Studies directed toward the synthesis of carba-D-arabinofuranose

Article abstract of DOI:10.1016/S0040-4039(00)01355-1

The key cyclopentene analog of carba-D-arabinofuranose was prepared in five steps from 2,3,5-tri-O-benzyl-D-arabinofuranose. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01355-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7801–7803
Studies directed toward the synthesis of
carba- -arabinofuranose
D
Mohindra Seepersaud and Yousef Al-Abed*
The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA
Received 14 June 2000; revised 3 August 2000; accepted 7 August 2000
Abstract
The key cyclopentene analog of carba-D-arabinofuranose was prepared in five steps from 2,3,5-tri-O-
benzyl- -arabinofuranose. © 2000 Elsevier Science Ltd. All rights reserved.
D
Keywords: cyclopentenes; metathesis; cyclization; cyclitols.
Infection by mycobacteria, such as Mycobacterium tuberculosis, causes tuberculosis.1 The
protective mycobacterial cell wall is composed of polysaccharide, proteins and lipids.2 The major
polysaccharide components are terminated with arabinofuranosyl hexasaccharide, which is
fundamental to the structural integrity of the cell wall.3 Recently, the biosynthesis of the
arabinofuranosyl moiety has been studied and it was suggested that targeting one or more of the
arabinose biosynthetic enzymes may result in a new drug for tuberculosis.4 Inhibitors of these
enzymes are an attractive approach since
malian glycoconjugates. During cell wall synthesis,
ally activated and transferred to the polysaccharide chain, therefore it was hypothesized that a
pseudo sugar carba analog of -arabinofuranose might provide stability to the activated form
D
-arabinofuranosyl residues are not found in mam-
D
-arabinofuranosyl residues are enzymatic-
D
and consequently inhibit the transfer process. These pseudo sugars have enhanced metabolic and
acid stability relative to the parent carbohydrate and have shown promising reaction profiles as
antiviral agents5 as well as glycosyl transferase substrates.6 There have been several synthetic
approaches to provide the pseudo sugar carba-
our program directed towards the synthesis of carbocyclic analogs of carbohydrates,8 we report
herein an efficient formal synthesis of carba- -arabinofuranose.
D
-arabinofuranose 1,2 (Scheme 1).7 As part of
D
* Corresponding author. E-mail: yal-abed@picower.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01355-1

7802
Scheme 1.
Logical retrosynthetic analysis suggests that carba- -arabinofuranoside could be obtained via
D
a hydrogenation on a cyclopentene intermediate 3. The cyclopentene could be obtained from a
ring closing metathesis (RCM)9 of a suitable diene precursor 4 which is assembled from a
carbohydrate source. The starting material of choice would be tri-O-benzyl-
5, since it possesses the key stereocenters at the C-2 and C-3 positions (Scheme 1).10
2,3,5-Tri-O-benzyl- -arabinofuranose 5 was treated with vinylmagnesium bromide to afford
D
-arabinofuranose
D
an inseparable mixture of diastereomers 6. The allylic center of the diol 6 was then selectively
protected using p-methoxybenzyl chloride at 0°C. Compound 7 was then oxidized under Swern
conditions to furnish 8 which was then converted via a Wittig reaction to the key diene
intermediate 9. Previously, we utilized Schrock’s catalyst for the RCM of diene systems.8 Using
these conditions, the diene 9 was refluxed with Schrock’s catalyst at 85°C for 10 h. Upon
quenching the reaction, a mixture of cyclopentenes was obtained. This separable mixture was
then subjected to flash column chromatography to afford the diastereomers 10b and 10a (62:38)
in 95% yield (Scheme 2).
Scheme 2. (a) Vinylmagnesium bromide, THF, 87%; (b) p-methoxybenzyl chloride, NaH, DMF, 0°C, 83%; (c)
(COCl)2, DMSO, Et3N, 77%; (d) methyltriphenylphosphonium bromide, n-BuLi, 89%; (e) Schrock’s catalyst (0.4
equiv.), 95%
As shown below, nOe studies of compound 10b and 10a resulted in similar percentile around
H1/H2. Interestingly, an nOe of 1.75% was observed between H2/H3 of compound 10b whilst no
nOe was observed for the same protons of 10a. Therefore, we can confirm that the isomer 10b
is b while the other isomer 10a is a.11

7803
In summary, we have described a formal synthesis of carba-
D
-arabinofuranose, since com-
pound 10b was converted to b-carba-
D
-arabinofuranose via diastereoselective hydrogenation.7a
Consequently it is expected that 10a can be converted to the corresponding a isomer. Of note,
our strategy provided an additional flexibility due to the selective protection of the pseudo
anomeric group as the PMB ether allowing for easy removal, inversion or derivatization as
required. The carba-arabinofuranose precursors 10b and 10a were prepared in five steps (47%
overall yield) using RCM.
Acknowledgements
The authors would like to thank the Patterson Foundation for their support.
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1
11. (a) Spectral data for 10a: H NMR (CDCl3, 500 MHz) l 3.80 (s, 3H), 4.13 (ABq, J=13.4 Hz, Dl=0.05 ppm,
2H), 4.22 (t, J=4.0 Hz, 1H), 4.44 (m, 1H), 4.47 (m, 1H), 4.51 (ABq, J=11.8 Hz, Dl=0.07 ppm, 2H), 4.52 (ABq,
J=11.6 Hz, Dl=0.05 ppm, 2H), 4.62 (ABq, J=11.8 Hz, Dl=0.05 ppm, 2H), 4.63 (ABq, J=11.6 Hz, Dl=0.05
ppm, 2H), 5.90 (s, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.30 (m, 17H). 13C NMR (C6D6, 67.5 MHz) l 54.5, 66.8, 70.6,
71.7, 71.8, 72.5, 85.4, 85.8, 92.2, 113.8, 126–129 (several signals), 130.9, 138.8, 138.9, 139.0, 143.5, 159.5. MS (ES)
1
m/z (M+NH4+), 554 (base peak), 391, 279. (b) Spectral data for 10b: H NMR (CDCl3, 500 MHz) l 3.89 (s, 3H),
3.99 (t, J=5.1 Hz, 1H), 4.14 (ABq, J=14.0 Hz, Dl=0.05 ppm, 2H), 4.50 (m, 1H), 4.52 (ABq, J=1.9 Hz, Dl=0.02
ppm, 2H), 4.54 (ABq, J=11.5 Hz, Dl=0.06 ppm, 2H), 4.61 (ABq, J=11.3 Hz, Dl=0.23 ppm, 2H), 4.68 (ABq,
J=11.8 Hz, Dl=0.12 ppm, 2H), 4.78 (d, J=4.6 Hz, 1H), 5.98 (s, 1H), 6.85 (d, J=8.1 Hz, 2H), 7.30 (m, 17H).
13C NMR (C6D6, 67.5 MHz) l 54.5, 66.9, 70.1, 71.6, 72.4, 72.6, 77.0, 85.8, 86.0, 113.8, 125.7, 126–128 (several
signals), 129.4, 131.3, 138.7, 139.0, 139.2, 147.2, 159.4. MS (ES) m/z (M+NH4+), 554 (base peak), 391, 279.
.
.