Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues

Article abstract of DOI:10.3762/bjoc.12.39

Efficient routes were developed for the diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues. The key steps of the synthesis were the easy accessibility of different types of arms in term of con

Full text of DOI:10.3762/bjoc.12.39

Diastereoselective synthesis of new O-alkylated and
C-branched inositols and their corresponding
fluoro analogues
Charlotte Collet*1,2,§, Françoise Chrétien1,2, Yves Chapleur1,2
and Sandrine Lamandé-Langle*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 353–361.
1Université de Lorraine, Vandoeuvre-les-Nancy F-54500, France and
2CNRS, UMR 7565, Vandoeuvre-les-Nancy F-54506, France
doi:10.3762/bjoc.12.39
Received: 17 November 2015
Accepted: 11 February 2016
Published: 25 February 2016
Email:
Charlotte Collet* - c.collet@nancyclotep.com;
Sandrine Lamandé-Langle* - sandrine.langle@univ-lorraine.fr
Associate Editor: J. N. Johnston
* Corresponding author
§ Present address: Nancyclotep, Plateforme d’imagerie moléculaire,
Vandoeuvre-les-Nancy F-54500, France
© 2016 Collet et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
C-branched; diastereoselective; fluoroinositols; inositols; O-alkylated
Abstract
Efficient routes were developed for the diastereoselective synthesis of new O-alkylated and C-branched inositols and their corre-
sponding fluoro analogues. The key steps of the synthesis were the easy accessibility of different types of arms in term of configu-
ration (myo and scyllo), the linking method and length, which could modulate the biological properties. These inositol derivatives,
bearing an arm terminated either with a hydroxy group or a fluorine atom, could be interesting candidates for diastereoisomeric
intermediates and biological evaluations, especially for PET imaging experiments.
Introduction
Inositol is a trivial name used to describe cyclohexanehexol characteristic aggregation in Alzheimer disease (AD), and more
compounds. Nine stereoisomers exist differing in the relative specifically Aβ42 peptide allowing its conformational change
orientation of the hydroxy groups, the most naturally abounding and its stabilization into small, nonfibrillar complexes, less
and biologically important is myo-inositol [1,2]. The chemistry toxic for neuronal cells [20-23]. The most efficient representa-
of inositols has been the theme of several investigations in the tive, scyllo-inositol, was shown to be able to reduce plaque
past few years [3,4]. Indeed inositols and their phosphorylated burden and to improve the performance on memory tasks in
or glycosylated [5] derivatives are involved in various biologi- animal models of Alzheimer disease [24-29]. Scyllo-inositol
cal processes [6-19]. In recent years, studies have shown that was recently used in human clinical trials for the treatment of
inositol derivatives interact with the β-amyloid protein (Aβ), patients suffering from AD [30,31].
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Beilstein J. Org. Chem. 2016, 12, 353–361.
McLaurin has also demonstrated that the corresponding fluoro- and metabolic stability [35-40]. Moreover fluorinated inositols
inositol (1-fluoro-1-deoxy-scyllo-inositol) was also a good could be useful for PET imaging applications.
candidate to limit this aggregation. However, in vivo studies in
animal models of Alzheimer disease with 1-[18F]fluoro-1- Results and Discussion
deoxy-scyllo-inositol used as radiotracer for positron emission Our strategy to prepare new alkylated inositol compounds and
tomography (PET) have shown that this compound crosses the their corresponding fluoro analogues was based on the use of
blood brain barrier (BBB) with difficulty [32]. The same PET the known benzylated myo-2-inosose 7 [41] that can be easily
imaging studies using the diastereoisomeric compound of myo obtained at large scale from commercially available myo-inos-
configuration (2-[18F]fluoro-2-deoxy-myo-inositol), did not get itol. The introduction of the arm into the inositol backbone
better results [33]. On the other hand, these radiotracers have through an O–C linker (O-alkylated) or a C–C linker
shown interesting features in the diagnosis of breast cancer with (C-branched) to afford diastereoselectively myo- and scyllo-de-
this imaging technique [33,34].
rivatives was the key step. In the case of the O-alkylated inosi-
tols a three carbon arm was envisioned whereas for the
Considering the synthetic and biological importance of inositol C-branched derivatives two and three carbon atom arms were
analogues, the design of new inositol derivatives to study their used. For the fluorinated inositols, we developed a synthetic
biological properties and to understand their binding mecha- route with easily removing protecting groups, as acetates, suit-
nisms with molecular targets, for instance through radiolabeled able for PET imaging application [42].
compounds, seems judicious.
Synthesis of O-alkylated myo- and scyllo-
inositol derivatives bearing a hydroxylated
arm
Thus we planned to study new synthetic inositols of myo- and
scyllo-configuration equipped with different carbon chains
linked either on one hydroxy group, i.e., O-alkylated, or
C-branched derivatives retaining the six hydroxy groups of the
inositol (Figure 1). These new inositol members could repre-
sent attractive tools for the development of further inositol ana-
logues. Indeed, this arm could improve some properties as the
lipophilicity for example and should allow the easy anchoring
of various groups or molecules, such as carbohydrates for ex-
ample.
The synthesis of the targeted hydroxylated O-alkylated inosi-
tols myo-1 and scyllo-1 (Scheme 1, see Supporting Information
File 1 for full experimental data) started with a sodium borohy-
dride reduction of the benzylated myo-2-inosose 7 in isopropyl
alcohol at room temperature to give a mixture of the myo- and
scyllo-inositol diastereoisomers myo-8 and scyllo-8. The mix-
ture was separated by column chromatography to afford the
pure myo- and scyllo-inositol derivatives in 58% and 30%
yields, respectively. The selectivity of this reduction was lower
compared to previously published results [43]. A diastereoiso-
meric ratio of 4:1 myo-8/scyllo-8 was estimated by 1H NMR
when the same reduction was done in a dichloromethane/metha-
nol mixture. This selectivity can be explained by a chelation of
the sodium ion with the two OBn adjoining the ketone, which
Two arm lengths of two or three carbons were envisioned, on
the C2 for the myo-series and on the C1 for the scyllo-series,
ending with a hydroxy group or a fluorine atom. Indeed the ad-
dition of fluorine could improve chemical properties including
lipophilicity, brain penetration, enhanced binding interaction
Figure 1: Structures of targeted synthetic inositol derivatives.
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Beilstein J. Org. Chem. 2016, 12, 353–361.
hindered the upper face. For our strategy having a moderate derivatives myo-1 and scyllo-1 were obtained quantitatively by
selectivity is of great advantage to continue the synthesis with removing of the benzyl protecting groups of compounds myo-10
both isolated diastereoisomers myo-8 and scyllo-8. Next, the and scyllo-10 by hydrogenation under pressure [45] using palla-
ether link was created by the reaction of alcohols myo-8 and dium hydroxide as catalyst.
scyllo-8 with allyl bromide under classical conditions in the
Synthesis of O-alkylated myo- and scyllo-
presence of NaH at reflux [44] to afford myo-9 and scyllo-9 in
good yield of 80% and 82%, respectively. The hydroxylated inositol derivatives bearing a fluorinated arm
arm was obtained by hydroboration using BH3 on the unsatu- The fluoro analogues of myo-1 and scyllo-1 were then prepared
rated compounds myo-9 and scyllo-9 followed by an oxidation through a synthetic strategy that involves easily removable
with H2O2/NaOH allowing the access to myo-10 and scyllo-10 acetates on the inositol ring (Scheme 2, see Supporting Informa-
in 78% and 75% yield, respectively. The O-alkylated inositol tion File 1 for full experimental data).
Scheme 1: Synthesis of O-alkylated inositol derivatives 1. Reagents and conditions: a) NaBH4, iPrOH, rt, 2 h, 58 and 30%; b) allyl bromide, NaH,
70 °C, 2 h, 80–82%; c) BH3, THF, rt, 6 h then H2O2, NaOH, rt, 12 h, 75–78%; d) Pd(OH)2, MeOH/CH2Cl2/H2O 10:10:1 (v/v/v), 45 psi, 18 h, quantita-
tive.
Scheme 2: Synthesis of O-alkylated fluorinated inositol derivatives 2.
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Beilstein J. Org. Chem. 2016, 12, 353–361.
The compounds myo-11 and scyllo-11 were obtained in 80% pounds scyllo-14 and scyllo-15 and showed correlations be-
and 76% yield, respectively in a one pot reaction by the treat- tween H3/H5 and the hydrogen on the vinylic or allylic arm re-
ment of myo-1 and scyllo-1 with triphenylmethyl chloride in spectively fully in agreement with a scyllo-inositol configura-
pyridine and a catalytic amount of DMAP at 40 °C for three tion.
days followed by the addition of acetic anhydride [46]. The
trityl group in myo-11 and scyllo-11 was cleaved without acetyl
migration using FeCl3 [47] to afford myo-12 and scyllo-12 in
good yields. The primary hydroxy groups can be easily con-
verted into fluorine by action of DAST in dichloromethane in
less than 5 minutes to give myo-13 and scyllo-13 in 95 and 92%
yield, respectively [48]. All protecting groups of myo-13 and
scyllo-13 were removed by the treatment with Na0 in MeOH
[49], which gave quantitatively the fully deprotected fluori-
nated O-alkylated inositols myo-2 and scyllo-2.
Synthesis of C-branched myo- and scyllo-
inositol derivatives bearing a hydroxylated
arm
Figure 2: nOe correlations for C-alkenylated inositol intermediates.
The synthesis of C-branched inositols was investigated using
two different arm lengths, with either two or three carbon
atoms. The introduction of these substituents was performed by
a Grignard reaction in THF with vinyl- or allylmagnesium bro-
mide on benzylated myo-2-inosose 7 (Scheme 3, see Support-
ing Information File 1 for full experimental data). The reaction
gave in both cases diastereoisomeric myo- and scyllo-inositols,
in a 60:40 proportion, respectively. The myo-inositol diastereo-
isomers were obtained in a larger proportion, due to the favored
equatorial attack as compared to the axial one. Fortunately, this
poor selectivity was associated with an easy separation by
column chromatography giving myo-14 and scyllo-14 bearing a
two carbon chain in 56% and 37% yield, respectively. The cor-
responding compounds myo-15 and scyllo-15 having an allyl
substituent were obtained in 53% and 38% yields, respectively.
Having the C-alkenylated inositols in hand, the synthesis of
C-branched inositol compounds with hydroxylated two or three
carbon atom arms could be achieved (Scheme 4, see Support-
ing Information File 1 for full experimental data).
Unsaturated C-branched inositols 14 and 15 lead to the corre-
sponding hydroxylated compounds 16 and 17, after hydro-
boration using BH3 in THF at 0 °C followed by conventional
oxidation using H2O2/NaOH, in 70–80% yield. Subsequent cat-
alytic hydrogenation under pressure with Pd(OH)2 as the cata-
lyst [45] allowed to obtaining quantitatively the fully hydroxyl-
ated inositols myo-3, scyllo-3, myo-4 and scyllo-4 as a new
hydroxylated inositol family.
Synthesis of C-branched myo- and scyllo-
inositol derivatives bearing a fluorinated two
carbons arm
For the synthesis of fluorinated C-branched inositols with a two
carbon atoms arm, a similar strategy as developed for the
O-alkylated inositols was chosen to access the fluorinated com-
The configuration of the diastereoisomers was determined with
1H and nOe NMR experiments (Figure 2). For compounds myo-
14 and myo-15 correlations between H1/H3 and the alkenyl
proton of the arm were observed confirming the equatorial ori-
entation of the substituent and therefore the myo-inositol config-
uration. The same experiments were performed with com-
Scheme 3: Synthesis of C-alkenylated inositol intermediates.
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Beilstein J. Org. Chem. 2016, 12, 353–361.
Scheme 4: Synthesis of C-branched inositol derivatives 3 and 4.
pounds bearing easily removable acetyl protecting groups myo-3 and scyllo-3, the first step was the protection of the pri-
(Scheme 5, see Supporting Information File 1 for full experi- mary hydroxy group with trityl chloride, followed by peracety-
mental data). Starting from the fully hydroxylated inositols lation with acetic anhydride in a one pot reaction [46]. Myo-18
Scheme 5: Synthesis of C-branched fluorinated inositol derivatives 5. Reagents and conditions: a) TrCl, DMAP (cat), pyridine, 3 days, 70 °C, then
Ac2O, rt, 2 h, 70–74%; b) isopropenyl acetate, p-TSA, 80 °C, 2 h; c) FeCl3, CH2Cl2, rt, 18 h or 15 min, 45–72%; d) DAST, CH2Cl2, rt; e) TsCl, Et3N,
CH2Cl2, rt, 3 h, 70–71%; f) isopropenyl acetate, p-TSA, 80 °C, 2 h, 78–99%; g) KF, 18-crown-6, CH3CN or TBAF, CH3CN or KHF2, 18-crown-6,
CH3CN; h) KF; 18-crown-6; CH3CN, rt, 2 h, 70%; i) Na0 (cat), MeOH, rt, 2 h, quantitative.
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Beilstein J. Org. Chem. 2016, 12, 353–361.
and scyllo-18 were obtained in 74 and 70% yield, respectively. tion or cyclization were identified depending on the experimen-
It is worthy to note that the tertiary hydroxy group in myo-18 tal procedure.
and scyllo-18 remained unprotected under these conditions. The
literature data are rather contradictory concerning the acetyla- From these results, the fluorination was finally investigated on
tion of this tertiary alcohol using acetic anhydride [50,51]. With myo-22 and scyllo-22 derivatives, which were not acetylated on
regard to a PET application, the protection of this hydroxy the tertiary position; in order to avoid the acyl migration. The
group is of paramount importance since the free hydroxy group treatment of myo-22 with KF, 18-crown-6 in acetonitrile [53] at
could impair the incorporation of the radioactive fluorine. room temperature (optimal conditions) furnished the fluori-
Therefor several methods of acetylation were carried out on nated compound myo-25 in 70% yield. The 19F NMR spectrum
myo-14, which was used as model. The best results for the acet- showed only one signal at −217 ppm (triplet of triplet,
ylation of the tertiary alcohol in good yield was obtained with J = 48 Hz, J = 28 Hz) establishing the formation of the ex-
the transesterification method using isopropenyl acetate as pected fluorinated product. Unfortunately, in the case of the
acylating agent and p-toluenesulfonic acid as catalyst at 80 °C isomeric scyllo-22 whatever the conditions used, the desired
for 2 h [52]. Unfortunately, when these reaction conditions were fluoro compound scyllo-25 could not be obtained; three differ-
applied on the tritylated compounds myo-18 and scyllo-18 we ent cyclized byproducts were formed. Finally, Zemplen [49]
were unable to obtain the fully protected products myo-19 and deprotection was performed on compound myo-25 to afford
scyllo-19; we only got several compounds without trityl group myo-5 quantitatively.
due to the acidic reaction conditions. So we decided to cleanly
Synthesis of C-branched myo- and scyllo-
remove this troublesome group using FeCl3 in dichloromethane
inositol derivatives bearing a fluorinated three
carbon atoms arm
Having in hand myo-4 and scyllo-4, the development of
C-branched inositols fluorinated on the three carbon atoms arm
was carried out by the same methodology as used for the
C-branched two carbon atoms chain (Scheme 6, see Supporting
Information File 1 for full experimental data).
for 18 h at room temperature [47]. Under these conditions the
compound scyllo-20 was obtained in a good yield (72%) while
myo-20 was obtained only in a poor yield (15%) due to the for-
mation of byproducts proceeding from cyclization and/or
acetate migration. By reducing the reaction time to 15 minutes
the byproducts formation could be lowered to 10% and myo-2
was obtained in 45% isolated yield. It is worthy to note that
41% of the starting material was recovered.
The selective protection of the primary hydroxy group with
At this stage, the fluorination was tested using DAST [48] on trityl chloride, followed by peracetylation with acetic an-
myo-20 and scyllo-20. Unfortunately, the desired fluorinated hydride in one pot was carried out [46]. Compounds myo-26
products myo-21 and scyllo-21 were not obtained; instead elimi- and scyllo-26 were obtained in 67% and 70% yields, respective-
nation reaction and the formation of unidentified products were ly. However, as already observed for the two carbon-atoms-
observed. Hence, tosylation was next performed, in order to arm-branched compounds, the tertiary hydroxy group remained
allow the nucleophilic substitution with fluoride at a later stage. unprotected. As explained above, the protection of this hydroxy
For this, compounds myo-20 and scyllo-20 were reacted with group is mandatory for labeling with [18F]-fluoride with regard
tosyl chloride in the presence of a catalytic amount of triethyl- to a PET application. Therefore the acetylation of myo-26 and
amine at room temperature for 3 h to give tosylated myo-22 and scyllo-26 using the transacetylization protocol [52] gave the
scyllo-22 in 70 and 71% yield, respectively. Next, acetylation of fully acetylated products myo-27 and scyllo-27 in 56% and 52%
the tertiary alcohol was performed before fluorination. The isolated yields, respectively. The moderate yields could be ex-
utilization of isopropenyl acetate as solvent in the presence of plained by the presence of detritylated fully acetylated byprod-
p-TSA at 80 °C for 2 h [52] gave the corresponding acetylated ucts due to the acidic reaction conditions. Next, deprotection of
compounds myo-23 and scyllo-23 in good to excellent yields. the trityl group from myo-27 and scyllo-27 was performed using
The access to fluorinated compounds by nucleophilic substitu- FeCl3 in dry dichloromethane at room temperature overnight
tion was investigated starting from these fully acetylated inosi- [47]. The hydroxylated products myo-28 and scyllo-28 were ob-
tols. The fluorination reactions using potassium fluoride, tained in 63% and 70% yields, respectively. The fluorination of
18-crown-6 in acetonitrile at 70 °C [53], TBAF in acetonitrile at compounds 28 was carried out with DAST as fluorinating agent
60 °C for 2 h [54] or KHF2 and 18-crown-6 in acetonitrile for in dichloromethane at room temperature for 5 min [48] and the
2 h at 60 °C [55] were performed. However, 19F NMR analyses fluoro-compounds myo-29 and scyllo-29 were obtained in
of the reaction mixtures did not show any fluorine incorpora- excellent yields of 95% and 91%, respectively. Finally,
tion. Various types of compounds resulting from the migration Zemplen deprotection [49] of the acetyl groups was carried out
of the tertiary acetate to the primary position, elimination reac- to furnish quantitatively the fully deprotected fluoro-inositols
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Beilstein J. Org. Chem. 2016, 12, 353–361.
Scheme 6: Synthesis of C-branched fluorinated inositol derivatives 6. Reagents and conditions: a) TrCl, DMAP (cat), pyridine, 3 d, rt, then Ac2O, rt,
2 h, 67–70%; b) isopropenyl acetate, p-TSA, 80 °C, 2 h, 52–56%; c) FeCl3, CH2Cl2, rt, 18 h, 63–70%; d) DAST, CH2Cl2, rt, 5 min, 91–95%; e) Na0
(cat), MeOH, rt, 2 h, quantitative.
myo-6 and scyllo-6. The obtained diastereoisomeric compounds term of configuration (myo and scyllo), linking method and
myo-6 and scyllo-6 having a C–C linked three carbon-atoms length, which could modulate the biological properties. The
arm represent a new class of inositols.
series bearing an arm terminated by a hydroxy group could
provide interesting candidates for biological evaluations but
The above results demonstrate that the new O-alkylated and also as useful diastereoisomeric intermediates to anchor various
C-branched inositols with myo- and scyllo-configuration were groups such as carbohydrates, for example, opening up new
available in a highly diastereoselective way. Different types of avenues for the total synthesis of new inositol derivatives. The
arm were easily introduced on the inositol ring. For the O-alky- synthesized inositol derivatives with fluorinated arms could be
lated series, the hydroxylated (myo-1 and scyllo-1) as well as more specifically interesting candidates for PET imaging exper-
fluorinated derivatives (myo-2 and scyllo-2) were synthesized in iments. Their potential use as radiotracers is under current in-
a simple and efficient manner. Concerning the C-branched fluo- vestigation.
rinated inositols, the synthesis of compounds having a three car-
bon atoms arm (myo-6 and scyllo-6) was easier than the corre-
Supporting Information
sponding compounds substituted with the two carbon atoms arm
where only compound myo-5 could be obtained. Indeed with the
Supporting Information File 1
chain being longer, the formation of byproducts originating
from cyclization and migration, favored by the proximity of the
inositol ring and preferential transition states, was avoided. The
synthetic routes are convenient and could provide sufficient ma-
terial for biological study.
Experimental procedures, characterization data and copies
of 1H, 13C, and 19F NMR spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-39-S1.pdf]
Conclusion
Acknowledgements
In conclusion, novel families of O-alkylated and C-branched
inositols with a two or three carbon atoms arm and their corre-
sponding fluoro analogues were synthesized in an efficient and
diastereoselective manner. Noteworthy aspects of this method-
ology are the easy accessibility of different types of arms in
We thank the Ministère de l’enseignement supérieur for a
doctoral fellowship to CC. This work was partially supported by
funding from INSERM (PNR-IMA0701). The authors also
thank B. Fernette for NMR technical assistance and F. Dupire
for mass spectrometry.
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