Lanthanide Triflates/N-Iodosuccinimide for Chemoselective Coupling of n-Pentenyl Donors in Oligosaccharide Assembly

Article abstract of DOI:10.1055/s-2003-44999

Armed n-pentenyl glycosides (NPGs) react (a) readily with scandium and indium (III) triflates, (b) moderately with samarium and lanthanum counterparts, and (c) not at all with ytterbium counterpart. However the last salt reacts readily with n-pentenyl orthoesters (NPOE). These chemoselectivities of n-pentenyl donors towards lanthanide salts therefore permit hydroxyl-bearing armed NPGs to function as acceptors towards NPOE donors. This concept is demonstrated by synthesis of a tetrasaccharide.

Full text of DOI:10.1055/s-2003-44999

LETTER
301
Lanthanide Triflates/N-Iodosuccinimide for Chemoselective Coupling of
n-Pentenyl Donors in Oligosaccharide Assembly
Lanthanide
T
riflate
.
s/
N
-Iodosuc
N
cinimide for
C
hem
.
oselective
C
J
oupling ayaprakash, Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc., (NPG) 4118 Swarthmore Road, Durham, North Carolina 27706, USA
E-mail: Dglucose@aol.com
Received 8 August 2003
double bond in 5. The latter is now ready to serve as a
donor. This protocol enables efficient use of 1, and the
strategy has been used to advantage in reports from our
laboratory.3
Abstract: Armed n-pentenyl glycosides (NPGs) react (a) readily
with scandium and indium (III) triflates, (b) moderately with samar-
ium and lanthanum counterparts, and (c) not at all with ytterbium
counterpart. However the last salt reacts readily with n-pentenyl
orthoesters (NPOE). These chemoselectivities of n-pentenyl donors
towards lanthanide salts therefore permit hydroxyl-bearing armed
NPGs to function as acceptors towards NPOE donors. This concept
is demonstrated by synthesis of a tetrasaccharide.
Nevertheless, protection/deprotection episodes, even as
mild as those in Scheme 1a, can never be taken for granted
and hence are best avoided. Chemoselective processes
provide one solution. Thus, one can rely on differences in
the glycon, as in armed/disarmed strategies,4,5 latent/ac-
tive,6 orthogonal,7 semi-orthogonal,8 or in the aglycon.9 In
this manuscript, we describe a process in which the
chemoselectivity relies on the nuanced reaction of lan-
thanide salts with various n-pentenyl glycosyl donors.
We recently reported that orthoesters10 can be efficiently
rearranged to b-hydroxy esters, e.g. 6 → 7, by treatment
with ytterbium (III) triflate (Scheme 1b). On the other
hand, with an n-pentenyl orthoester (NPOE) such as 8
(Scheme 2), the reaction leads to a disarmed n-pentenyl
glycoside (NPG)11 9. The process is known12 to go
through a dioxolenium ion, 1213,14 by loss and reattach-
ment of n-pentenyloxy anion. The reverse process is also
well established, in that disarmed NPG 9 can generate
dioxolenium ion 12 via the oxocarbenium ion 13.
Key words: lanthanide triflates, N-Iodosuccinimide, n-pentenyl
glycosides
Protecting groups are a necessary evil in the synthesis of
complex oligosaccharides. It is therefore a worthwhile ob-
jective to convert this defect into an advantage to enhance
stereo, chemo, and regioselective outcomes. A parallel
and complementary aim is to reduce the number of dis-
crete key starting materials that must be furnished in order
to execute the synthetic plan. An early strategy for the lat-
ter aim is exemplified in Scheme 1.1 A portion of an NPG,
1, is protected to obtain a donor, 2, while another portion
is dibrominated to obtain an acceptor, 3. Coupling of both
under the agency of iodonium ion affords a product, 4,
which upon subsequent debromination2 regenerates the
Scheme 1
SYNLETT 2004, No. 2, pp 0301–0305
0
2.
0
2.
2
0
0
4
Advanced online publication: 16.12.2003
DOI: 10.1055/s-2003-44999; Art ID: S08503ST
© Georg Thieme Verlag Stuttgart · New York

302
K. N. Jayaprakash, B. Fraser-Reid
LETTER
(0.0 kcal/mol)
"armed" donor
n-pentenyl orthoester
"disarmed" donor
(NPOE)
O
O
O
O
O
1. NaOMe
2. AlkX
3 steps
Yb(OTf)3
quantitative
aldose
O
O
O
O
R
10
OAlk
O
9
8
R
I
I+
- PentOH
+ PentOH
O
I+
Yb(OTf)3
NIS
I
O
O
O
I
δ+
O
O
O
O
O
R
R
O
OAlk
O
δ+
O
O
11
12
13
14
R
oxocarbenium ion
(140.0 kcal/mol)
2-O-acyl oxo-
carbenium ion
furanylium ion
dioxolenium ion
(133.1 kcal/mol)
(145.6 kcal/mol)
Scheme 2
The high reactivity of glycosyl orthoesters vis a vis ‘ordi- terpart 10. The order therefore is: 8 >>>> 10 >> 9. Further
nary’ donors is evident in the studies of Kochetkov and support for this ranking has come from recent high level
co-workers,15 and our protocol for comparing donor reac- calculations14 which yield the transition energies shown in
tivities,16 show that an NPOE, 8, is infinitely more reac- brackets against the appropriate structures in Scheme 2,
tive than the corresponding disarmed NPG, 9; and as is 133.1 kcal/mol, 140.0 kcal/mol and 145.6 kcal/mol for di-
well known, the latter is less reactive than the armed coun- oxolenium >>>> armed >> disarmed intermediates.
OR
O
BnO
BnO
BnO
BnO
HO
OBn
O
BnO
OR
O
M(OTf)3
(i)
a
BnO
+
BnO
OBn
O
BnO
Br
BnO
Br
O
O
O
BnO
Br
Br
15
O
17
16
a R = Bn
b R = Bz
a R = Bn
b R = Bz
BnO
OBn
O
OBn
O
OBn
M(OTf)3
(i)
BnO
O
O
BnO
BnO
16
O
+
BnO
Br
BnO
b
Br
OR
O
19
OR
18
a R = Bn
b R = Bz
a R = Bn
b R = Bz
OBn
O
BnO
BnO
BnO
M(OTf)3
(i)
HO
BnO
BnO
O
15a
c
O
BnO
BnO
+
O
OBn
OMe
OBn
20
21
OMe
OBn
O
M(OTf)3
(i)
d
BnO
BnO
18a
20
+
O
O
BnO
BnO
OBn
OBn
22
OMe
(i) NIS. CH2Cl2, 0 °C--> room temp.
M = Sc, In, La, Sm or Yb
Scheme 3
Synlett 2004, No. 2, 301–305 © Thieme Stuttgart · New York

LETTER
Lanthanide Triflates/N-Iodosuccinimide for Chemoselective Coupling
303
Table 1 Reaction of Acceptor 16 with Armed and Disarmed n-Pentenyl Glycosides under the Agency of Lewis Acids and N-
Iodosuccinimide17,18
Entry
Lewis acid
Sc(OTf)3
Donor
Time
Product
Yield (%)
i
15a
18a
15b
18b
30 min
30 min
15 min
20 min
17a
19a
17b
19b
98
89
92
78
ii
iii
iv
v
vi
vii
viii
In(OTf)3
Sm(OTf)3
La(OTf)3
Yb(OTf)3
15a
18a
15b
18b
50 min
50 min
30 min
30 min
17a
19a
17b
19b
96
97
91
86
ix
x
xi
xii
15a
18a
15
24 h
24 h
36 h
36 h
17a
19a
–
23
54
No reaction
No reaction
18b
–
xiii
xiv
xv
15a
118
15b
18b
24 h
24 h
36 h
36 h
–
19a
–
No reaction
37
No reaction
No reaction
xvi
–
xvii
xviii
xix
15a
18a
15b
18b
36 h
36 h
36 h
36 h
–
–
–
–
No reaction
No reaction
No reaction
No reaction
xx
The results with Yb(OTf)3 encouraged us to explore the tion against electrophile-induced activation. The b-gluco-
use of this,11 and other lanthanide salts, as Lewis acid side 18a, was therefore examined. Table 1 shows that
surrogates to generate iodonium ion (I+) from N-iodosuc- the only difference with the mannoside 15a is with respect
cinimide (NIS) for activating n-pentenyl donors.
to the lanthanum salt, in that the glucoside gives some di-
saccharide, 19a (Table 1, entries xiii vs. xiv).
We found that coupling of the armed donor 15a with the
dibrominated NPG acceptor 16,3 occurred readily with
scandium (III) and indium (III) triflates at to give disac-
charide 17a (Scheme 3) in near quantitative yields
(Table 1, entries i and v). With the corresponding samari-
um salt, the coupling was uselessly slow, being incom-
plete after 24 hours at room temperature (Table 1, entry
ix). The lanthanum and ytterbium counterparts (Table 1,
entries xiii and xvii) failed to induce any reaction even af-
ter 24 hours and 36 hours, respectively, at room tempera-
ture.
The disarmed, 2-O-benzoyl manno and gluco counter-
parts 15b and 18b were next tested and found to behave
similarly towards the acceptor 16. Thus scandium and in-
dium triflates induced smooth coupling at 0 ºC (Table 1,
entries iii/iv and vii/viii) while samarium, lanthanum and
ytterbium triflates were ineffective, even after 36 hours at
room temperature (Table 1, entries xi vs. xii, xv vs. xvi
and xix vs. xx).
Were the results in Table 1 due to the hindered nature of
the C4-OH in acceptor 16. In order to answer this ques-
tion, acceptor 20 with a primary-OH was examined
It was of interest to determine whether the foregoing re-
sults were specific to donor 15a, since the high anomeric
effect of such a-mannosides19 confers substantial protec-
Table 2 Reaction of Acceptor 20 with Armed n-Pentenyl Glycosides under the Agency of Lewis Acids and N-Iodosuccinimide17
Entry
Lewis acid
In(OTf)3
Donor
Time
Product
Yield (%)
i
ii
15a
18a
20 min
20 min
21
22
94
93
iii
iv
La(OTf)3
Sm(OTf)3
Yb(OTf)3
15a
18a
24 h
24 h
21
22
20
40
v
vi
15a
18a
24 h
24 h
21
22
30
58
vii
viii
15a
18a
36 h
24 h
–
–
No reaction
No reaction
Synlett 2004, No. 2, 301–305 © Thieme Stuttgart · New York

304
K. N. Jayaprakash, B. Fraser-Reid
LETTER
R'O
R'O
R'O
Ph
OBn
O
O
O
OBz
O
BnO
BnO
3 steps
O
BnO
BnO
1. NaOMe
2. BnBr
Yb(OTf)3
O
RO
RO
mannose
O
O
25
23
R'
24
a R' = Bn
b R' = TBDMS
a R' = Bn
R
a H
b Bn Bn
c H TBDMS
d Bn TBDMS
b R' = TBDMS
Yb(OTf)3
H
i
ii
Yb(OTf)3
iii
no reaction
no reaction
Scheme 4
(Schemes 3c and 3d). The sample results in Table 2 for obtain 23b, or selectively protected, rearranged and then
several salts, show that the selectivities do not appear to processed routinely to obtain the disarmed and then armed
be based on steric hindrance. Thus indium triflate gave NPGs 24 and 25 respectively.
excellent yields of disaccharides 21 and 22, lanthanum
and samarium triflates moderate yields, while ytterbium
triflate failed to promote any coupling.
The function of the salt in these couplings is to generate
IOTf, the concentration of which is tied to the Lewis acid-
ity of the salt. Being a comparatively mild salt Yb(OTf)3
The subtle selectivities in Tables 1 and 2 encouraged at- generates a concentration of IOTf that is sufficient for
tempts to use these salts as chemoselective agents with n- the transition energy of an NPOE, but not an NPG
pentenyl donors, that would complement the electronic, (Scheme 2). Thus when NPGs 24 and 25 were treated in-
and torsional armed/disarmed strategies currently used in dependently with N-iodosuccinimide and ytterbium(III)
oligosaccharide syntheses.20 Apart from being the only triflate, both were recovered unchanged. These results
type of 1,2-orthoesters currently in use as glycosyl donors, suggested that armed or disarmed NPGs could serve as ac-
NPOEs allow ready deployment of different protecting ceptors towards orthoester donors. The feasibility of this
groups. Thus, triol 23a, was either directly benzylated to strategy was demonstrated as shown in Scheme 5. The
BnO
HO
BnO
Ph
OR
O
O
O
OBn
O
(i)
BnO
BnO
BnO
BnO
O
O
BnO
BnO
+
98%
O
O
23b
26
OBn
O
BnO
BnO
O
27
(ii)
a R = Bz
b R = H
92%
BnO
OBz
O
23d
(i)
BnO
BnO
RO
OR'
O
O
OTBDMS
BnO
BnO
O
BnO
BnO
23b
O
BnO
BnO
O
BnO
BnO
O
(i)
O
BnO
BnO
85%
O
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
O
28
O
29
(ii)
a R=TBDMS;R'=Bz
b R=TBDMS;R'=H
88%
(i) NIS, Yb(OTf)3, CH2Cl2; (ii) NaOMe, MeOH, CH2Cl2
Scheme 5
Synlett 2004, No. 2, 301–305 © Thieme Stuttgart · New York

LETTER
Lanthanide Triflates/N-Iodosuccinimide for Chemoselective Coupling
(6) (a) Roy, R.; Andersson, F. Tetrahedron Lett. 1993, 33,
305
acceptor alcohol 26 and NPOE 23b upon treatment with
NIS and ytterbium triflate in CH2Cl2 at 0 ºC afforded the
dimannan 27 in 98% yield. Debenzoylation afforded alco-
hol 27b, which was coupled, under the agency of ytterbi-
um triflate, with orthoester 23d to give 28. A repeat of the
debenzoylation (to give 28b) and then reuse of 23b af-
forded tetramannan 29.
6053. (b) Boons, G.-J.; Isles, S. Tetrahedron Lett. 1994, 35,
3593.
(7) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116,
12073.
(8) Demchenko, A. V.; Meo, C. D. Tetrahedron Lett. 2002, 43,
8819.
(9) Lahmann, M.; Oscarson, O. Can. J. Chem. 2002, 80, 889.
(10) Schlueter, U.; Lu, J.; Fraser-Reid, B. Org. Lett. 2003, 5, 255.
(11) Jayaprakash, K. N.; Radhakrishnan, K. V.; Fraser-Reid, B.
Tetrahedron Lett. 2002, 43, 6955.
(12) Chemistry of the O-Glycosidic Bond; Bochkov, A. F.;
Zaikov, G. E., Eds.; Pergamon Press: Oxford, UK, 1979.
(13) Recent calculations have shown that the charges can
sometimes be distributed to the pyran oxygen thereby giving
tri, as well as di, oxolenium ions.14
(14) Fraser-Reid, B.; Grimme, S.; Piacenza, M.; Mach, M.;
Schlueter, U. Chem.–Eur. J. 2003, 9, 4687.
(15) Kochetkov, N. K.; Khorlin, A. Y.; Bochkov, A. F.
Tetrahedron 1967, 23, 693.
(16) Wilson, B. G.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 317.
(17) A typical procedure for the glycosidation is as follows:
Acceptor (1 equiv) and and n-pentenyl donor (3 equiv) were
dissolved together in a small amount of toluene and
azeotroped to dryness. The residue was dried overnight
under vacuum, and then dissolved in anhyd CH2Cl2 (5 mL)
at 0 °C under Ar atmosphere. NIS (4 equiv) was added to the
solution and after stirring for few minutes, the Lewis acid
(0.3–0.5 equiv) was added and slowly warmed to r.t. The
reaction was monitored by TLC, and when complete,
quenched with NaHCO3 and sodium thiosulfate solutions.
The organic layer was extracted with CH2Cl2, washed with
water, and dried over Na2SO4. The solvents were removed,
and the residue was purified by column chromatography.
(18) When 1.3 equiv of donor were used, the yields with 15a,
15b, and 18a fell to 50%, 75% and 74%, respectively.
(19) Kirby, A. J. The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen; Springer-Verlag:
Heidelberg, 1983.
In summary, the data in Tables 1 and 2 show that armed
n-pentenyl glycosides (NPGs) react (a) readily with scan-
dium and indium (III) triflates, (b) moderately with sa-
marium and lanthanide counterparts, and (c) not at all with
ytterbium counterpart. On the other hand we have previ-
ously shown that ytterbium triflate reacts readily with n-
pentenyl orthoesters (NPOE). These chemoselectivities of
n-pentenyl donors towards lanthanide salts therefore per-
mit hydroxyl-bearing armed NPGs to function as accep-
tors towards NPOE donors. This concept is demonstrated
in Scheme 4 by synthesis of tetrasaccharide 29.
Acknowledgement
We are grateful to the Human Frontier Science Program Organiza-
tion, the Mizutani Foundation and the National Science Foundation
for support.
References
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(3) (a) Merritt, J. R.; Naisang, E.; Fraser-Reid, B. J. Org. Chem.
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(20) (a) Collins, P. M.; Ferrier, R. J. Monosaccharides, Their
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Synlett 2004, No. 2, 301–305 © Thieme Stuttgart · New York