Iodine/triethylsilane as a convenient promoter system for the activation of disarmed glycosyl trichloro- and N-(phenyl)trifluoroacetimidates

Article abstract of DOI:10.1055/s-2002-19770

Disarmed glycosyl trichoro- and N-(phenyl)trifluoroacetimidates can be efficiently activated by the combined reagent system I₂/Et₃SiH in the fast and high yielding glycosylation of primary and secondary saccharidic acceptors.

Full text of DOI:10.1055/s-2002-19770

LETTER
269
Iodine/Triethylsilane as a Convenient Promoter System for the Activation of
Disarmed Glycosyl Trichloro- and N-(Phenyl)trifluoroacetimidates
Activation of
G
lycosyl
a
T
richloro-
t
and
N
-
t
(
Pheny
e
l)trifluoroa
o
cetimidates Adinolfi, Gaspare Barone, Alfonso Iadonisi,* Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Via Cynthia 4, 80126 Napoli, Italy
Fax +39(81)674393; E-mail: iadonisi@unina.it
Received 8 November 2001
donors enabling the stereocontrolled synthesis of 1,2-
Abstract: Disarmed glycosyl trichoro- and N-(phenyl)trifluoroace-
trans glycosides. On this regard we considered that the ad-
dition of a catalytic amount of triethylsilane to the iodine
timidates can be efficiently activated by the combined reagent sys-
tem I2/Et3SiH in the fast and high yielding glycosylation of primary
could generate in situ a small amount of anhydrous HI po-
tentially able to activate the donors.6,7 In order to test this
hypothesis the model secondary acceptor 5 was treated
with a slight excess (1.3 mol) of several disarmed glycosyl
imidates (1–4) in the presence of iodine (1 mol) and trieth-
ylsilane (0.05 mol) (Table 1). The coupling yields were
dramatically influenced by the solvent and the best results
were obtained with a mixture 4:1 dichloromethane/aceto-
nitrile.8 Interestingly, acid washed 4Å molecular sieves
were also found decisive for the obtention of high yields
probably due to the capability of ordinary molecular
sieves to act as proton scavengers.9 From the data reported
in Table 1 two interesting results can be highlighted. First-
ly, donors equipped with a methoxycarbonyl protecting
group on the 2-OH (3 and 4) afforded higher yields than
the donors equipped with the more conventional acetyl
and benzoyl participating groups (compare entries 3 and 4
with entries 1 and 2). This result parallels our recent ob-
servations regarding the use of Yb(OTf)3 in the activation
of disarmed glycosyl trichloroacetimidates.3 Furthermore
the use of donor 410 equipped at the anomeric position
with the recently reported11 N-(phenyl)trifluoroacetimi-
date group furnished a better yield of 11 than the corre-
and secondary saccharidic acceptors.
Key words: carbohydrates, glycosylations, iodine, neighboring-
group effects, triethylsilane
Glycosylation reactions represent the key step for the syn-
thesis of oligosaccharides.1 These reactions are very often
promoted by the action of strong and moisture sensitive
acids whose handling and storage requires strictly anhy-
drous conditions. Thus, the research of mild and easy to
handle promoters for the glycosylation reactions repre-
sents an important topic for the research in this field. We
have recently reported2,3 the use of moisture stable lan-
thanide triflates in the activation of both armed and dis-
armed
trichloroacetimidate
donors.4
In
this
communication we wish to report an alternative and cheap
reagent system for the activation of the less reactive dis-
armed imidate donors.
Very recently one example of the use of iodine in the ac-
tivation of an armed tetrabenzylated glucosyl trichloro-
acetimidate was reported.5 We were attracted by the idea
to extend the use of this mild promoter to 2-O-acylated
O
OH
R1O
R1O
R2O
BnO
HO
BnO
Ph
O
O
O
O
O
O
R1O
O
R2O R3
R2O
O
BnO
OCH3
OCH3
O
1 R1 = R2 = Ac; R3 = α-OC(=NH)CCl3
2 R1 = R2 = Bz; R3 = α-OC(=NH)CCl3
5 R1 = H; R2 = Bn
6 R1 = Bn; R2 = H
7
8
3 R1 = Ac; R2 = -CO2Me; R3 = α-OC(=NH)CCl3
4 R1 = Ac; R2 = -CO2Me; R3 = -OC(=NPh)CF3
O
Ph
O
O
O
Ph
O
AcO
AcO
MeO2CO
R1O
R1O
R2O
AcO
AcO
MeO2CO
BnO
O
O
O
O
O
O
O
O
O
O
O
O
BnO
BnO
AcO
O
R2O
AcO
OCH3
BnO
O
MeO2CO
OCO2Me
BnO
OCH3
OCH3
O
MeO2CO
9 R1 = R2 = Ac
10 R1 = R2 = Bz
11 R1 = Ac; R2 = -CO2Me
OCO2Me
12
14
13
Figure 1
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0269,0270,ftx,en;G32701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

270
M. Adinolfi et al.
LETTER
sponding trichloroacetimidate 3 (compare entries 3 and
4). This could be ascribed to the presence of a phenyl sub-
stituent on the nitrogen of the 1-leaving group in 4, which
could prevent an undesired -elimination4 and minimize
undesired rearrangements.12
References
(1) For recent reviews: (a) Davis, B. G. J. Chem. Soc., Perkin
Trans. 1 2000, 2137. (b) Seeberger, P. H.; Haase, W. Chem.
Rev. 2000, 100, 4349.
(2) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 2000, 41, 9005.
Table 1 Glycosylation of Model Acceptor 5 with Imidate Donors
1–4
(3) Adinolfi, M.; Barone, G.; Iadonisi, A.; Mangoni, L.;
Schiattarella, M. Tetrahedron Lett. 2001, 42, 5967.
(4) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(5) Kharta, R. K. P.; Karkkainen, T. S.; Marsh, S. J.; Field, R. A.
Synlett 2001, 260.
(6) For an alternative use of I2 in the generation of anhydrous
HI: Chervin, S. M.; Abada, P.; Koreeda, M. Org. Lett. 2000,
2, 369.
(7) For the use of triethylsilane in the formal addition of HI to
alkenes: Barluenga, J.; Gonzalez, J. M.; Campos, P. J.;
Asensio, G. Angew. Chem., Int. Ed. Engl. 1985, 24, 319.
(8) Use of acetonitrile as the solvent resulted in lower
glycosylation yields due to concomitant side reactions of the
donor. On the other hand, in dichloromethane the reactions
occurred very sluggishly.
(9) (a) Weinstock, L. M.; Karady, S.; Roberts, F. E.;
Hoinowsky, A. M.; Brenner, G. S.; Lee, T. B. K.; Lumma,
W. C.; Sletzinger, M. Tetrahedron Lett. 1975, 16, 3979.
(b) Demchenko, A. V.; Boons, G.-J. J. Org. Chem. 2001, 66,
2547.
(10) This donor was prepared as an anomeric mixture ( / , 2:1)
by reacting the corresponding 1-hydroxyl sugar3 with N-
(phenyl)trifluoroacetimidoyl chloride in the presence of
diisopropylethylamine (overnight stirring in CH2Cl2 at r.t.,
yield 88%). The use of K2CO3 as the base (as reported in
ref.11) resulted in a very sluggish reaction.
Entry
Donor
Producta
Isolated yield
(%)
1
2
3
4
1
2
3
4
9
10
11
11
52
50
69
85
a All the disaccharides were identified by 1H and 13C NMR.
In order to prove the generality of the approach trifluoro-
acetimidate donor 4 was coupled with other saccharidic
acceptors (6–8) under the optimised13 conditions and in all
cases good yields were registered (Table 2).
Table 2 Glycosylation of Acceptors 6–8 with Donor 4
Entry
Acceptor
Producta
Isolated yield
(%)
1
2
3
6
7
8
12
13
14
72
69
74
(11) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405.
(12) (a) Unverzagt, C.; Seifert, J. Tetrahedron Lett. 2000, 41,
4549. (b) Zhu, T.; Boons, G.-J. Carbohydr. Res. 2000, 329,
709.
a All the disaccharides were identified by 1H and 13C NMR.
(13) Typical Procedure: Donor 4 (31 mg, 0.056 mmol) and
acceptor 5 (16 mg, 0.043 mmol) were dissolved in CH2Cl2
(600 L) in the presence of freshly activated acid washed 4Å
molecular sieves (purchased from Fluka). The mixture was
cooled at 0 °C (ice bath) and a solution of I2 in MeCN (0.36
M, 120 L, 0.043 mmol) and a solution of Et3SiH in MeCN
(0.06 M, 35 L, 0.002 mmol) were added. After 30 min the
temperature was allowed to raise to r.t. After one additional
hour the mixture was diluted with CH2Cl2 and washed with
an aq solution of NaHCO3 containing sodium thiosulfate.
The organic phase was concentrated and the residue was
chromatographed on a short silica gel column eluted with 7:3
hexane/EtOAc. This purification afforded 27 mg of
disaccharide 113 (yield 85%).
(14) (a) Andrews, L. J.; Keefer, R. M. J. Am. Chem. Soc. 1959,
81, 1063. (b) Andrews, L. J.; Keefer, R. M. J. Am. Chem.
Soc. 1957, 79, 5169.
(15) Treatment of per-O-acetyl- -D-glucose with I2 and
triethylsilane (1.2 mol each) in refluxing CH2Cl2 for 20 min
resulted in the high yielding synthesis of the corresponding
-glycosyl iodide in analogy to the alternative system (RSH/
I2) reported in ref.6.
Interestingly, the reactions performed in the presence of
catalytic amounts of both iodine (10–20%) and triethylsi-
lane (5%) proceeded sluggishly. This evidence seems to
suggest that the formed HI does not activate the donor in
a direct manner, but presumably interacts with iodine to
afford the effective promoter. In this hypothesis it could
be pertinent to note that protic acids are known to assist
the X2 (X = Br or Cl) bond breaking in the electrophilic
aromatic halogenation.14
In conclusion we have shown that disarmed glycosyl
trichloroacetimidates and trifluoroacetimidates can be
very efficiently activated under the action of the conve-
nient combined system I2/Et3SiH.15 The substantial effect
exerted by the nature of the leaving group as well as the
participating group of the donor has been revealed.
Acknowledgement
Financial support by MURST (PRIN 2000-2001) and Università di
Napoli (Progetto Giovani Ricercatori) is acknowledged.
Synlett 2002, No. 2, 269–270 ISSN 0936-5214 © Thieme Stuttgart · New York