New 4-amino-5-H-2,3-dihydroisothiazole-1,1-dioxides from sugar α-aminonitriles using the CSIC reaction

Article abstract of DOI:10.1016/S0040-4039(00)02013-X

4-Amino-5H-2,3-dihydroisothiazole-1,1-dioxide ring was attached to a monosaccharide ring system by carbanion-mediated sulfonate intramolecular cyclisation (CSIC) of either secondary or tertiary aminoitrilesulfonamide carbohydrate derivatives using NaH, Cs

Full text of DOI:10.1016/S0040-4039(00)02013-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 593–595
New 4-amino-5-H-2,3-dihydroisothiazole-1,1-dioxides from sugar
a-aminonitriles using the CSIC reaction
Denis Postel,* Albert Nguyen Van Nhien, Pierre Villa and Gino Ronco
Laboratoire de Chimie Organique et Cine´tique, Groupe de Valorisation des Glucides Universite´ de Picardie-Jules Verne,
33 rue Saint Leu, 80039 Amiens, France
Received 12 October 2000; accepted 7 November 2000
Abstract—4-Amino-5-H-2,3-dihydroisothiazole-1,1-dioxide ring was attached to a monosaccharide ring system by carbanion-
mediated sulfonate intramolecular cyclisation (CSIC) of either secondary or tertiary aminonitrilesulfonamide carbohydrate
derivatives using NaH, Cs2CO3 or BuLi as a base. These new bicyclic systems were used as glycone precursors of aza analogues
of TSAO RT inhibitors. We report the first synthesis of an aza analogue of TSAO-m3T. © 2001 Elsevier Science Ltd. All rights
reserved.
sively to synthesise various sulfonates from
cyanohydrins2–4 and to sulfonamides from aminoni-
triles.4–8 Also, Camarasa used the CSIC reaction for
Carbanion-mediated sulfonate intramolecular cyclisa-
tion (CSIC) was first reported by Go´mez de las Heras
in 1988.1 Since then, this reaction has been used exten-
Scheme 1. (a) CH3SO2Cl, DMAP–pyridine; (b) CH3-I, K2CO3, acetone; (c) NaH, acetonitrile; (d) Cs2CO3, acetonitrile.
Keywords: a-aminonitriles; CSIC reaction; 4-amino-5-H-2,3-dihydroisothiazole-1,1-dioxide ring; TSAO.
* Corresponding author. Tel.: 03 22 82 75 70; fax: 03 22 82 75 68; e-mail: denis.postel@sc.u-picardie.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02013-X

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D. Postel et al. / Tetrahedron Letters 42 (2001) 593–595
the synthesis of 3%-spiro-5¦-(4¦-amino-1¦,2¦-oxathiol-
2¦,2¦-dioxide) nucleosides (TSAO nucleosides), which
represents a particular type of specific HIV-1 RT
inhibitor.9 Marco-Contelles widely studied the scope
and limitations of the CSIC reaction using derivatives
of aldehydes and ketone.5–8 He demonstrated that the
central nitrogen atom of aminonitrilesulfonamides
would have to be fully substituted in order for the
CSIC reaction to proceed, otherwise the amino nitro-
gen would be removed to give insoluble sodium salts of
the alkylsulfonamidonitriles. Whatever the initial sulfo-
nate or sulfonamide, the carbanion is generated by the
removal of a proton from the methylene neighbouring
the SO2 group with non-nucleophilic bases such as
DBU, NaH and Cs2CO3.
tion (Scheme 2).12 However, no CSIC reaction was
observed for the benzoylated derivative 8 and the initial
compound was not finally recovered.
These interesting results showed that a fully substituted
central nitrogen atom, in the sugar aminonitrilesulfon-
amides studied, is not necessary for the CSIC reaction
to take place if an alkyl lithium is used as base.
Over the last decade, extensive structure–activity rela-
tionship studies on TSAO derivatives have been con-
ducted.2,9,13,14 In order to prepared aza analogues of
these non-nucleoside RT inhibitors, we first synthesised
the thymine and uracil a-aminonitrilesulfonamide
nucleoside derivatives. CSIC reaction of the key
nucleoside intermediates gave [3-N-methyl-1-[2%,5%-
Recently, we have reported the stereoselective synthesis
bis-O-(tert-butyldimethylsilyl)-b-D-ribofuranosyl]thy-
of the
D
-allose (1a–d) and
D
-ribose (2a–d, 3 and 4)
mine]-3%-spiro-3¦-(4¦-amino-5-H-2¦-methyl-2¦,3¦-dihy-
droisothiazole-1¦,1¦-dioxide) (21) and [3-N-methyl-1-
a-aminonitriles from the corresponding uloses using
titanium(IV) isopropoxide as a mild Lewis acid catalyst
and TMSiCN as a cyanating agent.10
[2%,5%-bis-O-(tert-butyldimethylsilyl)-b-D-ribofuranosyl]-
uracil]-3%-spiro-3¦-(4¦-amino-5-H-2¦-methyl-2¦,3¦-dihy-
droisothiazole-1¦,1¦-dioxide) (22), which are the first
aza analogues of TSAO-m3-T and TSAO-m3-U.15
We now report the derivatisation of these a-aminoni-
triles using the CSIC reaction to obtain novel monosac-
charides possessing
a
4-amino-5-H-2,3-dihydro-
isothiazole-1,1-dioxide ring system at position 3 of the
furanose ring. As a first approach, we restricted the
cyclisation study to N-H and N-Me sulfonamide
derivatives. Compounds 1a, 2a, 3 and 4 were reacted
with methanesulfonyl chloride to give the sulfonamides
5, 6, 7 and 8, respectively (Scheme 1). N-Methylation
was performed using MeI and K2CO3 in acetone or
acetonitrile to give 9–12, which were cyclised with either
NaH or Cs2CO3 to give the target monosaccharide
derivatives 13–14, respectively, in good yields (Scheme
1).11
In conclusion, we have demonstrated that sugar a-
aminonitriles are important key intermediates for the
synthesis of systems in which a 3-(4-amino-5-H-2-
methyl-2,3-dihydroisothiazole-1,1-dioxide) ring is at-
tached to a furanose ring using the CSIC reaction. The
preliminary results reported herein proved that cyclisa-
tion could be achieved from a secondary sulfonamide
group using alkyllithium as a base. This strategy
appears to provide convenient access to a new range of
aza analogues of TSAO nucleosides (ATSAOs). Studies
in this direction are in progress.
It is notable that under similar basic CSIC reaction
conditions no reaction was observed with the sulfon-
amides 5–8. This lack of reactivity would be explained
by the removal of the acidic hydrogen atom from the
nitrogen atom of the sulfonamide group to give the
corresponding insoluble salt.8 Alternatively, an excess
of butyl lithium was used with the objective of generat-
ing the lithium salt which would be expected to be
sufficiently soluble to undergo a second attack of the
base leading to the carbanion required for the cyclisa-
Scheme 2. (e) BuLi–THF.

D. Postel et al. / Tetrahedron Letters 42 (2001) 593–595
595
Acknowledgements
Hz, H-4), 4.38 (s, 2H, NH2), 3.40 (d, H, H-5), 2.77 (s, 3H,
CH3-N), 1.64 (s, 3H, CH3), 1.34 (s, 3H, CH3). 13C NMR
(CDCl3) l 151.9 (1C, C-4%), 143.2 (3C, C ipso), 128.5,
127.8, 127.1 (15C, trityl), 113.0 (1C, CH3CCH3), 103.4
(1C, C-1), 93.2 (1C, C-5%), 87.4 (1C, C trityl), 84.2 (1C,
C-2), 74.8 (1C, C-4), 70.4 (1C, C-3), 60.9 (1C, C-5), 26.4
(1C, CH3-N), 26.0 (1C, CH3), 25.8 (1C, CH3).
We thank the Conseil Re´gional de Picardie and the
Ministe`re Franc¸ais de la Recherche for financial sup-
port, M. Pillon for technical support and G. Mackenzie
for helpful discussions.
12. Spectroscopic values for 18: 1H NMR (CDCl3) l 7.40–
7.23 (m, 15H, H trityl), 5.86 (d, 1H, J1,2=4.0 Hz, H-1),
5.22 (s, 1H, H-5%), 4.85 (s, 1H, NH), 4.48 (d, 1H, H-2),
4.46 (s, 2H, NH2), 4.00 (t, 1H, J4,5=5.0 Hz, H-4), 3.48 (d,
2H, H-5), 1.51 (s, 3H, CH3), 1.31 (s, 3H, CH3). 13C NMR
(CDCl3) l 152.1 (1C, C-4%), 143.3 (3C, C ipso), 128.6,
127.9, 127.2 (15C, trityl), 113.5 (1C, CH3CCH3), 103.7
(1C, C-1), 94.1 (1C, C-5%), 87.6 (1C, C trityl), 81.8 (1C,
C-2), 79.3 (1C, C-4), 69.3 (1C, C-3), 60.5 (1C, C-5), 26.4
(1C, CH3), 26.1 (1C, CH3).
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