A study of n-pentenylorthoesters having manno, gluco and galacto configurations in regioselective glycosylations

Article abstract of DOI:10.1016/j.carres.2006.09.022

Kochetkov's extensive investigations of glycosyl orthoester and their analogs as glycosyl donors revealed that the alkyl derivatives were plagued by competition between the departing alcohol and the incoming acceptor. n-Pentenyl orthoesters (NPOEs) obviat

Full text of DOI:10.1016/j.carres.2006.09.022

Carbohydrate Research 342 (2007) 490–498
A study of n-pentenylorthoesters having manno, gluco and
galacto configurations in regioselective glycosylationsI
K. N. Jayaprakash and Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc., 595 F Weathersfield Road, Fearrington Post 595 F,
Pittsboro, NC 27312, USA
Received 14 August 2006; accepted 26 September 2006
Available online 4 October 2006
Dedicated to the memory of Professor Nikolay K. Kochetkov
Abstract—Kochetkov’s extensive investigations of glycosyl orthoester and their analogs as glycosyl donors revealed that the alkyl
derivatives were plagued by competition between the departing alcohol and the incoming acceptor. n-Pentenyl orthoesters (NPOEs)
obviate competition by sequestering the departing pentenyl alcohol as a 2-halomethyl tetrahydrofuran. Exquisitely regioselective
glycosidations of diol acceptors can be carried out with NPOEs triggered specifically with Yb(OTf)3/NIS. However with Sc(OTf)3,
double glycosidation is the major reaction. manno, gluco and galacto NPOEs have been investigated. The latter two, which require a
different experimental procedure for the manno counterpart, also give an excellent regioselectivity with Yb(OTf)3, but the yields are
much lower than with manno.
Ó 2006 Elsevier Ltd. All rights reserved.
Keywords: n-Pentenylorthoesters; Regioselective glycosidation; Lanthanide triflates
1. Introduction
In the interim, the power of Koenigs–Knoor reaction5
had been established as the preferred method of glyco-
side synthesis; but it would take a further 10 years for
the attendant stereoselectivity to be rationalized by
Frush and Isbell in a seminal paper entitled sugar acet-
ates, acetylglycosyl halides, and orthoacetates in relation
to the Walden inversion.6 The paper recognized the
advantage of orthoesters as isolable surrogates for the
Koenigs–Knoor reaction via protic or Lewis acid-cata-
lyzed rearrangement, 1!27 (see Scheme 1). In a notable
development Hanessian and Banoub extended the meth-
odology to furanosyl systems in 19758.
The prolonged impact of glycosyl orthoesters on carbo-
hydrate chemistry may be judged by the fact that the
very first (1945) issue of Advances in Carbohydrate
Chemistry (later Advances in Carbohydrate Chemistry
and Biochemistry) contained a 50-page review by Pacsu,
one of the leading physical organic chemists of the day.1
The first evidence of this structural type was Fischer’s
‘methyl L-rhamnoside triacetate’, which contained an
‘alkali-resistant acetate’.2 Ten years elapsed before the
anomaly was clarified by the assignment of glycosyl
orthoester functionality 1 to the structure in question,
by independent studies in the laboratories of Freuden-
berg3 and Haworth.4
Kochetkov and Backinowsky9 extended the genre to
1,2-thioorthoesters, 3, which then joined thioglycosides
as emerging glycosyl donors,10 and Kochetkov subse-
quently introduced the internal orthoester 4 as a sub-
strate for a high-level cationic polymerization.11 This
activity led to the novel cyanoethylidene analogs which,
upon careful study, were found to exhibit different
responses to Lewis acid salts. For example, structure 5
upon treatment with trityl perchlorate (TrClO4), under-
went concatenation resulting in a linear polysaccharide
q This work was supported by a grant from the National Science
Foundation (CHE-0243436).
Corresponding author. E-mail: dglucose@aol.com
NPG is a private non-profit organization with laboratories at
Centennial Campus, North Carolina State University, Raleigh, NC
27606, USA.
*
0008-6215/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.09.022

K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
491
O
O
O
O
acid
OAc
OAlk
O
R
O
R
trans
O
O
SAlk
OCOR
O
OAlk
O
O
1
2
3
4
Ph
OH
O
OTr
O
OH
OH
O
TrClO4
O
O
OAc
O
OH
O
O
HO
AcO
HO
HO
CN
CN
O
O
OH
OH
15
5
6
Scheme 1.
O
O
"acid"
O
O
O
Ph
O
OCOPh
7
8
+
I
"acid"
O
+
I
HO
+
I
HO
+
O
O
O
Ph
O
9
I
+
O
O
12
O
O
+
Ph
O
O
11
10
Oacceptor
OCOPh
I
13
12
OCOPh
Scheme 2.
6.12 On the other hand, by the use of silver triflate, cyclic
1!6-oligosaccharides could also be prepared from these
novel pseudo-orthoesters.13
Kochetkov’s interest in compounds such as 5 arose
initially from the challenges he faced by using normal
orthoesters, for example, 1, as the glycosyl donors.
Thus, he found that the departed alcohol, AlkOH, com-
peted with the acceptor-OH12 for the donor.
An n-pentenyl orthoester (NPOE) such as 7 (Scheme
2) obviates such competition by presenting optional
pathways. Thus, the usual acid-catalyzed rearrangement
gives the disarmed n-pentenyl glycoside (NPG), 8.
However, when presented with iodonium ion, I+, cyclic
iodonium ion, 9, comes into play, so that the pentenyl-
OH is removed as iodomethyl tetrahydrofuran 12. The
acceptor-OH therefore faces no competition from the
departing alcohol with respect to the formation of glyco-
side 13.
Recently, our focus has been on the issues of regio-
selectivity in the glycosidation of acceptor polyols15 in
the hope of reducing the number of protecting/depro-
tecting episodes that burdens the oligosaccharide assem-
bly.16 The burden is not only time consuming, but may
be problematic because of the sometimes erratic behav-
iors of the protecting groups. In this manuscript, we
report on some of our recent observations which sup-
port the view that excellent regioselective glycosidation
of polyols can be achieved by the specific use of glycosyl
orthoester donors promoted by ytterbium triflate/NIS.
2. Results and discussion
Isbell’s seminal paper described above, established that
a donor’s O-2 protecting group can influence stereo-
selectivity in glycosidations.6 That the same influence
can be exerted by O-2 protecting groups on chemoselec-
tive couplings was demonstrated by the armed/disarmed
strategy of saccharide coupling.17 More recently, a third
phenomenon, regioselectivity, has been demonstrated in
A further advantage is that NPOE can replace a
disarmed n-pentenyl glycoside, 8, which is much less
reactive, and also prone to addition across the double
bond, a problem never encountered with NPOEs.14

492
K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
Yb(OTf)3
or
Sc(OTf)3
O
O
O
Ph
OPent
or
7
O
O
O
O
OCOPh
8
OCOPh
+
OH
I
15
HO
HO
+
(a)
I
OH
O
14
O
O
O
O
O
+
OCH2Ph
OCH2Ph
18
OH
OCH2Ph
17
16
Sc(OTf)
NIS
3
Yb(OTf)
or
Sc(OTf)
O
O
3
ROH
+
8 or 16
OR
O
(b)
ROH
3
+
O
O
OCXPh
7
Yb(OTf)
NIS
NIS
3
Ph
19 (X = O
or H2)
Scheme 3.
publications from our laboratory.15,18 Thus, as illus-
trated with diol 14 (Scheme 3a) a disarmed n-pentenyl
glycoside (NPG), for example, 8 may exhibit a highly
regioselective glycosidation promoted by I+ leading to
a single product, for example, 15. By contrast, an armed
NPG, for example, 16, is promiscuous, leading to mix-
tures, for example, 17 and 18. These observations have
been extended to thioglycosides, promoted by I+, and
trichloroacetimidates, promoted by Lewis acids,19 and
may therefore be general for all donors.
The n-pentenyl orthoesters (NPOEs), for example, 7,
were found to display the same exclusive regioselectivity
as their disarmed counterparts, for example, 8, but affor-
ded much higher yields of product 15. NPOEs, there-
fore, have been adopted as the preferred tools for
probing the regioselective reactions of polyols.20
In this connection, we investigated the reactions of
scandium (Sc(OTf)3) and ytterbium (Yb(OTf)3) triflates
with N-iodosuccinimide to generate the iodonium ion
needed to activate the n-pentenyl group.21 First, both
salts were found to induce the normal orthoester to gly-
coside rearrangement, for example, 7!8. However, very
nuanced differences were found with NIS-induced gly-
cosidations.22 Thus, as seen in Scheme 3b, the glycosida-
tion of an alcohol, ROH, with an NPOE, 7, can be
induced by either salt reacting with NIS, affording glyco-
side 19 (X = O). However, disarmed and armed NPGs,
for example, 8 and 16, are triggered only by the stronger
Lewis acid salt Sc(OTf)3—not by Yb(OTf)3.20
Scheme 4 provides a case in point. Diol 20 and NPOE
21 gave disaccharide 22 with a complete regioselectivity
when Yb(OTf)3/NIS was used. However, with Sc(OTf)3/
Ph
O
O
Ph
O
O
O
Ph
O
O
HO
O
O
O
Ph
OMe
+
M(OTf)3 /NIS
O
O
BnO
BnO
BnO
BnO
BnO
BnO
O
O
+
OMe
O
O
BnO
BnO
BnO
OBn
OBn
OBn
O
o
DCM/ 0 C
HO
O
O
OH
OMe
OBz
OBz
20
21
23
22
OBz
M(OTf)3
Yb only 17
-
(62%)
(70%)
Sc 1.15
1
Scheme 4. See Ref. 20.

K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
493
OBz
BnO
O
BnO
BnO
OBz
O
BnO
BnO
a)
+
O
BnO
OBn
O
BnO
HO
O
OBn
O
26
HO
BnO
HO
OMe
25 (76%)
OBz
O
BnO
BnO
BnO
OBz
O
OMe
OBz
O
24
BnO
BnO
BnO
BnO
+
O
O
BnO
OBn
O
b)
OBn
O
BnO
BnO
HO
BnO
O
OMe
OMe
25 (35%)
27 (57%)
OBz
O
BnO
BnO
BnO
OBn
HO
BnO
HO
c)
O
OBz
Yb(OTf)3 / NIS
BnO
BnO
BnO
OBn
O
o
O
DCM /0 C
OBn
O
O
+
O
BnO
OMe
BnO
HO
O
OBn
OBn
26
O
O
BnO
OMe
29 (70%)
OBn
28
OBz
O
BnO
BnO
BnO
OBz
O
BnO
BnO
BnO
OBn
O
HO
Yb(OTf)3 / NIS
d)
BnO
O
o
OBn
O
HO
DCM /0 C
+
O
BnO
HO
O
26
O
30
31 (72%)
Scheme 5. Glycosidation of some 3,6-mannosidyl diols with n-pentenyl orthoester 21 (2 equiv) in the presence of a lanthanide triflate and NISà.
NIS the double glycosidation product 23 was formed in
substantial amount.
glycosidation with chemoselective discriminations.
Thus, while NPOE 21 reacts, both the armed acceptor
30 and the disarmed by-product 26 are not affected by
the promoter in use, Yb(OTf)3/NIS. The advantage of
the chemoselectivity is that product 31 can serve as,
either as a donor or an acceptor for future reactions in
which Sc(OTf)3/NIS would be the activator.
The studies in Schemes 4 and 5 utilized manno NPOE
21. The corresponding gluco analog 32, used recently in
the synthesis of b-1!2-mannans,27 displayed several
differences with 21, which prompted us to carry out theo-
retical studies28 to seek clarification. These studies have
revealed unexpected differences between diastereomeric
That this salt-induced chemoselectivity could be
twinned with regioselective glycosylation was tested on
the diols shown in Scheme 5. Branched 3,6-trimannans
motifs occur in ubiquitous high-mannose glycopro-
teins23 and hence regioselective preparation from the
corresponding acceptor polyol precursors is of inter-
est.24,25 The treatment of known26 diol 24 with 2 equiv
of NPOE 21, gave the monoglycosylated product 25
with exquisite regioselectivity (Scheme 5a), along with
disarmed NPG 26 arising from the Yb(OTf)3-catalyzed
rearrangement of 21. By contrast, the use of Sc(OTf)3/
NIS (Scheme 5b) gave trisaccharide 27 mainly, since this
combination of reagents could also activate any 26 pro-
duced, to glycosylate (some of) disaccharide 25.
à The diol and NPOE 21 (2 equiv) were dissolved in a small amount of
toluene, the solution was evaporated to dryness, and kept overnight
under vacuum. Methylene chloride (5 mL) was added, the solution
cooled to 0 °C, NIS (3 equiv) was added and the resulting solution
was stirred for several minutes. Yb(OTf)3 or Sc(OTf)3 (0.3 equiv) was
then added, and stirring continued for 10 min. Standard processing
followed.15c
An excellent prospect for general regioselectivity is
evident from the results in Scheme 5c and d, which show
the formation of the monoglycosylated products 29 and
31 by the action of Yb(OTf)3/NIS. The example in
Scheme 5d is notable for combining regioselective

494
K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
manno
gluco
150
O
135
O
+
O
+
+
O
O
O
132
133
O
O
O
O
O
O
+
37
39
38
dioxolenium
36
Me
Me
trioxolenium
117
dioxolenium
trioxolenium
not
observed
120
116
O
Me
Cl
17
O
O
15
O
O
O
Me35Cl
34
OBn
0
BnO
BnO
BnO
BnO
BnO
O
O
Ph
OPent
O
O
O
BnO
BnO
BnO
O
O
O
O
Ph
OPent
Ph
32
33OPent
21
Chart 1. Conversion of model glycosyl orthoesters into di(tri)oxolenoum ions– (B3-LYP/TZVP Transition Energies (non-bold) shown in
kcal/mol).
glycosyl 1,2-orthoesters such as 21, 32, and 33. Thus,
chlorides 34 and 35 (Chart 1) were used as models for
the diastereomeric orthoester donors having manno
(21) and gluco/galacto (32/35) configurations respec-
tively. The loss of chloride ion leads to the familiar
dioxolenium ions 37 and 38; however, in the manno case,
a discrete trioxolenium ion 36 was also found which,
interestingly, is of a lower energy than the dioxolenium
counterpart 37. Notably, a search for a similar trioxole-
nium ion (39) as a partner for 38 was unsuccessful.28
In Chart 1, the transition energies between the ground
states and cationic intermediates are indicated. It is seen
that manno model 34 is more stable than the gluco/
galacto counterpart 35, whereas the reverse is true for
the corresponding dioxolenium intermediates 37 and
38. Consequently, gluco/galacto NPOEs corresponding
to 35 should be more reactive. Would they be also less
regioselective?
In order to answer this question, we first tested diol 30,
which had been used in Scheme 5d. It was immediately
apparent that the experimental procedure, footnoted in
Scheme 5 (where a solution containing manno NPOE 21
and acceptor was treated with NIS followed by Yb(OTf)3)
failed completely when applied to gluco or galacto analogs.
The inverse procedure, footnoted in Scheme 6, where the
NPOE was the last ingredient added was required.
The results with acceptor 30, in Schemes 5d and 6a,b
show that manno NPOE 21 was best at 72%. With gluco
NPOE 32, regioselectivity was good, but the yield of
product 40 was only 34%. On the other hand, with
galacto counterpart 33, the yield of the regioselective
product 42 was greatly improved at 60%.
Notably, galacto NPOE 33 gave better results than
gluco NPOE 32 (Scheme 6b vs a) and in order to see
whether this finding was general, we tested two other
acceptors, 44 and 47. Indeed, the results in Scheme 6c–f
show that the results for gluco NPOEs were not as good
as for the galacto—although the high regioselectivity
was maintained.
3. Conclusions
There are significant reactivity differences between dia-
stereomeric n-pentenylorthoester glycosyl donors. As a
consequence, experimental conditions for using manno
donors, cannot be extended to gluco and galacto coun-
terparts. Nevertheless, all three analogous donors are
capable of regio and chemoselective reactions with diol
acceptors, albeit to different degrees of efficiency.
4. Experimental
NMR spectra were recorded on a Varian 300 MHz spec-
trometer and chemical shifts are reported relative to
internal TMS. Mass spectrometry was performed at
the Duke University Department of Chemistry Mass
– For a full account of related calculations see Ref. 28.

K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
495
BnO
O
BnO
BnO
BnO
BnO
O
O
BnO
a)
O
O
OBn
O
BzO
BnO
HO
+
BzO
OBn
OBn
O
HO
BnO
HO
41
O
40 (33%)
BnO
BnO
OBn
O
O
30
OBn
O
O
OBn
O
BnO
BzO
BnO
HO
+
b)
c)
BzO
43
OMe
42 (60%)
BnO
BnO
BnO
O
O
BzO
AllO
BnO
OH
O
+
41
OH
O
HO
AllO
BnO
OMe
45 (31%)
OBn
44
OMe
BnO
BnO
O
O
d)
OH
O
43
BzO
AllO
BnO
+
OMe
46 (41%)
Ph
OH
O
O
BnO
BnO
BnO
O
O
41
+
O
e)
f)
OMe
BzO
(trace)
48
OH
O
Ph
O
O
HO
Ph
OMe
47
OBn
O
OBn
BnO
OH
O
O
O
43
+
O
OMe
BzO
49 (15%)
Scheme 6. Regioselective glycosidations with gluco and galacto n-pentenyl orthoesters 32 and 33, respectively, with Yb(OTf)3/NIS§.
Spectrometry Facility. MALDI was measured on an
Applied Biosystems Voyager DE-Pro Workstation.
The reactions were usually conducted under an argon
atmosphere. Thin layer chromatography (TLC) was
done on plates (Riedel-de Haen) coated with Silica Gel
60F 254, detection was by UV, spraying or dipping in
a solution of ammonium molybdate (6.25 g) and ceriu-
m(IV) sulfate (25 g) in 10% aqueous sulfuric acid
(250 mL) and subsequent heating. Flash column chro-
matography was performed on silica gel (spectrum SIL
58, 230–400 mesh, grade 60) using mixtures of hexane
and ethyl acetate as eluants. Dichloromethane and tolu-
ene were distilled from CaH2. N-Iodosucciminide (NIS)
was crystallized from hot methylene chloride/hexane,
dried, and kept under high-vacuum. The b-D-mannopyr-
anose 1,2-pent-4-enyl orthobenzoates {n-pentenylortho-
esters (NPOEs)} 21,15c 32,27a n-pentenyl glycosides
(NPGs) 26,28 41,27a 4330 and diols 24,15b 30,29 44,15a
4715a were prepared as described previously.
§ The diol and NPOE (2.2 equiv) were dissolved separately in small
amounts of toluene, the solutions were evaporated to dryness, and
kept overnight under vacuum. The diol was dissolved in methylene
chloride (5 mL), the solution cooled to 0 °C, NIS (2.5 equiv) was
added, followed by Yb(OTf)3 (0.3 equiv). After stirring for a few
minutes, methylene chloride solution of the NPOE was then added
dropwise over ꢀ15 min. Standard processing15c followed.

496
K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
4.1. Glycosidation conditions (A) using manno NPOE 21
73.29, 72.24, 71.98, 71.40, 70.68, 69.72, 69.08, 66.81,
55.13. MS for C55H58O12 Calcd 910.39. Found 933.4
[M+Na].
The acceptor (1 equiv) and NPOE 21 (2 equiv) were dis-
solved together in a small quantity of toluene, azeotr-
oped to dryness and kept overnight under vacuum.
The acceptor was dissolved in dry CH2Cl2 (5 mL) cooled
to 0 °C under an argon atmosphere, NIS (3 equiv) was
added, and after stirring for 5 min, the lanthanide salt
(0.3 equiv) was added. The reaction was monitored by
TLC, and when complete, the reaction was quenched
with 10% aqueous sodium thiosulfate and saturated so-
dium bicarbonate solutions, extracted with CH2Cl2, and
purified by chromatography.
4.5. Methyl 2,4-di-O-benzyl-6-O-(2-O-benzoyl-3,4,6-tri-
O-benzyl-a-D-mannopyranosyl)-a-D-mannopyranoside 25
and methyl 2,4-di-O-benzyl-3,6-di-O-(2-O-benzoyl-3,4,6-
tri-O-benzyl-a-D-mannopyranosyl)-a-D-mannopyranoside
27
Diol 24 (0.021 g, 0.056 mmol) glycosidated with NPOE
21 using Sc(OTf)3 in procedure (A) gave trisaccharide
27 (0.060 g) and the above described disaccharide 25
(0.016) in an overall yield (92%). For 27: 1H NMR
(CDCl3, 300 MHz): d 8.09 (d, 7.5 Hz, 2H), 8.02 (d,
7.8 Hz, 2H), 7.52 (m, 2H), 7.01–7.38 (m, 42H), 5.77
(dd, J 1.6, 3.00 Hz, 1H), 5.74 (dd, J 1.8, 3.2 Hz), 5.34
(d, J 1.8 Hz, 1H), 5.11 (d, J 1.6 Hz, 1H), 3.68–4.93 (m,
33H), 3.25 (s, 3H). 13C NMR (CDCl3, 75 MHz): d
165.68, 165.62, 138.88, 138.79, 138.72, 138.39, 138.11,
133.29, 130.24, 130.19, 129.12, 128.70, 128.60, 128.56,
128.52, 128.24, 128.15, 127.98, 127.91, 127.83, 127.76,
127.74, 127.67, 99.99, 98.48, 78.98, 78.53, 75.53, 75.36,
74.74, 74.55, 74.36, 73.82, 73.71, 72.77, 72.72, 72.08,
71.91, 71.48, 71.35, 69.73, 69.43, 69.31, 69.05, 66.84,
55.13. MS for C89H90O18 Calcd 1446.61. Found 1469.6
[M+Na].
4.2. Glycosidation conditions (B) using gluco and galacto
NPOEs 27 and 28
The diol (1 equiv) and NPOE 32 or 33 (2.2 equiv) were
dissolved separately in small quantities of toluene,
azeotroped to dryness, and kept overnight under vac-
uum. The diol was dissolved in dry CH2Cl2 (5 mL)
cooled to 0 °C under an argon atmosphere, NIS
(2.5 equiv) was added, and after stirring for 5 min, the
Yb(OTf)3 (0.3 equiv) was added and stirred for a few
minutes. To the above mixture, a dichloromethane solu-
tion of the donor was added dropwise over a period of
15 min. TLC was checked and quenched the reaction
mixture with satd NaHCO3 and 10% sodium thiosulfate
solutions, which was extracted with CH2Cl2 and dried
over Na2SO4. Solvents were removed under diminished
pressure and the residue was purified by chromato-
graphy to give the desired compound.
4.6. Methyl (2-O-benzoyl-3,4,6-tri-O-benzyl-a-D-manno-
pyranosyl)-(1!6)-2,4-di-O-benzyl-3-a-D-mannopyran-
osyl)-(1!4)-2,3,6-tri-O-benzyl-b-D-mannopyranoside 29
Diol 28 (0.024 g, 0.030 mmol) was treated with NPOE
21 and Yb(OTf)3 using procedure (A) to give 29
(0.028 g, 70%). For 29: H NMR (CDCl3, 300 MHz):
4.3. Preparation of galactose orthoester 33
1
Galactose NPOE 33 was made according the general
procedure reported earlier.25 1H NMR (CDCl3,
300 MHz): d 7.58 (m, 2H), 7.20–7.40 (m, 18H), 5.94
(d, J 4.8 Hz, 1H), 5.64–5.83 (m, 1H), 3.33–5.02 (m,
14H), 2.13–2.06 (m, 2H), 1.70–1.59 (m, 2H). MS for
C39H42O7 Calcd 622.29. Found 645.4 [M+Na].
d 8.05 (d, J 2.5 Hz, 2H), 7.56 (d, J 7.5 Hz, 1H), 7.02–
7.34 (m, 42H), 5.69 (dd, J 1.8, 3.00 Hz, 1H), 5.25 (s,
1H), 5.14 (d, J 11.00 Hz, 1H), 5.01 (d, J 1.8 Hz, 1H),
3.49–4.89 (m, 33H), 3.39 (s, 3H), 2.23 (d, J 9.00 Hz,
1H). 13C NMR (CDCl3, 75 MHz): d 165.54, 138.89,
138.73, 138.64, 138.24, 138.03, 133.98, 130.17, 129.08,
128.66, 128.60, 128.53, 128.48, 128.38, 128.34, 128.28,
128.16, 128.04, 127.88, 127.67, 127.28, 99.27, 98.47,
97.95, 81.65, 80.43, 79.44, 78.13, 76.32, 75.49, 79.99,
74.48, 73.62, 73.44, 72.50, 72.00, 71.66, 71.39, 70.03,
69.55, 69.15, 68.88, 66.61, 55.62. MS for C82H86O17
Calcd 1342.59. Found 1365.7 [M+Na].
4.4. Methyl 2,4-di-O-benzyl-6-O-(2-O-benzoyl-3,4,6-tri-
O-benzyl-a-D-mannopyranosyl)-a-D-mannopyranoside 25
Diol 24 (0.031 g, 0.084 mmol) was treated with NPOE
21 under glycosidation condition (A) using Yb(OTf)3
1
to give title compound 25 (0.056 g, 76%). For 25: H
NMR (CDCl3, 300 MHz): d 8.09 (d, J 7.5 Hz, 2H),
7.55 (t, J 7.5 Hz, 1H), 7.16–7.38 (m, 27H), 5.72 (dd, J
1.6, 3.2 Hz, 1H), 5.11 (d, J 1.6 Hz, 1H), 3.57–4.92 (m,
22H), 3.28 (s, 3H), 2.40 (d, J 10 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): d 165.72, 138.75, 138.69, 138.13,
137.87, 133.31, 130.23, 129.12, 128.86, 128.58, 128.56,
128.36, 128.28, 128.14, 127.85, 127.80, 127.76, 127.68,
98.29, 97.92, 78.81, 77.84, 75.55, 75.00, 74.56,
4.7. Pent-4-enyl 2-O-benzoyl-3,4,6-tri-O-benzyl-a-D-manno-
pyranosyl-(1!6)-2,4-di-O-benzyl-3-a-D-mannopyran-
oside 31
Diol 30 (0.090 g, 0.210 mmol) and NPOE donor 21 were
treated with Yb(OTf)3 under condition (A) to give com-
1
pound 31 (0.145 g, 72%). H NMR (CDCl3, 300 MHz):
d 8.10 (d, J 7.2 Hz, 2H), 7.56 (t, J 7.5 Hz, 1H), 7.12–7.39

K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
497
(m, 27H), 5.72–5.86 (m, 1H), 5.76 (dd, J 1.6, 3.00 Hz)
5.13 (d, J 1.5 Hz, 1H), 4.48–5.05 (m, 10H), 3.59–4.17
(m, 11H), 3.37–3.42 (m, 1H), 2.43 (d, J 10.2 Hz, 1H),
2.06–2.14 (m, 2H), 1.60–1.70 (m, 2H). 13C NMR
(CDCl3, 75 MHz): d 165.66, 138.74, 138.67, 138.63,
138.16, 137.89, 133.28, 130.21, 128.59, 128.54, 128.49,
128.47, 128.33, 128.30, 128.12, 127.90, 127.79, 127.74,
127.67, 115.24, 98.29, 96.82, 78.99, 78.14, 76.74, 75.56,
75.56, 75.08, 74.53, 73.68, 73.26, 72.31, 71.97, 71.47,
70.49, 69.20, 69.01, 67.27, 66.77. MS for C59H64O12
Calcd 964.44. Found 987.4 [M+Na].
4.10. Methyl 2-O-benzoyl-3,4,6-tri-O-benzyl-b-D-gluco-
pyranosyl-(1!6)-2,4-di-O-benzyl-3-a-D-mannopyran-
oside 45
Diol 44 (0.046 g, 0.148 mmol) and donor 32 (0.202 g,
2.2 equiv), NIS (0.083 g, 2.5 equiv) were treated with
Yb(OTf)3 under conditions (B) to give compound 45
(0.038 g, 31%). 1H NMR (CDCl3, 300 MHz): d 7.99
(d, J 8.00 Hz, 2H), 7.50 (t, J 8.00 Hz, 1H), 7.10–7.37
(m, 22H), 5.68–5.81 (m, 1H), 5.32 (t, J 8.5 Hz, 1H),
5.03–5.15 (m, 2H), 4.51–4.83 (m, 9H), 3.37–4.20 (m,
14H), 3.02 (s, 3H), 2.41 (br s, 1H). 13C NMR (CDCl3,
75 MHz): d 165.28, 138.30, 138.14, 138.08, 137.96,
134.89, 133.16, 130.16, 129.99, 128.60, 128.56, 128.47,
128.44, 128.19, 128.15, 128.03, 127.96, 127.79, 116.64,
101.82, 100.06, 83.08, 80.07, 78.29, 75.53, 75.36, 75.31,
74.50, 29.19, 73.95, 73.76, 72.10, 70.71, 69.20, 69.02,
68.43, 54.79. MS for C51H56O12 Calcd 860.38. Found
883.3 [M+Na].
4.8. Pent-4-enyl 2-O-benzoyl-3,4,6-tri-O-benzyl-b-D-gluco-
pyranosyl-(1!6)-2,4-di-O-benzyl-3-a-D-mannopyranoside
40
Diol 30 (0.050 g, 0.117 mmol), donor 32 (0.160 g,
2.2 equiv), NIS (0.066 g, 2.5 equiv) were treated with
Yb(OTf)3 (0.022 g, 0.3 equiv) by using procedure (B) de-
1
scribed above to give compound 40 (0.037 g, 33%). H
4.11. Methyl 2-O-benzoyl-3,4,6-tri-O-benzyl-b-D-galac-
topyranosyl-(1!6)-2,4-di-O-benzyl-3-a-D-mannopyran-
oside 46
NMR (CDCl3, 300 MHz): d 7.94 (d, J 7.00 Hz, 2H),
7.08–7.57 (m, 28H), 5.68–5.80 (m, 1H), 5.37 (t, J
8.1 Hz, 1H), 3.37–4.99 (m, 24H), 3.00–3.07 (m, 1H),
2.17 (d, J 9.6 Hz, 1H), 2.00–2.10 (m, 2H), 1.44–1.49
(m, 2H). 13C NMR (CDCl3, 75 MHz): d 165.01,
138.63, 138.32, 138.10, 137.98, 137.89, 133.25, 133.09,
133.30, 133.02, 129.93, 129.07, 128.77, 128.696, 128.61,
128.56, 128.49, 128.42, 128.19, 128.16, 128.11, 128.03,
127.97, 127.92, 127.81, 127.78, 127.74, 114.92, 101.84,
96.54, 83.07, 78.57, 78.38, 75.65, 75.33, 74.74, 74.64,
74.33, 74.03, 73.80, 72.94, 72.00, 70.39, 69.22, 69.14,
66.86, 30.63, 28.81. MS for C59H64O12 Calcd 964.44.
Found 987.2 [M+Na].
Diol 44 (0.094 g, 0.29 mmol), donor 33 (0.361 g,
2 equiv), NIS (0.165 g, 2.5 equiv) were treated with
Yb(OTf)3 under conditions (B) to give compound 46
(0.103 g, 41%). 1H NMR (CDCl3, 300 MHz): d 8.01
(d, J 7.00 Hz, 2H), 7.53 (t, J 7.5 Hz, 1H), 7.14–7.41
(m, 22H), 5.68–5.80 (m, 1H), 5.70 (dd, J 9.9, 7.8 Hz,
1H), 5.03–5.17 (m, 2H), 5.01 (d, J 11.5 Hz, 1H),
3.37–4.69 (m, 2H), 3.01 (s, 3H), 2.48 (d, J 3.3 Hz, 1H).
13C NMR (CDCl3, 75 MHz): d 165.43, 138.62, 138.19,
138.05, 137.87, 134.92, 133.04, 130.45, 130.07,
128.66, 128.62, 128.51, 128.49, 128.42, 128.15, 128.06,
127.99, 127.95, 127.85, 127.78, 116.64, 102.30, 99.99,
80.17, 80.10, 74.81, 74.63, 73.95, 73.89, 72.81,
72.32, 72.16, 72.03, 70.75, 69.12, 68.88, 68.48,
54.77. MS for C51H56O12 Calcd 860.38. Found 883.3
[M+Na].
4.9. Pent-4-enyl 2-O-benzoyl-3,4,6-tri-O-benzyl-b-D-galac-
topyranosyl-(1!6)-2,4-di-O-benzyl-3-a-D-mannopyran-
oside 42
Diol 30 (0.055 g, 0.128 mmol), donor 33 (0.159 g,
2 equiv), and NIS (0.072 g, 2.5 equiv) were treated with
Yb(OTf)3 (0.024 g, 0.3 equiv) using procedure (B) to
4.12. Methyl 2-O-benzoyl-3,4,6-tri-O-benzyl-b-D-galacto-
pyranosyl-(1!3)-4,6-O-benzylidene-a-D-mannopyrano-
side 48
1
give compound 42 (0.073 g, 60%). H NMR (CDCl3,
300 MHz): d 7.96 (d, J 7.2 Hz, 2H), 7.55 (t, J 7.2 Hz,
1H), 7.11–7.37 (m, 22H), 5.68–5.80 (m, 1H), 5.73 (dd,
J 9.9, 7.7 Hz, 1H), 5.01 (d, J 11.5 Hz, 1H), 4.92–4.96
(m, 2H), 3.37–4.72 (m, 21H), 2.98–3.03 (m, 1H), 2.21
(d, 9.6 Hz, 1H), 1.95–2.04 (m, 2H), 1.40–1.47 (m,
2H). 13C NMR (CDCl3, 75 MHz): d 165.18, 138.65,
138.41, 138.03, 137.93, 137.87, 132.96, 130.57, 130.10,
128.75, 128.66, 128.47, 128.41, 128.36, 128.14, 128.11,
128.06, 127.85, 127.75, 127.70, 114.87, 102.27, 96.45,
80.20, 78.54, 77.03, 74.81, 74.71, 73.94, 73.88, 72.90,
72.80, 71.16, 72.00, 71.97, 70.36, 69.12, 68.85,
68.811. MS for C59H64O12 Calcd 964.44. Found 987.3
[M+Na].
Diol 47 (0.040 g, 0.140 mmol), donor 33 (0.174 g,
2 equiv), NIS (0.080 g, 2.5 equiv) were treated with
Yb(OTf)3 under conditions (B) to give compound 48
(0.017 g, 15%). 1H NMR (CDCl3, 300 MHz): d 8.05
(d, J 7.5 Hz, 2H), 7.04–7.58 (m, 23H), 5.59 (s, 1H),
5.56 (dd, J 9.5, 7.8 Hz, 1H), 4.94 (d, J 11.4 Hz, 1H),
3.98–4.70 (m, 20H), 3.67 (s, 3H), 2.87 (d, J 1.8 Hz,
1H). 13C NMR (CDCl3, 75 MHz): d 166.09, 138.47,
138.37, 138.22, 137.94, 137.83, 137.75, 133.50, 133.27,
130.13, 130.09, 129.99, 129.79, 129.54, 128.65, 128.61,
128.56, 128.52, 128.45, 128.21, 128.16, 128.09, 128.00,

498
K. N. Jayaprakash, B. Fraser-Reid / Carbohydrate Research 342 (2007) 490–498
16. Khan, S. H.; O’Neill, R. A. Modern Methods in Carbo-
hydrate Synthesis; Harwood: Amsterdam, 1996; Schmidt,
R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212–235;
Osborn, H.; Khan, T. Oligosaccharides. Their Synthesis
and Biological Roles; Oxford University Press: Oxford,
2000; Boons, G. J. Tetrahedron 1996, 52, 1095; Paulsen, H.
Angew. Chem., Int. Ed. Engl. 1982, 21, 155–173; Sinay, P.
Pure Appl. Chem. 1978, 50, 1437–1451.
127.92, 127.86, 127.83, 127.75, 127.72, 127.64, 100.12,
96.70, 91.25, 77.48, 76.47, 75.08, 75.02, 74.96, 74.86,
74.72, 74.04, 73.91, 73.87, 73.67, 73.51, 73.11, 72.90,
72.44, 71.87, 69.83, 69.51, 68.60. MS for C48H50O12
Calcd 818.33. Found 841.3 [M+Na].
17. Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-
Reid, B. J. Am. Chem. Soc. 1988, 110, 5583–5584.
18. Fraser-Reid, B.; Cristobal Lopez, J. C.; Radhakrishnan,
K. V.; Mach, M.; Schlueter, U.; Gomez, A.; Uriel, C.
J. Am. Chem. Soc. 2002, 124, 3198–3199; Anilkumar, G.;
Nair, L. G.; Fraser-Reid, B. Org. Lett. 2000, 2, 2587–
2589.
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