Ytterbium(III) trifluoromethanesulfonate for specific activation of n-pentenyl orthoesters in the presence of acid-sensitive functionalities

Article abstract of DOI:10.1016/S0040-4039(02)01590-3

Various Lewis acids have been examined as agents which react with N-iodosuccinimide to release iodonium ion for activating n-pentenylorthoester (NPOE) donors, particularly for coupling to acceptors that have acid-labile protecting groups. Although many of

Full text of DOI:10.1016/S0040-4039(02)01590-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6953–6955
Ytterbium(III) trifluoromethanesulfonate for specific activation of
n-pentenyl orthoesters in the presence of acid-sensitive
functionalities
K. N. Jayaprakash, K. V. Radhakrishnan and Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc. (NPG), 4118 Swarthmore Road, Durham, NC 27706, USA
Received 27 July 2002; accepted 31 July 2002
Abstract—Various Lewis acids have been examined as agents which react with N-iodosuccinimide to release iodonium ion for
activating n-pentenylorthoester (NPOE) donors, particularly for coupling to acceptors that have acid-labile protecting groups.
Although many of the reagents do not tolerate cyclic acetals, BF3·Et2O does. However, the latter cleaves p-methoxybenzyl (PMB),
making it possible to use this Lewis acid to simultaneously promote coupling of NPOEs and remove PMB groups. Of several
transition metal salts investigated, ytterbium triflate is outstanding in its ability to promote NPOE coupling with complete
preservation of acid-labile protecting groups. © 2002 Elsevier Science Ltd. All rights reserved.
The ability to finesse reactions of n-pentenyl glycosyl
donors by using different sources of halonium ions was
first demonstrated ten years ago, in a synthesis of a
blood group tetrasaccharide.1 Prior to that, protic acid
induced reactions of N-halosuccinimides, long used for
aromatic halogenations,2 had been introduced for NPG
activation in 19903 and extended to thioglycoside4,5
counterparts shortly thereafter. This source of iodo-
nium ion has since enjoyed widespread application.6–9
However, the acids employed as catalysts to generate
the iodonium ion can obviously threaten some com-
monly used protecting groups, a problem which
becomes increasingly worrisome as the oligosaccharide
targets becomes more and more complex.
dimethylsilyltriflate to activate N-iodosuccinimide
(NIS) led to 3a, indicating significant loss of the cyclo-
hexylidine-protecting group13 (Table 1, entry i). On the
other hand, use of boron trifluoride etherate (Table 1,
entry ii) led to excellent retention of the acetal, afford-
ing pseudodisaccharide 3b in 95% yield.
The p-methoxybenzyl (PMB) protecting group, which is
known to be unpredictable with respect to its stability
to acids,14 was chosen for a study in which both donor
and acceptor possessed acid labile protecting groups.
Thus upon treatment of the donor 1b and acceptor 2
with BF3·Et2O/NIS, the product 3c, obtained in 93%
yield had suffered loss of the PMB group but, notably,
retention of the cyclohexylidene group (entry iii).
The widespread use of Lewis Acids10 and transition
metal salts11 in organic synthesis of acid-catalyzed reac-
tions has demonstrated the subtlety of which these
reagents are capable. It therefore occurred to us that
these reagents might be capable of generating halonium
ions, while permitting the survival of acid labile protect-
ing groups. In this manuscript, we report some exam-
ples in connection with these investigations.
Under comparable conditions, use of triphenylboron or
triphenylborate as Lewis acids with N-iodosuccinimide,
led to complex mixtures (entries iv and v). Better suc-
cess was had with 0.3 equiv. of trispentafluorophenyl-
boron, in that coupling was effective, giving 3d,15 albeit
accompanied by substantial amounts of the PMB cleav-
age product 3c (entry vi). We then examined scandium
triflate, the virtues of which have been championed in
recent reports, notably by Kobayashi.16,17 Although use
of 0.3 equiv. of the reagent resulted in moderate cou-
pling, the result was again compromised by substantial
cleavage of the PMB protecting group (entry vii).
For our test case, we choose to examine the coupling of
the n-pentenyl orthoester (NPOE) 1a, and the cyclo-
hexylidinated inositol 212 (Scheme 1). Prior work had
shown that use of triethylsilyltriflate or tert butyl
Turning our attention to ytterbium(III) triflate,18 we
found that after a reaction time of 5 min, a quantitative
* Corresponding author. Tel.: (919) 493 6113; fax: (919) 493 6113;
e-mail: dglucose@aol.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01590-3

6954
K. N. Jayaprakash et al. / Tetrahedron Letters 43 (2002) 6953–6955
Scheme 1.
Table 1. Lewis acid-catalyzed coupling of acceptor 2 (1
equiv.) with n-pentenyl glycosyl donors (3 equiv.)
Entry
Donor Lewis Acid
(equiv.)
Product(s)
(ratio)
Yield (%)
i
ii
iii
iv
1a
1a
1b
1b
TESOTf (0.3) 3a
BF3·Et2O (0.3) 3b
BF3·Et2O (0.3) 3c
Modest
95
93
Ph3B (0.3)
Complex
mixture
Complex
mixture
v
1b
(PhO)3B
vi
1b
1b
1b
4
(C6F5)3B (0.3) 3d+3c (7:3)
Sc(OTf)3 (0.3) 3d+3c (7:3)
Yb(OTf)3 (0.3) 3d
70
49
vii
viii
ix
Quantitative
90
Yb(OTf)3 (0.3)
5
Figure 1.
yield of the product 3d was obtained (entry viii). This
excellent result prompted us to test the gluco NPOE 4.
Efficient coupling with acceptor 2, in the presence of
0.3 equiv. of Yb(OTf)3 gave product 5 in 90% yield
(entry ix).
on a novel procedure for effecting this process, involv-
ing reaction with polymer supported sulfonamides.19
For example treatment of 6a and 6c with BF3·Et2O20
removed the PMB groups, giving 6b and 6d, respec-
tively, in ꢀ90% yields.
With respect to acid-labile protecting groups, entry viii
shows that Yb(OTf)3 allows survival of both PMB and
cyclohexylidene groups, while BF3·Et2O cleaved the
former, but not the latter (entries i and ii). In this
connection, the ready and selective cleavage of the
PMB group with BF3·Et2O (Fig. 1) deserves to be noted
in light of the recent report by Hinkling and Kiessling
In conclusion, careful choice of a transition metal salt
or a Lewis acid permits exquisite control over the
reactions of n-pentenyl donors, without affecting cer-
tain acid labile protecting groups. The excellent results
from the use of Yb(OTf)3 for the NPOE reaction in
Scheme 1 is a promising observation which is under
further development in our labs.

K. N. Jayaprakash et al. / Tetrahedron Letters 43 (2002) 6953–6955
6955
References
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1
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