Synthesis of D-arabinofuranosides using propane-1,3-diyl phosphate as the anomeric leaving group

Article abstract of DOI:10.1016/S0040-4039(01)01327-2

2′,3′,5′-Tri-O-benzyl-D-arbinofurano-1-O-propane-1,3- diylphosphate was activated with TMSOTf to afford 1-O-linked arabinofuranosides with good stereoselectivity.

Full text of DOI:10.1016/S0040-4039(01)01327-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6615–6618
Synthesis of
D
-arabinofuranosides using propane-1,3-diyl
phosphate as the anomeric leaving group
Yuan Li and Gurdial Singh*
Department of Chemistry, University of Sunderland, Sunderland SR1 3SD, UK
Received 20 June 2001; revised 9 July 2001; accepted 20 July 2001
Abstract—2%,3%,5%-Tri-O-benzyl-
D-arbinofurano-1-O-propane-1,3-diylphosphate was activated with TMSOTf to afford 1-O-linked
arabinofuranosides with good stereoselectivity. © 2001 Elsevier Science Ltd. All rights reserved.
The fight against bacterial infections has become
severely compromised by the ability of bacterial organ-
isms, in particular, to mutate rapidly and become resis-
tant to the drugs employed. The design of new
pharmaceutical agents to deal with various disease
states has led to a thriving pharmaceutical industry.
The role played by chemists in the development of new
agents is seen as being pivotal to the continued success
of these endeavours. This role has been further
strengthened by the advances made in understanding
the mechanisms that pertain in infection processes at
the molecular level. In this regard the importance of
carbohydrate structures in such events has come to the
fore during the last two decades, which has been
directly responsible for the re-emergence of interest in
their chemistry.
charide epitope 13 so as to understand the importance
of this motif, and has resulted in an examination of the
glycosylation reaction of arabinose. Central to the syn-
thesis of the arabinose epitope is the ability of forming
disaccharides that are 1,5-a-linked in a stereochemical
manner with good efficiency.4
We have previously reported that the displacement of
diphenylphosphinates derived from tri-O-benzyl-D-
ribofuranose invariably resulted in poor stereoselectiv-
ity in its coupling reaction with a range of glycosyl
acceptors.5 In our recent investigations we have success-
fully used propane-1,3-diyl phosphates to prepare a
wide range of pyranosides with excellent stereochemical
control.6
Currently the two diseases most prevalent in both the
developing and developed countries are malaria and
tuberculosis (TB), with HIV currently following in their
footsteps. In the case of TB, there has been no signifi-
cant decrease in world-wide mortality despite the
advent of sanatoria and chemotherapy. It is estimated
that about one third of the world population is infected
with Mycobacterium tuberculosis and that each year
there are three million deaths as a result of this infec-
tion.1 The drug resistance of mycobacteria is due to
their cell walls having unusually low permeability which
makes it difficult to deliver therapeutic agents. Their
cell walls contain large amounts of C60–C90 fatty acids,
mycolic acids, that are covalently linked to arabino-
galactan.2 As a direct consequence of this a great deal
of effort has focused on the synthesis of the hexa-sac-
* Corresponding author. Tel.: +44 191 515 3094; fax: +44 191 515
3148; e-mail: gurdial.singh@sunderland.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01327-2

6616
Y. Li, G. Singh / Tetrahedron Letters 42 (2001) 6615–6618
In order to extend the scope of this methodology to
form glycofuranosides, we investigated the possibility of
using propane-1,3-diyl phosphate as the leaving group
phosphate 4 had a single resonance at lP −8.7 indicat-
ing that the reaction had proceeded with excellent
stereocontrol.
at the anomeric centre of tri-O-benzyl-D-arabinofura-
nose. Additionally, we believed the use of the propane-
1,3-diyl phosphate activating group would allow us to
determine the significance of steric interactions in the
subsequent transition states, as the anomeric effect in
furanoses is equal in the stabilisation of both a- and
b-anomers. In this paper we present our findings aimed
at establishing this linkage efficiently. Treatment of
With the availability of the phosphate 4 we proceeded
to investigate the displacement of the propane-1,3-diyl
phosphate group with a range of acceptors. In the first
instance we studied the displacement reaction of phos-
phate 4 with n-octanol as the acceptor, in the presence
of a catalytic amount of trimethylsilyl triflate as the
activator.
tri-O-benzyl- -arabinofuranose 2 with propane-1,3-diyl
D
phosphoryl chloride 3 afforded the phosphate 4 in 80%
yield after flash column chromatography on silica, as a
colourless oil. Unlike the pyranose case, propane-1,3-
diyl phosphate 4 proved to be relatively unstable and
was used within 14 days of preparation and storage at
−23°C.
We were gratified to observe that the reaction pro-
ceeded in a yield of 67% with the b-isomer being the
major product, Table 1; {[h]D −45.9 (c 1.1, CHCl3); lit.7
[h]D −49.6 (c 1.4, CHCl3)}. Similarly, using isopropanol
as the acceptor afforded the corresponding a- and
b-furanosides. Support for the assignment of the stereo-
1
The stereochemistry of phosphate 4 was assigned on the
chemistry at the anomeric centre followed from the H
1
basis of its H NMR spectrum, wherein a JH-P 4.3 Hz
NMR of 5a in that the H-1 signal was found to
resonate at l 5.16 and appeared as a singlet, whilst for
5b the H-1 resonance occurred at l 5.02 and appeared
was observed for the anomeric proton which had a
resonance at l 5.98. In its 31P NMR spectrum the
Table 1.

Y. Li, G. Singh / Tetrahedron Letters 42 (2001) 6615–6618
6617
as a doublet with J 4.1 Hz. Additional support for this
assignment was gained from its 13C NMR8 spectrum,
where a resonance at lC 104.18 was indicative of an
a-linkage at the anomeric centre of the 2,3,5-tri-O-ben-
zylarabinofuranose, whilst for the b-linkage9 this was
found at 98.71. Changing the acceptors to more heavily
oxygenated substrates including those derived from car-
bohydrates had an unexpected outcome, in that the
stereoselectivity of the coupling reaction changed from
being b-selective and became a-selective. For the accep-
tor 4-epi-podophyllotoxin, glycosylation occurred
regioselectively at the secondary alcohol. In the case of
the methyl shikimate derivative we obtained exclusively
the a-isomer. All of the coupling reactions that we
investigated proceeded in good yields. In the case where
we formed a C-5 arabinofuranoside linkage with a
catalytic amount of TMSOTf we obtained the b-isomer
as the major product. This stereoselectivity could be
changed to provide the a-disaccharide by the use of one
equivalent of TMSOTf as the activator. In the latter
case the reaction is most likely proceeding via an oxo-
nium ion intermediate,10 whilst in the reactions with
‘simple’ alcohols the reaction occurs via a mixed path-
way with the SN2 process dominating.
D’Souza, F. W.; Ayers, J. D.; McCarren, P. R.; Lowary,
T. L. J. Am. Chem. Soc. 2000, 122, 1251–1260.
5. Singh, G.; Tranoy, I. Carbohydr. Lett. 1998, 3, 79–84.
6. (a) Vankayalapati, H.; Singh, G.; Tranoy, I. J. Chem.
Soc., Chem. Commun. 1998, 2129–2130; (b) Vankayalap-
ati, H.; Singh, G. Tetrahedron Lett. 1999, 40, 3925–3928;
(c) Vankayalapati, H.; Singh, G. Tetrahedron: Asymmetry
2000, 11, 125–138; (d) Vankayalapati, H.; Singh, G. J.
Chem. Soc., Perkin Trans. 1 2000, 2187–2193.
7. Subramanian, V.; Lowary, T. L. Tetrahedron 1999, 55,
5965–5976.
8. Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O.;
Matsuura, H. Carbohydr. Res. 1989, 185, 27–38;
anomeric carbons in b-arabinofuranosides resonate
between 100 and 104 ppm whilst those in a-arabinofura-
nosides resonate between 105 and 110 ppm.
9. All new compounds gave satisfactory spectral, microana-
lytical and/or high-resolution mass spectral data. The
ratios and yields in parentheses refer to isolated yields of
compounds after column chromatography. Selected data:
4 [h]D +19.5 (c 1.3, CHCl3); wmax (film)/cm−1 1610; lH
(270 MHz, CDCl3) 1.49–1.56 (1H, m), 2.12–2.20 (1H, m),
3.57–3.68 (2H, m), 3.96 (1H, dd, J 4.8, 1.0 Hz), 4.20–4.42
(5H, m), 4.41–4.68 (7H, m), 5.98 (1H, d, JH-P 4.3 Hz),
7.21–7.37 (15H, m); lC (67.8 MHz, CDCl3) 25.60 (JC-P
7.3 Hz), 68.52 (JC-P 7.0 Hz), 68.81 (JC-P 7.3 Hz), 69.43,
71.77, 71.79, 73.17, 83.14, 84.04, 86.77 (JC-P 7.5 Hz),
103.14 (JC-P 5.2 Hz), 127.48, 127.50, 127.64, 127.70,
127.79, 128.16, 128.19, 128.26, 136.84, 137.24, 137.72; lP
(121.5 MHz, CDCl3) −8.7; m/z (CI, NH3). Found:
We have thus demonstrated that tri-O-benzyl-L-ara-
binofuranose can be converted into O-linked arbino-
furanosides with high stereoselectivity where the
anomeric centre bears a propane-1,3-diylphosphate
function as the leaving group, which further added to
the versatility of the type of activation for the prepara-
tion of glycosides.
+
MNH4 558.2256, C29H37NO8P requires 558.2257. 5a
(Isopropyl) [h]D +57.2 (c 1.1, CHCl3); lH (270 MHz,
CDCl3) 1.16 (3H, d, J 6.1 Hz), 1.22 (3H, d, J 6.3 Hz),
3.55–3.68 (2H, m), 3.90–4.01 (3H, m), 4.18–4.23 (1H, m),
4.45–4.61 (6H, m), 5.16 (1H, s), 7.21–7.34 (15H, m); lC
(67.8 MHz, CDCl3) 21.46, 23.59, 68.97, 69.73, 71.90,
72.04, 73.31, 80.09, 83.56, 88.80, 104.18, 127.53, 127.63,
127.72, 127.76, 127.79, 127.88, 128.29 (2C), 128.40,
Acknowledgements
We thank EPSRC for financial support and for access
to the high resolution mass spectrometry service at the
University of Wales, Swansea (director Professor D. E.
Games). We express our thanks to Dr. B. Harrison
(Bristol-Myers Squibb, Ireland) for providing the 4-epi-
podophyllotoxin used in these studies.
+
137.69, 138.00, 138.18; m/z (CI, NH3). Found: MNH4
480.2745, C29H38NO5 requires 480.2750; 5b (Isopropyl)
[h]D −55.0 (c 1.1, CHCl3); lH (270 MHz, CDCl3) 1.13
(3H, d, J 6.1 Hz), 1.16 (3H, d, J 6.4 Hz), 3.53–3.58 (2H,
m), 3.83–3.92 (1H, m), 4.01–4.12 (3H, m), 4.52–4.70 (6H,
m), 5.02 (1H, d, J 4.1 Hz), 7.20–7.37 (15H, m); lC (67.8
MHz, CDCl3) 21.43, 23.38, 69.64, 72.15, 72.20, 72.82,
73.20, 79.86, 83.58, 83.92, 98.71, 127.48, 127.53, 127.61,
127.71, 127.78, 128.03, 128.23, 128.26, 128.32, 137.71,
References
1. Enarson, D. A.; Murry, J. F. In Tuberculosis; Rom, W.
M.; Garay, S., Eds.; Little, Brown and Co.: Boston, 1996;
pp. 57–75.
+
138.03, 138.24; m/z (CI, NH3). Found: MNH4 480.2754,
C29H38NO5 requires 480.2750. 5a (D-Arabinose) [h]D +
2. (a) Brennan, P. J.; Nikaodo, H. Annu. Rev. Biochem.
1995, 64, 29–63; (b) Besra, G. S.; Brennan, P. J. Biochem.
Soc. Trans. 1997, 25, 845–850.
3. (a) Chatterjee, D.; Khoo, K. H. Glycobiology 1998, 8,
113–120; (b) Schlesinger, L. S. Curr. Top. Microbiol.
1996, 215, 71.
4. (a) Ayers, J. D.; Lowary, T. L.; Morehouse, C. B.; Besra,
G. S. Bioorg. Med. Chem. Lett. 1998, 8, 437–442; (b)
D’Souza, F. W.; Cheshev, P. E.; Ayers, J. D.; Lowary, T.
L. J. Org. Chem. 1998, 63, 9037–9044; (c) Mereyala, H.
B.; Hotha, S.; Gurjar, M. K. J. Chem. Soc., Chem.
Commun. 1998, 685–686; (d) D’Souza, F. W.; Lowary, T.
L. Org. Lett. 2000, 2, 1493–1495; (e) Gujar, M. K.;
Reddy, L. K.; Hotha, S. Org. Lett. 2001, 3, 321–323; (f)
58.2 (c 1.6, CHCl3); lH (270 MHz, CDCl3) 3.36 (3H, s),
3.54–3.66 (2H, m), 3.70 (1H, dd, J 11.6, 3.6 Hz), 3.86–
3.94 (2H, m), 3.98–4.07 (3H, m), 4.15–4.23 (2H, m),
4.40–4.60 (10H, m), 4.91 (1H, s), 5.16 (1H, s), 7.18–7.34
(25H, m); lC (67.8 MHz, CDCl3) 54.87, 66.08, 69.63,
71.85, 71.90, 72.05, 72.31, 73.33, 80.53, 80.66, 83.22,
83.53, 88.08, 88.38, 106.40, 107.21, 127.54, 127.62, 127.67,
127.73, 127.79, 127.86, 128.17, 128.29, 128.34, 128.36,
137.57, 137.63, 137.93, 138.10; m/z (CI, NH3). Found:
+
MNH4 764.3799, C46H54NO9 requires 764.3799. 5b (
D
-
Arabinose) [h]D −9.2 (c 1.5, CHCl3); lH (270 MHz,
CDCl3) 3.33 (3H, s), 3.51–3.61 (3H, m), 3.77–3.84 (2H,
m), 3.98 (1H, d, J 1.8 Hz), 4.04–4.12 (3H, m), 4.22–4.28
(1H, m), 4.42–4.67 (10H, m), 4.92 (1H, s), 5.06 (1H, d, J

6618
Y. Li, G. Singh / Tetrahedron Letters 42 (2001) 6615–6618
3.8 Hz), 7.17–7.36 (25H, m); lC (67.8 MHz, CDCl3)
20 min, which indicated that no epimerisation was occur-
ring at the anomeric centre. However, treatment with 1
equiv. of TMSOTf resulted in a substantial amount of
the a-isomer being formed, further addition, after 20 min
of activator (1.5 equiv.) resulted in complete conversion
to the a-anomer within 40 min. The pure a-isomer was
also subjected to the above reaction conditions and no
conversion to the b-anomer was observed. We thank a
referee for suggesting this additional experiment.
54.79, 67.73, 71.79, 71.87, 71.93, 72.04, 72.43, 73.11,
80.36, 81.11, 83.24, 83.49, 84.16, 87.89, 100.91, 107.20,
127.46, 127.58, 127.60, 127.63, 127.66, 127.71, 127.74,
127.77, 127.86, 128.21, 128.25, 128.27, 128.34, 137.41,
137.74, 138.06, 138.12; m/z (CI, NH3). Found: MNH4
764.3789, C46H54NO9 requires 764.3799.
+
10. The pure b-isomer (isopropyl) was treated with a catalytic
amount of TMSOTf under the reactions conditions for