Selective formation of 1,3-oxazolidine-2-thiones on ketohexose templates

Article abstract of DOI:10.1055/s-2004-830886

Thiocyanic acid condensation on selectively protected ketohexose led to the isolation of five out of the seven possible 1,3-oxazolidine-2-thiones (OZT). The four isomeric spiro-OZT synthesized showed promising biological activity against D-fructose transp

Full text of DOI:10.1055/s-2004-830886

LETTER
1945
Selective Formation of 1,3-Oxazolidine-2-thiones on Ketohexose Templates
S
elective Formatio
r
n of 1,3-
n
Oxazolidine
a
-
2-thiones
o
u
n
K
etohexos
d
e
T
emplates Tatibouët,*a Scott Lawrence,b Patrick Rollin,a Geoffrey D. Holmanb
a
ICOA – UMR 6005, Université d’Orléans, BP 6759, 45067 Orléans, France
Fax +33(2)38417281; E-mail: arnaud.tatibouet@univ-orleans.fr
b
Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
Received 18 May 2004
Dedicated to the memory of Professor Christian Pedersen, a gentleman in glycochemistry.
different OZTs (Scheme 1). Per-O-silylation of standard
Abstract: Thiocyanic acid condensation on selectively protected
ketohexose led to the isolation of five out of the seven possible 1,3-
oxazolidine-2-thiones (OZT). The four isomeric spiro-OZT synthe-
sized showed promising biological activity against D-fructose trans-
port.
mixtures resulting from preliminary experiments has
shown the fused furano derivative 4 to be the major
product (30% yield) from D-fructose. Similarly, L-sorbose
afforded a 50% yield of the C-5 epimer of 4, however no
simple reaction allowed a selective and efficient forma-
tion of those compounds.10 With a view to developing
better functionalized and more selective GLUT5 inhibi-
tors, the methodology to prepare efficiently various keto-
hexose-derived OZTs is needed to be developed.
Key words: carbohydrates, bicyclic compounds, spiro compounds,
D-fructose, 1,3-oxazolidine-2-thione
Among chiral auxiliaries, 1,3-oxazolidine-2-thiones
(OZT) have attracted important interest because of their
various applications in different synthetic transforma-
tions.1 These simple structures, closely related to the pop-
ular chiral oxazolidinones,2 have been explored in
asymmetric Diels–Alder reactions and asymmetric alkyl-
ations of their N-enoyl derivatives, but mostly in conden-
sations of their N-acyl derivatives on aldehydes which
have shown interesting features in anti-selective aldol re-
actions.3 All those major advances have proven helpful in
the total synthesis of biologically important natural prod-
ucts.4 In addition, OZT offer some advantages over ox-
azolidinones – namely high UV absorption or facile N-
acylation and -deacylation.5 Preparation of chiral OZT
can easily be performed reacting a b-aminoalcohol with
thiophosgene under basic conditions, but some natural
chiral oxazolidinethiones can also be produced by con-
trolled myrosinase degradation of glucosinolates like pro-
goitrin.6 In glycochemistry, OZT have long been studied:
preparation is either effected by reacting aminosugars
with thiophosgene under basic conditions or condensing
thiocyanic acid on unprotected carbohydrates.7 Fewer de-
velopments on the resulting complex bicyclic OZT have
been described. Exploration of the synthesis of indolizi-
dine-type iminosugars has been reported through an ele-
gant intramolecular ring closure using the OZT as
nitrogen nucleophile.8 Formation of OZT at the anomeric
position of carbohydrates has led to the development of
base-modified or sugar-modified nucleosides; it was also
exploited to mimic the hexoketose conformations in in-
hibiting fructose transporter GLUT5.9 The preparation of
OZT on hexoketoses is far from being a trivial reaction
despite the simple conditions used (KSCN, HCl, H2O). In-
deed, that reaction can be expected to produce up to seven
Scheme 1
A selective O-protection of D-fructose would indeed re-
duce the number of possibilities. 3-O-Protection would
only allow formation of the spiro-derivatives 1 and 2 or
oxazolinethione 5, whereas 1-O-protection would only
lead to fused structures 3 and 4. Benzyl protected deriva-
tives were selected as a model to study the selectivity of
formation of OZT on a ketohexose structure. The ether
protecting group should resist the strongly acidic condi-
tions required to form OZT. Various protected D-fructose
derivatives could be readily prepared in reasonable over-
all yields through classical protection–deprotection
glycochemistry, using mainly diisopropylidenation–ben-
zylation procedures. A standard two-step sequence is rep-
resented in the following: (1) isopropylidene deprotection
(aqueous TFA); (2) condensation with pseudohalogen
HSCN produced the OZT (Scheme 2).
SYNLETT 2004, No. 11, pp 1945–1948
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6
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9
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Advanced online publication: 04.08.2004
DOI: 10.1055/s-2004-830886; Art ID: D12204ST
© Georg Thieme Verlag Stuttgart · New York

1946
A. Tatibouët et al.
LETTER
We have previously described the formation of fused de- 14. Both epimers were isolated in a 1:6.5 (a:b) ratio albeit
rivatives of type 4, through 1-O-protection with benzyl or in a moderate 30% yield over the three-step sequence.
allyl groups on either di-O-isopropylidene D-fructose or
One other possibility to reduce the number of spiranic
forms was to prevent the 5-to-2 cyclization resulting into
furano derivatives. A 5-O-benzyl derivative would in this
case be appropriate, however in our hands, standard ap-
L-sorbose 6 and 7.9d Of the two possible structures expect-
ed in the D-fructo series, only the fused furano-OZT 8 was
detected and isolated (Scheme 2). This result is consistent
with molecular modeling: the enthalpy of formation was
proaches to produce a 5-O-benzylated ketohexose failed.
calculated using MOPAC parameters, showing a greater
Whereas the preparation of the di-O-benzoylated com-
stability (>7 kcal/mol) of 4 against 3.
pound 15 was straightforward,11 all attempts to benzylate
the remaining hydroxyl under basic or acidic conditions
only resulted in migration of the benzoyl groups and ben-
zylation shifted to the O-3 position to afford compound 16
(Scheme 4).
We therefore turned our attention to the 3,4,5-tri-O-ben-
zyl D-fructopyrano derivative 17, which should lead to the
spiro-pyrano forms. Selective deprotection of the 4,5-O-
isopropylidene of 9, then perbenzylation gave 17 in 64%
overall yield. The expected spiro-pyrano OZT 18 were
obtained in reasonable yield of 53%, but the two epimers
could only be separated after acetylation with difficulties
and rather low yields – 16% (19b) and 9% (19a) – due to
relative instability of the N-acetyl spiro-pyrano OZT.
Scheme 2
The 3,4-di-O-benzylated D-fructopyrano derivative 20
(Scheme 5) could also be a precursor of choice to form
OZT. Readily available through a methodology devel-
oped in our group,11 it would limit the possibilities for
spiro-furano and -pyrano derivatives. Application of the
usual two-step process afforded, with an overall yield of
60%, a mixture of OZT in which the spiro-furano forms
22 predominated over the spiro-pyrano forms 21 in a 2:1
ratio. After column chromatography separation of 21
from 22, acetylation allowed isolation of each epimer
either furano-23a and -23b (37% and 35% yield, respec-
tively) or pyrano-24a and -24b (41% and 27% yield,
respectively).12
A 3-O-benzylated D-fructose derivative was produced
from 1,2:4,5-di-O-isopropylidene-b-D-fructopyranose (9)
under standard conditions11 to yield compound 10
(Scheme 3). Transient 3-O-benzylated D-fructose result-
ing from acidic hydrolysis was reacted with thiocyanic
acid without intermediate purification. This sequence af-
forded a mixture of isomeric spiro-OZT 11 and 12, which
was difficult to separate, thus necessitating post-function-
alization. Standard acetylation did not improve separabil-
ity: only the peracetylated a-spiro-furanose 13 could be
isolated in 13% yield. In contrast, acetalation with acetone
led to a separable mixture of spiro-pyranose derivatives
Scheme 3
Synlett 2004, No. 11, 1945–1948 © Thieme Stuttgart · New York

LETTER
Scheme 4
Scheme 5
Selective Formation of 1,3-Oxazolidine-2-thiones on Ketohexose Templates
1947
Acknowledgment
The authors wish to thank the CNRS, MRC (UK) and the Université
d’Orléans for financial support.
References
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The present study describes the first selective formation of
oxazolidinethiones on ketohexose templates with a char-
acterization of five out of the seven possible structures.
This will allow development of new inhibitors of the D-
fructose transporter GLUT5 built from ketohexose tem-
plate structures. In a first approach, after isopropylidene
removal under acidic conditions of compound 14b, the re-
sulting 4,5-diol compound was engaged in inhibition tests
on CHO cells overexpressing GLUT5: an encouraging in-
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with 1-O-benzylated derivatives 8 – D-fructo: 32.6 mM, L-
sorbo: 17.4 mM – which showed a much lower inhibition
potential. The Ki measured for 14b comparable with best
inhibition observed with some oxazolidinones (L-sorbose:
3.1 mM).9d Further exploration in GLUT5 transporter
inhibition of the structure-activity relationship for all
various 1,3-oxazolidine-2-thione and 1,3-oxazolidine-2-
thione possibilities on ketohexose templates is under cur-
rent effort.
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Synlett 2004, No. 11, 1945–1948 © Thieme Stuttgart · New York

1948
A. Tatibouët et al.
LETTER
(m, 10 H, H-Ar). 13C NMR (62.5 MHz, CDCl3): d = 20.7
(7) (a) Zemplen, G.; Gerecs, A.; Rados, M. Ber. 1936, 39, 748.
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(OAc), 28.0 (NAc), 62.9 (C-6), 72.9 (CH2Ph), 73.6 (C-1),
74.0 (CH2Ph), 78.0 (C-5), 80.9 (C-4), 83.3 (C-3), 100.5
(C-2), 127.9, 128.2, 128.4, 128.6, 128.7, 128.9, 136.6, 137.4
(C-Ar), 170.4 (CO), 172.1 (CO), 185.7 (CS). MS (IS+):
m/z = 508.0 [M + Na]+, 486 [M + H]+, 466.0 [M – Ac + Na]+.
Anal. Calcd for C25H27NO7S: C, 61.84; H, 5.61; N, 2.89.
Found: C, 61.61; H, 5.59; N, 2.88. Spiro-furano OZT 23b:
[a]D25 +7.0 (c 1.2, CHCl3). 1H NMR (250 MHz, CDCl3):
d = 2.07 (s, 3 H, OAc), 2.75 (s, 3 H, NAc), 4.05 (d, 1 H,
J1a,1b = 10.1 Hz, H-1b), 4.11 (ddd, 1 H, J4,5 = 7.5 Hz,
J5,6a = 3.4 Hz, J5,6b = 7.6 Hz, H-5), 4.20 (d, 1 H, J3,4 = 6.5 Hz,
H-3), 4.31 (dd, 1 H, J6a,6b = 11.8 Hz, H-6b), 4.41 (d, 1 H, H-
1a), 4.43 (dd, 1 H, H-6a), 4.53 (dd, 1 H, H-4), 4.55 (d, 1 H,
J = 11.7 Hz, CH2Ph), 4.60 (d, 1 H, J = 11.4 Hz, CH2Ph),
4.66 (d, 1 H, J = 11.4 Hz, CH2Ph), 4.68 (d, 1 H, J = 11.7 Hz,
CH2Ph), 7.21–7.40 (m, 10 H, H-Ar). 13C NMR (62.5 MHz,
CDCl3): d = 21.0 (OAc), 27.6 (NAc), 65.1 (C-6), 73.2
(CH2Ph), 73.6 (CH2Ph), 77.6 (C-1), 80.9 (C-5), 84.2 (C-4),
87.1 (C-3), 99.5 (C-2), 127.8, 128.2, 128.3, 128.7, 128.9,
136.6, 137.5 (C-Ar), 171.0 (CO), 172.7 (CO), 186.4 (CS).
MS (IS+): m/z = 508.0 [M + Na]+, 466.0 [M – Ac + Na]+.
Anal. Calcd for C25H27NO7S: C, 61.84; H, 5.61; N, 2.89.
Found: C, 61.48; H, 5.81; N, 2.63.
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(12) General Protocol for the Formation of 23 and 24: 1,2-O-
Isopropylidene-3,4-di-O-benzyl-b-D-fructopyranose 20 (1.1
g, 2.75 mmol) was dissolved in a cooled solution of TFA–
H2O (3:2) and stirred at r.t. overnight. The crude solution
was evaporated and co-evaporated with toluene (3 times);
the residue was suspended in H2O containing KSCN (670
mg, 6.87 mmol) and 37% HCl (0.57 mL) was added. The
resulting solution was heated for 3 d at 50 °C, then cooled
and extracted with EtOAc (3 times). The organic phases
were collected and washed with NaHCO3 until neutral, then
with brine and dried over MgSO4. The residue obtained after
evaporation was purified on column chromatography using
petroleum ether–EtOAc (1:1 mixture). Spiro-furano OZT 22
(410 mg, 1.02 mmol, 37% yield) was isolated as the first
fraction then spiro-pyrano OZT 21 (250 mg, 0.62 mmol,
22% yield). Each fraction was acetylated (Ac2O 2 mL,
pyridine 5 mL, 24 h); after co-evaporation with toluene, the
residue was purified on column chromatography using
petroleum ether–EtOAc mixtures (8:2 for furano OZT and
7:3 for pyrano OZT). Spiro-furano OZT 23a (155 mg, 0.32
mmol, 37% yield) and then 23b (150 mg, 0.31 mmol, 35%
yield) was isolated. Spiro-furano OZT 23a: [a]D25 +134.0 (c
1.0, CHCl3). 1H NMR (250 MHz, CDCl3): d = 1.99 (s, 3 H,
OAc), 2.70 (s, 3 H, NAc), 3.86 (dd, 1 H, J3,4 = 8.0 Hz,
Spiro-pyrano OZT 24b (50 mg, 0.10 mmol, 27% yield) and
then 24a (75 mg, 0.15 mmol, 41% yield) were also isolated.
Spiro-pyrano OZT 24b: [a]D25 –98 (c 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): d = 2.12 (OAc), 2.68 (NAc), 3.76 (d, 1
H, J3,4 = 8.8 Hz, H-3), 3.90 (dd, 1 H, J5,6b = 2.6 Hz,
J6a,6b = 12.7 Hz, H-6b), 4.06 (d, 1 H, J1a,1b = 9.6 Hz, H-1b),
4.38 (d, 1 H, H-1a), 4.41 (dd, 1 H, J5,6a = 1.3 Hz, H-6a), 4.42
(dd, 1 H, J4,5 = 3.9 Hz, H-4), 4.49 (d, 1 H, J = 10.6 Hz,
CH2Ph), 4.60 (d, 1 H, J = 11.4 Hz, CH2Ph), 4.69 (d, 1 H,
J = 10.6 Hz, CH2Ph), 4.92 (d, 1 H, J = 10.6 Hz, CH2Ph),
5.51 (m, 1 H, H-5), 7.16–7.37 (m, 10 H, H-Ar). 13C NMR
(62.5 MHz, CDCl3): d = 21.2 (OAc), 28.0 (NAc), 66.1 (C-
6), 67.3 (C-5), 71.8 (CH2Ph), 75.6 (C-3), 77.1 (C-4), 78.5
(C-1), 97.7 (C-2), 127.8, 128.1, 128.3, 128.6, 128.7, 137.3,
137.5 (C-Ar), 170.4 (CO), 174.7 (CO), 187.9 (CS). MS
(IS+): m/z = 508.0 [M + Na]+, 466.0 [M – Ac + Na]+, 444.0
[M – Ac + H]+. Anal. Calcd for C25H27NO7S: C, 61.84; H,
5.61; N, 2.89. Found: C, 61.68; H, 5.48; N, 2.85. Spiro-
pyrano OZT 24a: [a]D25 +45.0 (c 1.2, CHCl3). 1H NMR (250
MHz, CDCl3): d = 2.23 (s, 3 H, OAc), 2.65 (s, 3 H, NAc),
3.45 (dd, 1 H, J4,3 = 10.2 Hz, J4,5 = 2.1 Hz, H-4), 3.57 (dd, 1
H, J5,6b = 1.3 Hz, J6a,6b = 14.0 Hz, H-6b), 4.04 (dd, 1 H,
J5,6a = 1.3 Hz, H-6a), 4.38 (d, 1 H, J1a,1b = 9.3 Hz, H-1b),
4.54 (d, 1 H, J = 11.4 Hz, CH2Ph), 4.59 (d, 1 H, J = 11.4 Hz,
CH2Ph), 4.73 (d, 1 H, J = 11.4 Hz, CH2Ph), 4.76 (d, 1 H, H-
1a), 4.85 (d, 1 H, J = 11.4 Hz, CH2Ph), 5.06 (d, 1 H, H-3),
5.34 (m, 1 H, H-5), 7.21–7.33 (m, 10 H, H-Ar). 13C NMR
(62.5 MHz, CDCl3): d = 21.2 (OAc), 28.1 (NAc), 64.0 (C-
6), 66.9 (C-5), 70.6 (C-1), 72.0 (CH2Ph), 73.6 (C-3), 75.7
(CH2Ph), 78.2 (C-4), 97.3 (C-2), 127.9, 128.1, 128.2, 128.6,
137.3, 137.6 (C-Ar), 170.7 (CO), 172.0 (CO), 186.7 (CS).
MS (IS+): m/z = 508.0 [M + Na]+, 466.0 [M – Ac + Na]+,
444.0 [M – Ac + H]+. Anal. Calcd for C25H27NO7S: C, 61.84;
H, 5.60; N, 2.88. Found: C, 61.72; H, 5.57; N, 2.88.
J4,5 = 9.1 Hz, H-4), 3.95 (dd, 1 H, J5,6b = 4.4 Hz, J6a,6b = 12.5
Hz, H-6b), 4.14 (d, 1 H, J1a,1b = 10.0 Hz, H-1b), 4.22 (dd, 1
H, J5,6a = 2.3 Hz, H-6a), 4.46 (ddd, 1 H, H-5), 4.50 (d, 1 H,
J = 11.4 Hz, CH2Ph), 4.63 (d, 1 H, J = 11.4 Hz, CH2Ph),
4.63 (d, 1 H, J = 11.7 Hz, CH2Ph), 4.73 (d, 1 H, J = 11.7 Hz,
CH2Ph), 4.94 (d, 1 H, H-1a), 5.09 (d, 1 H, H-3), 7.23–7.38
Synlett 2004, No. 11, 1945–1948 © Thieme Stuttgart · New York