Synthesis of unnatural 2- and 3-deoxyfuranose analogues

Article abstract of DOI:10.1016/j.tetlet.2014.05.011

This Letter describes the synthesis of two racemic analogues of unnatural 3′-deoxy and 2′-deoxy sugars, where a phosphorus atom replaces the carbon atom in the 2′- or 3′-position. Two methods of four- and 5-steps were developed affording these new unnatur

Full text of DOI:10.1016/j.tetlet.2014.05.011

Accepted Manuscript
Synthesis of Unnatural 2- and 3-Deoxyfuranose Analogues
Bénédicte Dayde, Claire Pierra, Gilles Gosselin, Dominique Surleraux, Amadou
Tidjani Ilagouma, Arie Van der Lee, Jean-Noël Volle, David Virieux, Jean-Luc
Pirat
PII:
S0040-4039(14)00787-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.011
TETL 44601
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 April 2014
2 May 2014
5 May 2014
Please cite this article as: Dayde, B., Pierra, C., Gosselin, G., Surleraux, D., Ilagouma, A.T., Van der Lee, A., Volle,
J-N., Virieux, D., Pirat, J-L., Synthesis of Unnatural 2- and 3-Deoxyfuranose Analogues, Tetrahedron Letters
(
2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.011
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Synthesis of Unnatural 2- and 3-Deoxyfuranose Analogues
a
b
b,c
b
d
Bénédicte Dayde, Claire Pierra, Gilles Gosselin, Dominique Surleraux, Amadou Tidjani Ilagouma, Arie
e
a
,a
,a
Van der Lee, Jean-Noël Volle, David Virieux,* Jean-Luc Pirat *
a
AM N, Institut Charles Gerhardt, UMR 5253, ENSCM, 8, rue de l'Ecole Normale, 34296 Montpellier – France.
Idenix Pharmaceuticals, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189
2
b
Montpellier Cedex 4 – France.
c
DACAN, Institut Max Mousseron, UMR 5247, Université Montpellier 2, F-34095 Montpellier – France
Département de Chimie, Faculté des Sciences, Université Abdou Moumouni, B.P. 10662, Niamey - Niger.
Institut Européen des membranes, cc047 Université de Montpellier 2, 34095, Montpellier - France.
d
e
Corresponding authors: Pirat Jean-Luc, Tel: 0033 467 147 243, fax: 0033 467 144 313, jean-
luc.pirat@enscm.fr; Virieux David, tel: 0033 467 144 314, fax: 0033 467 144 313, david.virieux@enscm.fr
Keywords:
deoxysugars analogs; oxaphospholane; Pudovik reaction; P-alkylation reaction.
Abstract
This paper describes the synthesis of two racemic analogues of unnatural 3’-deoxy and 2’-deoxy sugars,
where a phosphorus atom replaces the carbon atom in the 2’- or 3’-positions. Two methods of four- and 5-
steps were developed affording these new unnatural sugar analogues.
Introduction
Carbohydrates are an ubiquitous class of biomolecules with a great array of diversity, both in structure and
biological functions. 2’- or 3’-deoxypentofuranoses 1 and furthermore deoxynucleosides are of great
1
interest in medicinal chemistry. In this context, cyclic sugar analogues in which the anomeric carbon atom
2
is replaced by a phosphorus have received continuous attention in the literature. We have already
3
explored the synthesis of acyclic nucleoside phosphonates, and unnatural cyclic sugar analogues
4
containing a phosphorus atom at the anomeric position, both in the deoxyribose and deoxyxylose series 2.
Herein, we report the preparation of new deoxyfuranoses in their racemic form, with the phosphorus atom
replacing the carbon atom at the 2’-position (3) or 3’-position (4) of the heterocyclic tetrahydrofurane core
(Figure 1).
Figure 1. Natural sugar 1 and unnatural deoxyfuranose analogues 2-4
A) Synthesis of targeted unnatural 2-deoxyfuranoses 3
First of all, hypophosphorous acid has been dried from the commercial aqueous solution (50% w/w),
5
scrupulously complying a temperature below 35°C to avoid disproportionation during concentration. Then,
6
7
ethyl-diethoxymethyl H-phosphinate 5, rather unstable but more reactive than the corresponding
8
hypophosphorous ester, was preferred as starting precursor. This P-protected H-phosphinate 5 was
obtained from an esterification and a P-alkylation reaction catalyzed by p-toluenesulfonic acid (PTSA)
between dry hypophosphorous acid (1 eq.) and triethyl orthoformate (2 eq.) (Scheme 1). Ethyl-
diethoxymethyl hydrogenophosphinate 5 which was purified by distillation under reduced pressure in 48%
31
yield and 94% of purity (determined by P-NMR) can be used immediately or stored under nitrogen
atmosphere in the fridge.

Preparation of the unnatural 3-deoxy furanose 3 took place from the protected H-phosphinate 5 in a
convenient one pot sequence. Firstly, H-phosphinate 5 was quantitatively transformed into the trivalent
9
silylphosphonite 6, by refluxing H-phosphinate 5 with 1.7 equivalent of hexamethyldisilazane (HMDS).
After removal of excess of HMDS, the silylphosphonite 6 was diluted in THF under nitrogen and a silyl-
Abramov reaction was performed by the addition of 2-(benzyloxymethyl)oxirane 7 in the presence of ZnCl2
as Lewis acid catalyst. Subsequent cleavage of the trimethylsilyl (TMS) residue from the intermediate 8 was
achieved by addition of a hydrochloric solution (4N) to the reaction mixture. The protected 3-
deoxyfuranoses analogues 3 were obtained by a spontaneous 5-exo-tet cyclization in 44% yield for the
overall sequence (Scheme 1). At this stage, four different diastereomers 3a-d were formed in 33/37/15/14
ratio according to the presence of three chiral centers. From the mixture of the four diastereomers, two of
them were isolated separately as colorless oils after column chromatography on silica gel and were entirely
1
characterized by H-NMR.
1
All the H-NMR characteristics of both diastereomers were determined, but the JHH and JHP coupling
constants were too close to unambiguously attribute the relative configuration of each chiral center. Even
NOESY experiments revealed inconclusive. The last step of this sequence was the removal of the benzyl
group by catalytic hydrogenolysis (H , Pd/C). Then, starting from the pure diastereomer 3c, 5-hydroxy
2
deoxyfuranose analogue 9c was isolated as a single diastereomer in 94% yield. Whatever the
stereochemistry, we developed a simple and affordable method for an access to racemic 3-deoxy-2-
furanose where the anomeric carbon is directly linked to three heteroatoms. This particular type of
phospha-acetal is known to easily release formaldehyde upon treatment in acid conditions and this is why
10
the ethoxy group of acetal was conserved.
Scheme 1. Synthesis of the 3-deoxypentofuranose3a-d and 9.
i) HMDS, 3h, reflux; ii) 2-(benzyloxymethyl)oxirane 7, ZnCl , THF, 3h 60°C, then 16h RT; iii) HCl 4N, 30min RT, 44%; iv) H , Pd/C, 10%,
2
2
EtOH, atm. pressure, RT, 48h, 94%.
B) Synthesis of targeted 3-deoxyfuranoses analogue 4
Oxaphospholane derivatives 4a-d were synthesized through a five step sequence. The first step consisted in
an esterification of dry hypophosphorous acid by isopropyl alcohol, according to Gallagher and coworkers
11
methodology. Due to the disproportionation of the hypophosphorous acid upon heating, the reaction was
conducted in benzene rather than toluene in order to reduce this side reaction (Scheme 2). The resulting
isopropyl hypophosphite was directly reacted with allyl bromide in the presence of a solution of sodium
isopropoxide in THF at room temperature. The allyl-H-phosphinate 10 was obtained in 70% yield and a
31
purity of 98% determined by P NMR. The next step was the Pudovik reaction (ie the phosphoaldol
reaction) meaning the addition of the isopropyl allyl-H-phosphinate 10 to benzyloxyacetaldehyde in the
presence of catalytic amount of triethylamine. Under thermal heating, three weeks were necessary for the
complete consumption of the H-phosphinate 10. By contrast, phosphinates 11a-b were obtained in 64%
yield as a mixture of two diastereomers and a 56/44 ratio, under -wave activation at 150°C after only 15
12
min. This microwave-assisted Pudovik reaction was characterised by a spectacular acceleration, and
13
interestingly no disproportionation by-products were observed, even at this high temperature. The
31
diastereomer ratio given by HPLC were in good agreement with those obtained directly by P NMR
experiments. A pure diastereomer was successfully isolated by crystallization from the crude mixture.
Single crystals were analysed by X-ray experiments confirming the structure and (±)-P(R), C(S) relative

stereochemistry (Figure 2). The like (±)-P(S), C(S) and the unlike (±)-P(R), C(S) showed some structural
31
differences in P NMR chemical shift (like:  = 46.48 ppm; unlike:  = 46.92 ppm) and retention times on
chiral HPLC (like pair: 12.2 min and 16.1 min and unlike pair: 14.9 min and 19.8 min).
Figure 2. X-ray structure of one diastereomer 11 of relative configuration (±)-P(R), C(S).
The following step was the ozonolysis of the diastereomeric mixture of alkenes 11a-b, according to Malet
14
and coworkers methodology, which after treatment with PPh , allowed a quantitative conversion and the
3
formation of a mixture of two acyclic diastereomers 12a-b. In solution, the aldehydes 12a-b were present in
different forms. As classically observed with sugars, a subsequent ring closure occurred, producing the -
and -pentafuranose forms 13a-d. The existence of this ring-opening / ring-closure equilibrium between
the aldehydes 12a-b and cyclic furanose analogues 13a-d has been confirmed by a NOESY experiment. The
exchange connectivities in the NOESY experiment attested by the presence of correlation signals between
the CH of aldehydes (open-forms) and those of the CH anomeric groups (furanose forms) suggested a
15
dynamic equilibrium between the different diastereomers of the cyclic-forms and the acyclic-forms.
Scheme 2. Synthesis of the cyclic analogues of deoxyribose.
i) iPrOH, benzene, 16h, reflux, 100%; ii) H C=CH-CH -Br, NaOiPr, iPrOH, 70%; iii) Benzyloxyacetaldehyde, NEt , Toluene, -wave 15
2
2
3
min, 150°C, 64%; iv) a) O , -70°C, 10min, b) PPh , 65%; v) PTSA, MeOH, RT, 10 h, vi) Amberlite IR 120, toluene, 50°C, 3h, >95%.
3
3
In order to shift the equilibrium towards the cyclic deoxyribose 4a-d, the mixture constituted by 12a-b and
3a-d was heated in methanol under acidic conditions forming the acetals 14a-b. They were directly heated
1
under thermodynamic conditions in the presence of a sulfonic acid resin. The four deoxyfuranose
diastereomers analogues 4a-d were obtained almost quantitatively and in 28% overall yield from readily
affordable precursors. Nevertheless, all attempts to separate the four diastereomers by normal or reverse
phase chromatography failed.
Conclusion
In conclusion, 4- or 5-step syntheses in racemic series syntheses were developed to afford new
deoxyfuranoses analogues in good yields and incorporating a phosphorus atom replacing a carbon atom in
the 2’-position or 3’-position of the cyclic furanose ring. Further work directed at the synthesis of
nucleosides incorporating these unnatural sugar analogues and their biological applications are currently
underway and will be reported in due course.
Acknowledgments

This research was supported in part by a grant from IDENIX and from the Agence Nationale de la Recherche
et de la Technologie (ANRT).
Supplementary Material
Experimental procedures and characterization data of new compounds were provided in supplementary
material.
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Synthesis of Unnatural 2- and 3-Deoxyfuranose Analogues
a
b
Bénédicte Dayde,
Claire Pierra,
Gilles
b,c
b
Gosselin, Dominique Surleraux, Amadou
Tidjani Ilagouma, Arie Van der Lee, Jean-Noël
Volle, David Virieux, Jean-Luc Pirat
d
e
a
*,a
*,a