Synthesis of L-ascorbic acid derivatives as potential bone remodeling agents taking advantage of the Mitsunobu reaction

Article abstract of DOI:10.1016/S0040-4020(02)01185-7

The synthesis of ascorbic acid derivatives 7a-d is described. Starting from alkenylacetates 1a-d subjected to a hydrosilylation reaction, the resulting hydroxy chloro silanes 3a-d were obtained in high yield. The latter compounds were reacted with potassium phthalimide followed with hydrazine hydrate to give the amino silanols 5a-d. Ascorbic acid was then alkylated on its 3-hydroxy position to give 7a-d by means of a Mitsunobu reaction.

Full text of DOI:10.1016/S0040-4020(02)01185-7

Tetrahedron 58 (2002) 9249–9256
Synthesis of L-ascorbic acid derivatives as potential bone
remodeling agents taking advantage of the Mitsunobu reaction
*
´ ´ ´
Gil Vilac¸a, Cyril Rubio, Jacques Susperregui, Laurent Latxague and Gerard Deleris
´ ´
INSERM U-443—Groupe de Chimie Bioorganique, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat,
F-33076 Bordeaux Cedex, France
Received 16 January 2002; revised 4 September 2002; accepted 16 September 2002
Abstract—The synthesis of ascorbic acid derivatives 7a–d is described. Starting from alkenylacetates 1a–d subjected to a hydrosilylation
reaction, the resulting hydroxy chloro silanes 3a–d were obtained in high yield. The latter compounds were reacted with potassium
phthalimide followed with hydrazine hydrate to give the amino silanols 5a–d. Ascorbic acid was then alkylated on its 3-hydroxy position to
give 7a–d by means of a Mitsunobu reaction. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
differentiation of osteoblastic cells.5 Furthermore, it favors
bone mineralization.6 Therefore, we have synthesized four
ascorbic acid derivatives including a silyl alkyl chain of
variable length, ended by a masked amino group to
eventually form an amide linkage with a suitable
biomaterial.
Treatment of severe bone fractures or bone diseases may
need the use of a bone graft.1 In the autograft procedure,
bone fragments are taken from the patient’s own body,
however, the human body does not posses much spare bone
which limits the usefulness of this method, especially for
important bone losses. As an alternative, allograft uses bone
taken from a deceased donor, but the risk of rejection or of
infectious diseases may arise. Presently, the use of synthetic
material to replace lost bone is becoming a better choice as
new biomaterials continue to come onto the market.2 The
ideal bone substitute must be biocompatible and osteo-
inductive.3 To favor both processes, we investigated the
possibility of synthesizing molecules that once covalently
linked to a suitable biomaterial, might behave as osteoblasts
‘concentrators’ on biomaterial surfaces through their
specific interaction with membrane components. Then,
osteoblasts could synthesize extracellular matrix and, after-
wards, colonization could favor bone regeneration and
growth. Membrane proteins represent one of the most
attractive molecular targets as they are cell specific. Among
them, carriers seem the most promising one since, unlike
receptors, they do not induce cellular response. Further-
more, interactions between carriers and a more or less plane
biomaterial would leave enough free carriers on cells to
ensure sufficient transport of required metabolites. We took
into account two of them: nucleic bases,4 and ascorbic acid.
The latter is an inexpensive carbohydrate used as a vitamin,
a drug or in the food industry as antioxidant. It also plays an
important role in biology. Actually, it is essential for the
formation of bone, and necessary for the in vitro
2. Results and discussion
The key steps of the synthesis are (1) a hydrosilylation
reaction and (2) a Mitsunobu reaction involving ascorbic
acid and an appropriate silyl alcohol. The latter compound
also possesses a masked amino group to allow its further
linkage to a suitable biomaterial by means of an amide bond.
The acetoxy compounds 1b–d were obtained in nearly
quantitative yield from the parent alcohols with acylchloride
in pyridine/diethylether (Scheme 1), whereas allylacetate 1a
is commercially available.
The hydrosilylation reaction is a versatile reaction com-
monly used in organosilicon chemistry with no equivalent in
carbon chemistry.7 Anyway, as already noted in a previous
work,8 molecules subjected to hydrosilylation in the
presence of chloroplatinic acid as a catalyst, cannot hold
acidic protons (e.g. NH, NH2 or OH groups) and must be
protected first, hence the choice for the acetoxy group to
mask the unsaturated starting alcohols. Therefore, acetates
Keywords: ascorbic acid derivatives; silicon; Mitsunobu reaction; bone.
*
Corresponding author. Tel.: þ33-557-571001; fax: þ33-557-571002;
e-mail: gerard.deleris@bioorga.u-bordeaux2.fr
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01185-7

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G. Vilac¸a et al. / Tetrahedron 58 (2002) 9249–9256
Scheme 2. (a) ClCH2Si(H)Me2, H2PtCl6, THF; (b) MeOH, PTSA.
1a–d reacted with chloromethyldimethylsilane and H2PtCl6
in anhydrous THF to yield the desired acetoxy silyl
derivatives 2a–d (Scheme 2, step a).
A transesterification of the latter compounds catalyzed with
p-toluenesulphonic acid in methanol, gave the various silyl
alcohols 3a–d in excellent yield (Scheme 2, step b). From
this step, two strategies could be considered depending on
whether the amino moiety was introduced early or later
during the synthesis.
Scheme 4. (a) Potassium phthalimide/DMF; (b) N2H4/EtOH, crude yields
indicated; (c) BOC2O/Et3N/CH2Cl2; (d) ascorbic acid/PPh3/DEAD.
In the latter case (Scheme 3), the versatility of the
Mitsunobu reaction allowed the intermolecular dehydration
to take place under mild conditions, resulting in the ether
linkage in compounds 8a–d. In this way, we avoided the
use of alkoxide alkylation (Williamson reaction) unsuitable
for a base sensitive molecule like ascorbic acid. It is known
that intermolecular coupling of alcohols with DEAD/PPh3
usually does not occur with the exception of alkyl aryl, enol
and cyclic dialkyl ether formation,9 or—more recently—
fluoro ethers.10 Usual alcohols may be too weakly acidic for
good results in the Mitsunobu reaction.11 Taking advantage
of this difference in reactivity of the0Mitsunobu reaction,
ethers 8a–d were obtained from OH-3 of ascorbic acid in a
30–50% yield range, despite the absence of any protecting
group on the other hydroxyles. In the hope of still improving
this yield, a search0in the litterature indicated that new redox
systems like 1,1 -(azodicarboxyl)-dipiperidine-tributyl-
phosphine (ADDP-TBP), N,N,N0,N0-tetramethylazodicar-
boxylate-tributylphosphine (TMAD-TBP) or N,N,N0,N0-
tetraisopropylazodicarboxylate-tributylphosphine (TIPA-
TBP) act as better reagents than the traditionnal DEAD/
PPh3 in the case of high pKa nucleophiles.12 Unfortunately,
the use of the commercially available TMAD-TBP proved
to be unsuccessful in our hands.
In order to obtain the final compounds, the azido precursors
9a–d were synthesized with sodium azide in DMSO,13
although in moderate crude yields (8–38%). Afterwards,
every attemp made to generate the amino moiety did not
succeed: LAH reduction, tributyltin hydride reduction in
AIBN,14 or catalytic hydrogenation (H2/Pd). Displacement
of the chlorine atom with potassium phthalimide failed
equally. Another possibility was to synthesize the amino
precursor before the Mitsunobu reaction takes place.
Therefore, chlorosilanols 3a–d treated with potassium
phthalimide gave the N-protected derivatives 4a–d in
good yield (Scheme 4, step a). Unfortunately, the direct
use of these compounds with DEAD/PPh3/ascorbic acid
gave only very poor yield of the desired Mitsunobu product
along with most of unreacted 4.
From this result, we inferred that the phthalimido moiety
was incompatible with the Mitsunobu reaction conditions,
and another N-protective group was the obvious solution.
For this purpose, the t-butoxycarbonyl group is widely used
in organic chemistry (especially in peptide synthesis). From
the phthalimido derivatives 4a–d reacted with hydrazine
hydrate, the free amino silanols 5a–d were obtained in
nearly quantitative yield (Scheme 4, step b). A purification
Scheme 3. Mitsunobu reaction from 3a–d (a) ascorbic acid, PPh3/DEAD,
THF; (b) NaN3/DMSO.

G. Vilac¸a et al. / Tetrahedron 58 (2002) 9249–9256
9251
Table 1. 13C NMR (d, ppm, in DMSO-d6) of ascorbic acid and compound
8a
chromatography was performed on Merck precoated silica
gel 60F254 0.25 mm plates and visualized under UV light or
by staining with KMnO4 (1% solution). Column and flash
chromatography were performed using SDS silica gel
(70–200 and 230–400 mesh, respectively).
Ascorbic acid
Compound 8a
C-10
C-20
C-30
C-40
C-50
C-60
170.6
117.9
152.9
74.6
68.4
61.9
170.6
118.9
150.7
74.4
68.6
61.8
4.2. General procedure for the preparation of alkenyl
acetates 1b–d
A solution of unsaturated alcohol in pyridine and anhydrous
diethyl ether (15 mL) was boiled under reflux, and acetyl
chloride was added dropwise over 60–90 min. The resulting
mixture was heated another 1 h, then filtered and the filtrate
concentrated under reduced pressure to give the correspond-
ing acetates used in the next step without further
purification.
of compound 5a on a chromatography column (silica gel)
resulted in numerous degradation products. Therefore, all
the amino silanols were used in the next step without further
purification. The amino protection of 5a–d was conducted
with di-tert-butyl dicarbonate at room temperature to give
the more stable 6a–d compounds. Eventually, the presence
of a residual labile proton on the nitrogen atom, did not
prevent the Mitsunobu reaction with ascorbic acid to take
place, to give 7a–d in rather good yields.
4.2.1. 3-Buten-1-yl acetate (1b). It was obtained from
3-buten-1-ol (5.0 g, 69.0 mmol), pyridine (5.47 g, 69 mmol)
and acetyl chloride (5.43 g, 69 mmol); colorless oil (6.75 g,
1
85%). H NMR (CDCl3): d¼1.80 (s, 3H, CH3CvO), 2.15
(q, J¼6.9 Hz, 2H, CH2CH2OAc), 3.88 (t, J¼6.9 Hz,
2H, CH2OAc), 4.85 (m, 2H, CHvCH2), 5.53 (m, 1H,
CHvCH2). 13C NMR (CDCl3): d¼20.46 (CH3CvO),
32.82 (CH2CH2OAc), 63.11 (CH2OAc), 116.78
(CH2vCH), 133.8 (CHvCH2), 170.44 (CvO). IR (film):
1742 (CvO), 1640 (CvC).
Throughout this work, it was hypothesized that the
Mitsunobu reaction proceeds with the more acidic OH-30
of ascorbic acid as depicted in Schemes 3 and 4. However,
one may ask whether or not the OH-20 or even the primary
OH-60 are good candidates to form an ether bond? In a 13
C
NMR comparative study of ascorbic acid and compound 8a,
we did not notice any chemical shift change clear enough to
prove our first hypothesis (Table 1).
4.2.2. 4-Penten-1-yl acetate (1c). It was obtained from
4-penten-1-ol (5.0 g, 58.0 mmol), pyridine (4.59 g,
58 mmol) and acetyl chloride (4.54 g, 58 mmol); colorless
oil (6.89 g, 92%). 1H NMR (CDCl3): d¼1.58 (m, 2H,
CH2CH2CH2), 1.89 (s, 3H, CH3CvO), 1.98 (m, 2H,
vCH–CH2), 3.93 (t, J¼6.5 Hz, 2H, CH2OAc), 4.85 (m,
2H, CHvCH2), 5.53 (m, 1H, CHvCH2). 13C NMR
(CDCl3): d¼20.46 (CH3CvO), 27.46 (CH2CH2OAc),
29.69 (CH2CHv), 63.43 (CH2O), 114.85 (CH2vCH),
137.08 (CHvCH2), 170.44 (CvO). IR (film): 1742
(CvO), 1640 (CvC), 1244 (Si–C def.), 842 (Si–C
strech.).
Therefore, a detailed NMR study using hetero multiple bond
coherence (HMBC) was conducted on the model compound
8a, showing cross correlations0 from the g-methylene
protons (relative to Si) to the C-3 carbon of ascorbic acid.
This clearly indicates that the etherification step occurred at
position 30 of ascorbic acid.
3. Conclusion
We have described the synthesis of four new compounds
7a–d, using an unusual application of the Mitsunobu
reaction. The latter compounds can be seen as ascorbic acid
derivatives. We expect from deprotected 7 to bind to a
suitable biomaterial via a peptidic bond and to act in vivo as
an potential donnor of vitamin C if needed by osteoblatic
cells, favoring the formation of new bone tissue.
4.2.3. 5-Hexen-1-yl acetate (1d). It was obtained from
5-hexen-1-ol (5.0 g, 50.0 mmol), pyridine (3.95 g,
50 mmol) and acetyl chloride (3.90 g, 50 mmol); colorless
oil (6.98 g, 98%). 1H NMR (CDCl3): d¼1.26 (m, 2H,
CH2CH2CH2O), 1.46 (m, 2H, CH2CH2CH2O), 1.84 (s, 3H,
CH3CvO), 1.89 (m, 2H, vCH–CH2), 3.87 (t, J¼6.8 Hz,
2H, CH2OAc), 4.80 (m, 2H, CHvCH2), 5.65 (m, 1H,
CHvCH2). 13C NMR (CDCl3): d¼19.90 (CH3CvO),
24.32 (CH2CH2OAc), 27.18 (CH2CHv), 32.42
(CH2vCH–CH2), 63.38 (CH2O), 113.35 (CH2vCH),
137.35 (CHvCH2), 170.44 (CvO). IR (film): 1742
(CvO), 1640 (CvC), 842 (Si–C strech.).
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded with a Bruker AC
200 spectrometer (200 and 50 MHz, resp.); chemical shifts
are given in ppm values referenced to the residual solvent
peak from tetramethylsilane (dH¼7.24 ppm and dC¼
77.7 ppm for CDCl3). 2D NMR experiments were recorded
with a Bruker AMX 500 spectrometer. Infrared spectra were
measured using neat samples on NaCl plates on a Bruker
4.3. General procedure for the preparation of
(chloromethyldimethylsilanyl)alkyl ethanoates 2a–d
To a solution of unsaturated acetate and chloromethyl-
dimethylsilane in boiling THF, was added chloroplatinic
acid (0.1 mL of a 0.1N sol. in iPrOH). The solution turned
brown within a few minutes and was stirred for 2 h. A small
quantity of charcoal powder was then added and reflux
continued for half an hour. The reaction mixture was cooled
IFS-25 spectrometer; wave numbers are given in cm21
.
Mass spectra (LSIMS-HRMS) were recorded on a
AutoSpec-Q Fisons-Instruments spectrometer. Thin layer

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G. Vilac¸a et al. / Tetrahedron 58 (2002) 9249–9256
to rt, filtered and concentrated under reduced pressure to
give the corresponding silyl esters used in the next step
without further purification.
rinsed with water, and extracted with dichloromethane; the
extracts were combined, washed with water, dried on
magnesium sulfate, and evaporated to give the crude
product used in the next step without further purification.
4.3.1. 3-(Chloromethyldimethylsilanyl)propyl ethanoate
(2a). It was obtained from commercial allyl acetate (3.00 g,
23 mmol) and chloromethyldimethylsilane (2) (2.71 g,
25 mmol); colorless oil (4.26 g, 88%). Bp (0.9 mm Hg)¼
858C. 1H NMR (CDCl3): d¼0.05 (s, 6H, Si(CH3)2), 0.59 (m,
3H, CH3Si), 1.58 (m, 2H, SiCH2CH2), 1.97 (s, 3H, CH3CO),
4.4.1. 3-(Chloromethyldimethylsilanyl)propan-1-ol (3a).
It was obtained from 2a (4 g, 19 mmol) and PTSA (0.76 g,
4 mmol) in absolute methyl alcohol (150 mL); colorless oil
(2.92 g, 92%). 1H NMR (CDCl3): d¼0.06 (s, 6H, Si(CH3)2),
0.63 (m, 2H, SiCH2), 1.57 (m, 2H, SiCH2CH2), 2.77 (s,
2H, CH2Cl), 3.58 (t, J¼6.7 Hz, 2H, CH2OH). 13C NMR
(CDCl3): d¼23.97 (Si(CH3)2), 10.06 (SiCH2), 27.40
(SiCH2CH2), 30.85 (CH2Cl), 66.15 (CH2OH). IR (film):
3356 (OH), 1252 (Si–C def.), 842 (Si–C strech.).
2.72 (s, 2H, CH2Cl), 3.95 (t, J¼7.5 Hz, 2H, CH2OAc). 13
C
NMR (CDCl3): d¼24.80 (Si(CH3)2), 49.57 (SiCH2), 20.83
(CH3CO), 22.79 (SiCH2CH2), 29.85 (CH2Cl), 66.60
(CH2OAc), 170.9 (CvO). IR (film): 1742 (CvO), 1252
(Si–C def.), 842 (Si–C strech.).
4.4.2. 4-(Chloromethyldimethylsilanyl)butan-1-ol (3b). It
was obtained from 2b (10.6 g, 47 mmol) and PTSA (1.78 g,
9.4 mmol) in absolute methyl alcohol (300 mL); colorless
oil (7.95 g, 93%). 1H NMR (CDCl3): d¼0.05 (s, 6H,
Si(CH3)2), 0.59 (m, 2H, SiCH2), 1.43 (m, 2H, SiCH2CH2-
CH2), 1.52 (m, 2H, SiCH2CH2), 2.73 (s, 2H, CH2Cl), 3.56
(t, J¼6.8 Hz, 2H, CH2OH). 13C NMR (CDCl3): d¼24.71
(Si(CH3)2), 13.38 (SiCH2), 19.75 (SiCH2CH2), 30.21
(CH2Cl), 36.28 (SiCH2CH2CH2), 62.17 (CH2OH). IR
(film): 3356 (OH), 1256 (Si–C def.), 846 (Si–C strech.).
4.3.2. 4-(Chloromethyldimethylsilanyl)butyl ethanoate
(2b). It was obtained from (1b) (7.0 g, 61 mmol) and
chloromethyldimethylsilane (2) (7.0 g, 65 mmol); colorless
oil (10.68 g, 78%). Bp (0.9 mm Hg)¼988C. 1H NMR
(CDCl3): d¼0.06 (s, 6H, Si(CH3)2), 0.61 (m, 2H, SiCH2),
1.35 (m, 2H, SiCH2CH2CH2), 1.61 (m, 2H, SiCH2CH2),
1.99 (s, 3H, CH3CvO), 2.73 (s, 2H, CH2Cl), 4.01 (t,
J¼7.4 Hz, 2H, CH2O). 13C NMR (CDCl3): d¼24.18
(Si(CH3)2), 13.28 (SiCH2), 19.93 (SiCH2CH2), 19.98
(CH3CvO), 30.10 (CH2Cl), 32.09 (CH2CH2OAc), 63.09
(CH2O), 171.11 (CvO). IR (film): 1730 (CvO), 1256 (Si–
C def.), 846 (Si–C strech.).
4.4.3. 5-(Chloromethyldimethylsilanyl)pentan-1-ol (3c).
It was obtained from 2c (5.3 g, 22 mmol) and PTSA (0.85 g,
4.4 mmol) in absolute methyl alcohol (200 mL); colorless
oil (4.19 g, 97%). 1H NMR (CDCl3): d¼0.03 (s, 6H,
Si(CH3)2), 0.61 (m, 2H, SiCH2), 1.40 (m, 4H, Si(CH2)2-
CH2CH2), 1.50 (m, 2H, SiCH2CH2), 2.73 (s, 2H, CH2Cl),
3.56 (t, J¼7.0 Hz, 2H, CH2OH). 13C NMR (CDCl3): d¼
24.76 (Si(CH3)2), 13.59 (SiCH2), 23.33 (SiCH2CH2), 29.48
(SiCH2CH2CH2), 30.30 (CH2Cl), 32.30 (CH2CH2OH),
62.69 (CH2OH). IR (film): 3356 (OH), 1256 (Si–C def.),
842 (Si–C strech.).
4.3.3. 5-(Chloromethyldimethylsilanyl)pentyl ethanoate
(2c). It was obtained from (1c) (3.20 g, 25 mmol) and
chloromethyldimethylsilane (2) (2.71 g, 25 mmol); color-
1
less oil (4.72 g, 80%). Bp (0.9 mm Hg)¼1088C. H NMR
(CDCl3): d¼0.06 (s, 6H, Si(CH3)2), 0.61 (m, 2H, SiCH2),
1.30–1.38 (m, 4H, CH2CH2CH2O), 1.60 (m, 2H, SiCH2-
CH2), 2.01 (s, 3H, CH3CvO), 2.74 (s, 2H, CH2Cl), 4.02
(t, J¼6.5 Hz, 2H, CH2O). 13C NMR (CDCl3): d¼24.65
(Si(CH3)2), 13.53 (SiCH2), 20.96 (CH3CvO), 23.18
(SiCH2CH2), 28.19 (SiCH2CH2CH2), 29.61 (CH2Cl),
30.25 (CH2CH2OAc), 64.45 (CH2O), 171.25 (CvO). IR
(film): 1742 (CvO), 1256 (Si–C def.), 846 (Si–C strech.).
4.4.4. 6-(Chloromethyldimethylsilanyl)hexan-1-ol (3d).
It was obtained from 2d (9.27 g, 37 mmol) and PTSA (1.4 g,
7.4 mmol) in absolute methyl alcohol (350 mL); colorless
oil (7.81 g, 94%). 1H NMR (CDCl3): d¼0.06 (s, 6H,
Si(CH3)2), 0.60 (m, 2H, SiCH2), 1.31 (m, 6H, Si(CH2)2-
CH2CH2CH2), 1.54 (m, 2H, SiCH2CH2), 2.74 (s, 2H,
CH2Cl), 3.60 (t, J¼7.5 Hz, 2H, CH2OH). 13C NMR
(CDCl3): d¼24.65 (Si(CH3)2), 13.54 (SiCH2), 23.43
(SiCH2CH2), 25.30 (SiCH2CH2CH2), 30.36 (CH2Cl),
32.30 (CH2CH2CH2OH), 33.14 (CH2CH2OH), 62.95
(CH2OH). IR (film): 3334 (OH), 1252 (Si–C def.), 848
(Si–C strech.).
4.3.4. 6-(Chloromethyldimethylsilanyl)hexyl ethanoate
(2d). It was obtained from (1d) (6.72 g, 47 mmol) and
chloromethyldimethylsilane (2) (5.10 g, 47 mmol); color-
1
less oil (9.27 g, 78%). Bp (0.9 mm Hg)¼1258C. H NMR
(CDCl3): d¼0.05 (s, 6H, Si(CH3)2), 0.61 (m, 2H, SiCH2),
1.30 (m, 6H, CH2CH2CH2CH2OAc), 1.54 (m, 2H,
SiCH2CH2), 2.00 (s, 3H, CH3CvO), 2.73 (s, 2H, CH2Cl),
4.00 (t, J¼6.8 Hz, 2H, CH2OAc). 13C NMR (CDCl3): d¼
24.63 (Si(CH3)2), 13.55 (SiCH2), 23.39 (SiCH2CH2),
25.51 (SiCH2CH2CH2), 28.48 (SiCH2CH2CH2CH2), 30.33
(CH2Cl), 33.00 (CH2CH2OAc), 64.56 (CH2OAc), 170.5
(CH3CvO). IR (film): 1738 (CvO), 1248 (Si–C def.), 846
(Si–C strech.).
4.5. General procedure for the preparation of
phtalimidomethyldimethylsilanyl alcohols 4a–d
A mixture of chloromethyldimethylsilanyl alcohol, potas-
sium phthalimide, anhydrous DMF and ca. 10 mg of crown
ether (18-C-6) was stirred for 24 h under nitrogen at 1208C.
The mixture was cooled, then filtered, and the filtrate
evaporated under reduced pressure. The remaining residue
was poured into water and extracted with dichloromethane;
the organic extracts were washed with water, dried over
magnesium sulphate, concentrated, then chromatographed
on silica gel with hexane/ethyl acetate (6:4) as eluant.
4.4. General procedure for the preparation of
chloromethyldimethylsilanyl alcohols 3a–d
Chloromethyldimethylsilanyl alkyl ethanoate was added
under nitrogen to a solution of p-toluenesulphonic acid in
methyl alcohol. After stirring for 24 h at room temperature,
the solution was concentrated under reduced pressure,

G. Vilac¸a et al. / Tetrahedron 58 (2002) 9249–9256
9253
4.5.1. 3-(Phthalimidomethyldimethylsilanyl)propan-1-ol
(4a). It was obtained from 3a (2 g, 12 mmol), potassium
phthalimide (2.22 g, 12 mmol), 18-C-6, and DMF (40 mL);
the crude product used in the next step without further
purification.
1
pale yellow oil (1.26 g, 37%). H NMR (CDCl3): d¼0.05
4.6.1. 3-(Aminomethyldimethylsilanyl)propan-1-ol (5a).
It was obtained from 4a (0.65 g, 2.35 mmol), hydrazine
hydrate (0.3 mL, 9.4 mmol) and absolute ethanol (20 mL);
faint yellow oil (0.32 g, 92%). 1H NMR (CDCl3): d¼0.02 (s,
6H, Si(CH3)2), 0.57–0.65 (m, 2H, SiCH2), 1.50–1.65 (m,
2H, SiCH2CH2), 2.19 (s, 2H, CH2N), 2.60 (broad s, 3H, OH,
NH2), 3.56 (t, J¼6.2 Hz, 2H, CH2OH). 13C NMR (CDCl3):
d¼24.53 (Si(CH3)2), 9.53 (SiCH2), 26.87 (SiCH2CH2),
30.30 (CH2N), 64.57 (CH2OH). IR (film): 3272 (NH2, OH),
1252 (Si–C def.), 840 (Si–C def.).
(s, 6H, Si(CH3)2), 0.55–0.63 (m, 2H, SiCH2), 1.50–1.65
(m, 2H, SiCH2CH2), 1.94 (broad s, 1H, OH), 3.16 (s, 2H,
CH2N), 3.56 (t, J¼6.5 Hz, 2H, CH2OH), 7.61–7.78 (m, 5H,
Pht.). 13C NMR (CDCl3): d¼23.74 (Si(CH3)2), 10.37
(SiCH2), 26.69 (SiCH2CH2), 27.96 (CH2N), 65.29 (CH2O),
122.88 (CH Pht.), 132.17 (Pht. quat. C), 133.64 (CH Pht.),
168.50 (CvO). IR (film): 3472 (OH), 1708 (CvO), 1248
(Si–C def.), 836 (Si–C strech.).
4.5.2. 4-(Phthalimidomethyldimethylsilanyl)butan-1-ol
(4b). It was obtained from 3b (3 g, 16 mmol), potassium
phthalimide (3 g, 16.2 mmol), 18-C-6, and DMF (50 mL);
pale yellow oil (3.53 g, 75%). 1H NMR (CDCl3): d¼0.07 (s,
6H, Si(CH3)2), 0.57–0.65 (m, 2H, SiCH2), 1.34–1.65 (m,
4H, SiCH2CH2CH2), 3.18 (s, 2H, CH2N), 3.62 (t, J¼5.7 Hz,
2H, CH2OH), 7.63–7.80 (m, 4H, Pht.). 13C NMR (CDCl3):
d¼23.69 (Si(CH3)2), 14.26 (SiCH2), 19.58 (SiCH2CH2),
27.97 (SiCH2CH2CH2), 36.19 (CH2N), 62.03 (CH2OH),
122.85 (CH Pht.), 132.15 (quat. C Pht.), 133.62 (CH Pht.),
168.50 (CvO). IR (film): 3460 (OH), 1704 (CvO), 1252
(Si–C def.), 836 (Si–C strech.).
4.6.2. 4-(Aminomethyldimethylsilanyl)butan-1-ol (5b). It
was obtained from 4b (2 g, 6.8 mmol), hydrazine hydrate
(1.3 mL, 27.4 mmol) and absolute ethanol (90 mL); yellow
oil (1.05 g, 94%). 1H NMR (CDCl3): d¼20.02 (s, 6H,
Si(CH3)2), 0.50–0.58 (m, 2H, SiCH2), 1.29–1.59 (m, 4H,
SiCH2CH2CH2), 2.16 (s, 2H, CH2N), 2.68 (broad s, 3H,
NH2, OH), 3.56 (t, J¼6 Hz, 2H, CH2OH). 13C NMR
(CDCl3): d¼24.71 (Si(CH3)2), 13.05 (SiCH2), 19.71
(SiCH2CH2), 29.75 (Si(CH2)2CH2), 36.04 (CH2NH2),
61.51 (CH2OH). IR (film): 3356 (NH2, OH), 1252 (Si–C
def.), 836 (Si–C def.).
4.5.3. 5-(Phthalimidomethyldimethylsilanyl)pentan-1-ol
(4c). It was obtained from 3c (2.39 g, 12.2 mmol),
potassium phthalimide (2.27 g, 12.2 mmol), 18-C-6 and
4.6.3. 5-(Aminomethyldimethylsilanyl)pentan-1-ol (5c).
It was obtained from 4c (1.55 g, 5 mmol), hydrazine hydrate
(1 g, 0.02 mol) and absolute ethanol (50 mL); yellow oil
(0.8 g, 91%). 1H NMR (CDCl3): d¼0.01 (s, 6H, Si(CH3)2),
0.51–0.59 (m, 2H, SiCH2), 1.27–1.33 (m, 4H, Si(CH2)2-
CH2CH2), 1.43–1.53 (m, 2H, SiCH2CH2), 2.17 (s, 2H,
CH2N), 3.12 (broad s, 3H, OH, NH2), 3.54 (t, J¼6.4 Hz, 2H,
CH2OH). 13C NMR (CDCl3): d¼24.62 (Si(CH3)2), 13.72
(SiCH2), 23.39 (SiCH2CH2), 29.51 (Si(CH2)2CH2CH2),
32.28 (CH2N), 62.26 (CH2OH). IR (film): 3356 and 3272
(NH2, OH), 1252 (Si–C def.), 840 (Si–C strech.).
1
DMF (40 mL); pale yellow oil (2.84 g, 76%). H NMR
(CDCl3): d¼0.04 (s, 6H, Si(CH3)2), 0.54–0.62 (m, 2H,
SiCH2), 1.29–1.37 (m, 4H, Si(CH2)2CH2CH2), 1.52 (m, 2H,
SiCH2CH2), 3.15 (s, 2H, CH2N), 3.58 (t, J¼6.4 Hz, 2H,
CH2OH), 7.61–7.78 (m, 4H, Pht). 13C NMR (CDCl3):
d¼23.59 (Si(CH3)2), 14.66 (SiCH2), 23.27 (SiCH2CH2),
28.06 (Si(CH2)2CH2), 29.46 (Si(CH2)3CH2), 32.33 (CH2N),
62.75 (CH2OH), 122.86 (CH pht.), 132.22 (Pht. quat. C),
133.59 (CH pht.), 168.48 (CvO). IR (film): 3460 (OH),
1712 (CvO), 1244 (Si–C def.), 840 (Si–C strech.).
4.6.4. 6-(Aminomethyldimethylsilanyl)hexan-1-ol (5d). It
was obtained from 4d (2.73 g, 8.5 mmol), hydrazine hydrate
(1.6 mL, 34 mmol) and absolute ethanol (60 mL); yellow
oil (1.48 g, 91%). 1H NMR (CDCl3): d¼20.01 (s, 6H,
Si(CH3)2), 0.48–0.56 (m, 2H, SiCH2), 1.28 (m, 6H,
HOCH2(CH2)3), 1.45–1.52 (m, 2H, SiCH2CH2), 2.15
(s, 2H, CH2NH2), 2.60 (large s, 3H, NH2, OH), 3.54
(t, J¼6.5 Hz, 2H, CH2OH). 13C NMR (CDCl3): d¼24.73
(Si(CH3)2), 13.60 (SiCH2), 25.33 (SiCH2CH2), 29.68
(CH2N), 32.61 (Si(CH2)3CH2), 33.15 (Si(CH2)4CH2),
62.45 (CH2OH). IR (film): 3356 and 3272 (NH2, OH),
1252 (Si–C def.), 840 (Si–C strech.).
4.5.4. 6-(Phthalimidomethyldimethylsilanyl)hexan-1-ol
(4d). It was obtained from 3d (2.5 g, 12 mmol), potassium
phthalimide (2.4 g, 13 mmol), 18-C-6, and DMF (30 mL);
pale yellow oil (2.94 g, 76%). 1H NMR (CDCl3): d¼0.04 (s,
6H, Si(CH3)2), 0.54–0.62 (m, 2H, SiCH2), 1.30–1.60 (m,
8H, SiCH2(CH2)4), 3.14 (s, 2H, CH2N), 3.57 (t, J¼6.5 Hz,
2H, CH2OH), 7.60–7.80 (m, 4H, Pht.). 13C NMR (CDCl3):
d¼23.71 (Si(CH3)2), 14.42 (SiCH2), 23.28 (SiCH2CH2),
25.24 (Si(CH2)2CH2), 27.88 (CH2N), 32.40 (Si(CH2)3CH2),
33.05 (Si(CH2)4CH2), 62.30 (CH2OH), 122.67 (CH Pht.),
131.97 (Pht. quat. C), 133.49 (CH Pht.), 168.25 (CvO). IR
(film): 3440 (OH), 1704 (CvO), 1252 (Si–C def.), 840
(Si–C strech.).
4.7. General procedure for the preparation of tert-
butylaminomethyldimethylsilanyl alcohols 6a–d
4.6. General procedure for the preparation of
aminomethyldimethylsilyl alcohols 5a–d
To a solution of aminomethyldimethylsilanyl alcohol and
triethylamine in dichloromethane or chloroform, was added
(Boc)2O under inert atmosphere. After stirring at rt for 24 h,
the solution was washed with acidic water (NaHSO4,
3£30 mL, pH 3), then with water, the organic layer
separated, dried (MgSO4), filtrated and concentrated under
reduced pressure. The residue was applied to a column of
silica gel eluted with dichloromethane/methyl alcohol
(95:5) to give the pure compound.
A solution of (phthalimidomethyldimethylsilanyl)alkanol
and hydrazine hydrate in absolute ethyl alcohol, was stirred
for 24 h at reflux under nitrogen. The resulting mixture was
cooled, filtered, and the filtrate evaporated under reduced
pressure. The remaining residue was washed with dichloro-
methane, filtered again, and the filtrate concentrated to give

9254
G. Vilac¸a et al. / Tetrahedron 58 (2002) 9249–9256
4.7.1. 3-(tert-Butylaminomethyldimethylsilanyl)-pro-
pan-1-ol (6a). It was obtained from 5a (0.6 g, 40 mmol),
(Boc)2O (0.87 g, 40 mmol) and triethylamine (0.40 g,
40 mmol) in chloroform (40 mL); colorless oil (0.50 g,
50%). 1H NMR (CDCl3): d¼0.03 (s, 6H, Si(CH3)2), 0.53–
0.61 (m, 2H, SiCH2), 1.41 (s, 9H, C(CH3)3), 1.52–1.63 (m,
2H, SiCH2CH2), 2.60 (d, J¼5.6 Hz, 2H, CH2NH), 3.58
(t, J¼6.4 Hz, 2H, CH2OH). 13C NMR (CDCl3): d¼24.53
(Si(CH3)2), 9.64 (SiCH2), 26.07 (SiCH2CH2), 28.37
(C(CH3)3), 29.21 (CH2N), 65.20 (CH2OH), 79.06
(C(CH3)3), 156.89 (CvO). IR (film): 3356 (NH, OH),
1692 (CvO), 1252 (Si–C def.), 1172 (COO), 840 (Si–C
strech.).
2158C, DEAD was added dropwise over a period of ca.
15 min, followed by ascorbic acid and a solution in THF of
tert-butylaminomethyldimethylsilyl alcohol (6a–d) or
chloromethyldimethylsilanyl alcohol (3a–d) respectively.
The mixture was stirred under nitrogen at this temperature
for 24 h. The resulting light brown mixture was filtered, and
the filtrate concentrated under reduced pressure. The oily
residue was applied to a silicagel column eluted with
dichloromethane/methyl alcohol (97:3) to give the pure
compound.
4.8.1. Ascorbic acid 3-(3-(tert-butylaminomethyl-di-
methylsilanyl)propyl) oxide (7a). It was obtained from
6a (0.5 g, 2.0 mmol), ascorbic acid (0.44 g, 2.5 mmol),
triphenylphosphine (0.65 g, 2.5 mmol), DEAD (0.43 g,
2.5 mmol) and THF (15 mL); colorless oil (0.23 g, 28%).
1H NMR (CDCl3): d¼0.02 (s, 6H, Si(CH3)2), 0.54–0.63 (m,
2H, SiCH2), 1.39 (s, 9H, C(CH3)3), 1.62–1.78 (m, 2H,
SiCH2CH2), 2.57 (d, J¼5.6 Hz, 2H, SiCH2NH), 3.70–3.73
(m, 2H, CH2O), 3.90 (m, 1H, H-50), 4.33–4.43 (m, 2H, H-
60), 4.63 (d, J¼1.3 Hz, 1H, H-40). 13C NMR (CDCl3):
d¼24.58 (Si(CH3)2), 9.36 (SiCH2), 23.88 (SiCH2CH2),
28.33 (C(CH3)3), 28.99 (CH2N), 63.23 (CH2O), 69.99
(C-50), 73.94 (C-60), 76.21 (C-40), 79.35 (C(CH3)3), 119.02
(C-20), 150.74 (C-30), 157.12 (CvO Boc), 172.04 (CvO
ascorbic ac.). IR (film): 3356 (NH, OH), 1756 (CvO), 1684
(CvC), 1256 (Si–C def.), 1164 (COO), 844 (Si–C strech.).
HRMS obsd. m/z 428.17166 C17H31O8NSi (MþNaþ)
requires 428.17164.
4.7.2. 4-(tert-Butylaminomethyldimethylsilanyl)-butan-
1-ol (6b). It was obtained from 5b (1 g, 62 mmol),
(Boc)2O (1.35 g, 62 mmol) and triethylamine (0.62 g,
62 mmol) in dichloromethane (40 mL); colorless oil
(0.74 g, 45%). 1H NMR (CDCl3): d¼0.02 (s, 6H,
Si(CH3)2), 0.52–0.60 (m, 2H, SiCH2), 1.41 (s, 9H,
C(CH3)3), 1.46–1.61 (m, 4H, SiCH2(CH2)2), 2.58 (d,
J¼5.7 Hz, 2H, CH2NH), 3.62 (t, J¼6.2 Hz, 2H, CH2OH).
13C NMR (CDCl3): d¼24.51 (Si(CH3)2), 13.56 (SiCH2),
19.69 (SiCH2CH2), 28.39 (C(CH3)3), 29.18 (Si(CH2)2CH2),
36.22 (CH2N), 62.20 (CH2OH), 79.04 (C(CH3)3), 164.50
(CvO). IR (film): 3356 (NH, OH), 1692 (CvO), 1252 (Si–
C def.), 1172 (COO), 840 (Si–C strech.).
4.7.3. 5-(tert-Butylaminomethyl-dimethylsilanyl)-pen-
tan-1-ol (6c). It was obtained from 5c (0.8 g, 45.6 mmol),
(Boc)2O (1 g, 45.6 mmol) and triethylamine (0.46 g,
45.6 mmol) in dichloromethane (40 mL); colorless oil
(0.90 g, 75%). 1H NMR (CDCl3): d¼0.01 (s, 6H,
Si(CH3)2), 0.50–0.58 (m, 2H, SiCH2), 1.29–1.37 (m, 4H,
Si(CH2)2CH2CH2), 1.41 (s, 9H, C(CH3)3), 1.53–1.57 (m,
2H, SiCH2CH2), 2.57 (d, J¼5.5 Hz, 2H, CH2NH), 3.60 (t,
J¼6.4 Hz, 2H, CH2OH). 13C NMR (CDCl3): d¼24.49
(Si(CH3)2), 13.93 (SiCH2), 23.38 (SiCH2CH2), 28.39
(C(CH3)3), 29.19 (CH2N), 29.48 (Si(CH2)2CH2), 32.33
(Si(CH2)3CH2), 62.75 (CH2OH), 79.00 (C(CH3)3), 156.87
(CvO). IR (film): 3356 (NH, OH), 1692 (CvO), 1252
(Si–C def.), 1172 (COO), 840 (Si–C strech.).
4.8.2. Ascorbic acid 3-(4-(tert-butylaminomethyl-di-
methylsilanyl)butyl) oxide (7b). It was obtained from 6b
(0.95 g, 36 mmol), ascorbic acid (0.79 g, 45 mmol), tri-
phenylphosphine (1.18 g, 45 mmol), DEAD (0.78 g,
1
45 mmol) and THF (15 mL); orange oil (0.62 g, 41%). H
NMR (CDCl3): d¼0.03 (s, 6H, Si(CH3)2), 0.55–0.63 (m,
2H, SiCH2), 1.36–1.50 (m, 2H, Si(CH2)2CH2), 1.42 (s, 9H,
C(CH3)3), 1.67–1.80 (m, 2H, SiCH2CH2), 2.59 (d,
J¼5.5 Hz, CH2NH), 3.76–3.80 (m, 2H, CH2O), 3.96 (m,
1H,0H-50), 4.43–4.51 (m, 2H, H-60), 4.65 (d, J¼2 Hz, 1H,
H-4 ). 13C NMR (CDCl3): d¼24.41 (Si(CH3)2), 13.38
(SiCH2), 19.59 (SiCH2CH2), 28.39 (C(CH3)3), 29.03
(CH2N), 32.96 (Si(CH2)2CH2), 63.47 (CH2O), 70.17
(C-50), 71.44 (C-60), 76.34 (C-40), 79.40 (C(CH3)3), 118.84
(C-20), 150.17 (C-30), 157.17 (CvO Boc), 171.67 (CvO
ascorbic ac.). IR (film): 3356 (OH, NH), 1756 (CvO), 1684
(CvC), 1252 (Si–C def.), 1172 (COO), 840 (Si–C strech.).
HRMS obsd. m/z 442.18731 C18H33O8NSi (MþNaþ)
requires 442.18729.
4.7.4. 6-(tert-Butylaminomethyldimethylsilanyl)hexan-1-
ol (6d). It was obtained from 5d (3.48 g, 18 mmol), (Boc)2O
(3.93 g, 18 mmol) and triethylamine (1.82 g, 18 mmol) in
chloroform (120 mL); colorless oil (4.16 g, 79%). 1H NMR
(CDCl3): d¼0.01 (s, 6H, Si(CH3)3), 0.50–0.58 (m, 2H,
SiCH2), 1.27–1.37 (m, 6H, Si(CH2)2-CH2CH2CH2), 1.41
(s, 9H, C(CH3)3), 1.47–1.56 (m, 4H, SiCH2CH2), 2.58 (d,
J¼5.5 Hz, 2H, CH2NH), 3.60 (t, J¼6.4 Hz, 2H, CH2OH).
13C NMR (CDCl3): d¼24.53 (Si(CH3)2), 13.83 (SiCH2),
23.45 (SiCH2CH2), 25.29 (SiCH2CH2), 27.33 (Si(CH2)2-
CH2), 28.36 (C(CH3)3), 29.21 (CH2N), 32.55 (Si(CH2)3-
CH2), 33.12 (Si(CH2)4-CH2), 62.71 (CH2OH), 78.94
(C(CH3)3), 156.88 (CvO). IR (film): 3356 (NH, OH),
1692 (CvO), 1252 (Si–C def.), 1172 (COO), 840 (Si–C
strech.).
4.8.3. Ascorbic acid 3-(5-(tert-butylaminomethyl-di-
methylsilanyl)pentyl) oxide (7c). It was obtained from 6c
(0.90 g, 3.4 mmol), ascorbic acid (0.74 g, 4.2 mmol),
triphenylphosphine (1.10 g, 4.2 mmol), DEAD (0.73 g,
4.2 mmol) and THF (15 mL); colorless oil (0.63 g, 42%).
1H NMR (CDCl3): d¼0.01 (s, 6H, Si(CH3)2), 0.50–0.58 (m,
2H, SiCH2), 1.28–1.37 (m, 4H, Si(CH2)2CH2CH2), 1.39 (s,
9H, C(CH3)3), 1.62–1.72 (m, 2H, SiCH2CH2), 2.56 (d,
J¼5.5 Hz, 2H, CH2NH), 3.72–3.76 (m, 2H, CH2O), 3.88–
0
0
0
0
0
4.8. General procedure for the preparation of ascorbic
acid derivatives 7a–d and 8a–d
3.95 (td, J5 ,6 ¼5.7 Hz, J5 ,4 ¼2.1 Hz, 1H, H-5 ), 4.38–4.49
(m, 2H, H-60), 4.63 (d, J¼2.1 Hz, 1H, H-40). 13C NMR
(CDCl3): d¼24.47 (Si(CH3)2), 13.86 (SiCH2), 23.23
(SiCH2CH2), 28.37 (C(CH3)3), 29.22 (Si(CH2)2CH2CH2,
To a mixture of triphenylphosphine in anhydrous THF at

G. Vilac¸a et al. / Tetrahedron 58 (2002) 9249–9256
9255
CH2N), 63.29 (CH2O), 70.12 (C-50), 71.92 (C-60), 76.28
(C-40), 79.19 (C(CH3)3), 118.98 (C-20), 150.85 (C-30),
157.05 (CvO Boc), 172.09 (CvO ascorbic ac.). IR
(film): 3336 (NH, OH), 1756 (CvO), 1684 (CvC), 1252
(Si–C def.), 1164 (COO), 840 (Si–C strech.). HRMS obsd.
m/z 456.20296 C19H35O8NSi (MþNaþ) requires
456.20294.
10.5 mmol), ascorbic acid (2.29 g, 13 mmol), triphenylphos-
phine (3.40 g, 13 mmol), DEAD (2.26 g, 13 mmol) and
THF (15 mL); orange oil (1.57 g, 42%). 1H NMR (CDCl3):
d¼0.08 (s, 6H, Si(CH3)2), 0.58–0.66 (m, 2H, SiCH2), 1.29–
1.46 (m, 4H, Si(CH2)2CH2CH2), 1.64–1.78 (m, 2H,
SiCH2CH2), 2.75 (s, 2H, CH2Cl), 3.75–3.83 (m, 2H,
CH2O), 3.93 (m, 1H, H-50), 4.43–4.56 (m, 2H, H-60), 4.63
(d, J¼1.6 Hz, 1H, H-40). 13C NMR (CDCl3): d¼24.62
(Si(CH3)2), 13.56 (SiCH2), 23.27 (SiCH2CH2), 29.25
(Si(CH2)2CH2CH2), 30.28 (CH2Cl), 63.45 (CH2O), 70.11
(C-500), 72.09 (C-60), 76.56 (C-40), 118.89 (C-20), 150.95
(C-3 ), 172.27 (CvO ascorbic ac.). IR (film): 3356 (OH),
1750 (CvO), 1690 (CvC), 1252 (Si–C def.), 1068
(CH2Cl), 842 (Si–C strech.).
4.8.4. Ascorbic acid 3-(6-(tert-butylaminomethyl-di-
methylsilanyl)hexyl) oxide (7d). It was obtained from 6d
(1.16 g, 4 mmol), ascorbic acid (0.88 g, 5 mmol), tri-
phenylphosphine (1.31 g, 5 mmol), DEAD (0.87 g,
5 mmol) and THF (20 mL); faint yellow oil (0.83 g, 46%).
1H NMR (CDCl3): d¼0.01 (s, 6H, Si(CH3)2), 0.50–0.58 (m,
2H, SiCH2), 1.25–1.36 (m, 6H, Si(CH2)2CH2CH2CH2),
1.42 (s, 9H, C(CH3)3), 1.66–1.72 (m, 2H, SiCH2CH2), 2.57
(d, J¼5.5 Hz, 2H, CH2NH), 3.78 (m, 2H, CH2O), 3.94 (m,
1H,0H-50), 4.43–4.49 (m, 2H, H-60), 4.65 (d, J¼2.2 Hz, 1H,
H-4 ). 13C NMR (CDCl3): d¼24.44 (Si(CH3)2), 13.78
(SiCH2), 23.35 (SiCH2CH2), 24.96 (C-4), 28.42 (C(CH3)3),
29.41 (Si(CH2)3CH2, CH2N), 32.76 (Si(CH2)4CH2), 63.48
(CH2O), 70.28 (C-50), 72.10 (C-60), 76.47 (C-40), 79.27
(C(CH3)3), 118.84 (C-20), 150.22 (C-30), 157.08 (CvO
Boc), 171.66 (CvO ascorbic ac.). IR (film): 3356 (NH,
OH), 1756 (CvO), 1690 (CvC), 1252 (Si–C def.), 1161
(COO), 848 (Si–C strech.). HRMS obsd. m/z 470.21861
C20H37O8NSi (MþNaþ) requires 470.21859.
4.8.8. Ascorbic acid 3-(6-(chloromethyldimethyl-silanyl)-
hexyl) oxide (8d). It was obtained from 3d (0.80 g,
3.83 mmol), ascorbic acid (0.84 g, 4.78 mmol), triphenyl-
phosphine (1.25 g, 4.78 mmol), DEAD (0.83 g, 4.78 mmol)
and THF (15 mL); orange oil (0.57 g, 40%). 1H NMR
(CDCl3): d¼0.09 (s, 6H, Si(CH3)2), 0.60–0.68 (m, 2H,
SiCH2), 1.32–1.42 (m, 6H, SiCH2CH2(CH2)3), 1.66–1.79
(m, 2H, SiCH2CH2), 2.76 (s, 2H, CH2Cl), 3.80 (m, 2H,
CH2O), 3.91–3.98 (td, J¼5.5, 2.3 Hz, 1H, H-50), 4.42–4.53
(m, 2H, H-60), 4.65 (d, 1H, H-40). 13C NMR (CDCl3):
d¼24.62 (Si(CH3)2), 13.56 (SiCH2), 23.39 (Si(CH2)3CH2),
30.35 (CH2Cl), 33.03 (Si(CH2)4CH2), 63.44 (CH2O), 70.06
(C-500), 72.19 (C-60), 76.56 (C-40), 118.81 (C-20), 150.69
(C-3 ), 172.00 (CvO ascorbic ac.). IR (film): 3356 (OH),
1756 (CvO), 1690 (CvC), 1252 (Si–C def.), 1062
(CH2Cl), 848 (Si–C strech.).
4.8.5. Ascorbic acid 3-(3-(chloromethyldimethyl-sila-
nyl)-propyl) oxide (8a). It was obtained from 3a (2 g,
12 mmol), ascorbic acid (2.64 g, 15 mmol), triphenylphos-
phine (3.93 g, 15 mmol), DEAD (2.61 g, 15 mmol) and
THF (15 mL); dark orange oil (2.00 g, 51%). 1H NMR
(CDCl3): d¼0.11 (s, 6H, Si(CH3)2), 0.63–0.71 (m, 2H,
SiCH2), 1.67–1.79 (m, 2H, SiCH2CH2), 2.78 (s, 2H,
CH2Cl), 3.74–3.89 (m, 2H, CH2O), 3.97 (m, 1H, H-50),
Acknowledgements
4.38–4.50 (m, 2H, H-60), 4.65 (d, J¼1.8 Hz, 1H, H-40). 13
C
We would like to acknowledge our referees for pertinent
´
remarks and financial support from Conseil Regional
d’Aquitaine (Fonds Commun Aquitaine Euskadi Navarre)
and Ligue contre le Cancer.
NMR (CDCl3): d¼24.75 (Si(CH3)2), 9.11 (SiCH2), 23.85
(SiCH2CH2), 29.97 (CH2Cl), 63.48 (CH2O), 70.04 (C-50),
74.24 (C-60), 76.59 (C-40), 118.20 (C-20), 151.50 (C-30),
172.00 (CvO ascorbic ac.). IR (film): 3356 (OH), 1756
(CvO), 1690 (CvC), 1252 (Si–C def.), 1062 (CH2Cl), 844
(Si–C strech.).
References
4.8.6. Ascorbic acid 3-(4-(chloromethyldimethyl-sila-
nyl)butyl) oxide (8b). It was obtained from 3b (1.64 g,
9.1 mmol), ascorbic acid (2 g, 11.3 mmol), triphenylphos-
phine (2.97 g, 11.3 mmol), DEAD (1.97 g, 11.3 mmol) and
THF (15 mL); dark orange oil (1.21 g, 31%). 1H NMR
(CDCl3): d¼0.09 (s, 6H, Si(CH3)2), 0.62–0.70 (m, 2H,
SiCH2), 1.29–1.50 (m, 2H, SiCH2CH2CH2), 1.68–1.82 (m,
2H, SiCH2CH2), 2.77 (s, 2H, CH2Cl), 3.77–3.83 (m, 2H,
CH2O), 3.94 (m, 1H, H0-50), 4.45–4.55 (m, 2H, H-60),
4.65 (d, J¼2 Hz, 1H, H-4 ). 13C NMR (CDCl3): d¼24.64
(Si(CH3)2), 13.26 (SiCH2), 19.58 (SiCH2CH2), 30.19
(CH2Cl), 33.15 (Si(CH2)2CH2), 63.38 (CH2O), 70.00
(C-500), 71.72 (C-60), 76.99 (C-40), 118.81 (C-20), 146.24
(C-3 ), 172.09 (CvO ascorbic ac.). IR (film): 3356 (OH),
1750 (CvO), 1690 (CvC), 1252 (Si–C def.), 1068
(CH2Cl), 842 (Si–C strech.).
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