Synthesis of 3-sila derivatives of L-ascorbic acid via Mitsunobu reaction

Article abstract of DOI:10.1055/s-2002-34900

Various 3-sila derivatives of L-ascorbic acid were synthesized in satisfactory yields. The ether link was formed by an unusual aspect of the Mitsunobu reaction, without the need of protecting the remaining hydroxy groups.

Full text of DOI:10.1055/s-2002-34900

1910
LETTER
Synthesis of 3-Sila Derivatives of L-Ascorbic Acid via Mitsunobu Reaction
S
ynthesis of 3-Sil
y
a
D
erivative
r
s
of
L
-A
i
scorbic
l
A
cid via Mit
Rsunobu Reactionubio, Jacques Susperregui, Laurent Latxague, Gérard Déléris*
Unité INSERM 443, Groupe de Chimie Bio-organique, Université V. Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex,
France
Fax +33(5)57571002; E-mail: gerard.deleris@u-bordeaux2.fr
Received 12 September 2002
Abstract: Various 3-sila derivatives of L-ascorbic acid were syn-
thesized in satisfactory yields. The ether link was formed by an un-
usual aspect of the Mitsunobu reaction, without the need of
protecting the remaining hydroxy groups.
Key words: Mitsunobu reaction, ethers, silicon compounds, ascor-
bic acid, bioorganic chemistry
Figure 1 General structure of the L-ascorbic acid derivatives
synthesized.
In the search for new materials able to satisfy the mechan-
ical properties of natural bone and moreover to participate
in the natural processes of bone remodeling,1 we investi-
gated the possibility of synthesizing molecules that once
covalently linked to a suitable biomaterial might behave
as osteoblast concentrators on biomaterial surfaces
through their specific interaction with membrane proteins.
Afterwards, osteoblasts could synthesize extracellular
matrix, which will favor colonization and bone regenera-
tion. In this approach, we used L-ascorbic acid, an inex-
pensive carbohydrate which plays an important role in
bone biology.2 More particularly, this natural compound
is not synthesized de novo by osteoblasts, and has to be in-
corporated via a specific carrier located in the cell mem-
brane.3 We present herein the synthesis of different L-
ascorbic acid derivatives embodying a variable silicon
linker (Figure 1) designed as inhibitors of L-ascorbic acid
carrier,4 with the aim of linking them to a biomaterial via
the silylated moiety.
compounds 1b, 1c and 1d were obtained with very satis-
factory yields (>96%) from their parent alcohols, whereas
allylacetate 1a is commercially available (Scheme 1). The
hydrosilylation reaction of compounds 1a–d with chloro-
butyldimethylsilane and hexachloroplatinic acid in an-
hydrous THF, afforded the acetoxysilyl compounds 2a–
d.6 In the next step, methanolysis led to the corresponding
new silyl alcohols 3a–d in a nearly quantitative yield.
To improve rigidity of the molecular structure, an element
of unsaturation was introduced in the silicon moiety.
Therefore, starting from propargyl acetate and chlorobu-
tyldimethylsilane, hydrosilylation as before led to the un-
saturated acetoxy silyl compounds 4a and 4b, with
proportions of 40% for 4a and 60% for 4b respectively
(Scheme 2).7
Unfortunately, both acetates 4a and 4b appeared to be in-
separable via silica gel chromatography. Therefore, meth-
anolysis of the acetoxy functions was conducted on the
crude mixture to give the corresponding silyl alcohols 5a
and 5b (Scheme 2) now separable by silica gel chroma-
tography. Nevertheless, this purification step required
In this work, two families of L-ascorbic acid analogues
can be considered depending on the saturated or unsatur-
ated nature of the silicon chain. The saturated sila moieties
3a–d were synthesized according to a pathway we had al-
ready described in a previous paper.5 The alkenyl acetoxy
Scheme 1 i: CH3COCl, pyridine, Et2O reflux (except 1a which is commercially available); ii: Cl(CH2)4Si(H)Me2, H2PtCl6, THF; iii: p-TSA,
MeOH.
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1910,1912,ftx,en;D00802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of 3-Sila Derivatives of L-Ascorbic Acid via Mitsunobu Reaction
1911
Scheme 2 i: H2PtCl6, THF; ii: p-TSA, MeOH.
several successive columns to give rather low amounts of of several and unprotected hydroxyle groups on the ascor-
each pure alcohol (never more than 20% of each alcohol bic acid moiety (and though none of them is a primary
pure after each chromatography step). Satisfactory spec- one, which could be favourable for an SN2 occuring reac-
1
troscopic data (200.13 MHz H NMR, 50.32 MHz 13C tion as the Mitsunobu), ethers 6–13 were obtained via
NMR) were obtained for all new compounds: 2a–d, 3a–d, Mitsunobu reaction with an average 25% yield
4a–b, and 5a–b.
(Scheme 3).11 This confirms that the –OH at position 3,
which is the more acid (pKa ~ 4.1), is the one which reacts
first under these conditions. The position of the ether link-
age was confirmed via 2-dimensionnal NMR experiments
HMQC and HMBC. Besides, though the shielding (2.2
ppm) of C-3 of the ascorbic acid was consistant with the
formation of an ether linkage at this position, the changes
in the chemical shifts were not clear enough to prove the
linkage position by themselves. So, we decided to perform
bi-dimensional NMR experiments to unambiguously
prove the formation of the ether linkage at the presumed
position.
Obviously, a better method had to be used for synthesiz-
ing the next unsaturated compounds 5c and 5d (Figure 2)
from propargyl acetate and chloromethyldimethyl silane
with H2PtCl6. As pointed out in a previous paper,8 Candi-
da antarctica lipase undergoes almost quantitative enzy-
matic hydrolysis of only one of the acetate isomers.
Therefore, after separation and subsequent methanolysis
of the remaining acetate, the two silyl alcohols 5c and 5d
were obtained in over 90% global yield.
In summary, the alkoxysilyl derivatives of L-ascorbic acid
6–13 were successfully synthesized using Mitsunobu re-
action conditions. This result clearly points out a novel
and promising application of the Misunobu reaction, and
enhances the use of already well-known conditions. In the
future, these new analogues of L-ascorbic acid will be test-
ed according to their potency to inhibit the natural L-
ascorbic acid carrier of osteoblastic human cells, prior to
being incorporated in models of bone filling biomaterials.
Figure 2 Structures of the silyl alcohols generated via enzymatic
conditions.
Previous descriptions of the spread out use of the Mit-
sunobu reaction (with DEAD/PPh3 as reagents) has point-
ed out that intermolecular coupling of alcohols usually
does not occur under these conditions, with exception of
alkyl aryl, enol and defined cyclic dialkyl ether formation9
or, more recently, fluoro ethers.9 This absence of reactiv-
ity of usual alcohols may be a result of their too weak
acidic characteristics.10 In our case, whatever the presence
Acknowledgement
Financial support from the Direction Générale des Armées and the
Conseil Régional d’Aquitaine (Fonds Commun Aquitaine Euskadi
Navarre) is gratefully acknowledged.
Scheme 3 i: L-ascorbic acid, DEAD, PPh3, THF.
Synlett 2002, No. 11, 1910–1912 ISSN 0936-5214 © Thieme Stuttgart · New York

1912
C. Rubio et al.
LETTER
25.5 (SiCH2CH2), 35.3 [Si(CH2)2CH2], 37.5 (CH2CH2Cl),
44.6 (CH2Cl), 63.48 (CH2O), [70.1, 74.2, 76.45, 118.3,
151.12, 172.14 for Asc. Ac.].
References
(1) (a) Yan, W.-Q.; Nakamura, T.; Kawanabe, K.; Nishigochi,
S.; Oka, M.; Kokubo, T. Biomaterials 1997, 18, 1185.
(b) Damien, C. J.; Parsons, J. R. J. Applied Biomat. 1991, 2,
187. (c) Laing, P. G. Biomaterials 1994, 15, 403.
(2) (a) Franceschi, R. T.; Iyer, B. S. J. Bone Mineral Res. 1992,
7, 235. (b) Hammarstrom, L. Acta Physiol. Scand., Suppl.
289 1966, 70, 1.
(3) Wilson, J. X.; Dixon, S. J. J. Membrane Biol. 1989, 111, 83.
(4) Qutob, S.; Dixon, S. J.; Wilson, J. X. Endocrinology 1998,
139, 51.
Compound 8: 1H NMR: = 0.10 [s, 6 H, (CH3)2Si], 0.63–
0.70 [m, 4 H, (CH2Si)2], 1.28–1.40 {m, 6 H,
[SiCH2(CH2)2CH2]}, 1.51–1.56 (m, 2 H, CH2CH2O), 1.72
(q, 2 H, J = 7.1 Hz, CH2CH2Cl), 3.5 (t, 2 H, J = 6.3 Hz
CH2Cl), 3.78–3.83 (m, 2 H, OCH2), [3.92, 4.45, 4.64 for
Asc. Ac.]. 13C NMR: = –4.70 [(CH3)2Si], 9.11 (SiCH2),
14.2 (SiCH2), 23.85 (SiCH2CH2), 25.5 (SiCH2CH2), 32.5
[Si(CH2)3CH2], 35.3 {[Si(CH2)2CH2]}, 37.5 (CH2CH2Cl),
44.6 (CH2Cl), 63.48 (CH2O), [70.12, 74.25, 76.25, 118.5,
151.4, 171.8 for Asc. Ac.].
(5) Thibon, J.; Latxague, L.; Déléris, G. J. Org. Chem. 1997, 62,
4635.
Compound 9: 1H NMR: = 0.10 [s, 6 H, (CH3)2Si], 0.63–
0.70 [m, 4 H, (CH2Si)2], 1.26–1.38 [m, 8 H,
(6) (a) Ryan, J.; Menzie, G.; Speier, J. L. J. Am. Chem. Soc.
1960, 82, 3601. (b) Weber, W. Silicon Reagents for Organic
Synthesis; Springer Verlag: Berlin, 1983. (c) Latxague, L.;
Thibon, J.; Guillot, C.; Moreau, S.; Déléris, G. Tetrahedron
Lett. 1994, 35, 5869.
(7) Latxague, L.; Thibon, J.; Déléris, G. Tetrahedron Lett. 1998,
39, 4025.
(8) Rubio, C.; Latxague, L.; Déléris, G.; Coulon, D. J.
Biotechnol. 2001, 92, 61.
(SiCH2CH2CH2)2], 1.53–1.59 (m, 2 H, CH2CH2O), 1.71 (q,
2 H, J = 7.0 Hz CH2CH2Cl), 3.5 (t, 2 H, J = 6.3 Hz, CH2Cl),
3.79–3.84 (m, 2 H, OCH2), [4.01, 4.45, 4.6 for Asc. Ac.]. 13
NMR: = –4.70 [(CH3)2Si], 9.11 (SiCH2), 14.2 (SiCH2),
C
23.85 (SiCH2CH2), 25.5 (SiCH2CH2), 29.1 [Si(CH2)4CH2],
32.5 [Si(CH2)3CH2], 35.3 {[Si(CH2)2CH2]}, 37.5
(CH2CH2Cl), 44.6 (CH2Cl), 63.5 (CH2O), [70.2, 74.0, 76.4,
118.2, 151.3, 172.1 for Asc. Ac.].
Compound 10: 1H NMR: = 0.22 [s, 6 H, (CH3)2Si], 0.53–
0.58 [m, 2 H, (CH2Si], 1.31–1.35 (m, 2 H, SiCH2CH2), 1.70
(q, 2 H, J = 7.1 Hz, CH2CH2Cl), 2.83 (s, 2 H, CH2Cl), 3.83–
3.89 (m, 2 H, –O–CH2CH=CH), [3.7, 3.9, 4.67 for Asc. Ac.],
5.85–5.95 (d, 1 H, J = 24.2 Hz, =CH–Si), 6.25–6.31 (td, 1 H,
J = 24.2 Hz, =CH–CH2). 13C NMR: = –4.82 [(CH3)2Si],
9.11 (SiCH2), 21.0 (SiCH2CH2), 29.7 (CH2Cl), 37.1
(CH2CH2Cl), 63.2 (OCH2C=CH2), 124.4 (=CH–CH2), 147.7
(=CH–Si), [69.9, 74.9, 76.5, 119.5, 150.2, 172.0 for Asc.
Ac.].
(9) (a) Hugues, D. L. Org. React. 1992, 42, 350. (b)Hugues, D.
L. Org. React. 1992, 42, 352. (c) Falk, J. R.; Yu, J.; Cho, H.-
S. Tetrahedron Lett. 1994, 35, 5997.
(10) Mitsunobu, O. Synthesis 1981, 1.
(11) All NMR experiments were conducted in CDCl3. For
convenience, proton and carbon chemical shifts for the L-
ascorbic acid moiety are detailed for compound 6 only. For
all other molecules (7–13) a single list is provided and
attributions for L-ascorbic acid (Asc. Ac.) can be derived
from the reference compound 6.
Compound 11: 1H NMR: = 0.22 [s, 6 H, (CH3)2Si], 0.52–
0.60 [m, 2 H, (CH2Si], 1.30–1.35 (m, 2 H, SiCH2CH2), 1.70
(q, 2 H, J = 7.1 Hz, CH2CH2Cl), 2.83 (s, 2 H, CH2Cl), [3.72,
3.93, 4.67 for Asc. Ac.], 5.07–5.11 (m, 2 H, CH2C=CH2),
5.72 (dd, 2 H, 2J = 7.5 Hz, 4J = 2.3 Hz, C=CH2). 13C NMR:
= –4.82 [(CH3)2Si], 9.11 (SiCH2), 21.0 (SiCH2CH2), 30.5
(CH2Cl), 37.1 (CH2CH2Cl), 63.20 (OCH2C=CH2), 128.50
(CH2C=CH2), 143 (CH2C=CH2), [69.9, 74.9, 76.4, 119.5,
150.2, 172.5 for Asc. Ac.].
General Procedure for Mitsunobu Reaction:
In a typical experiment, a mixture of ascorbic acid (12
mmol) and triphenylphosphine (12 mmol) was suspended in
anhyd THF (15 mL) and kept at –10 °C under nitrogen in a
Schlenck tube. Then, chloroalkylhydroxysilane (9.6 mmol)
and DEAD (12 mmol) in THF (5 mL) were added dropwise
over 1 h. The reaction mixture was kept at –10 °C for 24 h
before being filtered, concentrated and purified by
chromatography.
Compound 6: 1H NMR: = 0.10 [s, 6 H, (CH3)2Si], 0.62–
0.70 [m, 4 H, (CH2Si)2], 1.26–1.38 (m, 2 H, SiCH2CH2),
1.52–1.58 (m, 2 H, CH2CH2O), 1.70 (q, 2 H, J = 7.0 Hz,
CH2CH2Cl), 3.51 (t, 2 H, J = 6.3 Hz, CH2Cl), 3.75–3.80 (m,
2 H, OCH2), 3.90–3.95 (m, 1 H, H5), 4.40–4.45 (m, 2 H, H6),
4.64 (d, 1 H, H4). 13C NMR: = –4.70 [(CH3)2Si], 9.11
(SiCH2), 14.2 (SiCH2), 23.85 (SiCH2CH2), 25.5
(SiCH2CH2), 37.5 (CH2CH2Cl), 44.6 (CH2Cl), 63.48
(CH2O), 70.04 (C5), 74.24 (C6), 76.36 (C4), 118.20 (C2),
151.20 (C3), 172.02 (C1).
Compound 12: 1H NMR: = 0.22 [s, 6 H, (CH3)2Si], 2.83 (s,
2 H, CH2Cl), 3.69–3.75 (m, 2 H, H6), [3.93, 4.3, 4.7 for Asc.
Ac.], 5.85–5.95 (d, 1 H, J = 24.1 Hz;, =CH–Si), 6.25–6.31
(td, 1 H, J = 24.1 Hz, =CH–CH2). 13C NMR. = –4.82
[(CH3)2Si], 29.70 (CH2Cl), 63.20 (OCH2C=CH2), 124.46
(=CH–CH2), 147.67 (=CH–Si), [69.90, 74.9, 76.45, 119.45,
150.2, 172.1 for Asc. Ac.].
Compound 13: 1H NMR: = 0.22 [s, 6 H, (CH3)2Si], 2.83 (s,
2 H, CH2Cl), 3.70–3.75 (m, 2 H, H6), [3.93, 4.3, 4.7 for Asc.
Ac.], 5.08–5.14 (m, 2 H, CH2C=CH2), 5.71 (dd, 2 H, 2J = 7.5
Hz, 4J = 2.3 Hz, C=CH2). 13C NMR: = –4.82 [(CH3)2Si],
30.5 (CH2Cl), 63.20 (OCH2C=CH2), 128.50 (CH2C=CH2),
143 (CH2C=CH2), [69.90, 74.90, 76.45, 119.45, 150.20,
172.05 for Asc. Ac.].
Compound 7: 1H NMR: = 0.10 [s, 6 H, (CH3)2Si], 0.62–
0.70 [m, 4 H, (CH2Si)2], 1.26–1.38 [m, 4 H, (SiCH2CH2)2],
1.53–1.58 (m, 2 H, CH2CH2O), 1.70 (q, 2 H, J = 7.0 Hz,
CH2CH2Cl), 3.5 (t, 2 H, J = 6.3 Hz, CH2Cl), 3.75–3.80 (m, 2
H, OCH2), [4.0, 4.45, 4.64 for Asc. Ac.]. 13C NMR: = –4.70
[(CH3)2Si], 9.11 (SiCH2), 14.2 (SiCH2), 23.85 (SiCH2CH2),
Synlett 2002, No. 11, 1910–1912 ISSN 0936-5214 © Thieme Stuttgart · New York