Stereoselective synthesis of 2,6-dideoxy; 3,6-dideoxy; 2,3,6-trideoxy-inositol 1,4,5-trisphosphate and 6-deoxy-inositol 1,3,4,5-tetrakisphosphate analogues from 6-deoxy-d-inositol precursors

Article abstract of DOI:10.1016/S0040-4020(00)01112-1

The novel 2,6-dideoxy-2,2-difluoro; 2,6-dideoxy-2-fluoro; and 2,3,6-trideoxy-2,3-difluoro-Ins(1,4,5) tris(dibutyl)phosphates and 6-deoxy-D-chiro-inositol 1,3,4,5-tetrakis(dibutyl)phosphate analogues were synthesized in optically pure form. Modification of Ins(1,4,5)P₃ and Ins(1,3,4,5)P₄ analogues by lipophilic substituents has been investigated in order to produce neutral phosphate derivatives aimed to be incorporated in cell membrane for in vivo evaluation.

Full text of DOI:10.1016/S0040-4020(00)01112-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1161±1167
Stereoselective synthesis of 2,6-dideoxy; 3,6-dideoxy;
2,3,6-trideoxy-inositol 1,4,5-trisphosphate and 6-deoxy-inositol
1,3,4,5-tetrakisphosphate analogues from
6-deoxy-d-inositol precursors
a a,p
Aloõsio Antonio Alves Benõcio, Adilson David Da Silva, Mauro Vieira De Almeida,
a
Â
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Maria Mirtes Da Silva and Stephane Dov Gero
b
b
Â
a
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Ã
Departamento de Quõmica, Instituto de Ciencias Exatas, Universidade Federal de Juiz de Fora, 36036-330 Juiz de Fora MG, Brazil
bInstitut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-Yvette Cedex, France
Â
This article is dedicated to the memory of Stephane Dov Gero, who passed away on 16 November 1998
Received 28 April 2000; accepted 21 November 2000
AbstractÐThe novel 2,6-dideoxy-2,2-di¯uoro; 2,6-dideoxy-2-¯uoro; and 2,3,6-trideoxy-2,3-di¯uoro-Ins(1,4,5)tris(dibutyl)phosphates and
6-deoxy-d-chiro-inositol 1,3,4,5-tetrakis(dibutyl)phosphate analogues were synthesized in optically pure form. Modi®cation of Ins(1,4,5)P3
and Ins(1,3,4,5)P4 analogues by lipophilic substituents has been investigated in order to produce neutral phosphate derivatives aimed to be
incorporated in cell membrane for in vivo evaluation. q 2001 Elsevier Science Ltd. All rights reserved.
It is conceivable that inhibitors of the key enzymes of the
phosphoinositide cascade, as phosphatases or kinases, could
be of medicinal interest. For example, intracellular signaling
pathways mediating the effects of oncogenes on cell growth
and transformation offer novel targets for the development
of anticancer drugs.1
5-phosphatase, and the rational chemical design of agonists,
antagonists and enzyme inhibitors.
Several inositol ring-modi®ed and phosphate-modi®ed
analogues have been synthesized and progress has been
made in understanding the role of phosphate and hydroxyl
groups in determining activity of second messengers.3
As a result of the stimulation of cell surface receptors by a
variety of ligands, the membrane-located phosphatidylino-
sitol 4,5-bisphosphate is hydrolyzed by phospholipase C to
1D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and
diacylglycerol. The further metabolism of Ins(1,4,5)P3 is
quite complex and involves the action of various kinases
and phosphatases. An important initial transformation is
the phosphorylation of Ins(1,4,5)P3 through the action of
an ATP-dependent 3-kinase to give 1D-myo-inositol
1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]. While the role
of this metabolite is still under study, the suggestion has
been made that it may play a role in re®lling the intracellular
The D-3-substituted myo-inositol analogues are selective
inhibitors of the growth of v-sis-transformed NIH 3T3
cells.4 Furthermore the 6-deoxy Ins(1,4,5)P3 has already
been shown to be a full agonist for Ca21 release in perme-
abilized SH-SY5Y human neuroblastoma cells, a relatively
potent Ins(1,4,5)P3 5-phosphatase inhibitor and a weak
substrate for Ins(1,4,5)P3 3-kinase.5
The optically active starting material, 6-deoxy Ins(1,5) diol
1, was prepared from d-galactose (Scheme 1) according to
our earlier developed methodology, using Ferrier rearrange-
ment in the stereoselective sugar to cyclitol transformation
step.6
Ca21 stores with extracellular Ca21 2
.
A major challenge is now the elucidation of the structural
basis for interaction of Ins(1,4,5)P3 both with its receptor
and with the metabolic enzymes Ins(1,4,5)P3 3-kinase and
1. Results and discussion
In view of the inhibition of the 3-kinase and 5-phosphatase
by 2-, 3- or 6-deoxy substituted Ins(1,4,5)P3 derivatives
and after the success accounted on the transmembrane
incorporation of lipophilic derivatives of Ins(1,4,5)P3,3 the
Keywords: inositol 1,4,5-trisphosphate; phosphoinositide cascade; lipo-
philic substituents.
Corresponding author. Fax: 1(32)-3229-3314;
e-mail: david@quimica.ufjf.br
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01112-1

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A. A. A. Benõcio et al. / Tetrahedron 57 (2001) 1161±1167
1162
Scheme 1.
preparation of the 2-, 3- and 6-deoxy Ins(1,4,5)P3 deriva-
tives in more lipophilic forms seemed attractive. Addition-
ally, the ¯uorine atom is a suitable isostere for a hydroxy
group. Such an isosteric replacement was viewed as giving
rise to a compound which in terms of its physiochemical
properties should still be close enough to inositol to enter
into the cell via a carrier-mediated process. Furthermore in
the last decade a number of deoxy-¯uoro-myo-Ins(1,4,5)P3
and deoxy-¯uoro-scyllo-Ins(1,4,5)P3 analogues have shown
interesting biological results.7
presence of Pd/C 10%, produced the 3-O-benzoyl-2,6-
dideoxy-2,2-di¯uoro-myo-inositol 7. The latter compound
was phosphorylated by reaction with bisbutyloxy(diiso-
propylamino)phosphine and tetrazole, followed by oxi-
dation with t-BuOOH, leading to the protected 2,2-
di¯uoro-tris(dibutyl)phosphate 8 in 55% yield. Saponi®-
cation of the ester intermediate 8, under basic medium in
dichloromethane, afforded the 2,2-di¯uoro-tris(dibutyl)-
phosphate 9 in quantitative yield.
In order to produce the 2,3,6-trideoxy-2,3-di¯uoro-
Ins(1,4,5)tris(dibutyl)phosphate 14 the following methods
were adopted (Scheme 3). The alcohol 4 was treated with
the (diethylamino)sulfurtri¯uoride (DAST) with inversion
of con®guration to yield the 3-O-benzoyl-1,4,5-tri-O-
benzyl-2,6-dideoxy-2-¯uoro-scyllo-inositol 10, in 90%
yield. Removal of the benzoyl group on 10 under basic
conditions gave 11, in 76% yield, which was ¯uorinated
with DAST, with inversion of con®guration to yield the
2,3-di¯uoro 12 in 75% yield. Hydrogenolysis of the benzyl
groups afforded the 2,3-di¯uoro 13 in 55% yield, which was
allowed to be phosphorylated in the presence of bisbutyl-
oxy(diisopropylamino)phosphine and tetrazole, followed by
oxidation with t-BuOOH, leading to 14 in 55% yield.
Keeping these considerations in mind, we justi®ed the
synthesis of 2,6-dideoxy-2,2-di¯uoro-Ins(1,4,5)tris(dibutyl)-
phosphate 9, 2,6-dideoxy-2-¯uoro-Ins(1,4,5)tris(dibutyl)-
phosphate 17 and 2,3,6-trideoxy-2,3-di¯uoro-Ins(1,4,5)-
tris(dibutyl)phosphate 14 and 6-deoxy-d-chiro-Ins(1,3,4,5)-
tetrakis(dibutyl) phosphate 22.
Compound 1 was treated with benzyl bromide and sodium
hydride in DMF to give the tri-O-benzyl derivative 2 in 93%
yield (Scheme 2). Hydrolysis of the cyclohexylidene ketal,
under mildly acidic conditions, afforded the protected deoxy
myo-inositol 3, in 95% yield, which presented two free
hydroxyls at the 2 and 3 positions. The benzoylation of
diol 3 was carried out, in 96% yield, by treatment with
benzoyl chloride in pyridine to give the intermediate 4,
which was oxidized in the presence of TPAP/NMO to
give the 2-inosose 5 in 80% yield. Conversion of this ketone
into the 2,2-di¯uoro derivative 6 was accomplished in 62%
yield using (diethylamino)sulfur tri¯uoride (DAST). The
hydrogenolysis of the protected 2,2-di¯uoro 6, in the
The deprotection of the intermediate 10 was achieved by
hydrogenolysis of benzyl groups to give 15 in quantitative
yield (Scheme 4). The 2,6-dideoxy-2-¯uoro-Ins(1,4,5)tris-
(dibutyl)phosphate 16 was prepared from the triol 15, in
73% yield, by the same phosphorylation procedure
described above. Cleavage of benzoyl group of 16 was
Scheme 2.

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A. A. A. Benõcio et al. / Tetrahedron 57 (2001) 1161±1167
1163
Scheme 3.
Scheme 4.
accomplished in 95% yield by treatment with sodium
n-butoxide in dichloromethane.
2. Conclusion
We have illustrated the potentiality of deoxy cyclitol
precursors, stereoselectively produced from d-galac-
tose,8,9 to be used for the synthesis of optically pure
As described recently,8 the protected 6-deoxy Ins(3,4)diol
19 is easily available from cyclohexanone a-hydroxyl
(Scheme 1). Saponi®cation of the diester intermediate 19
(Scheme 5), under basic medium, afforded the tetrol 20 in
86% yield, which was allowed to be phosphorylated in the
presence of bisbutyloxy(diisopropylamino)phosphine and
tetrazole, followed by oxidation with t-BuOOH, leading
to the tetrakis(dibutyl)phosphate 21 in 55% yield. Hydro-
genolysis, in the presence of Pd/C 10% in AcOEt, of
intermediate 21 furnished the lipophilic tetrakis(dibutyl)-
phosphate 22 in 85% yield.
2,6-dideoxy-2,2-di¯uoro;
2,6-dideoxy-2-¯uoro
and
2,3,6-trideoxy-2,3-di¯uoro-Ins(1,4,5)tris(dibutyl)phosphates
and 6-deoxy-d-chiro-inositol 1,3,4,5-tetrakis(dibutyl)phos-
phate analogues. The 6-deoxy analogues of the well-
known second messenger Ins(1,4,5)P3, possessing
a
promising biological effect on permeabilized cells,3
have been transformed into lipophilic forms in order to
assume their incorporation through the membrane of intact
cells.
Scheme 5.

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A. A. A. Benõcio et al. / Tetrahedron 57 (2001) 1161±1167
1164
Preliminary success encountered in vivo in the incorpo-
ration of lipophilic analogues of Ins(1,4,5)P3 into cell
membrane encouraged the investigation of lipophilic
2,6-dideoxy, 3,6-dideoxy, 2,3,6-trideoxy Ins(1,4,5)P3 and
6-deoxy Ins(1,3,4,5)P4 analogues on Ca21 mobilization.
3.4. 3,4,6-Tri-O-benzyl-2-O-benzoyl-1-one-5-deoxy-d-
myo-inositol 5
N-oxy-4-methylmorpholine (67.25 mg, 0.57 mmol), tetra-n-
propylammonium perruthenate (13 mg, 0.04 mmol) and
molecular sieves (200 mg) were added to a solution of 4
(200 mg, 0.38 mmol) in anhydrous dichloromethane
(4 mL). The mixture was stirred for 12 h before addition
of isopropanol (1 mL). The stirring was maintained for
30 min before concentration and ®ltration through silica
gel (eluent: AcOEt/heptane). The ®ltrate was concentrated
under reduced pressure and used without further puri®cation
(80%); [a]D1ˆ14.18 (c 1.0; CHCl3); mp 122±1258C; IR
1750 cm21. H NMR (300 MHz; CDCl3) d: 5.5 (d, 1H,
H-2, J2±3ˆ10); 4.2 (dd, 1H, H-6, J6±5eqˆ4, J6±5axˆ10); 3.9
(m, 2H, H-4, H-3); 2.6 (m, 1H, H-5eq); 1.8 (q, 1H, H-5ax,
J5ax±4ˆJ5ax±5eqˆ10); 13C NMR (75.50 MHz; CDCl3) d: 199
(C-1); 82 (C-4); 80 (C-6); 78 (C-2); 75 (C-3); 34 (C-5);
(Found C, 76.36; H, 6.17; C34H32O6 requires C, 76.10; H,
6.01%).
3. Experimental
3.1. 1,4,5-Tri-O-benzyl-2,3-O-cyclohexylidene-6-deoxy-
d-myo-inositol 2
NaH (250 mg, 10.4 mmol) was added, under argon, to diol 1
(1.14 g, 2.22 mmol) dissolved in N,N-dimethylformamide
(15 mL). The mixture was stirred for 10 min before benzyl-
bromide (2.46 mL, 10 mmol) was added. The solution was
stirred for 12 h then methanol was added. The reaction
mixture was extracted and the organic layer concentrated
to dryness. Flash chromatography on silica gel (eluent:
AcOEt/heptane) gave the myo-inositol 2 (93%). [a]Dˆ
1
2398 (c 0.27; CH2Cl2); H NMR (250 MHz; CDCl3) d:
3.5. 1,4,5-Tri-O-benzyl-3-O-benzoyl-2,2-di¯uoro-6-
deoxy-d-myo-inositol 6
4.3 (t, 1H, H-2, J2±1ˆJ2±3ˆ3); 4.1 (dd, 1H, H-3, J3±4ˆ12);
3.6 (m, 2H, H-4, H-1); 3.3 (m, 1H, H-5); 2.1 (m, 1H, H-6eq);
1.9 (q, 1H, H-6ax, J6ax±1ˆJ6ax±5ˆJ6ax±6eqˆ12); 13C NMR
(62.5 MHz; CDCl3) d: 85 (C-4); 80 (C-3); 77 (C-5); 74
(C-2); 72 (C-1); 30 (C-6); (Found C, 76.86; H, 7.52;
C33H38O5 requires C, 77.01; H, 7.44%).
Diethylaminosulfur tri¯uoride (0.3 mL, 2 mmol) was added
to a solution of the ketone 5 (500 mg, 0.9 mmol) in anhy-
drous dichloromethane (5 mL). The solution was stirred for
20 h at room temperature before addition of methanol
(5 mL). The reaction mixture was extracted and the organic
layer concentrated to dryness. Flash chromatography on
silica gel (eluent: AcOEt/heptane) gave the di¯uoro 6
(62%). [a]Dˆ22.38 (c 1.0; CHCl3); mp 60±628C; 1H
NMR (200 MHz; CDCl3) d: 5.4 (m, 1H, H-3); 3.8 (t, 1H,
H-4, J4±5ˆJ3±4ˆ9); 3.7±3.5 (m, 2H, H-1, H-5); 2.6 (m, 1H,
H-6eq); 1.8 (q, 1H, H-6ax, J6ax±1ˆJ6ax±6eqˆJ6ax±5ˆ12); 13C
NMR (50 MHz, CDCl3) d: 123±120±116 (C-2, J2±Fˆ252);
81 (C-4, J4±Fˆ7); 76 (C-5); 73 (C-1, J1±Fˆ19); 71 (C-3,
J3±Fˆ19); 32 (C-6, J6±Fˆ7); (Found C, 72.17; H, 6.02;
C34H32F2 requires C, 71.94; H, 5.86%).
3.2. 1,4,5-Tri-O-benzyl-6-deoxy-d-myo-inositol 3
Methanol (10 mL, 0.23 mol) and HCl (0.6 mL, 0.02 mmol)
were added to the inositol 2 (1.0 g, 1.9 mmol). The solution
was stirred at 608C for 15 h. The reaction mixture was
extracted and the organic layer concentrated to dryness.
The residue was puri®ed by ¯ash chromatography on silica
gel (eluent: AcOEt/heptane) to give the inositol 3 (98%).
1
[a]Dˆ4.98 (c 1.0; CHCl3); H NMR (300 MHz; CDCl3) d:
4.7 (d, 1H, H-3, J2±3ˆ0, J3±4ˆ9); 4.2 (sl, 1H, H-2); 3.8 (t,
1H, H-4, J4±5ˆ9); 3.5 (m, 2H, H-1, H-5); 2.2 (dt, 1H, H-6eq,
J6eq±5ˆJ6eq±1ˆ3, J6eq±6axˆ12); 2.0 (q, 1H, H-6ax, J6ax±5
ˆ
3.6. 3-O-Benzoyl-2,6-dideoxy-2,2-di¯uoro-d-myo-
inositol 7
J6ax±1ˆJ6ax±6eqˆ12); 13C NMR (75.50 MHz, CDCl3) d: 82
(C-4); 78 (C-5); 75 (C-2); 74 (C-3); 70 (C-1); 30 (C-6);
(Found C, 74.24; H, 7.01; C27H3O5 requires C, 74.63; H,
7.00%)
Di¯uoro 6 (250 mg, 0.4 mmol) was dissolved in the mini-
mum amount of AcOEt and hydrogenated for 2 h under
3 psi, in the presence of Pd/C 10% (36 mg). The catalyst
was removed by ®ltration on silica gel (eluent: AcOEt) and
the solvent evaporated to afford the desired compound 7 in
93% yield. [a]Dˆ9.28 (c 0.6; CH3OH); mp 194±1968C; 1H
NMR (300 MHz; CD3OD) d: 5.2 (dd, 1H, H-3, J3±4ˆ10);
4.5±4.3 (dt, 1H, H-2, J2±Fˆ52); 3.9 (m, 1H, H-5); 3.6 (m,
1H, H-1); 3.5 (t, 1H, H-4, J4±5ˆ10); 2.2 (m, 1H, H-6eq); 0.8
(q, 1H, H-6ax, J6ax±1ˆJ6ax±6eqˆ12); 13C NMR (75.50 MHz;
CD3OD) d: 169 (CyO); 136±130 (Ph); 122±119±115 (C-2,
J2±Fˆ224); 77 (C-4); 75 (C-3); 71 (C-5); 69 (C-1); 32 (C-6);
(Found C, 54.31; H, 5.05; C13H14O5F2 requires C, 54.19; H,
4.90%).
3.3. 1,4,5-Tri-O-benzyl-3-O-benzoyl-6-deoxy-d-myo-
inositol 4
To a solution of diol 3 (725 mg, 1.6 mmol) in pyridine
(10 mL) was added benzoyl chloride (0.3 mL, 2.10 mmol).
The solution was stirred at 108C for 20 min, extracted with
CH2Cl2 (2£50 mL) and the organic layer was evaporated
under reduced pressure. The residue was puri®ed by ¯ash
chromatography on silica gel (eluent: AcOEt/heptane) to
afford the benzoylated inositol 4 (80%). [a]Dˆ47.08 (c
1
1.0; CHCl3); mp 135±1368C; H NMR (300 MHz; CDCl3)
d: 5.1 (d, 1H, H-3, J3±4ˆ10); 4.5 (sl, 1H, H-2); 4.2 (t, 1H,
H-4, J4±5ˆ10); 3.6 (m, 2H, H-1, H-5); 2.3 (m, 1H, H-6eq);
2.1 (q, 1H, H-6ax, J6ax±5ˆJ6ax±6eqˆJ6ax±1ˆ12); 13C NMR
(75.50 MHz; CDCl3) d: 80 (C-4); 78 (C-5); 75 (C-3); 74
(C-1); 69 (C-2); 30 (C-6); (Found C, 73.56; H, 6.41;
C34H34O6 requires C, 73.36; H, 6.19%).
3.7. 3-O-Benzoyl-2,6-dideoxy-2,2-di¯uoro-d-myo-
inositol-1,4,5-tris(dibutyl)phosphate 8
To di¯uoro 7 (86 mg, 0.3 mmol) was added dibutoxy(diiso-
propylamino)phosphine (480 mg, 1.7 mmol) and the

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A. A. A. Benõcio et al. / Tetrahedron 57 (2001) 1161±1167
1165
mixture was dried for 0.5 h under vacuum (0.05 mmHg).
3.10. 1,4,5-Tri-O-benzyl-2,6-dideoxy-2-¯uoro-scyllo-
inositol 11
Sublimated tetrazole (389 mg, 5.55 mmol), dissolved in
dry acetonitrile (10 mL) was added under argon to the
mixture. The solution was stirred under argon at room
temperature for 3 h. The solution was diluted with CH2Cl2
before t-BuOOH (1.07 mL, 11.12 mmol) was added. The
solution was stirred under argon at room temperature for
12 h. Aqueous sodium thiosulfate was added for neutrali-
zation. The product was separated by chromatography on
silica gel (eluent: AcOEt/heptane 8:2) (73%). [a]Dˆ14.68 (c
1.0; CHCl3); mp 62±658C; 1H NMR (300 MHz; CDCl3) d:
5.5 (m, 1H, H-3); 4.8 (m, 2H, H-1, H-2); 4.4 (m, 1H,
H-4); 4.1 (m, 12H, OCH2CH2CH2CH3); 2.7 (q, 1H, H-6eq,
J6eq±5ˆJ6eq±1ˆJ6ax±6eqˆ8); 2.1 (m, 1H, H-6ax); 1.7 (m, 12H,
OCH2CH2CH2CH3); 1.4 (m, 12H, OCH2CH2CH2CH3); 0.9
(m, 18H, OCH2CH2CH2CH3); 13C NMR (75.50 MHz;
CDCl3) d: 120±117±114 (C-2, J2±Fˆ201); 79 (C-5); 75
(C-4); 72 (C-1); 69 (C-3); 68 (OCH2CH2CH2CH3); 34
(C-6); 32 (OCH2CH2CH2CH3); 19 (OCH2CH2CH2CH3);
13 (OCH2CH2CH2CH3); (Found C, 50.83; H, 7.41;
C37H65O14P3F2 requires C, 50.83; H, 7.61%).
To a solution of compound 10 (140 mg, 0.26 mmol) in
AcOEt (5 mL) was added a solution of sodium hydroxide
(200 mg) in methanol (10 mL). The mixture was stirred for
24 h at room temperature before concentration and ®ltration
through silica (eluent: ethyl acetate). The ®ltrate was
concentrated under reduced pressure and used without
further puri®cation (76%). [a]Dˆ22.98 (c 0.8; CHCl3);
1
mp 82±858C; H NMR (300 MHz; CDCl3) d: 4.4 (dt, 1H,
H-2, J2±Fˆ51; J2±1ˆJ2±3ˆ10); 3.5 (m, 4H, H-3, H-4, H-1,
H-5); 2,4 (m, 1H, H-6eq); 1.5 (m, 1H, H-6ax); 13C NMR
(75.50 MHz; CDCl3) d: 100±99 (C-2, J2±Fˆ183); 85 (C-4,
J4±Fˆ9); 78 (C-3); 76 (C-5); 75 (CH2Ph); 74 (C-1); 33 (C-6,
J6±Fˆ9); (Found C, 74.30; H, 6.84; C27H29O4F requires C,
74.28; H, 6.69%).
3.11. 1,4,5-Tri-O-benzyl-2,3,6-trideoxy-2,3-di¯uoro-neo-
inositol 12
Diethylaminosulfur tri¯uoride (0.08 mL, 0.60 mmol) was
added to
a
solution of mono¯uoro 11 (100 mg,
3.8. 2,6-Dideoxy-2,2-di¯uoro-d-myo-inositol-1,4,5-
tris(dibutyl)-phosphate 9
0.23 mmol) in anhydrous dichloromethane (6 mL). The
mixture was stirred for 10 h under argon at room tempera-
ture before addition of methanol (10 mL). The reaction
mixture was extracted and the organic layer concentrated
to dryness. Flash chromatography on silica gel (eluent:
AcOEt/heptane) of the residue gave the di¯uoro 12 (75%).
[a]Dˆ3.48 (c 1.0; CHCl3); mp 104±1068C; 1H NMR
(300 MHz; CDCl3) d: 5.0 (dd, 1H, H-3, J3±F3ˆ51); 4.4
(dd, 1H, H-2, J2±3ˆ3, J2±F2ˆ47); 4.0±3.8 (m, 2H, H-1,
H-5); 3.4 (dd, 1H, H-4, J3±4ˆ3); 2.4 (m, 1H, H-6eq); 1.4
(m, 1H, H-6ax); 13C NMR (75.50 MHz; CDCl3) d: 95 (C-2,
J2±F2ˆ189, J2±F3ˆ24); 92 (C-3, J3±F3ˆ189, J3±F2ˆ24); 80
(C-4); 76 (C-5); 75 (C-1); 32 (C-6); (Found C, 73.69; H,
6.64; C27H28O3F2 requires C, 73.95; H, 6.43%).
A solution of sodium butoxide (0.1 mol/L) in dichloro-
methane was added to compound 8 (86 mg, 0.1 mmol)
and the mixture was stirred for 6 h. The reaction mixture
was extracted and the organic layer concentrated to dryness.
The residue was puri®ed by ¯ash chromatography on silica
gel (eluent: AcOEt/heptane 8:2) to furnish the triphos-
phate 9 (67%). [a]Dˆ0.448 (c 2.5; CHCl3); 1H NMR
(300 MHz; CDCl3) d: 4.4 (m, 3H, H-1, H-4, H-5); 4.1 (m
12H, OCH2CH2CH2CH3); 3.7 (m, 1H, H-3); 2.6 (m, 1H, H-
6eq); 2.1 (m, 1H, H-6ax); 1.7 (m, 12H, OCH2CH2CH2CH3);
1.4 (m, 12H, OCH2CH2CH2CH3); 0.9 (t, 18H,
OCH2CH2CH2CH3); 13C NMR (62.50 MHz, CDCl3) d: 80
(C-1); 71-70 (C-3, C-4, C-5); 68 (OCH2CH2CH2CH3);
33±32 (OCH2CH2CH2CH3); 30 (C-6); 19 (OCH2CH2CH2CH3);
14 (OCH2CH2CH2CH3); (Found C, 47.38; H, 8.16;
C30H61O13P3F2 requires C, 47.36; H, 8.08%).
3.12. 2,3,6-Trideoxy-2,3-di¯uoro-neo-inositol 13
Compound 12 (80 mg, 0.48 mmol) dissolved in the mixture
of AcOEt/MeOH (10 mL, 1:1) was hydrogenated by the
same procedure described to obtain 7 from 6 (90%).
1
[a]Dˆ211.18 (c 1.0; CH3OH); mp 193±1968C; H NMR
3.9. 1,4,5-Tri-O-benzyl-3-O-benzoyl-2,6-dideoxy-2-
¯uoro-scyllo-inositol 10
(300 MHz; CDCl3) d: 4.9 (m, 1H, H-3); 4.2 (m, 1H, H-2);
3.9 (m, 1H, H-1); 3.6 (m, 1H, H-5); 3.3 (m, 1H, H-4); 2.1
(m, 1H, H-6eq); 1.2 (m, 1H, H-6ax); 13C NMR (75.50 MHz,
CDCl3) d: 96 (C-2, J2±Fˆ168); 93 (C-3, J3±Fˆ168); 75
(C-4); 69 (C-5); 68 (C-1); 38 (C-6, J6±Fˆ9).
A solution of myo-inositol 4 (1.22 g, 2.26 mmol) in anhy-
drous dichloromethane (25 mL) was cooled to 08C before
addition of diethylaminosulfur tri¯uoride (0.6 mL,
4.5 mmol) under argon. The solution was stirred for 2 h
under argon at room temperature before addition of metha-
nol (10 mL). The mixture was extracted and the organic
layer concentrated to dryness. The residue was chromato-
graphed on silica gel (eluent: AcOEt/heptane) to give the
mono¯uoro 10 (90%). [a]Dˆ0.88 (c 1.0; CHCl3); mp 94±
3.13. 2,3,6-Trideoxy-2,3-di¯uoro-neo-inositol-1,4,5-
tris(dibutyl)-phosphate 14
The di¯uoro 13 (30 mg, 0.18 mmol) was added to dibutoxy-
(diisopropylamino)phosphine (300 mg, 1 mmol) and the
mixture was dried for 0.5 h under reduced pressure
(0.05 mmHg). Sublimated tetrazole (0.08 mg, 11.4 mmol),
dissolved in dry acetonitrile (5 mL) was added under argon
to the mixture. The solution was stirred under argon for 3 h
and diluted with CH2Cl2 before t-BuOOH (0.21 mL,
2.1 mmol) was added. The solution was stirred under
argon at room temperature for 20 h. Aqueous thiosulfate
and sodium solution was added for neutralization. After
1
958C; H NMR (300 MHz; C6D6) d: 5.6 (dd, 1H, H-3,
J2±3ˆ9, J3±4ˆ12); 4.5 (m, 1H, H-2, J2±Fˆ50); 3.3 (t, 1H,
H-4, J4±5ˆ12); 3.1 (m, 2H, H-1, H-5); 2.0 (m, 1H, H-6eq);
1.3 (q, 1H, H-6ax, J6ax±6eqˆJ6ax±1ˆJ6ax±5ˆ12); 13C NMR
(75.50 MHz; C6D6) d: 92 (C-2, J2±Fˆ187); 81 (C-4,
J4±Fˆ7); 73 (C-5); 72 (C-1, J1±Fˆ19); 71 (C-3, J3±Fˆ19);
31 (C-6, J6±Fˆ9); (Found C, 75.59; H, 6.22; F, 3.20;
C34H33O5F requires C, 75.53; H, 6.19; F, 3.51%).

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A. A. A. Benõcio et al. / Tetrahedron 57 (2001) 1161±1167
1166
extraction with dichloromethane the organic layer was
puri®ed by chromatography on silica gel (eluent: AcOEt/
heptane 8:2) to yield 14 in 55% yield. [a]Dˆ28.68 (c 0.8;
H-2, H-4, H-5); 3.7 (t, 1H, H-3, J3±4ˆJ3±2ˆ10); 2.6
(m, 1H, H-6eq); 1.9 (m, 1H, H-6ax); 1.7 (m, 12H,
OCH2CH2CH2CH3); 1.4 (m, 12H, OCH2CH2CH2CH3); 0.9
(m, 18H, OCH2CH2CH2CH3); 13C NMR (75.50 MHz;
CDCl3) d: 92±90 (C-2); 74 (C-5); 72 (C-1); 70±68 (C-3,
C-4); 32 (C-6); (Found C, 47.71; H, 8.19; P, 12.35;
C30H62O13P3F requires C, 47.92; H, 8.44; P, 12.36%).
1
CHCl3); H NMR (300 MHz; CDCl3) d: 4.5±4.2 (dd, 1H,
H-3, J3±Fˆ51, J3±4ˆ12); 4.7 (m, 1H, H-5); 4.6±4.1 (m, 3H,
H-1, H-4, H-2); 4.2 (m, 12H, OCH2CH2CH2CH3); 2.8 (m,
1H, H-6eq); 1.7 (m, 13H, H-6ax, OCH2CH2CH2CH3);
1.4 (m, 12H, OCH2CH2CH2CH3); 0.9 (m, 18H,
OCH2CH2CH2CH3); 13C NMR (75.50 MHz; CDCl3) d: 92
and 89 (C-3, J3±Fˆ180); 91 and 88 (C-2, J2±Fˆ180); 76
(C-4); 72±71 (C-1, C-5); 68 (OCH2CH2CH2CH3); 34
(C-6); 33 (OCH2CH2CH2CH3); 20 (OCH2CH2CH2CH3);
15 (OCH2CH2CH2CH3); (Found C, 48.51; H, 8.12;
C30H61O12P3F2 requires C, 48.38; H, 8.24%).
3.17. 2-O-Benzyl-6-deoxy-d-chiro-inositol 20
To a solution of chiro-inositol 19 (2.8 g, 6 mmol) in ethyl
acetate (10 mL) was added a solution of sodium hydroxide
(400 mg) in methanol (10 mL). The mixture was stirred for
4 h at room temperature before concentration and puri®-
cation by chromatography on RP8 (eluent: AcOEt/MeOH)
1
3.14. 3-O-Benzoyl-2,6-dideoxy-2-¯uoro- scyllo-inositol
15
(90%). [a]Dˆ22.88 (c 1.2; CH3OH); H NMR (300 MHz;
CD3OD) d: 4.8 (m, 2H, OCH2Ph); 4.0 (m, 2H, H-1, H-3);
3.6 (m, 2H, H-2, H-5); 3.5 (m, 1H, H-4); 2.8 (m, 2H, H-6eq,
H-6ax); 13C NMR(75.50 MHz; CD3OD) d: 80 (C-2); 74
(C-4); 70 (C-3); 68 (C-5); 66 (C-1); 38 (C-6); (Found C,
60.16; H, 7.17; C13H18O5´1/3H2O requires C, 60.33; H,
7.23%).
Mono¯uoro 10 (1.10 g, 2.03 mmol) dissolved in a mixture
of AcOEt/EtOH (10 mL, 8:2) was hydrogenated for 2 h
under 3 psi, in the presence of the Pd/C (800 mg). The
catalyst was removed by ®ltration in celite and the ®ltrate
was evaporated to dryness to afforded 15 in quantitative
yield. [a]Dˆ11.78 (c 1.0; CHCl3). mp 183±1858C, 1H
NMR (300 MHz; CD3OD) d: 5.35 (dd, 1H, H-3, J3±2ˆ9,
J3±4ˆ12); 4.5 (dt, 1H, H-2, J2±Fˆ52, J2±1ˆ9); 4.0 (m, 1H,
H-4); 3.7 (m, 2H, H-1, H-5); 2.3 (m, 1H, H-6eq); 1.6 (q, 1H,
H-6ax, J6ax±1ˆJ6ax±5ˆ12); 13C NMR (75.50 MHz; CD3OD)
d: 167 (OCOPh); 97 (C-2, J2±Fˆ184); 76 (C-4, J4±Fˆ9); 75
(C-1, J1±Fˆ18); 70 (C-5); 68 (C-3, J3±Fˆ18); 37 (C-6);
(Found C, 53.54; H, 5.85; C13H15O5F´5/4H2O requires C,
53.64; H, 5.94%).
3.18. 2-O-Benzyl-6-deoxy-d-chiro-inositol-1,3,4,5-
tetra(dibutyl)-phosphate 21
The tetrol 20 (100 mg, 0.4 mmol) was dissolved in THF
(7 mL) and cooled to 08C under argon. n-Butyllithium
1.6 M solution in hexane was added (0.1 mL, 1.0 mmol).
The temperature was cooled to 2408C and di-n-butyl phos-
phoryl chloride (0.72 g, 3.14 mmol) was added. The mixture
was stirred for 1 h extracted with CH2Cl2 and the organic
layer concentrated to dryness. The product was separated by
chromatography on silica gel (eluent: AcOEt/heptane 8:2)
(30%). [a]Dˆ213.28 (c 1.0; CH3OH). 1H NMR (300 MHz;
CDCl3) d: 4.8±4.4 (m, 5H, H-1, H-3, H-2, H-5, H-4); 3.9
(m, 16H, OCH2CH2CH2CH3); 2.5±2.0 (m, 2H, H-6eq,
H-6ax); 1.5 (m, 16H, OCH2CH2CH2CH3); 1.2 (m, 16H,
OCH2CH2CH2CH3); 0.7 (m, OCH2CH2CH2CH3); 13C
NMR (75.50 MHz; CDCl3) d: 74 (C-1); 73 (C-3); 72
(C-2); 71 (C-5, C-4); 66 (OCH2CH2CH2CH3); 31
(OCH2CH2CH2CH3); 30 (C-6); 19 (OCH2CH2CH2CH3);
14 (OCH2CH2CH2CH3); (Found C, 53.21; H, 8.73;
C45H86O17P4 requires C, 52.83; H, 8.47%).
3.15. 3-O-Benzoyl-2,6-dideoxy-2-¯uoro-scyllo-inositol-
1,4,5-tris(dibutyl)phosphate 16
Compound 15 (250 mg, 0.93 mmol) was phosphorylated in
73% yield by the same procedure described to obtain 14
1
from 13. [a]Dˆ28.68 (c 0.8; CHCl3); mp 44±468C; H
NMR (300 MHz; CDCl3) d: 5.5 (t, 1H, H-3, J3±4ˆJ3±2
ˆ
12); 4.7 (m, 3H, H-1, H-2, H-5); 4.4 (m, 1H, H-4); 4.1 (m,
12H, OCH2CH2CH2CH3); 2.9 (m, 1H, H-6eq); 1.9 (m, 1H,
H-6ax); 1.6 (12H, OCH2CH2CH2CH3); 1.4 (m, 12H,
OCH2CH2CH2CH3); 0.9 (m, 18H, OCH2CH2CH2CH3); 13C
NMR (75.50 MHz; CDCl3) d: 165 (PhCyO); 91 (C-2,
J2±Fˆ186); 77 (C-4); 71 (C-5, C-3); 70 (C-1); 67
(OCH2CH2CH2CH3); 32 (OCH2CH2CH2CH3); 31 (C-6);
18 (OCH2CH2CH2CH3); 13 (OCH2CH2CH2CH3); (Found
C,52.48; H, 7.69; P, 10.84; F, 2.16; C37H66O14P3F requires
C, 52.47; H, 7.85; P, 10.97; F, 2.24%).
3.19. 6-Deoxy-d-chiro-inositol-1,3,4,5-tetra(dibutyl)-
phosphate 22
The tetraphosphate 21 (100 mg, 0.1 mmol) dissolved in
AcOEt/EtOH (10 mL, 3:1) was hydrogenated for 3 h
under 3 psi, in the presence of the Pd/C catalyst (100 mg).
The catalyst was removed by ®ltration in silica (eluent:
AcOEt) and the solvent evaporated to obtain 22 in
3.16. 2,6-Dideoxy-2-¯uoro-scyllo-inositol-1,4,5-
tris(dibutyl)-phosphate 17
1
quantitative yield. [a]Dˆ2178 (c 1.9; CHCl3); H NMR
To a solution of mono¯uoro 16 (165 mg, 0.2 mmol) in
dichloromethane anhydrous (12 mL) was added a solution
of sodium n-butoxide (0.1 mol/L) in n-butyl alcohol. The
solution was stirred for 1 h, extracted with CH2Cl2 and the
organic layer concentrated to dryness. Flash chroma-
tography on silica gel (eluent: AcOEt/heptane 8:2) of the
residue gave the scyllo-inositol 17 (71%). [a]Dˆ22.28 (c
(300 MHz; CDCl3) d: 4.9 (m, 1H, H-4); 4.6 (m, 3H,
H-2, H-1, H-5); 4.3 (m, 1H, H-3); 4.1 (m, 16H,
OCH2CH2CH2CH3); 3.6 (m, 1H, OH); 2.4 (m, 1H, H-6eq);
2.3 (m, 1H, H-6ax); 1,7 (m, 16H, OCH2CH2CH2CH3);
1.3 (m, 24H, OCH2CH2CH2CH3); 1.0 (m, 24H,
OCH2CH2CH2CH3); 13C NMR (75.50 MHz; CDCl3) d:
75 (C-4, C-3); 72 (C-2); 69 (C-1, C-5); 68
(OCH2CH2CH2CH3); 32 (OCH2CH2CH2CH3); 30 (C-6);
19 (OCH2CH2CH2CH3); 14 (OCH2CH2CH2CH3); (Found
1
1.0; CHCl3); mp 105±1088C; H NMR (300 MHz; CDCl3)
d: 4.8 (m, 12H, OCH2CH2CH2CH3); 4.6±4.0 (m, 4H, H-1,

Â
A. A. A. Benõcio et al. / Tetrahedron 57 (2001) 1161±1167
1167
Ã
2. (a) Luckhoff, A.; Clapham, D. E. Nature (London) 1992, 355,
356. (b) Wilcox, R. A.; Challis, R. A. J.; Baudin, G.; Vasella,
A.; Potter, B. V. L.; Nahorski, S. R. Biochem. J. 1993, 294, 191.
3. Vieira de Almeida, M.; Dubreuil, D.; Cleophax, J.; Verre-
C, 49.01; H, 8.59; P, 13.32; C38H80O17P4 requires C, 48.92;
H, 8.64; P, 13.28%).
Â
Sebrie, C.; Pipelier, M.; Prestat, G.; Vass, G.; Gero, S. D.
Acknowledgements
Tetrahedron 1999, 55, 7251 and references therein.
4. (a) Dahl, J.; Jurczak, A.; Cheng, L. A.; Baker, D. C.; Benjamin,
T. L. J. Virol. 1998, 72, 3221. (b) Kozikowski, A. P.; Fauq,
A. H.; Powis, G.; Melder, D. C. J. Am. Chem. Soc. 1990, 112,
4528.
This research was supported by CNPq and Bayer-AG
Geschaftsbereich Pharma und Entwicklung Istitut. We
thank Dr. Jeannine Cleophax for many helpful discussions.
5. Safrany, S. T.; Wojcikiewicz, R. J. H.; Strupish, J.; Nahorski,
S. R.; Dubreuil, D.; Cleophax, J.; Gero, S. D.; Potter, B. V. L.
FEBS Lett. 1991, 278, 252.
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