Propargyloxycarbonyl (Poc) as a Protective Group for the Hydroxyl Function in Carbohydrate Synthesis

Article abstract of DOI:10.1021/ol027220x

(Matrix Presented) The propargyloxycarbonyl (Poc) group can be used for the selective protection of the hydroxyl function in carbohydrates and can be removed under neutral conditions using tetrathiomolybdate MoS₄^2- (1) in CH₃CN at room temperature. Under the conditions of deprotection benzylidine acetals, benzyl ethers, acetyl and levulinoyl esters, and allyl and benzyl carbonates are left untouched. It has also been shown that the new protective group (Poc) is compatible with acidic, basic, and also glycosylation conditions.

Full text of DOI:10.1021/ol027220x

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4731-4733
Propargyloxycarbonyl (Poc) as a
Protective Group for the Hydroxyl
Function in Carbohydrate Synthesis
Perali Ramu Sridhar and S. Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
scn@orgchem.iisc.ernet.in
Received November 3, 2002
ABSTRACT
The propargyloxycarbonyl (Poc) group can be used for the selective protection of the hydroxyl function in carbohydrates and can be removed
under neutral conditions using tetrathiomolybdate MoS 2- (1) in CH CN at room temperature. Under the conditions of deprotection benzylidine
4
3
acetals, benzyl ethers, acetyl and levulinoyl esters, and allyl and benzyl carbonates are left untouched. It has also been shown that the new
protective group (Poc) is compatible with acidic, basic, and also glycosylation conditions.
Many of the steps required in carbohydrate synthesis involve
selective protection and deprotection of hydroxyl groups. In
contrast with peptide synthesis, generalized methods cannot
be applied to oligosaccharide formation. The development
of solid-phase synthesis of oligosaccharides1 has been
hampered by the lack of effective differential protection/
deprotection strategies. In addition, problems are still en-
countered in achieving high yielding and stereoselective
couplings for multifunctional carbohydrate donors and ac-
ceptors.2 In this context, new protection/deprotection methods
will play an important role in carbohydrate chemistry.
The propargyloxycarbonyl (Poc) protecting group, which
has been developed in our laboratory, has served as an
efficient protective group for amines,3 as chemoselective
deprotection under neutral conditions using benzyltriethyl-
ammonium tetrathiomolybdate, [PhCH2NEt3]2MoS4 (1), can
be achieved. Moreover, Poc is stable under acidic and mild
basic conditions and the deprotected products can be isolated
by simple filtration.
In this letter we describe the first systematic study of the
application of Poc as a protecting group for the hydroxyl
function in carbohydrates.
The regioselective introduction of Poc group at the C-2
position of methyl-4,6-O-benzylidene-R-D-glucopyranoside
3 has been achieved using TMEDA as a base at -78 °C in
CH2Cl2.4 Using this methodology methyl-2-O-propargyloxy-
carbonyl-4,6-O-benzylidene-R-D-glucopyranoside 4 was syn-
thesized in 80% yield with none of the 3-O-protected
derivative. The only byproduct was the doubly protected
compound 5. On the other hand, reaction of methyl-4,6-O-
(p-methoxybenzylidene)-â-D-glucopyranoside 75 with Poc-
Cl using TMEDA as a base at -78 °C in CH2Cl2 gave
selectively the 3-hydroxy Poc-protected compound 8 in 75%
and doubly protected compound 9 in 20% yield, respectively.
In addition, selective protection of the 6-OH of methyl-2,3-
di-O-benzyl-R-D-glucopyranoside 10 with Poc-Cl was achieved
(1) (a) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F. J. Am.
Chem. Soc. 1997, 119, 449 and references therein. (b) Osborn, H. M. I.;
Khan, T. H. Tetrahedron 1999, 55, 1807. (c) Ling, R.; Yan, L.; Loebach,
J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan, N.; Gildersleeve, J.;
Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.; Khane, D. Science 1996,
274, 1520. (d) Zhu, T.; Boons, G. J. Angew. Chem., Int. Ed. Engl. 1998,
37, 1898.
(2) For recent reviews, see: (a) Arya, P.; Ben, R. N. Angew Chem., Int.
Ed. Engl. 1997, 36, 1280. (b) Paulsen, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1432.
(4) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A. Tetrahedron
Lett. 2000, 41, 9305.
(3) Sinha, S.; Ilankumaran, S.; Chandrasekaran, S. Tetrahedron Lett.
1999, 40, 771.
(5) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984,
2371.
10.1021/ol027220x CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2002

chemoselective deprotection methodology also proved ef-
fective for the cleavage of the 2-O-Poc group in the presence
of 3-O-Alloc to form 15 in excellent yield (90%). Treatment
of 4 with acetic anhydride in pyridine gave acetate 16.
Selective deprotection of 2-O-Poc in the presence of acetyl
ester has been achieved within 90 min to give 17 in 95%
yield. Levulinate esters have been used as one of the
orthogonal protecting groups in the presence of p-methoxy-
benzyl (PMB), tertiarybutyldiphenylsilyl (TBDPS), and chlo-
roacetyl (ClAc) function in oligosaccharide libraries synthe-
sis.13 Treatment of 4 with levulinic acid in the presence of
DCC, DMAP in CH2Cl2 gave 18. In this case also Poc group
has been deprotected in the presence of levulinoyl ester to
give 19 in 90% yield (Scheme 2).
Scheme 1. Selective Protection and Deprotection of the Poc
Groupa
Scheme 2. Chemoselective Deprotection of Poc Using
MoS4 - (1)a
2
a (a) PhCH(OMe)2, p-Ts-OH‚H2O, DMF. (b) Poc-Cl, TMEDA,
CH2Cl2, -78 °C. (c) p-MeOC6H4(OMe)2, p-TsOH‚H2O, DMF. (d)
Poc-Cl, TMEDA, CH2Cl2, -20 °C. (e) MoS42-, CH3CN, 28 °C.
to give 11 in 85% yield (Scheme 1). Treatment of 4, 5, 8, 9,
and 11 with MoS42- (1) gave the corresponding deprotected
products 3, 7, and 10, respectively, in excellent yield. These
results indicated that the benzylidine, p-methoxybenzy-
lidineacetals, and benzyl protecting groups are stable under
the conditions of deprotection.
The 3-hydroxy function of compound 4 was protected with
different protective groups that are widely applied in
carbohydrate chemistry. The benzyloxycarbonyl (Cbz) is
generally used as protecting group for amines6 in peptide
synthesis and for hydroxyl function in carbohydrate synthe-
sis.7 Reaction of 4 with benzyloxycarbonyl chloride (Cbz-
Cl) gave compound 12 in 92% yield. Treatment of 12 with
tetrathiomolybdate 1 gave chemoselectively Poc-deprotected
compound 13 in 92% yield. The allyloxycarbonyl (Alloc)
has also been used as protecting group for alcohols8 in
carbohydrate chemistry,8 as well as for amines in oligosa-
charide,10 peptide,11 and solid-phase oligonucleotide synthe-
sis.12 Treatment of 4 with allyloxycarbonyl chloride (Alloc-
Cl) in the presence of TMEDA in CH2Cl2 furnished 14. Our
a (a) Cbz-Cl, TMEDA, CH2Cl2, 0 °C. (b) Alloc-Cl, TMEDA,
CH2Cl2, 0 °C. (c) (CH3CO)2O, DMAP, pyridine. (d) Levulinic acid,
DCC, DMAP, CH2Cl2. (e) MoS42-, CH3CN, 28 °C.
We also used the Poc protecting group in the case of
glucosamine 20.14 The Poc-protected glucopyranose deriva-
tive 21 on treatment with tetrathiomolybdate 1 yielded the
free amine 22 (85%) (Scheme 3).
Scheme 3a
(6) (a) Wuensch, E.; Gref, W.; Keller, O.; Keller, W.; Wersin, G.
Synthesis 1986, 11, 958. (b) Munegumi, T.; Meng, Y.-Q.; Harada, K. Bull.
Chem. Soc. Jpn. 1989, 62, 2748. (c) Schmidt, U.; Kroner, M.; Beutler, U.
Synthesis 1988, 6, 475.
(7) (a) Teshima, T.; Nakajima, K.; Takahashi, M.; Shiba, T. Tetrahedron
Lett. 1992, 33, 363. (b) Depre, D.; Du¨ffels, A.; Green, L. G.; Lenz, R.;
Ley, S. V.; Wong, C.-H. Chem. Eur. J. 1999, 5, 3326. (c) Kobayashi, Y.;
Ishida, N.; Arai, M.; Shiozaki, M.; Hiraoka, T. Carbohydr. Res. 1991, 222,
83. (d) Dondoi, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
Synthesis 1998, 685. (e) Fukase, K.; Kinoshita, I.; Kanoh, T.; Nakai, Y.;
Hasuoka, A.; Kusumoto, S. Tetrahedron 1996, 52, 3897.
(8) Guibe, F.; Saint M’Leux, Y. Tetrahedron Lett. 1981, 22, 3591.
(9) Harada, T.; Yamada, H.; Tsukamoto, H.; Takahashi, T. J. Carbohydr.
Chem. 1995, 14, 165.
a (a) NaOMe, MeOH. (b) Poc-Cl, Et3N. (c) Ac2O, pyridine. (d)
MoS42-, CH3CN, 28 °C.
After optimizing the conditions for chemoselective depro-
tection of Poc, we focused our attention on the formation of
(10) Dominique, L.; Boullanger, P.; Bonoub, J.; Descotes. G. Can. J.
Chem. 1990, 68, 828.
(12) Hayakawa, Y.; Wakabayashi, S.; Kato, H, Noyori, R. J. Am. Chem.
Soc. 1990, 112, 1691.
(11) Dangles, O.; Guibe, F.; Balavoine, G.; Lavielle, S.; Marquet, A. J.
Org. Chem. 1987, 52, 4984.
(13) Wong, C.-H.; Ye, X. S.; Zhang, Z. J. Am. Chem. Soc. 1998, 120,
7137.
4732
Org. Lett., Vol. 4, No. 26, 2002

Poc group is stable18 to a variety of glycosylation conditions
for use in oligosaccharide synthesis.
Scheme 4a
General Procedure for Poc-Protected Carbohydrate
Derivatives. Synthesis of 6-O-Proporgyloxycarbonyl-r-
D-methyl-4,6-di-O-benzyl-glucopyranoside (11). To a cooled
(-60 °C) and stirred solution of compound 10 (0.20 g, 0.53
mmol) and TMEDA (53 µL, 0.32 mmol) in dichloromethane
(10 mL) was added dropwise propargyloxycarbonyl chloride
(70 µL, 0.58 mmol), and the mixture was stirred at -60 °C
for 0.5 h. TLC analysis (ethyl acetate/petroleum ether, 1:2
v/v) indicated the completion of the reaction. The mixture
was diluted with dichloromethane (20 mL) and washed with
water (10 mL) and brine (10 mL). The organic layer was
dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by chromatography on
silica gel to give 11 (0.199 g, 85%) as a colorless gum. IR
1
(thin film): 3490, 3285, 2126, 1753, cm-1. H NMR (300
MHz, CDCl3): δ 7.32-7.35 (m, 10H, phenyl), 5.03 (d, J )
11.7 Hz), 4.60-4.79 (m, 6H), 4.38 (bs, 1H), 3.78 (t, J )
9.3 Hz), 3.34-3.53 (m, 6H). 13C NMR (75 MHz, CDCl3):
δ 154.6, 138.6, 137.8, 128.5, 128.4, 127.9, 127.9, 127.8,
127.7, 98.0, 81.0, 79.5, 76.8, 75.7, 75.3, 73.0, 69.6, 68.9,
67.0, 55.3, 55.2. Low resolution MS: m/z 456 (M+). Anal.
calcd for C25H28O8: C, 65.78; H, 6.18. Found: C, 65.43; H,
6.19.
General Procedure for the Deprotection of Poc with
Tetrathiomolybdate 1. Deprotection of 11. To a well-stirred
solution of 11 (0.456 g, 1 mmol) in CH3CN (10 mL) was
added tetrathiomolybdate 1 (0.670 g, 1.1 mmol) all at once.
The reaction mixture was stirred for 3 h at room temperature
(28 °C). The solvent was removed under reduced pressure,
and the black residue was extracted with dichloromethane/
diethyl ether (1:1, 10 mL × 3) and filtered through a Celite
pad. The filtrate was concentrated, and the residue was
purified by chromatography on silicagel using ethyl acetate
to get compound 10 (0.355 g, 95%) as a solid, mp 79 °C,
lit.19 79-80 °C.
a (a) NIS, TMSOTf, CH2Cl2, 4 Å MS, 0 °C. (b) MoS42-, CH3CN,
28 °C. (c) TMSOTf, CH2Cl2, 4 Å MS, 0 °C.
disaccharides where Poc-protected carbohydrate derivatives
can be used as glycosyl acceptors.
We examined two typical glycosylation conditions that are
widely used in oligosaccharide synthesis. The reaction of
methyl glycoside 4 with thioglycoside 23 under Fraser-Reid
conditions15 (NIS/cat. TMSOTf) furnished compound 24 in
85% yield. Similarly the reaction of 4 with trichloroacetimi-
date 2616a under Schmidt conditions16 gave the disaccharide
27 in 86% yield. These experimental results indicate that
the Poc protective group could withstand Lewis acidic
conditions and also olefin reactive reagents such as NBS and
NIS, whereas allyloxycarbonyl (Alloc) is not compatible.9
Treatment of 24 and 27 with tetrathiomolybdate 1 in CH3-
CN at room temperature gave Poc-deprotected products 25
and 2817 in 92% and 91% yield, respectively (Scheme 4).
In conclusion, we have demonstrated that the Poc group
can be used effectively for orthogonal protection of hydroxyl
groups in carbohydrates and can be selectively deprotected
with tetrathiomolybdate 1. It has also been shown that the
Acknowledgment. The authors are thankful to the
Volkswagen Foundation, Germany for financial support of
this investigation. P.R.S. thanks Council of Scientific and
Industrial Research, New Delhi, for a senior research
fellowship.
(14) Boullanger, P.; Banoub, J.; Descotes, G. Can. J. Chem. 1987, 65,
1343.
(15) (a) Zhu, T.; Boons, G.-J. J. Am. Chem. Soc. 2000, 122, 10222. (b)
Zhu, T.; Boons, G. J. Chem. Eur. J. 2001, 7, 2382. (c) Konradsson, P.;
Udodong. U.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313. (d)
Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron Lett.
1990, 31, 1331.
1
Supporting Information Available: H and 13C spectra
of compounds 4, 5, 8, 9, 11-19, 24, 25, 27. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL027220X
(16) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980,
19, 731. (b) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(17) (a) Schene, H.; Waldmann, H. Eur. J. Org. Chem. 1998, 1227. (b)
Takeo, K.; Tei, S. Carbohydr. Res. 1986, 145, 307.
(18) The Poc protective group is not stable under catalytic hydrogenation
conditions.
(19) Bell, D. J.; Lorber, J. J. Chem. Soc. 1940, 453.
Org. Lett., Vol. 4, No. 26, 2002
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