised to 1,3-dihydrobenzo[c]furans with retention of chiral integrity at the C3 site thus allowing further elaboration to enantiomerically pure nucleoside analogues.

Full text of DOI:10.1016/S0957-4166(00)00488-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4995–5002
Facile separation of chiral 1,3-dihydrobenzo[c]furan
derivatives using a -xylose moiety as a protecting group
D
David F. Ewing,a Christophe Len,b,* Grahame Mackenzie,a Gino Roncob and Pierre Villab
aDepartment of Chemistry, University of Hull, Hull HU6 7RX, UK
bLaboratoire des Glucides, Universite´ de Picardie, F-80039 Amiens, France
Received 24 November 2000; accepted 4 December 2000
Abstract
1,2-O-Isopropylidene-a-D-xylofuranose has been used to protect one aldehyde group of o-phthalalde-
hyde. This chiral protecting group acts as a resolving agent and this leads to separable diastereoisomers
when a new stereogenic centre is created by the conversion of the second aldehyde group to a
benzyloxyhydroxyethyl chain. These separated diastereoisomers were cyclised to 1,3-dihydroben-
zo[c]furans with retention of chiral integrity at the C3 site thus allowing further elaboration to
enantiomerically pure nucleoside analogues. © 2001 Published by Elsevier Science Ltd.
1. Introduction
Nucleoside analogues are among the most effective of an increasing number of anti-HIV
drugs which have been developed for clinical use and 2%,3%-deoxynucleosides and 2%,3%-didehydro-
2%,3%-dideoxynucleosides such as AZT, ddC, ddA, d4T, with the b- -configuration, have been
D
approved for the treatment of AIDS.1–3 The importance of a 2%,3% double bond in the furanose
ring has been widely appreciated since Balzirini et al.4 demonstrated that d4T [1-(2,3-dideoxy-b-
D
-glycero-pent-2-enofuranosyl)thymine, 1] had potent activity against HIV and much effort has
been devoted to the synthesis of this and related unsaturated compounds.5 Notably d4T is less
toxic and less inhibitory to mitochondrial DNA replication than AZT.6 The lipophilicity of any
anti-viral compound is an important property and this is well illustrated by the enhanced
activity against cell lines of HIV and other retroviruses which is observed7 when d4T is
converted to the much more lipophilic alaninylmonophosphate derivative 2.
* Corresponding author. E-mail: christophe.len@sc.u-picardie.fr
0957-4166/00/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00488-2

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D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
We have shown recently8,9 that nucleoside analogues based on a 1,3-dihydrobenzo[c]furan
glycone as shown in compound 3 can be obtained readily. The thymine analogue of 3
corresponds to d4T with the double bond in the sugar ring incorporated into a benzene ring and
this bicyclic system will have increased lipophilicity. The synthesis of 3 and related pyrimidine
and purine nucleoside analogues requires access to the glycone, 1,3-dihydro-3-hydroxymethyl-1-
methoxybenzo[c]furan 4.
Various routes to the glycone 4 have been investigated8,9 starting in all cases from phthalalde-
hyde half-protected as the acetal with propan-1,3-diol and these routes are summarised in
Scheme 1. Since two new stereogenic centres are created in the formation of the dihydroben-
Scheme 1. Routes to 1,3-dihydrobenzo[c]furan glycone. Details of reagents are available elsewhere8b,9

D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
4997
zo[c]furan system by any of these routes, the extent to which the stereochemistry can be
controlled is an important aspect of this chemistry. In route 1 the epoxidation step gave the
racemic compound 6, and hence no stereocontrol was possible over the cyclisation step. Thus a
mixture of racemic diastereoisomers 8 and 9 was obtained (cis–trans ratio=1.5:1). This mixture
is difficult to separate and only the trans-isomer 9 was obtained stereochemically pure. Route 2
is similarly non-selective, giving a racemic cyanohydrin 10 which led to a mixture of racemic
diastereoisomers 13 and 14 (cis–trans ratio=1:1.25). Again only the trans-isomer could be
obtained in pure form.
Route 3 employed the Sharpless asymmetric dihydroxylation methodology10 which was
completely stereoselective in this case and the protected diol 16 was obtained in 100% ee [either
(S)-(+) or (R)-(−) depending on which of the two Sharpless reagents was used]. Cyclisation of
compounds (S)-(+)-16 and (R)-(−)16 was also stereospecific and thus both enantiomers of the
trans-form of the benzoylated glycone (1S,3S)-(+)-17 and (1R,3R)-(−) 17, respectively, were
obtained. Diastereoselectivity at the 1-position is always lost during attachment of a nucleoside
base but separation of the diastereoismers is relatively easy at the nucleoside stage and thus all
four pure enantiomers of nucleoside analogue 3 were obtained9 by route 3. This permits
independent evaluation of the influence of the stereochemistry of the C1 site (analogous to a/b
configurations in carbohydrates) and the C3 site (analogous to
D
/L-configurations in carbo-
hydrates). The potential of nucleosides with the unnatural -configuration as antiviral agents has
L
only recently been appreciated11 and hence further exploration of stereocontrol of the C3 site in
4 is worthwhile.
2. Results and discussion
As is evident from Scheme 1 access to the benzo[c]furan system starts conveniently from
phthalaldehyde with one aldehyde group protected. Previously propan-1,3-diol has been used to
form an acetal but, reasoning that a chiral protecting group might provide greater stereocontrol
in the generation a stereogenic centre from the second aldehyde group, we have sought to
protect phthalaldehyde with a sugar derivative. The formation of benzaldehyde acetals with
methyl hexopyranosides is a well established protocol for the protection of sugars12 but we have
found that although the reaction of o-phthalaldehyde with methyl b-
only one acetal stereoisomer, the yield is poor (15%). In contrast we have found that
1,2-O-isopropylidene-a-
-xylofuranose13 reacts with o-phthalaldehyde to form a benzylidene
D
-glucopyranoside gives
D
derivative 18, in 50% yield (Scheme 2). Although a new stereogenic centre is generated in the
1,3-dioxane ring only the diastereoisomer with the (S)-configuration (Fig. 1) at this new centre
is formed, presumably since the condensation is preferentially directed by the chiral furanose
ring.
MM2 modelling of 18 indicates that the dioxan ring adopts a chair conformation with an
equatorial phenyl group, as confirmed by a strong NOE interaction between the three axial
protons in this ring. Starting from the MM2 geometry the energy of each of the conformations
of 18 was evaluated by semi-empirical calculations at the PM3 level. The most stable form (Fig.
1) has the plane of the phenyl group exactly bisecting the dioxolan ring. The formyl group is
oriented exo with respect to the bicyclic system formed by the furanose and dioxolan rings and
the carbonyl bond is anti to the benzylidene group. Both the phenyl and formyl groups would
be expected to exhibit a twofold rotational potential and the other conformations were also

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D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
Scheme 2. Reagents and conditions: (i) 1,2-O-isopropylidene-a-
NaH, DMSO, rt; (iii) NaH, BnOH, DMF, 100°C; (iv) HOAc (80%), 60°C then MeOH/HCl (1%), rt
D
-xylofuranose, pTSA, THF, reflux; (ii) Me3SO+I−,
Figure 1. Lowest energy conformation of compound 18 (PM3 energy)
investigated. The conformer with the corresponding syn orientation of the carbonyl bond is 3.8
kJ mol−1 higher in energy. Rotation of the benzene ring in 18 by 180° gives a notional endo–anti
conformation. In fact the symmetry of this form is lower since the formyl group is twisted about
35° to point the formyl hydrogen to one or other of the dioxolan oxygen atoms (H···O
−1
,
separation ca. 2.5 A). These forms are about 5 kcal mol above the stable form in Fig. 2.

D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
4999
A stable conformation of the endo–syn type does not exist but a twisted configuration with the
phenyl group axial is over 5 kcal mol−1 higher in energy.
Figure 2. Configuration and conformation of epoxide 19 as determined by X-ray crystallography
With the chiral protecting group attached the sequence of reactions shown in Scheme 2 was
carried through. The epoxidation step8b afforded a mixture of stereoisomers 19 and 20 (arising
from the (S) and (R) configurations of the new stereogenic centre, respectively) in the ratio 1:1.
It is notable that the presence of a chiral protecting group has not produced any selectivity in
the formation of these epoxides. It is likely that the chiral influence of the xylose group is too
remote to exercise any stereocontrol. Separation of these epoxides was difficult but a pure sample
of 19 could be isolated in 14% yield by crystallisation. The configuration of this pure
diastereoisomer was established unequivocally by X-ray crystallography (Fig. 1). This structure
also confirms the configuration at the benzylidene carbon.
Compound 19 was easily converted to the benzylated diol 21 (by treatment with the sodium
salt of benzyl alcohol). However it was more efficient to convert the mixture of epoxides 19 and
20 to the mixture of the benzylated diols 21 and 22 since these diastereoisomers could be separated
cleanly by column chromatography. Thus the presence of a stereogenic protecting group has
achieved the desired objective by allowing the effective resolution of the stereogenic centre which
becomes C3 in the glycone. Removal of the chiral protecting group from compound 21 by
treatment with 80% acetic acid was followed by spontaneous cyclisation. Conversion to the
pseudo-glycosides with methanolic HCl gave a mixture of the diastereoisomers (1R,3S)-8 and
(1S,3S)-9. Since the C1 centre is always epimerised under these conditions it is evident that
cyclisation has occurred without any loss in the chiral integrity of the (S)-configuration at the
C3 centre. Similarly compound 22 gave the corresponding diastereoisomer mix with the
(R)-configuration at C3. We have already established that the analogues of 8 or 9 with a benzoyl
protecting group, prepared as pure C3 epimers by asymmetric induction, can be converted to
pyrimidine nucleosides by standard procedures.9 Although the C1 site is always epimerised the
cis-and trans-diastereoisomers of these nucleoside analogues are easily separated by chromatog-
raphy to give access to the four enantiomers arising from the two stereogenic centres in uracil
derivatives of type 3. Thus the use of 1,2-O-isopropylidene-a- -xylofuranose as a chiral protecting
D
group achieves the same result, in one set of reactions, as the use of the Sharpless catalytic
dihydroxylation reagents which of course requires two parallel reaction sequences.

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D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
3. Experimental
3.1. General
Melting points were determined on a digital melting-point apparatus (Electrothermal) and are
uncorrected. Optical rotations were recorded at 22°C in CHCl3 or MeOH solutions with a
digital polarimeter DIP-370 (Jasco) using a 1 dm cell and rotations are given in 10−1 deg cm2 g−1.
1H NMR and 13C NMR spectra were recorded in CDCl3 or Me2SO-d6 (internal Me4Si),
respectively, at 300.13 MHz and at 75.47 MHz (Bruker AM WB-300). Coupling constants (J)
are given in Hz. TLC was performed on Silica F254 (Merck) with detection by UV light at 254
nm or by charring with phosphomolybdic–H2SO4 reagent. Column chromatography was
effected on Silica Gel 60 (Merck, 230 mesh). Commercial reagents were supplied by Lancaster
or Across. Molecular modelling and molecular orbital calculations were performed by the MM2
and PM3 methods, respectively, using the MOPAC package as provided in the Chem3D suite
from ChemOffice. In all cases the reliability of a conformational minimum was rigorously
established by repeated minimisation from different points in the energy surface.
3.2. Syntheses
3.2.1. 3,5-O-(2-Formylbenzylidene)-1,2-O-isopropylidene-h-
D
-xylofuranose 18
A stirred mixture of o-phthalaldehyde (5.0 g, 37.73 mmol), 1,2-O-isopropylidene-a-
D
-
xylofuranose13 (7.1 g, 37.73 mmol), toluene-4-sulfonic acid (0.1 g) and tetrahydrofuran (50 mL)
was refluxed for 5 h. Triethylamine (2 mL) was added and the reaction mixture was cooled and
extracted with diethyl ether (20 mL). The extract was worked up and the crude product purified
by column chromatography (hexane–diethyl ether, 70:30) to afford 18 (5.6 g, 49%) as a solid,
mp 86.0–86.3°C; [h] +13 (c 1.0, CHCl3); 1H NMR (CDCl3): l 7.82, 7.59 (2H, m, H-3, H-6), 7.43,
7.50 (2H, m, H-4, H-5), 5.98 (1H, d, J1%,2% 3.6, H-1%), 5.92 (1H, s, CH), 4.51 (1H, d, J2%,3% 0, H-2%),
4.41 (1H, bs, H-4%), 4.37 (1H, d, H-5%a), 4.12 (1H, dd, J4%,5%b 1.6, J5%a,5%b 13.1, H-5%b), 4.08 (1H, bs,
H-3%), 1.44 (3H, s, Me), 1.24 (3H, s, Me). 13C NMR (CDCl3): l 192.4 (CHO), 138.2 (C-1), 133.9
(C-2), 133.4, 130.5, 129.5, 127.3 (C-3, C-4, C-5, C-6), 111.8 (Ciso), 105.5 (C-1%), 97.8 (CH), 83.6
(C-2%), 79.1 (C-4%), 72.0 (C-3%), 66.8 (C-5%), 26.6, 26.0 (Me). Anal. calcd for C16H18O6 (306.31): C
62.74; H 5.92; found: C 62.60, H 6.08.
3.2.2. 3,5-O-[2-((S)-Oxiranyl)benzylidene]-1,2-O-isopropylidene-h-
D
-xylofuranose 19 and
3,5-O-[2-((R)-oxiranyl)benzylidene]-1,2-O-isopropylidene-h- -xylofuranose 20
D
A mixture of trimethylsulfoxonium iodide (7.8 g, 35.3 mmol) and sodium hydride (1.1 g, 35.3
mmol) in dry dimethyl sulfoxide (100 mL) was stirred for 30 min at 10°C. A solution of
compound 18 (8.0 g, 26.1 mmol) in dimethyl sulfoxide (100 mL) was added dropwise to the
above mixture at 10°C and then the mixture stirred for 30 min at rt. Saturated aqueous NH4Cl
(200 mL) was added and the mixture extracted with diethyl ether. The extract was worked up
and the crude product purified by column chromatography (hexane–diethyl ether, 70:30) to give
a mixture of compounds 19 and 20 (4.2 g, 50%). A pure sample of 19 was obtained by careful
crystallisation from ethanol.
1
Compound 19. Mp 143.4–143.9°C, [h] +50.6 (c 1.0, CHCl3); H NMR (CDCl3): l 7.45 (2H,
m, H-3 and H-6), 7.27 (2H, m, H-4 and H-5), 6.01 (1H, d, J1%,2% 3.6, H-1%), 5.62 (1H, s, CH), 4.57

D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
5001
(1H, d, J2%,3% 0, H-2%), 4.44 (1H, d, H-5%a), 4.40 (1H, bs, H-4%), 4.27 (1H, dd, J 2.6, oxiranyl), 4.11
(1H, dd, J4%,5%b 1.7, J5%a,5%b 13.5, H-5%b), 4.11 (1H, bs, H-3%), 3.13 (1H, dd, J 5.6, oxiranyl), 2.67
(1H, dd, J 3.9, oxiranyl), 1.49 (3H, s, Me), 1.30 (3H, s, Me). 13C NMR (CDCl3): l 136.2 (C-1),
135.4 (C-2), 129.5, 127.6, 126.6, 124.6 (4C, C-3, C-4, C-5, C-6), 111.8 (Ciso), 105.6 (C-1%), 99.1
(CH), 83.7 (C-2%), 78.9 (C-4%), 72.0 (C-3%), 66.7 (C-5%), 50.9, 49.8 (oxiranyl), 26.6, 26.1 (Me). Anal.
calcd for C17H20O6 (320.34): C 63.74; H 6.29; found: C 63.67; H 6.40.
1
Compound 20. H NMR (CDCl3): l 7.49 (2H, m, H-6, H-3), 7.27 (2H, m, H-4, H-5), 5.99
(1H, d, J1%,2% 3.6, H-1%), 5.61 (1H, s, CH), 4.56 (1H, d, J2%,3% 0, H-2%), 4.42 (1H, d, H-5%a), 4.39 (1H,
bs, H-4%), 4.26 (1H, m, oxiranyl), 4.11 (1H, dd, J4%,5%b 1.7, J5%a,5%b 13.5, H-5%b), 4.10 (1H, bs, H-3%),
3.06 (1H, dd, oxiranyl), 2.62 (1H, dd, oxiranyl), 1.48 (3H, s, CH3), 1.29 (3H, s, Me). 13C NMR
(CDCl3): l 136.1 (C-1), 135.3 (C-2), 129.5, 127.5, 126.4, 124.5 (4C, C-3, C-4, C-5, C-6), 111.9
(Ciso), 105.6 (C-1%), 98.8 (CH), 83.8 (C-2%), 78.9 (C-4%), 72.0 (C-3%), 66.6 (C-5%), 50.8, 49.7
(oxiranyl), 26.7, 26.1 (Me).
3.2.3. 3,5-O-[2-((S)-2-Benzyloxy-1-hydroxyethyl)benzylidene]-1,2-O-isopropylidene-h-
furanose 21 and 3,5-O-[2-((R)-2-benzyloxy-1-hydroxyethyl)benzylidene]-1,2-O-isopropylidene-
h- -xylofuranose 22
Benzyl alcohol (1.2 g, 11.24 mmol) was added to a suspension of sodium hydride (337 mg,
D
-xylo-
D
11.24 mmol) in dry DMF (60 mL) and the mixture stirred at room temperature under nitrogen
for 30 min. A mixture of oxiranes 19 and 20 (4.0 g, 12.49 mmol) in DMF (20 mL) was added
dropwise and the mixture was stirred for a further 3 h at 100°C. The solution was poured into
ice-water and extracted with diethyl ether. The extract was worked up and the crude product
purified by column chromatography (hexane–acetone, 80:20) to afford a first component 21 (1.8
g, 34%) and a second component 22 (1.9 g, 36%).
This synthetic step was also applied to the pure diastereoisomer 19 to give compound 21,
identical in all respect to the sample obtained by chromatography.
1
Compound 21. [h] +23.6 (c 0.8, CHCl3); H NMR (CDCl3): l 7.56, 7.50 (2H, m, H-3, H-6),
7.36, 7.23 (2H, m, H-4, H-5), 6.02 (1H, d, J1%,2% 3.6, H-1%), 5.56 (1H, s, CH), 5.30 (1H, dd, J 2.9,
J 8.7, CH6 OH), 4.61 (2H, q, J 7.5, J 12.2, CH2Ph), 4.45 (1H, d, J2%,3% 0, H-2%), 4.35 (1H, d, H-5%a),
4.31 (1H, bs, H-4%), 4.07 (1H, bs, H-3%), 4.02 (1H, d, J5a%,5%b 13.1, H-5%b), 3.67 (1H, dd, J 3.1,
CH2OBn), 3.49 (1H, dd, J 10.0, J 8.9, CH2OBn), 3.10 (1H, s, OH), 1.51 (3H, s, Me), 1.30 (3H,
s, Me). 13C NMR (CDCl3): l 138.5 (Bn), 138.1 (C-1), 134.4 (C-2), 129.4, 127.6, 127.0, 126.7
(C-3, C-4, C-5, C-6), 128.4 (Bn), 127.6 (Bn), 111.8 (Ciso), 105.6 (C-1%), 98.4 (CH), 83.7 (C-2%),
78.8 (C-4%), 75.1 (CH2OBn), 72.9 (OCH2Ph), 72.0 (C-3%), 68.7 (CHOH), 66.7 (C-5%), 26.7, 26.2
(Me). Anal. calcd for C24H28O7 (428.48): C 67.28, H 6.59; found: C 67.17, H 6.85.
1
Compound 22. [h] −27.3 (c 0.6, CHCl3); H NMR (CDCl3): l 7.56, 7.45 (2H, m, H-3 and
H-6), 7.29 (2H, m, H-4 and H-5), 6.06 (1H, d, J1%,2% 3.4, H-1%), 5.52 (1H, s, CH), 5.32 (1H, dd,
J 2.9, J 8.7, CH6 OH), 4.56 (2H, q, J 7.5, J 12.2, CH2Ph), 4.50 (1H, d, J2%,3% 0, H-2%), 4.28 (1H,
d, H-5%a), 4.31 (1H, bs, H-4%), 4.04 (1H, bs, H-3%), 3.97 (1H, d, J5a%,5%b 13.1, H-5%b), 3.64 (1H, dd,
J 3.1, CH2OBn), 3.45 (1H, dd, J 10.0, J 8.9, CH2OBn), 3.10 (1H, s, OH), 1.49 (3H, s, Me), 1.28
(3H, s, Me). 13C NMR (CDCl3): l 138.9 (Bn), 138.0 (C-1), 134.3 (C-2), 129.4, 127.7, 127.0, 126.6
(C-3, C-4, C-5, C-6), 128.4 (Bn), 127.8 (Bn), 111.8 (Ciso), 105.6 (C-1%), 98.6 (CH), 83.8 (C-2%),
78.8 (C-4%), 75.5 (CH2OBn), 73.4 (OCH2Ph), 72.0 (C-3%), 69.2 (CHOH), 66.5 (C-5%), 26.7, 26.1
(Me). Anal. calcd for C24H28O7 (428.48): C 67.28, H 6.59; found: C 67.17, H 7.06.

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D. F. Ewing et al. / Tetrahedron: Asymmetry 11 (2000) 4995–5002
3.2.4. Cyclisation to stereoisomers of 3-benzyloxymethyl-1,3-dihydro-1-methoxybenzo[c]furan
8 and 9
Compound 21 (100 mg, 0.23 mmol) was taken up in 5.8 mL of 80% acetic acid and heated
at 60°C for 2 h. After evaporation and co-evaporation with toluene, the residue was dissolved
in methanolic HCl (1%, 2 mL) and the mixture stirred for 2 h at 20°C. Water (5 mL) was added
and the mixture extracted with diethyl ether. The extract was worked up and the crude product
purified by column chromatography (hexane–acetone, 95:05) to afford a 1:1 diastereoisomeric
mixture of (1R,3S)-8 and (1S,3S)-9 (37 mg, 58%). Similarly, compound 22 gave a mixture of
1
(1S,3R)-8 and (1R,3R)-9 (39 mg, 60%). In all cases the H and 13C NMR data were identical to
those for the racemic compounds.8b
Acknowledgements
We thank Professor G. Nowogrocki for the X-ray studies.
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