Synthesis of alkynes and alkynyl iodides bearing a protected amino alcohol moiety as functionalized amino acids precursors

Article abstract of DOI:10.1007/s11426-010-4072-2

Amino acid precursors in protected amino alcohol form are important synthons that can be used as building-blocks for the hemisynthesis of non-natural amino acids. Serine can be used as a common starting material for the synthesis of such compounds differe

Full text of DOI:10.1007/s11426-010-4072-2

SCIENCE CHINA
Chemistry
September 2010 Vol.53 No.9: 1921–1926
doi: 10.1007/s11426-010-4072-2
• ARTICLES •
Synthesis of alkynes and alkynyl iodides bearing a protected amino
alcohol moiety as functionalized amino acids precursors
AYED Charfedinne, PICARD Julien, LUBIN-GERMAIN Nadège,
UZIEL Jacques* & AUGE Jacques*
Université de Cergy-Pontoise, Laboratoire de Synthèse Organique Sélective et Chimie bioOrganique-EA 4505,
F-95000 Cergy-Pontoise, France
Received May 3, 2010; accepted June 23, 2010
Amino acid precursors in protected amino alcohol form are important synthons that can be used as building-blocks for the
hemisynthesis of non-natural amino acids. Serine can be used as a common starting material for the synthesis of such com-
pounds differently protected. Particularly, protected amino alcohols bearing an ethynyl and/or an iodoethynyl group can be
used in cross-couplings, in 1,3-dipolar cycloadditions and/or in Nozaki-Hiyama-Kishi type reactions. We thus demonstrated
that the efficiently protected amino alcohols derived from serine can be coupled to a sugar derivative by an indium mediated
alkynylation reaction. The conditions of this coupling are compatible with such functionalized derivatives and allow envisag-
ing an access to C-glycosylated amino acids.
amino alcohols, amino acids, oxazolidines, alkynyl iodides, C-glycoside, indium, alkynylation
Oxazolidine 2 is one of the most interesting such build-
ing-blocks as it can be easily prepared from Garner’s alde-
hyde 1 [2] itself derived from L- or D-serine. Meffre, Regi-
nato et al. [3, 4] described its synthesis according to one-pot
multicomponent process involving the in situ formation of
the Ohira reagent [5].
Oxazolidines being a very efficient protection of amino
alcohols, some other building-blocks seemed interesting to
us. Thus, the protection of the amino group was changed
and the synthons 7, 8 and 11 were synthesized. In addition,
iodoalkyne 13 bearing a silylated alcohol and a N,N-diben-
zylated amine was also prepared.
This type of building-blocks could be used for the prepa-
ration of C-glycosylated amino acids through coupling with
a sugar derivative. Introduced in peptide chains they can
lead to interesting glycopeptides presenting a strong link
between the sugar and the amino acid part.
We are particularly interested in the obtaining of such
building-blocks bearing an -ethynyl group and/or an -
iodoethynyl group as precursors of ethynylglycine and/or
1 Introduction
Amino acids present various important biological properties
such as enzyme inhibitors or more general as therapeutic
agents. Among the methods used for the synthesis of
non-natural amino acids, the hemisynthesis [1] starting from
natural chiral sources such as serine or other amino acids is
a very interesting approach as it avoids the introduction of
the chirality during the synthesis. It is indeed possible in
many cases to take advantage of the fact that the configura-
tion of the chiral center can be maintained during the syn-
thetic sequence. Various building-blocks have received a
large attention. Among them, those being amino alcohol
derivatives have the advantage not to present an acidic 
hydrogen atom and thus limit the risk of a racemization of
the amino acid chiral center during a particular step of the
synthetic pathway.
*Corresponding author (email: jacques.auge@u-cergy.fr; jacques.uziel@u-cergy.fr)
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
chem.scichina.com
www.springerlink.com

1922
AYED Charfedinne, et al. Sci China Chem September (2010) Vol.53 No.9
iodoethynylglycine. This kind of synthons can be efficiently
used in various reactions particularly Sonogashira cross-
couplings or 1,3-dipolar cycloadditions in the case of ter-
minal alkynes or Nozaki-Hiyama-Kishi (NHK) type al-
kynylations in the case of halogeno alkynes. We have re-
cently described the indium mediated alkynylation of car-
bonyl derivatives with alkynyl iodides under Barbier condi-
tions in chlorinated solvents [6, 7]. This reaction allows the
easy obtaining of the corresponding propargylic alcohols.
We have also extended it to the anomeric position of car-
bohydrates leading thus to the synthesis of C-glycosides
[8–11]. In this case the possession of such iodoethynylgly-
cine precursors allows us envisaging a pathway towards the
synthesis of C-glycosylated amino acids, more stable ana-
logues of Glc-Ser or other O-glycosylated amino acids.
In order to show the utility of the prepared building-
blocks, we used them in two indium mediated alkynylation
reactions of sugar derivatives, demonstrating that the condi-
tions recently developed in our laboratory [8, 9] are com-
patible with such functionalized derivatives. We first
showed that oxazolidine 3 in presence of indium reacts on
the aldehyde of a formylglucose and leads to the corre-
sponding propargylic alcohol 14. In addition, we also real-
ized the highly stereoselective alkynylation on the anomeric
position of glucal with the iodoalkyne 13 leading exclu-
sively to the  anomer of the corresponding C-glycoside 15.
After stirring for 24 h more, a saturated solution of NH4Cl
(200 mL) was added. The organic layer was washed with a
saturated solution of NH4Cl (200 mL) and with H2O (2 ×
200 mL). Each aqueous layer was extracted with CHCl3
(100 mL). The organic layers were assembled and dried
over MgSO4. The obtained product was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate:
9/1), leading to 2; yield 67% (1.32 g), Rf =0.6 (cyclohexane/
ethyl acetate: 8/2). 1H NMR (250 MHz, CDCl3):  4.49 (m,
1H), 3.95 (m, 2H), 2.21 (s, 1H, CCH), 1.5 (s, 3H), 1.45 (s,
12H). 13C NMR (62.9 MHz, CDCl3):  151.4 (CO), 94.5
(Cquat isopropyl), 82.7 (Cquat Boc), 80.4 (Cquat CC), 70.1
(CCH), 68.6 (CH2), 48.3 (CH), 28.4, 26.8, 25.8, 25.1, 24.3
(5 × CH3).
tert-Butyl (R)-4-iodoethynyl-2,2-dimethyloxazolidine-3-car-
boxylate (3)
In a mixture obtained by stirring for 30 min iodine (1.64 g,
6.46 mmol) and morpholine (1.53 mL, 17.57 mmol) in
benzene (7 mL) was added a solution of the above alkyne 2
in benzene (10 mL). The mixture was stirred for 24 h at
45 °C, then filtered and washed with diethyl ether (30 mL).
The filtrate was washed with a saturated solution of NH4Cl
(15 mL), with a saturated solution of NaHCO3 (15 mL),
with H2O (15 mL) and then dried over MgSO4. The ob-
tained product was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate: 9/1), leading to 3;
yield 90% (1.85 g), Rf = 0.6 (cyclohexane/ethyl acetate: 9/1).
mp 61 °C. []D =104 (c=3.4, CHCl3). 1H NMR (250 MHz,
CDCl3):  4.62 (m, 1H), 4.01 (m, 2H), 1.62 (s, 3H), 1.49 (s,
12H). 13C NMR (62.9 MHz, CDCl3):  151.4 (CO), 94.3
(Cquat isopropyl), 92.9 (Cquat CC), 80.4 (Cquat Boc), 68.5
(CH2), 50.0 (CH), 28.3, 26.8, 25.7, 24.9, 24.4 (5 × CH3),
1.3 (CI). IR:  = 1677, 2980 cm1. Anal. calcd for
C12H18INO3: C, 41.04; H, 5.17; N, 3.99; found: C, 41.10; H,
5.27; N, 3.84.
2 Experimental
2.1 General experimental
Infrared spectra were recorded on a Bruker Tensor 27 spec-
trophotometer. 1H and 13C NMR spectra were recorded on a
Bruker Avance 250 DPX and a JEOL ECX-400 spectrome-
ters. Elemental analyses were done at the Central Service of
Analysis (CNRS, Vernaison, France). High resolution mass
spectra were obtained with a JEOL GC Mate II apparatus.
Rotation values were recorded on a JASPO DIP 370 in-
strument. Melting points (uncorrected) were determined on
a Büchi B-545.
2.3 Synthesis of the (R)-3-(o-phenylbenzoyl)-4-iodo
ethynyl-2,2-dimethyl oxazolidine (8)
(R)-3-(o-Phenylbenzoyl)-2,2-dimethyloxazolidine-4-methanol (5)
2.2 Synthesis of the tert-butyl (R)-4-iodoethynyl-2,2-
Into a suspension of calcium chloride (3.44 g, 30.96 mmol)
in anhydrous THF (18 mL) was added a solution of methyl
(S)-3-(o-phenylbenzoyl)-2,2-dimethyloxazolidine-4-carbox-
ylate 4 (1.38 g, 4.05 mmol) in anhydrous ethanol (30 mL).
Sodium borohydrate (2 g, 52.86 mmol) was then added in
small portions at 20 °C. The mixture was stirred at room
temperature overnight. After addition of ethyl ether (60 mL)
the medium was hydrolyzed at 20 °C with a saturated so-
lution of Na2SO4. The organic layer was then washed with
brine (2 × 10 mL) and dried over MgSO4. The obtained
product 5 was purified by flash chromatography on silica
gel (cyclohexane/ethyl acetate: 4/6); yield 93% (1.28 g).
dimethyloxazolidine-3-carboxylate (3)
tert-Butyl (R)-4-ethynyl-2,2-dimethyloxazolidine-3-carboxylate
(2)
In a vigorously stirred solution of dimethyl 2-oxopropyl-
phosphonate (4.98 g, 30 mmol) in CHCl3 (70 mL) were
added at 0 °C 4-acetamidobenzenesulfonyl azide (7.2 g,
30 mmol) and potassium carbonate (4.2 g, 30.5 mmol). The
solution was stirred at this temperature for 48 h as a white
suspension was formed. Potassium carbonate (1.93 g, 14
mmol) was then added at 0 °C followed by a solution of
Garner’s aldehyde 1 (2 g, 8,72 mmol) in MeOH (70 mL).

AYED Charfedinne, et al. Sci China Chem September (2010) Vol.53 No.9
1923
Rf = 0.1 (cyclohexane/ethyl acetate: 4/6). []D = 185 (c =
1.1, CHCl3). H NMR (400 MHz, CDCl3):  7.44 (m, 9H,
Hz, 1H, CCH), 1.74 (s, 3H), 1.28 (s, 3H). 13C NMR (100
MHz, CDCl3):  167.7 (C=O), 139.5, 136.5, 129.7, 129.3,
128.9, 128.7, 128.1, 128.0, 127.7 (Ph), 96.1 (Cquat isopropyl),
81.4 (Cquat CC), 71.7 (CCH), 68.9 (CH2), 49.6 (CH), 26.2,
22.7 (2 × CH3). IR:  = 1613, 1739, 2176, 2983, 3058, 3287
cm1. HRMS calcd for C20H19NO2: 305.1416; found:
305.1414.
1
Ph), 3.69 (d, J = 8.7 Hz, 1H, CH2), 3.29 (dd, J=8.7, 8.2 Hz,
1H, CH2OH), 3.21 (m, 1H, CH), 3.16 (m, 1H, CH2OH),
3.01 (dd, 1H, J = 8.7, 5.0 Hz, CH2), 1.66 (s, 3H, CH3), 1.49
(sl, 1H, OH), 1.23 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3):  168.1 (CO), 139.5, 137.8, 136.6, 129.7, 129.1,
128.8, 128.1, 127.9, 127.7 (Ph), 95.5 (Cquat isopropyl), 65.0
(CH2), 62.1 (CH2OH), 58.9 (CH), 27.0 (CH3), 21.9 (CH3).
IR:  = 1610, 2982, 3409 cm1. HRMS calcd for C19H21NO3:
311.1521; found: 311.1534.
(R)-3-(o-Phenylbenzoyl)-4-iodoethynyl-2,2-dimethyloxazoli-
dine (8)
In a mixture obtained by stirring for 45 min iodine (6.28 g,
24.7 mmol) and morpholine (4.4 mL, 0.5 mmol) in benzene
(60 mL) was added a solution of the above (R)-3-(o-
phenylbenzoyl)-4-ethynyl-2,2-dimethyloxazolidine 7 in ben-
zene (15 mL). The mixture was stirred for 48 h at 45 °C,
then filtered and washed with diethyl ether (100 mL). The
filtrate was concentrated up to 30 mL and then washed with
a saturated solution of NH4Cl (2 × 20 mL), with a saturated
solution of NaHCO3 (20 mL), with H2O (20 mL) and then
dried over MgSO4. The obtained product was purified by
flash chromatography on silica gel (cyclohexane/ethyl ace-
tate: 9/1), leading to 8; yield 73% (5.2 g), Rf = 0.9 (cyclo-
(R)-3-(o-Phenylbenzoyl)-2,2-dimethyloxazolidine-4-formal
dehyde (6)
Into a solution of oxalyl chloride (3.6 mL, 42.4 mmol) in
CH2Cl2 (85 mL) was added dropwise at 78 °C a solution
of DMSO (6 mL, 84.8 mmol) in CH2Cl2 (15 mL). After 10
min the (R)-3-(o-phenylbenzoyl)-2,2-dimethyloxazolidine-
4-methanol 5 (8.8 g, 28.25 mmol) in CH2Cl2 (25 mL) was
added dropwise and the mixture was stirred for 30 min at
60 °C. Triethylamine (19.6 mL, 141 mmol) in CH2Cl2
(15 mL) was then added dropwise and after return to room
temperature water (45 mL) was added. The aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The organic layers
were assembled and washed with water (3 × 140 mL) and
brine (140 mL) and then dried over MgSO4. The obtained
product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate: 7/3), leading to 6; yield 76%
(6.65 g), Rf =0.1 (cyclohexane/ethyl acetate: 7/3). []D =84
1
hexane/ethyl acetate: 9/1). []D = 5 (c = 1.4, CHCl3). H
NMR (400 MHz, CDCl3):  7.42 (m, 9H, Ph), 3.87 (sl, 1H,
CH), 3.70 (d, J = 6.9 Hz, 1H, CH2), 3.23 (sl, 1H, CH2), 1.73
(s, 3H), 1.28 (s, 3H). 13C NMR (100 MHz, CDCl3): 
167.9 (C=O), 139.6, 137.6, 136.6, 129.8, 129.4, 128.9,
128.7, 128.3, 128.1, 127.7 (Ph), 96.2 (Cquat isopropyl), 91.7
(Cquat CC), 68.8 (CH2), 51.2 (CH), 26.1, 22.9 (2 × CH3),
1.3 (CI). IR:  = 1613, 2177, 2982 cm1. HRMS calcd for
C20H18INO2: 431.0383; found: 431.0379.
1
(c = 10.2, CHCl3). H NMR (400 MHz, CDCl3):  9.23 (s,
1H, CHO), 7.44 (m, 9H, Ph), 3.88 (dd, J = 7.5, 1.8 Hz 1H,
CH2), 3.65 (dl, J=6.8 Hz, 1H, CH), 3.28 (dd, J=7.5, 6.8 Hz,
1H, CH2), 1.71 (s, 3H), 1.30 (s, 3H). 13C NMR (100 MHz,
CDCl3):  196.9 (CO), 168.2 (CO), 139.3, 137.6, 136.2,
130.1, 129.6, 129.0, 128.3, 128.0 (Ph), 96.8 (Cquat isopropyl),
65.8 (CH), 63.9 (CH2), 25.8, 22.4 (2 × CH3). IR:  = 1641,
1735, 2177, 2984, 3061 cm1. HRMS calcd for C19H19NO3:
309.1379; found: 309.1365.
2.4 Synthesis of the (S)-3-benzyl-4-ethynyl-2,2-dimethyl-
oxazolidine (11)
(R)-3-Benzyl-2,2-dimethyloxazolidine-4-formaldehyde (10)
Into a solution of oxalyl chloride (2.6 mL, 30 mmol) in
CH2Cl2 (60 mL) was added dropwise at 78 °C a solution
of DMSO (4.6 mL, 64.8 mmol) in CH2Cl2 (10 mL). After
10 min, the (S)-3-benzyl-2,2-dimethyloxazolidine-4-methanol
9 (5.5 g, 25 mmol) in CH2Cl2 (30 mL) was added dropwise
and the mixture was stirred for 30 min at 60 °C. Triethyl-
amine (18 mL, 190 mmol) in CH2Cl2 (10 mL) was then
added dropwise and after return to room temperature water
(30 mL) were added. The aqueous layer was extracted with
CH2Cl2 (3 × 15 mL). The organic layers were assembled and
washed with water (3 × 100 mL) and brine (100 mL) and
then dried over MgSO4. The obtained product 10 (4.65 g,
84%) was used in the next step without any further purifica-
tion. 1H NMR (400 MHz, CDCl3):  8.87 (d, 1H, J=4.6 Hz,
CHO), 7.23 (m, 5H, Ph), 4.01 (dd, J=9.2, 8.7 Hz, 1H, CH2),
3.91 (d, J = 12.8 Hz 1H, CH2Ph), 3.80 (dd, J = 9.2, 6.0 Hz,
1H, CH2), 3.39 (d, J = 12.8 Hz 1H, CH2Ph), 3.29 (ddd, J =
(R)-3-(o-Phenylbenzoyl)-4-ethynyl-2,2-dimethyloxazolidine (7)
In a vigorously stirred solution of aldehyde 6 (5.26 g, 17
mmol) in MeOH (360 mL) were added at 0 °C potassium
carbonate (4.4 g, 31.8 mmol) and a solution of dimethyl
1-diazo-2-oxopropylphosphonate (5.53 g, 28.8 mmol) in
MeOH (5 mL). After 16 h stirring at room temperature the
medium was diluted with ethyl ether (400 mL), washed with
a 5% solution of sodium bicarbonate (50 mL) and dried
over MgSO4. The crude product was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate:
9/1), leading to 7; yield 97% (5.05 g), Rf =0.9 (cyclohexane/
ethyl acetate: 9/1). []D =6 (c=1.4, CHCl3). 1H NMR (400
MHz, CDCl3):  7.42 (m, 9H, Ph), 3.81 (sl, 1H, CH), 3.70
(d, J = 7.8 Hz, 1H, CH2), 3.16 (sl, 1H, CH2), 2.10 (d, J=1.8

1924
AYED Charfedinne, et al. Sci China Chem September (2010) Vol.53 No.9
8.7, 6.0, 4.6 Hz, 1H, CH), 1.39 (s, 3H), 1.25 (s, 3H). 13C
NMR (100 MHz, CDCl3):  201.3 (CO), 138.4, 129.5,
128.7, 128.0 (Ph), 96.9 (Cquat isopropyl), 70.6 (CH), 64.0
(CH2), 53.9 (CH2Ph), 27.1, 20.6 (2 × CH3).
C34H36NOISi: 629.1611; found: 629.1627.
2.6 Coupling reactions
tert-Butyl(R)-4-[3-hydroxy-3-(2,3,4,6-tetra-O-benzyl-D-gluco-
-C-pyranosyl)prop-1-ynyl]-2,2-dimethyloxazolidine-3-carbox-
ylate (14)
(S)-3-Benzyl-4-ethynyl -2,2-dimethyloxazolidine (11)
Into a solution of (R)-3-benzyl-2,2-dimethyloxazolidine-4-
formaldehyde 10 (1.4 g, 6.4 mmol) in methanol (95 mL)
was added K2CO3 (1.17 g, 8 mmol) under vigorous stirring.
Then dimethyl 1-diazo-2-oxopropylphosphonate (1.4 g, 7.6
mmol) in MeOH (5 mL) was added at 0 °C. After 16 h at
room temperature, the medium was diluted with ethyl ether
(150 mL) and washed with a 10% NaHCO3 solution. The
organic layer was dried over MgSO4 and the product was
purified by flash chromatography on silica gel (triethyl-
amine/cyclohexane: 1/1) leading to 11; yield 40% (0.55 g);
Rf = 0.85 (cyclohexane/ethyl acetate: 9/1). mp 48 °C. []D =
Indium (0.28 g, 2.4 mmol) was stirred during 1 h under
vacuum under vacuum/argon in a sealed tube. Then, a solu-
tion of tert-butyl (R)-4-iodoethynyl-2,2-dimethyloxazolidine-
3-carboxylate 3 (0.70 g, 2 mmol) and 2,3,4,6-tetra-O-benzyl-
1-formyl--D-glucopyranose (0.55 g, 1 mmol) in anhydrous
CH2Cl2 (15 mL) was introduced to the medium which was
refluxed overnight. The medium was then hydrolyzed with
a saturated solution of NaHCO3 (10 mL). The aqueous layer
was extracted with dichloromethane (2 × 10 mL). The or-
ganic layers were assembled and dried over MgSO4. The
obtained product was obtained as a mixture of two di-
astereomers in a 2/1 ratio that were separated by flash
chromatography on silica gel (petroleum ether/ethyl acetate:
8.5/1.5) leading to 14; yield 66% (0.51 g). Major di-
astereomer Rf = 0.5 (cyclohexane/ethyl acetate: 7/3). []D =
1
2 (c = 10.7, CHCl3). H NMR (400 MHz, CDCl3):  7.33
(m, 5H, Ph), 4.04 (dd, J = 7.3, 6.0 Hz, 1H, CH2), 3.98 (dd,
J = 7.3, 3.2 Hz 1H, CH2), 3.87 (d, J = 13.3 Hz, 1H, CH2Ph),
3.83 (d, J = 13.3 Hz 1H, CH2Ph), 3.76 (ddd, J=6.0, 3.2, 2.3,
Hz, 1H, CH), 2.36 (d, J = 2.3 Hz, 1H, CCH), 1.38 (s, 3H),
1.35 (s, 3H). 13C NMR (100 MHz, CDCl3):  139.3, 128.9,
128.4, 127.2 (Ph), 95.4 (Cquat isopropyl), 82.3 (CCH), 74.1
(CC), 70.6 (CH), 69.5 (CH2), 50.9 (CH), 49.0 (CH2Ph),
26.6, 24.1 (2 × CH3). HRMS calcd for C14H17NO: 215.1310;
found: 215.1321.
1
12 (c = 2.0, CHCl3). H NMR (250 MHz, CDCl3):  7.14
(m, 20H, Ph), 5.12–4.62 (m, 10H, CH2Ph, CHN and
CHOH), 3.88 (m, 2H, CH2O), 3.68–3.28 (m, 7H, 1-H, 2-H,
3-H, 4-H, 5-H, 6-H), 1.54 (s, 3H), 1.40 (s, 12H). 13C NMR
(62.9 MHz, CDCl3): 151.4 (CO), 138.4–137.7, 128.4–127.5
(Ph), 94.2 (Cquat isopropyl), 93.8 (CC), 86.7 (1-C), 83.9
(CC), 81.0 (Cquat Boc), 80.4, 78.9, 78.1, 77.9 (2-C, 3-C,
4-C, 5-C), 75.3, 75.2, 74.9, 73.3 (CH2Ph), 68.5 (6-C, CH2O),
61.4 (CHOH), 48.5 (CHN), 28.3, 26.8, 25.9, 25.2, 24.3
(CH3). IR: =1496, 1697, 2922, 3401 cm1. HRMS [M+NH4]+
calcd for C47H59N2O9: 795.4221; found: 795.4211. Minor
diastereomer Rf = 0.3 (cyclohexane/ethyl acetate: 7/3). []D
2.5 Synthesis of the (S)-1-iodo-3-dibenzylamino-4-(tert-
butyldiphenylsiloxy)but-1-yne (13)
After complete dissolution of iodine (1.22 g, 4.8 mmol) in
benzene (30 mL), morpholine (1.2 mL, 12 mmol) was
added and the mixture was stirred for 45 min until appear-
ance of an orange precipitate. The compound 12 (2.04 g, 4
mmol) in benzene (10 mL) was then added and the mixture
was heated at 50 °C for 48 h. The medium was cooled, di-
luted with ethyl ether (100 mL) and filtered. The filtrate was
reduced to 20 mL by evaporation under vacuum. The or-
ganic layer was washed with a saturated solution of NH4Cl
(2 × 15 mL), a saturated solution of NaHCO3 (15 mL), water
(20 mL) and then dried over MgSO4. The crude product was
purified on silica gel (cyclohexane/ethyl acetate: 95/5)
leading to 13; yield 70% (1.77 g); Rf = 0.8 (cyclohexane/
ethyl acetate: 9/1); mp 156 °C. []D = +9 (c = 2.5, CHCl3).
1H NMR (400 MHz, CDCl3):  7.38 (m, 20H, Ph), 3.96 (d,
J = 13.7 Hz, 2H, CH2Ph), 3.94 (m, 1H, CH), 3.88 (dd, J =
10.1, 6.9 Hz, 1H, CH2), 3.79 (dd, J=10.1, 6.0 Hz, 1H, CH2),
3.54 (d, J = 14.2 Hz, 2H, CH2Ph), 1.12 (s, 9H, tertBu). 13C
NMR (100 MHz, CDCl3):  129.8, 128.8, 128.4, 127.8,
127.1 (Ph), 91.7 (CC), 65.1 (CH), 65.1 (CH), 56.3 (CH2Ph),
55.7 (CH2), 26.9 (CH3 tertBu), 19.3 (Cquat tertBu), 0.1 (CI).
IR:  = 1588, 2247, 2929, 3067 cm1. HRMS calcd for
1
= 14 (c = 2.1, CHCl3). H NMR (250 MHz, CDCl3):  7.14
(m, 20H, Ph), 4.81–4.44 (m, 10H, CH2Ph, CHN and
CHOH), 3.85 (m, 2H, CH2O), 3.66–3.39 (m, 7H, 1-H, 2-H,
3-H, 4-H, 5-H, 6-H), 1.52 (s, 3H), 1.37 (s, 12H). 13C NMR
(62.9 MHz, CDCl3):  151.3 (CO), 138.4–137.9, 128.3–127.5
(Ph), 94.3 (Cquat isopropyl), 93.8 (CC), 86.7 (1-C), 85.6
(CC), 80.5 (Cquat Boc), 80.2, 79.9, 78.9, 78.3 (2-C, 3-C,
4-C, 5-C), 75.4, 75.2, 75.0, 73.1 (CH2Ph), 68.8, 68.4 (6-C,
CH2O), 61.5 (CHOH), 48.5 (CHN), 28.4, 26.9, 26.1, 25.1,
24.1 (CH3). IR:  = 1496, 1702, 2923, 3405 cm1. HRMS
[M+NH4]+ calcd for C47H59N2O9: 795.4221; found: 795.4216.
1-(4,6-di-O-Acetyl-2,3-dideoxy-D-erythrohex-2-enopyranosyl)-
(S)-3-dibenzylamino-4-(tert-butyldiphenylsiloxy)but-1-yne (15):
Indium bromide (0.36 g, 1.86 mmol) was stirred during 1 h
under vacuum/argon in a sealed tube. Then, a solution of
(S)-1-iodo-3-dibenzylamino-4-(tert-butyldiphenylsiloxy)but-
yne 13 (0.94 g, 1.5 mmol) and tri-O-acetyl-D-glucal (0.2 g,
0.74 mmol) in anhydrous CH2Cl2 (20 mL) was introduced
to the medium which was refluxed for 24 h. The mixture

AYED Charfedinne, et al. Sci China Chem September (2010) Vol.53 No.9
1925
was filtered over celite and the crude was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate:
8/2), leading to 15; yield 40% (0.53 g), Rf =0.4 (cyclohexane/
ethyl acetate: 8/2). []D =+1 (c=6.8, CHCl3). 1H NMR (400
MHz, CDCl3):  7.36 (m, 20H, Ph), 5.84 (ddd, J=10.1, 3.4,
1.4 Hz, 1H, 2-H), 5.72 (dd, J = 10.1, 1.8 Hz, 1H, 3-H), 5.25
(ddd, J = 8.2, 3.4, 1.8 Hz, 1H, 4-H), 5.01 (d, J =1.4 Hz, 1H,
1-H), 4.16 (m, 3H, 5-H, 6-H), 3.82 (d, J=14.0, 2H, CH2Ph),
3.73 (m, 2H, CH2), 3.65 (dd, J = 7.1, 3.4 Hz, 1H, CH), 3.41
(d, J = 14.0, 2H, CH2Ph), 2.01 (s, 3H, Ac), 1.98 (s, 3H, Ac),
0.96 (s, 9H). 13C NMR (100 MHz, CDCl3):  171.0, 170.4
(CO), 139.5, 135.6, 133.3 (Ph), 129.8 (2-C), 129.7, 128.8,
128.4, 127.7, 127.1 (Ph), 125.3 (3-C), 83.2 (CC), 81.7
(CC), 70.0 (5-C), 65.0 (CH2, 4-C), 64.3 (1-C), 63.3 (6-C),
55.7 (CH2Ph), 54.4 (CH), 26.9 (CH3 terbutyl), 21.1, 21.0
(2 × CH3, Ac), 19.3 (Cquat terbutyl). IR: =1742, 2932, 3029
cm1. HRMS calcd for C44H49NO6Si: 715.3329; found:
715.3331.
mediates a particular stability. It is noteworthy that many of
the compounds are crystalline making easier their manipu-
lation. The preparation of this synthon is performed from
ester 4 obtained in four steps from L-serine [13]. We selec-
tively reduced the methyl ester by sodium borohydrate in
the presence of calcium chloride at 20 °C, and then oxi-
dized the obtained alcohol under Swern conditions. The
aldehyde 6 was then transformed into the terminal alkyne
and the corresponding iodo alkyne according to the same
procedures used for the obtaining of 2 and 3 (Scheme 2).
3.3 Synthesis of the (S)-3-benzyl-4-ethynyl-2,2-dimethylox-
azolidine (11) and (S)-1-iodo-3-dibenzylamino-4-(tert-
butyldiphenylsiloxy)but-1-yne (13)
The precedent building-blocks bearing the amino group
under a carbamate or an amide form, we wanted also to ac-
cess to synthons with a tertiary amine functional group.
Thus the above alkyne 11 and iodoalkyne 13 were also pre-
pared. The first one was obtained by oxidation and ho-
mologation of alcohol 9 issued from D-serine after a three
step transformation [14]. The second one was reached by
iodination of the terminal alkyne 12 that results also from
D-serine after a six step transformation [15] (Scheme 3).
3 Results and discussion
3.1 Synthesis of the tert-butyl (R)-4-iodoethynyl-2,2-
dimethyloxazolidine-3-carboxylate (3)
This alkynyl iodide was obtained starting from Garner’s
aldehyde 1. This well known aldehyde presents the amino
alcohol part protected as a N-Boc oxazolidine. We prepared
it in five steps starting from L-serine according to the pro-
cedure described by Dondoni et al. [12]. The aldehyde was
then homologated into the terminal alkyne 2 by the Seyferth-
Colvin-Gilbert reaction using the Ohira-Bestman reagent i.e.
the dimethyl 1-diazo-2-oxopropylphosphonate. We chose
Meffre et al. modification [3] in which this diazo derivative
is prepared in situ from p-acetamidobenzenesulfonyl azide
and dimethyl 2-oxopropylphosphonate in presence of potas-
sium carbonate. The iodination was then achieved with a
high yield by reaction of iodine and morpholine in benzene
heated at 45 °C (Scheme 1).
Scheme 2 Reaction conditions: (i) NaBH4, CaCl2, EtOH, 20 °C, 2 h
then rt, 16 h, 93%; (ii) DMSO, (COCl)2, CH2Cl2, 78 °C then Et3N, 76%;
(iii) CH3COC(=N2)P(O)(OMe)2, K2CO3, MeOH, 0 °C, 1 h then rt, 16 h,
97%; (iv) I2, morpholine, benzene, 45 °C, 48 h , 73%.
3.2 Synthesis of the (R)-3-(o-phenylbenzoyl)-4-iodo
ethynyl-2,2-dimethyl oxazolidine (8)
The interest of this building-block lies in the presence of the
biphenylcarbonyl group that confers to the synthetic inter-
Scheme 3 Reaction conditions: (i) DMSO, (COCl)2, CH2Cl2, 78 °C then
Et3N, 84%; (ii) CH3COC(=N2)P(O)(OMe)2, K2CO3, MeOH, 0 °C, 1 h then
rt, 16 h, 40%; (iii) I2, morpholine, benzene, 45 °C, 48 h , 70%.
Scheme 1 Reaction conditions: (i) K2CO3, CHCl3, p-CH3CONHC6H4SO2N3,
CH3COCH2P(O)(OMe)2, 0 °C, 48 h then MeOH, 0 °C, 24 h, 67%; (ii) I2,
morpholine, benzene, 45 °C, 24 h , 90%.

1926
AYED Charfedinne, et al. Sci China Chem September (2010) Vol.53 No.9
3.4 Coupling reactions
amino acid precursors. As the described building-blocks
present diversely protected functional groups, they could be
introduced in reactions that use different conditions. As an
example we introduced two of these synthons in an indium
mediated alkynylation reaction of sugar derivatives
demostrating the compatibility of the coupling conditions
with such functionalized compounds.
Indium-promoted organometallic reactions have elicited
considerable attention since the discovery of the remarkable
reactivity of this metal [16]. Indium-mediated alkynylation
of carbonyl compounds and sugar derivatives was largely
developed in our laboratory [6–11]. In order to extend this
reactivity to more functionalized molecules, we first ex-
plored the reaction of alkynyl iodide 3 with 2,3,4,5-tetra-
O-benzyl-1-formylglucopyranose that was prepared in three
steps starting from perbenzylgluconolactone [17]. The cou-
pling proceeded efficiently in dichloromethane in presence
of metallic indium and the corresponding propargylic alco-
hol was obtained in 66% yield as a 2/1 mixture of two di-
astereomers that can be easily separated by flash chroma-
tography. In another hand, we also checked the C-glycosy-
lation by an alkynylation on the 1-position of tri-O-acetyl-
glucal. In this case, the Ferrier-type reaction with iodide
13 in presence of 2.4 equivalents of indium (I) bromide
in refluxing dichloromethane led to the corresponding
C-glycoside in 40% yield exclusively under the  anomer
form (Scheme 4).
1
2
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7
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These results are very promising as they allow envisaging
the access to carbonated analogues of glycosyl serines or
homoserines after deprotection of the amino acid part and
functionalization of the sugar moiety in the second case.
8
9
Picard J, Lubin-Germain N, Uziel J, Augé J. Indium mediated al-
kynylation in C-glycoside synthesis. Synthesis, 2006, 979–982
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2,2-dimethyl-3-oxazolidine carboxylate by oxidation of the alcohol.
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Scheme 4 Reaction conditions: (i) In, CH2Cl2, reflux, overnight, 66%; (ii)
InBr, CH2Cl2, reflux, 24 h, 40%.
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4 Conclusions
We described herein the synthesis of some alkynes and io-
doalkynes bearing a protected amino alcohol moiety as
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methods for the synthesis of -C-glycosides. Synlett, 1994, 705–708