Fluoridolysis of 5,6-epoxy carbohydrates: application to the synthesis of 5-fluoro lactosamine and isolactosamine glycosides

Article abstract of DOI:10.1016/j.tetasy.2009.03.025

The synthesis of 6-selenophenyl derivatives of β-1,3 and β-1,4 disaccharides has been explored for the purpose of extending our epoxide fluoridolysis methodology to the synthesis of 5-fluoro analogues of N-acetyl isolactosamine (isoLacNAc, lacto-N-biose) and N-acetyl lactosamine (LacNAc) glycosides. Successful synthesis of the C-6 selenium-containing disaccharides was achieved via Lewis acid-mediated donor and acceptor substrates, the latter containing a selectively protected C-6 hydroxyl group for ultimate conversion to the desired 6-selenophenyl disaccharides. In contrast, the use of selenium-containing acceptor substrates under a variety of conditions failed to yield the desired selenium-containing disaccharides. Oxidation of the 6-selenophenyl derivatives to the corresponding selenoxides followed by thermal elimination yielded the exocyclic olefins, which were converted to the 5,6-epoxides. Epoxide fluoridolysis yielded the desired target compounds, 5-fluoro β-octyl glycoside analogues of type 1 and type 2 glycans. The newly synthesized fluorine-containing disaccharides have potential application as fucosyltransferase substrates, both for mechanistic studies and in the chemoenzymatic synthesis of fluorine-containing oligosaccharides.

Full text of DOI:10.1016/j.tetasy.2009.03.025

Tetrahedron: Asymmetry 20 (2009) 781–794
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Fluoridolysis of 5,6-epoxy carbohydrates: application to the synthesis
of 5-fluoro lactosamine and isolactosamine glycosides
*
Tara L. Hagena, James K. Coward
Departments of Medicinal Chemistry and Chemistry, University of Michigan, 3622 Chemistry, 930 N. University, Ann Arbor, MI 48109-1055, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 6-selenophenyl derivatives of b-1,3 and b-1,4 disaccharides has been explored for the
purpose of extending our epoxide fluoridolysis methodology to the synthesis of 5-fluoro analogues of
N-acetyl isolactosamine (isoLacNAc, lacto-N-biose) and N-acetyl lactosamine (LacNAc) glycosides. Suc-
cessful synthesis of the C-6 selenium-containing disaccharides was achieved via Lewis acid-mediated
donor and acceptor substrates, the latter containing a selectively protected C-6 hydroxyl group for ulti-
mate conversion to the desired 6-selenophenyl disaccharides. In contrast, the use of selenium-containing
acceptor substrates under a variety of conditions failed to yield the desired selenium-containing disac-
charides. Oxidation of the 6-selenophenyl derivatives to the corresponding selenoxides followed by ther-
mal elimination yielded the exocyclic olefins, which were converted to the 5,6-epoxides. Epoxide
fluoridolysis yielded the desired target compounds, 5-fluoro b-octyl glycoside analogues of type 1 and
type 2 glycans. The newly synthesized fluorine-containing disaccharides have potential application as
fucosyltransferase substrates, both for mechanistic studies and in the chemoenzymatic synthesis of fluo-
rine-containing oligosaccharides.
Received 2 February 2009
Accepted 25 March 2009
Available online 4 May 2009
Dedicated to Professor George Fleet on the
occasion of his 65th birthday and in
recognition of his numerous important
contributions to the field of carbohydrate
chemistry
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
14.4),4 thereby affecting its nucleophilicity and possibly catalysis.5
Since the acetamide group at C-2 is required for nearly all glycosyl-
The use of glycosyl fluorides to investigate enzyme catalysis of
both glycosidases and glycosyltransferases has been exploited by
Withers and colleagues.1 Specifically, 2-deoxy-2-fluoro, 2-deoxy-
2,2-difluoro, and 5-fluoro derivatives have been studied exten-
sively to provide great insight into the catalytic mechanism and
structural basis for catalysis for a large group of glycosidases.2 In
addition, 2-deoxy-2-fluoro derivatives of sugar nucleotides have
been synthesized and used effectively to provide similar data for
several glycosyltransferases.3 In our own research on the mecha-
nism and inhibition of glycosyltransferases, the use of similarly
fluorinated derivatives of N-acetylglucosamine (GlcNAc) is of inter-
est. Detailed investigation of the effect of fluorine, judiciously
placed in donor or acceptor substrates, on reactions catalyzed by
glycosyltransferases provide data that further our understanding
of the mechanism of action (dissociative vs associative) of these
enzymes. For the donor substrate of glycosyl transferase-catalyzed
reactions, placing fluorine near a developing partial positive charge
in the transition state may lead to enzyme inhibition due to desta-
bilization of the transition state. Alternatively, in the acceptor sub-
strate, it is anticipated that the pKa of a proximal alcohol will be
lowered significantly as the result of an adjacent fluorine substitu-
ent; for example, C2H5OH (pKa 15.4) versus CH2FCH2OH (pKa
transferases that use GlcNAc derivatives as substrates, the use of 2-
fluoro derivatives was precluded. Therefore, the emphasis of our
research in this area has been on the synthesis of 5-fluoro GlcNAc
glycosides and pyrophosphates, and their use in enzymology.
In terms of methodology for the synthesis of 5-fluoro GlcNAc
derivatives, most relevant is the description of 2-acetamido-2-
deoxy-5-fluoro-a-L-idopyranosyl fluoride and its use in studying
the mechanism of action of a b-N-acetylglucosaminidase (ExoII)
from Vibrio furnisii.6 The synthesis of this molecule involved the
radical halogenation method pioneered by Ferrier and co-workers,7
followed by halogen exchange to afford the 5-fluoro derivative in
low yield, with the equatorial halogen (L-ido) predominating. More
recently, a similar approach has been employed in the synthesis of
5-fluoro GlcNAc derivatives containing a 2-azidoacetyl group for
use in proteomics research.8 We have reported a new method,
epoxide fluoridolysis, to synthesize 5-fluoro GlcNAc derivatives
as analogues of both donor and acceptor substrates.9 UDP-(5-F)-
GlcNAc, was evaluated as a substrate for CLS (UDP-GlcNAc:Glc-
NAc-P-P-Dol N-acetylglucosaminyltransferase, EC 2.4.1.141).10
The data indicated that the fluorinated donor served as a compet-
itive inhibitor of UDP-GlcNAc and not as a substrate. The fact that
the 5-fluoro analogue failed to act as a substrate but binds to the
active site as a competitive inhibitor is consistent with the hypoth-
esis that the adjacent electron-withdrawing fluorine destabilizes
the postulated oxocarbenium ion-like transition state. Similarly,
* Corresponding author. Tel.: +1 734 936 2843; fax: +1 734 647 4865.
E-mail address: jkcoward@umich.edu (J.K. Coward).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.025

782
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
(5-F)-GlcNAc-b-octyl glycoside was evaluated as an alternate
acceptor substrate for b-1,4 GalT (EC 2.4.1.38) from bovine milk.10
In this case, there was a minimal effect on kcat for the fluorinated vs
non-fluorinated substrates, suggesting little bond formation be-
tween the acceptor and the UDP-Gal donor. This result supports
a weakly associative (‘exploded SN2’) transition state with minimal
bond formation between the acceptor and donor substrates
(Fig. 1).10
An extension of this approach would be to investigate the effect
of positioning fluorine on glycosyltransferase acceptor substrates
at varying distances from the nucleophilic hydroxyl group. To the
best of our knowledge, this ‘proximity effect’ has not been investi-
gated previously in reactions catalyzed by glycosyltransferases.
Although other factors, such as relative stereochemistry of fluorine
at C-5 versus the hydroxyl group at C-4 or C-3 (syn vs anti, gauche
vs eclipsed) and the comparative structures of glycosyltransferase
active sites, are surely significant, evaluation of the effect of 5-flu-
oro substitution on distal hydroxyl groups to act as acceptor sub-
strates would provide valuable information. Herein, we describe
the synthesis of 5-fluoro analogues of N-acetyllactosamine (Lac-
NAc) and its 1,3-linked regioisomer, N-acetylisolactosamine (iso-
LacNAc, lacto N-biose). These fluorinated analogues are designed
FucT III has also been linked to an increase in tumor size in pros-
tate cancer cell line PC-3 due to an increase in cellular adhesion in
the stromal cells.12 Therefore, additional details on the mechanism
of FucT III-catalyzed glycosylation may lead to new inhibitors of
this enzyme that could potentially impede prostate cancer pro-
gression. Two fluorinated analogues, 1 and 2 (Fig. 2), could aid in
investigating the effects of fluorine on FucT III glycosyl acceptor
substrates by differentially affecting the pKa of the C-4 hydroxyl
versus the C-3 hydroxyl and potentially affect their ability to act
as acceptor substrates. The synthesis of isoLacNAc and LacNAc b-
octyl glycosides (3 and 4, respectively) was pursued initially to ob-
tain non-fluorinated substrates for comparative purposes in bio-
chemical
experiments.
Ultimately,
the
non-fluorinated
disaccharides proved to be key intermediates in the successful syn-
thesis of the target 5-fluoro analogues, 1 and 2. b-Octyl glycosides
are commonly used in glycosyl transfer enzymology due to their
facile separation from a radiolabeled donor substrate via binding
to a reverse-phase solid support (Sep-Pak) in an assay to evaluate
the enzymatic reaction.13
Extension of the previously reported epoxide fluoridolysis
methodology9 to a disaccharide framework should allow for the
synthesis of more complex fluorinated carbohydrates, including
the desired 5-fluoro isoLacNAc and LacNAc glycosides, 1 and 2
to assess the proximity effect in the reaction catalyzed by
a-1,3/
1,4-fucosyltransferase or FucT III (E.C. 2.4.1.65) (Fig. 2). FucT III is
involved in the biosynthesis of Lewis B blood group antigens and
fucosylates the free C-4 or C-3 hydroxyl groups of two GlcNAc-con-
taining disaccharides, type 1 (isoLacNAc) and type 2 (LacNAc),
respectively.11
(Fig. 3). A 5,6-epoxide, 6, obtained by dimethyldioxirane
(DMDO)-mediated epoxidation of the corresponding exocyclic ole-
fin,7, is opened with HFꢀpyridine to install the desired C-F bond at
C-5. Oxidative elimination of a C-6 phenylselenide, 8, in the pres-
ence of dihydropyran (DHP) results in the exocyclic olefin. Flexibil-
δ+
B
OH
OH
HO
HO
OH
H
OH
X
Glycosyltransferase
HO
HO
OH
δ−
+
O
O
δ
HO
HO
O
O
O
Y
OR
OH
HO
O
O
OR
HO
O-NDP
δ−
OR
Y
HO
X
Y
O
Y
X
Y
HO
X
Y
O
NDP
X = H, F
Y = OH, NHAc
Figure 1. Proposed glycosyltransferase transition state.
HO
OH
β-1,3-Disaccharide, isoLacNAc
OH
δ−
HO
O
O
OH
GDP
OH
O
OH
OH
δ+
HO
OH
OH
OH
FucT III
B
OH
OH
O
HO
δ−
HO
HO
O
O
HO
HO
H
OR
NHAc
O
O
O
HO
O
O
O GDP
OH
OR
OR
O
O
O
OR
X
O
OH
X
NHAc
OH
X
NHAc
OH
OH
1, X = F
HO
3
, X = H
OH
HO
HO
β-1,4-Disaccharide, LacNAc
OH
O
HO
HO
OH
OH
HO
O
O
O
OH
δ−
O
HO
B
FucT III
O
O
O
O
X
NHAc
OR
O
HO
H
OH
O
O
HO
OR
NHAc
X
δ−
δ
NHAc
O GDP
OH
HO
O
O
X
O
GDP
OH
OH
OH
OH
OH
HO
HO
HO
2
4
, X = F
, X = H
Figure 2. Proposed transition states for FucT III-catalyzed glycosyl transfer.

T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
783
OH
O
SePh
O
O
R4O
R3O
R4O
R3O
R4O
R3O
O
O
R4O
R3O
OR1
NHAc
OR1
NHAc
OR1
OR1
NHAc
NHAc
F
6
8
7
R1 = (CH2)7CH3
R3 = Ac or Gal
R4 = Ac or Gal
R6 = Ac or TBS
OR6
O
OH
O
Ph
R4O
R3O
R4O
R3O
O
NHAc
O
O
OR1
OR1
OR1
NHAc
R3O
NHAc
9
Figure 3. Epoxide fluoridolysis retrosynthetic analysis.
ity at C-3, C-4, and C-6 positions is achieved via an important ben-
zylidene intermediate, 9. Flexibility at the C-1 position is achieved
using either an octyl glycoside or a tert-butyldimethyl silyl ether
(TBS). Fluoridolysis in the GlcNAc series proceeds in good yields
(72–83%).9 However, epoxide fluoridolysis has not been reported
in GlcNAc-containing disaccharides such as isoLacNAc and LacNAc,
and is the subject of the research described in this paper.
In order to obtain the (5-fluoro) (iso)LacNAc glycosides, 1 and 2,
for evaluation as mechanistic probes of FucT III-catalyzed glycosyl-
ation, it is necessary to synthesize the C-6 phenylselenide-contain-
ing b-1,3 and b-1,4 octyl glycosides (Fig. 4). Formation of these
target compounds proved synthetically challenging as glycosyla-
tion has not been reported using selenium-containing glycoside
acceptors. There are two possibilities for forming the C-6 sele-
nium-containing disaccharides. One option involves the coupling
of phenylselenide monosaccharide acceptors 10 or 11 with a galac-
tosyl donor.
Alternatively, the phenylselenide is introduced after formation
of the desired disaccharide linkage using the non-seleno precursors
1214 or 13. Although the syntheses of the non-fluorinated disac-
charides, 3 and 4, have been reported previously in the litera-
ture,15,16 those syntheses did not provide for differentiation of
functionality at C-6. In the current research, synthesis of 3 and 4
has been achieved via routes that allow for incorporation of desired
functionality at C-6.
The phenylselenide glycosyl acceptor substrates, 15 and 17,
were then used as acceptors in glycosylation reactions with two
galactosyl donors (Table 1, 23, X = Br or OC(NH)CCl3) to form the
desired b-1,3 disaccharide. Glycosylation of acceptors containing
oxygen at C-6 (Table 1, entries 1–3 and 6) was explored under var-
ious reaction conditions using either a glycosyl bromide (Koenigs–
Knorr conditions) or a trichloroacetimidate donor. Formation of the
desired 1,3-disaccharide (Y = O) was observed in yields ranging
from 30% to 83%, The highest yield in the shortest reaction time
(Table 1, entry 6) was obtained using Lewis acid-mediated trichlo-
roacetimidate donor activation. Unfortunately, all attempts to form
the corresponding selenium-containing disaccharide (Y = Se) using
various combinations of acceptors and donors under identical con-
ditions (Table 1, entries 4, 5 and 7) failed. Acceptors were recov-
ered in near quantitative amounts, along with the hydrolysis
products derived from their respective donors.à
Similarly, formation of the b-1,4-disaccharide was observed
using oxygen-containing acceptors (X = O) (Table 2, entries 1, 4,
and 5), albeit in somewhat lower yields (trace—59%) than observed
in formation of the 1,3-disaccharides (Table 1).17 In the case of the
1,4-disaccharides, use of a lower temperature was required due to
the sensitivity of the protecting groups. Under a variety of less mild
reaction conditions, loss of either the TBS or Ac protecting groups
was observed. Again, all attempts to form the selenium-containing
disaccharides (X = Se) failed under identical conditions (Table 2,
entries 2, 3, and 6) shown to be effective for acceptors containing
oxygen at C-6. In these experiments, unlike those described above
for the 1,3-disaccharides, recovery of the acceptor was not always
possible. It is possible that the nucleophilic 6-SePh substituent re-
acts with the donor to form a selenonium salt, which can react
with any adventitious nucleophile (including water in the workup)
in a non-productive manner.
2. Results and discussion
The C-6 bromide 149 was displaced using PhSeH, NEt3, and
Bu4NI (as a phase-transfer catalyst) to form the phenylselenides,
15 (Scheme 1). The addition of Bu4NI dramatically decreased the
reaction time from five days to overnight. The free C-3–OH groups
were protected as a benzyloxymethyl (BOM) ether to form 16. The
resulting differentially protected glycosides 16 were transformed to
17 by removal of the C-4 benzoyl protecting group with NaOMe.
In addition to the selenium-containing glycosyl acceptor sub-
strates, the non-selenium-containing acceptor substrates were
synthesized (Scheme 2). Beginning with compound 1814, the pri-
mary C-6 position was protected as a TBS ether to form 19. Alter-
natively, the benzylidene 2014 was formed from 18 using
PhCH(OMe)2 and pTsOHꢀH2O. The C-3 alcohol of 20 was protected
by acetylation to provide 21. Benzylidene acetolysis followed by
protection of the primary C-6 alcohol as a silyl ether (TBS) gave
the acceptor, 22.
In order to circumvent this problem, the second proposed syn-
thetic route, outlined in Figure 4, involved installation of the 6-
SePh substituent following formation of the 1,3- and 1,4-disaccha-
rides. As shown in Scheme 3, the non-selenium containing disac-
charide 28 (Table 1, entry 6) was converted to the C-6
phenylselenide under Hannessian–Hullar conditions via displace-
ment of the C-6 bromide with PhSeH and NEt3 to give 29. In con-
trast to the positive rate effect observed in the synthesis of 6-
SePh glucosamine derivatives (Scheme 1, 14?15), the addition of
Bu4NI to reactions carried out in the pursuit of 29 resulted in sig-
nificant formation of a C-6 methyl by-product, presumably formed
via selenol-mediated reduction of the 6-iodomethyl intermediate.
à
This reaction sequence is important in order to avoid formation of an undesired
C-6 chloro by-product. The C-6 bromide must be displaced first by PhSeH. If the
reaction sequence is reversed, release of chloride from BOM–Cl during formation of
the 3-OBOM derivative results in a partial displacement of the C-6 bromide by
chloride, leading to a 3:1 mixture of C-6 Br and C-6 Cl products.
The 8-(methoxycarbonyl)octyl (MCO) glycosides were synthesized by standard
methods18 and used in some experiments tabulated in Tables 1 and 2. However, the
ester functionality of these glycosides was incompatible with hydrazinolysis condi-
tions required for subsequent removal of the N-phthaloyl protecting group. Therefore,
the MCO glycosides were not investigated further.

784
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
OAc
β−1,3 Disaccharide
SePh
O
AcO
AcO
O
BzO
HO
OH
F
OR1
OR1
OH
HO
SePh
O
OAc
X
X
+
+
AcO
AcO
OAc
O
O
NPht
HO
O
OR1
NHAc
BzO
O
HO
O
OR1
10
OAc
OH
NPht
OAc
AcO
AcO
O
Ph
1
O
O
O
HO
NPht
OAc
12
1,4 Disaccharide
β−
OAc
AcO
AcO
OTBS
O
O
OH
OAc
HO
AcO
AcO
X
X
HO
OH
SePh
O
+
+
OR1
OR1
O
O
AcO
OAc
O
HO
O
O
NPht
13
OR1
NHAc
OR1
HO
AcO
OH
OAc
OAc
SePh
F
AcO
AcO
NHAc
2
O
O
HO
BOMO
OAc
NPht
11
, R = (CH2)7CH3
, R = TBS
1
a
b
1
Figure 4. Disaccharide retrosynthetic analysis.
Br
PhSeH, NEt3,
SePh
O
Δ
Bu4NI, THF,
O
BzO
HO
BzO
HO
OR1
OR1
NPht
b
, 90% (2 steps)
NPht
14
15
SePh
SePh
O
BOM-Cl, DIEA,
THF, Δ
O
NaOMe, MeOH
BzO
BOMO
HO
OR1
NPht
OR1
BOMO
a
, 89%
a
, 81%
NPht
b, 87%
b, 88%
16
17
1
a
, R = (CH2)7CH3
b, R1 = TBS
Scheme 1.
Therefore, use of Bu4NI was avoided in the conversion of 28 to
by N- and O-acetylation produced 35. The non-fluorine containing
FucT III alternate substrate, 4 (Fig. 2), was formed in a similar man-
ner as that described for 3. It is of interest to note that the TBS ether
in 32 was removed under the hydrazinolysis conditions employed
(EtOH, 100 °C).
Installation of the 5,6 epoxide was performed in a three-step
process from the C-6 phenylselenides 30 and 35 (Scheme 5). In
the case of the b-1,3 isoLacNAc-b-octyl glycoside, 30, spontaneous
elimination of the selenoxide to the exocyclic olefin was observed
during the course of the oxidation. If the reaction time was ex-
tended, complete elimination was observed to give the olefin, 37,
in 87% yield. Treatment of 37 with DMDO provided the epoxide
29. The N-phthaloyl, O-benzoyl, and O-acetyl protecting groups
were removed by H2NNH2ꢀH2O, followed by global N- and O-acet-
ylation to yield the desired C-6 phenylselenide-containing disac-
charide glycoside 30. Formation of the non-fluorinated FucT III
alternate substrate, 3 (Fig. 2), was effected by removal of the ben-
zylidene and phthaloyl protecting groups to give 31, followed by
global N and O-acetylation, for ease of purification, and finally O-
deacylation to give 3.
In the b-1,4 disaccharide series, installation of the C-6 phenyl-
selenide proceeded by the removal of the C-6 TBS ether of 32 (Ta-
ble 2, entry 6) with HFꢀpyridine to give the free alcohol, 33 (Scheme
4). The C-6 phenylselenide, 34, was successfully formed in modest
yield using N-phenylseleno phthalimide (N-PSP) and PBu3.§,19
Removal of the phthaloyl and acetyl protecting groups, followed
38 in excellent yield with a 1:1 diastereomeric ratio of D-Glc:L-
Ido configurations. Spontaneous elimination of the selenoxide with
direct formation of the olefin, as described in the previous section,
was also observed in the b-1,4 disaccharide. However, elimination
was less facile and complete conversion to the olefin was not ob-
served. Therefore, the remaining selenoxide was thermally elimi-
nated in the presence of DHP to afford the exocyclic olefin, 39
§
Reaction of a model monosaccharide, N-phthaloyl-3,4-diacetyl-6-selenophenyl D-
glucosamine b-octyl glycoside, with PSP under identical conditions as those described
for the synthesis of 6d led to the desired 6-SePh derivative in a yield of 60%.18

T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
785
OH
O
PhCH(OMe)2
Ph
O
Ph
O
O
pTsOH·H2O
Ac2O, pyr.
a, 83%
O
O
HO
HO
O
OC8H17
OC8H17
74%
OC8H17
AcO
HO
Reference 14
NPht
21
NPht
18
NPht
20
TBS-Cl
81%
1. AcOH/H2O (1:1), Δ
2. TBS-Cl, imidazole,
DMF
imidazole
DMF
(2 steps)
OTBS
O
OTBS
O
HO
HO
HO
OC8H17
OC8H17
AcO
NPht
NPht
19
22
Scheme 2.
Table 1
Synthesis of 1,3-disaccharides (isoLacNAc, Type 1)
YR6
YR6
OAc
AcO
OAc
AcO
AcO
R4
O
O
O
R4
Conditions
O
O
O
HO
OR1
AcO
OR1
O
R2
R2
AcO
AcO
X
23
24
25
Entry
1
X
R1
R2
Y
R4
R6
Activator
Solvent, temperature
Yield (%)
45
Br
MCOa
NHAc
NHAc
NPht
O
AgOTf, 3 Å sieves
Hg(CN)2, CaSO4
Hg(CN)2, CaSO4
Hg(CN)2, CaSO4
CH2Cl2, 0 °C rt
CHC6H5
2
3
Br
Br
MCOa
C8H17
O
O
CH2Cl2, CH3NO2, 40 °C
CH2Cl2, CH3NO2, 40 °C
75
30
CHC6H5
CHC6H5
4
5
Br
Br
MCOa
TBS
NPht
NPht
Se
Se
Bz
Bz
C6H5
C6H5
CH2Cl2, CH3NO2, 40 °C
CH2Cl2, CH3NO2, 40 °C
0
0
Hg(CN)2, 3 Å sieves
6
OC(NH)CCl3
C8H17
NPht
NPht
O
TMS-OtTf, 3 Å sieves
CH2Cl2,ꢁ20 °C?rt
CH2Cl2, 0 °C
83
0
CHC6H5
7
OC(NH)CCl3
TBS
Se
Bz
C6H5
TMS-OtTf, 3 Å sieves
a
MCO = 8-(Methoxycarbonyl)octyl.
(Scheme 5). Epoxidation proceeded in excellent yields to give 40 as
a single diastereomer. Epoxide fluoridolysis of 38 (HFꢀpyridine) fol-
lowed by removal of the acetate protecting groups with methano-
lic ammonia provided the (5-F)-isoLacNAc b-octyl glycoside, 1
(23%, two steps). Similarly, epoxide fluoridolysis of 40 (HFꢀpyri-
dine), removal of the O-Ac protecting groups with methanolic
ammonia afforded the (5-F)-LacNAc b-octyl glycoside, 2 (37%,
two steps).
and 40. The epoxides were formed in a two-step oxidative elim-
ination from the corresponding phenylselenide-containing disac-
charides, 30 and 35. The C-6 phenylseleno disaccharides,
previously unreported in the literature,20 were achieved in good
yields only through the formation of (iso)LacNAc glycosides via
non-selenium containing acceptor and donor substrates. Use of
6-phenylselenide-containing glycosides as glycosylation acceptors
was not effective in formation of the desired disaccharide, pre-
sumably due to competing attack of the nucleophilic selenium
on the glycosyl donor. Epoxidation of 37 and 39 proceeded in
excellent yields, allowing for subsequent epoxide fluoridolysis at
the C-5 position. These newly synthesized (5-fluoro) (iso)LacNAc
glycosides are excellent candidates for use as mechanistic probes
of the reaction catalyzed by the glycosyltransferase, FucT III, and
other enzymes that use either isoLacNAc or LacNAc glycosides as
substrates.
3. Conclusion
In conclusion, this report records the first synthesis of disac-
charides containing fluorine selectively at one of the two C-5
positions, specifically (5-fluoro) (iso)LacNAc b-octyl glycosides.
These (5-fluoro) glycosides were synthesized by the epoxide fluo-
ridolysis method, using newly synthesized glycosyl epoxides, 38

786
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
Table 2
Synthesis of 1,4-Disaccharides (LacNAc, Type 2)
YR6
OAc
AcO
OAc
AcO
YR6
O
O
O
HO
R3O
Conditions
OR1
O
AcO
O
AcO
R3O
OR1
R2
AcO
X
AcO
R2
27
23
26
Entry
X
R1
R2
R3
Ac
BOM
BOM
Ac
Ac
H
BOM
Y
R6
Activator
Solvent, temperature
Yield (%)
1
2
3
4
5
6
7
Br
Br
Br
MCOa
TBS
TBS
C8H17
C8H17
C8H17
TBS
NHAc
NPht
NPht
NHAc
NPht
NPht
NPht
O
Se
Se
O
O
Bn
AgOTf, TMU, 3 Å sieves
AgOTf, TMU, 3 Å sieves
Hg(CN)2, CaSO4
TMS-OTf, 3 Å sieves
TMS-OTf, 3 Å sieves
TMS-OTf, 3 Å sieves
TMS-OTf, 3 Å sieves
CH2Cl2, 0 °C?rt
CH2Cl2, 0 °C?rt
CH2Cl2ꢀCH3NO2, 40 °C
CH2Cl2, ꢁ30 °C? rt
CH2Cl2, ꢁ50 °C
Trace
0
C6H5
C6H5
TBS
TBS
TBS
C6H5
0
OC(NH)CCl3
OC(NH)CCl3
OC(NH)CCl3
OC(NH)CCl3
37b
13
O
Se
CH2Cl2, ꢁ50 °C
56c,d
0
CH2Cl2, ꢁ50 °C
a
MCO = 8-(Methoxycarbonyl)octyl.
b
c
Conversion to product is 51% after recovery of unreacted acceptor (28%).
Following coupling, the free 3-hydroxy group was acetylated (Ac2O, pyr) to afford the desired product, 32 (Scheme 4), in 34% overall yield (two steps).
Use of BF3ꢀOEt2, 3 Å sieves (CH2Cl2, ꢁ50 °C) as activator with this donor–acceptor pair for an extended reaction time (1.5 h) led to complete loss of the TBS group.
d
Acetylation led to the peracetylated disaccharide, 36, in 55% yield (two steps).
OAc
AcO
AcO
Ph
O
O
O
O
O
CCl3
NH
+
OC8H17
X =
HO
AcO
23
R2
X
20
TMS-OTf,
3Å sieves,
CH2Cl2
83%
-20 °C to rt
OAc
AcO
AcO
Ph
O
O
1. AcOH/H2O, Δ
2. H2NNH2 H2O
EtOH, Δ
1. NBS, BaCO3,
O
O
OC8H17
CCl4, Δ
O
2. PhSeH, NEt3,
THF, Δ
NPht
OAc
.
3. Ac2O, pyr.
84%
(2 steps)
41%
28
(3 steps)
OAc
OAc
OAc
O
AcO
AcO
SePh
AcO
AcO
O AcO
O
OH
O
O
BzO
O
OC8H17
OC8H17
NHAc
OAc
NPht
31
29
.
1. H2NNH2 H2O,
EtOH, Δ
2. Ac2O, pyr.
NaOMe,
76%
(2 steps)
90%
MeOH
OH
OAc
AcO
SePh
OH
O
HO
HO
O
O AcO
O HO
OC8H17
NHAc
O
OC8H17
AcO
O
OAc
OH
NHAc
30
3
Scheme 3.
and 8-methoxycarbonyl octanol from Toronto Research Chemicals
(TRC), North York, Ontario, Canada. Water-sensitive reactions were
conducted under an argon atmosphere and used oven-dried glass-
ware, syringes and needles. Solvents were freshly distilled for
moisture-sensitive reactions: THF from benzophenone ketyl,
MeOH, NEt3, CH2Cl2 and pyridine from CaH2. CHCl3 was purified
4. Experimental
4.1. General procedures
All chemicals used were from Aldrich or Acros, except for BOM–
Cl from Tokyo Chemical Industry (TCI) America, Portland, Oregon

T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
787
OAc
AcO
AcO
OTBS
O
O
O
CCl3
NH
HO
HO
OC8H17
X =
+
AcO
23
NPht
19
X
1. TMS-OTf
3Å sieves
34%
CH2Cl2, -°50 C
2. Ac2O, pyr.
(2 steps)
AcO
AcO
OAc
O
OTBS
O
O
OC8H17
NPht
OAc AcO
1. H2NNH2·H2O
EtOH, Δ
.
HF pyr.
32
70%
(2 steps)
CH3CN
2. Ac2O, pyr.
92%
AcO
AcO
OAc
O
AcO
AcO
OAc
O
OH
O
OAc
O
O
O
OC8H17
OC8H17
OAc
AcO AcO
AcO
NHAc
NPht
36
33
N-PSP, PBu3,
CH2Cl2, -20 °C
NaOMe,
MeOH
41%
40%
HO
HO
OH
O
AcO
AcO
OAc
O
OH
O
SePh
O
O
O
OC8H17
NHAc
OC8H17
OH HO
OAc AcO
NPht
4
34
1. H2NNH2·H2O,
EtOH, Δ
2. Ac2O, pyr.
88%
(2 steps)
AcO
AcO
OAc
O
SePh
O
O
OC8H17
NHAc
OAc AcO
35
Scheme 4.
by passing through a column of activated Al2O3. AgOTf was puri-
fied by azeotropic removal of impurities with toluene. Flash col-
umn chromatography used 230–400 mesh Whatman silica gel.
sodium as the ion. Dimethyldioxirane (DMDO) was prepared as de-
scribed.21 The following carbohydrates were synthesized as de-
scribed in the literature: 14a,14 14b,915a,9 18,14 20,14
(X = Br),22 and 23 (X = OC(NH)CCl3).22
, 23
TLC was run on Whatman 250 lm silica plates with UV fluores-
cence detected by short wave UV. 1H and 13C NMR spectra were re-
corded on a Bruker Avance DRX-500 or 300 spectrometers or
Varian 300 or 400 spectrometers. 1H NMR chemical shifts (d) for
CDCl3 or CD3OD are in ppm using TMS as the reference at
0.00 ppm. 1H NMR chemical shifts (d) for spectra obtained in D2O
were referenced to HOD at 4.79 ppm. 13C NMR chemical shifts (d)
for CDCl3 or CD3OD are in ppm using the center solvent peak of
CDCl3 at 77.00 ppm as the reference and CD3OD at 49.00 ppm as
the reference. 19F NMR chemical shifts were referenced to TFA at
0 ppm as an external standard to TFA in CDCl3. NMR assignments
were based upon 1H J values, 1H COSY, and HETCOR. Diastereo-
meric ratio of 5,6 epoxides was determined by 1H NMR and 1H
NOESY analysis. Mass spectra were recorded on a Micromass LCT
Time-of-Flight mass spectrometer by electrospray ionization using
4.2. t-Butyldimethylsilyl 4-O-benzoyl-2,6-dideoxy-2-
phthalamido-6-phenylseleno-b-D-glucopyranoside 15b
To compound 14b (500 mg, 0.85 mmol) in 20 mL of THF were
added NEt3 (0.36 mL, 2.54 mmol), PhSeH (0.27 mL, 2.54 mmol),
and NBu4I (15 mg, 42
flux. Additional portions of NEt3 (0.36 mL, 2.54 mmol), PhSeH
(0.27 mL, 2.54 mmol), and NBu4I (15 mg, 42 mol) were added
lmol), and the solution was brought to re-
l
after 18 h. After 44 h, the reaction mixture was cooled and diluted
with 150 mL CH2Cl2. The solution was washed with 150 mL satu-
rated NaHCO3, H2O, and saturated NaCl solutions. The solution
was dried with Na2SO4, filtered, and the filtrate concentrated.
The crude oil was purified using flash column chromatography

788
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
OAc
AcO
AcO
AcO
AcO
SePh
O
OAc
O
SePh
O
O
AcO
O
OC8H17
O
OR1
AcO
OAc
OAc
NHAc
NHAc
30
35
NaIO4,
NaHCO3,
MeOH/H2O
1. NaHCO3, NaIO4,
MeOH/H2O
2. DHP, Δ
40%
87%
(2 steps)
AcO
AcO
OAc
O
OAc
O
AcO
AcO
O
AcO
O
O
OC8H17
O
OC8H17
NHAc
AcO
OAc
OAc
NHAc
37
39
DMDO
CH2Cl2, 0 °C
DMDO
CH2Cl2, 0 °C
92%
95%
OAc
AcO
AcO
AcO
AcO
OAc
O
O
O
O
O AcO
O
OAc
OC8H17
O
O
OC8H17
NHAc
AcO
NHAc
OAc
38
40
1. HF·pyr
CH2Cl2,
-78 °C
2. NH3 (g),
MeOH
1. HF·pyr
CH2Cl2,
-78 °C
2. NH3 (g),
MeOH
23%
37%
(2 steps)
(2 steps)
OH
HO
HO
HO
OH
O
OH
O
OH
O
O
HO
O
OC8H17
HO
O
OC8H17
NHAc
HO
OH
OH
NHAc
F
F
2
1
Scheme 5.
(hexanes/EtOAc, 3:1) to afford 15b (510 mg, 90%) as a colorless so-
lid: 1H NMR (CDCl3) d 7.96 (d, 2H, NPht), 7.85 (m, 2H, NPht), 7.73
(m 2H, Bz), 7.60 (m, 1H, Bz), 7.49 (m, 2H, Bz), 7.44 (m, 2H, SePh),
7.22 (m, 3H, SePh), 5.49 (d, 1H, J = 8.0 Hz, H1), 5.09 (dd, 1H,
J = 9.1 Hz, H4), 4.61 (m, 1H, J = 10.8, 6.2 Hz, H3), 4.27 (dd, 1H,
J = 10.8, 8.0 Hz, H2), 4.00 (m, 1H, J = 8.6, 3.0 Hz, H5), 3.16 (m, 2H,
H6), 2.57 (d, 1H, J = 6.3 Hz, OH), 0.73 (s, 9H, tBu), 0.13 (s, 3H,
CH3-TBS), 0.04 (s, 3H, CH3-TBS). 13C NMR (CDCl3) d 166.92,
134.38, 133.93, 132.68, 131.89, 130.80, 130.14, 129.36, 129.21,
128.77, 127.20, 123,59, 109.82, 93.66, 74.08, 73.42, 59.58, 29.87,
25.55, 17.72, ꢁ3.82, ꢁ5.45. MS (ES, Na+): m/z (relative intensity)
690.1 (100). HRMS (M+Na+) calcd for C33H37NO7SeSiNa,
690.1402; found 690.1403.
Na2SO4, filtered, and the filtrate concentrated. The crude oil was
purified using flash column chromatography (hexanes/EtOAc,
3:1) to afford compound 16a (120 mg, 81%) as a colorless oil/solid.
1H NMR (CDCl3) d 8.02 (m, 2H, Pht), 7.98 (m, 2H, Pht), 7.60 (m, 2H,
Bz), 7.72 (m, 3H, ArH of BOM), 7.84 (m, 2H, ArH of BOM), 7.33 (m,
5H, PhSe), 7.17 (m, 3H, Bz), 5.21 (m, 1H, J = 8.5 Hz, H1), 4.76 (m, 1H,
H4), 4.64–4.60 (d, 2H, –O–CH2-O-Bn), 4.50 (m, 1H, J = 7.2 Hz, H3),
4.36 (dd, 1H, J = 8.6 Hz, H2), 4.05 (d, 2H, –O–CH2-Ph), 3.88 (m,
2H, CH2, octyl), 3.47 (m, 1H, J = 12.5, 8.9, 6.2 Hz, H5), 3.16 (dd,
1H, J = 13.1, 9.0 Hz, H6), 3.06 (dd, 1H, J = 13.0, 2.5 Hz, H6), 1.24
(br s, 12H, CH2-octyl), 0.81 (br s, 3H, CH3). 13C NMR (CDCl3) d
165.21, 137.74, 136.98, 136.92, 133.91, 133.58, 133.44, 132.25,
131.45, 129.72, 128.94, 128.56, 128.45, 128.07, 127.96, 127.80,
127.77, 127.73, 127.54, 127.10, 126.78, 98.29, 95.98, 75.55, 74.15,
71.77, 69.57, 67.21, 64.00, 60.99, 55.73, 43.63, 31.57, 29.16,
29.10, 29.03, 25.72, 22.50, 14.13.
4.3. 4-O-Benzoyl-2-phthalamido-2,6-dideoxy-3-O-[(benzyloxy)
methyl]-6-phenylseleno-octyl-b-D-glucopyranoside 16a
To a stirred solution of 15a (125 mg, 0.19 mmol) in 5 mL THF
were added DIEA (0.18 mL, 1.03 mmol) and BOMCl (0.13 mL,
0.94 mmol) and the reaction was brought to reflux. After 71 h,
the reaction mixture was cooled and diluted with 25 mL CH2Cl2
and washed with 25 mL saturated NaHCO3 solution and the aque-
ous layer was washed with 25 mL CH2Cl2. The combined organic
layers were washed with 50 mL saturated NaCl solution, dried with
4.4. t-Butyldimethylsilyl 4-O-benzoyl-3-O-[(benzyloxy)methyl]-
2,6-dideoxy-2-phthalamido-6-phenylseleno-b-D-
glucopyranoside 16b
To a stirred solution of 15b (500 mg, 0.75 mmol) in 15 mL of
THF were added DIEA (0.72 mL, 4.12 mmol) and BOM–Cl
(0.52 mL, 3.75 mmol) and the solution was brought to reflux. Addi-

T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
789
tional portions of DIEA (0.72 mL, 4.12 mmol) and BOM–Cl
(0.52 mL, 3.75 mmol) were added after 17 h. After 42 h, the reac-
tion mixture was cooled and diluted with 100 mL CH2Cl2. The solu-
tion was washed with 100 mL saturated NaHCO3 and the aqueous
layer was washed with 100 mL CH2Cl2. The combined organic lay-
ers were washed with 100 mL saturated NaCl solution and was
dried with Na2SO4, filtered, and the filtrate concentrated. The crude
oil was purified using flash column chromatography (hexanes/
EtOAc, 5:1) to afford 16b (450 mg, 76%) as a colorless oil/solid:
1H NMR (CDCl3) d 8.00 (m, 2H, Bz), 7.73 (br s, 2H, NPht), 7.62 (m,
2H, NPht), 7.46 (m 3H, Bz), 7.38 (m, 2H, Bz), 7.34 (m, 3H, ArH of
BOM), 7.21 (m, 3H, SePh), 7.09 (m, 2H, SePh), 6.81 (m, 2H, ArH of
BOM), 5.47 (d, 1H, J = 8.1 Hz, H1), 5.31 (dd, 1H, J = 9.5 Hz, H4),
4.80 (dd, 1H, J = 10.8, 8.9 Hz, H3), 4.76 (d, 1H, J = 7.2 Hz, O–CH2-
Ph/Bn), 4.63 (d, 1H, J = 7.2 Hz, O–CH2-Ph/Bn), 4.39 (dd, 1H,
J = 10.8, 8.1 Hz, H2), 4.08 (s, 2H, O–CH2–O-Bn), 3.94 (ddd, 1H,
J = 12.5, 9.5, 2.9 Hz, H5), 3.19 (m, 1H, H6), 3.10 (m, 1H, J = 12.9,
2.9 Hz, H6), 0.69 (s, 9H, tBu), 0.14 (s, 3H, CH3-TBS), 0.02 (s, 3H,
CH3-TBS). These spectral data are in agreement with those given
in the literature.9
0.75–0.0.71 (br s, 9H, TBS), 0.13 (m, 3H, TBS) 0.08 (m, 3H, TBS).
13C NMR (CDCl3)
168.80, 167.99, 136.53, 134.25, 132.11,
d
131.32, 129.17, 128.65, 128.16, 127.96, 127.86, 126.97, 123.58,
123.22, 96.29, 93.63, 82.48, 75.60, 74.38, 70.51, 57.43, 60.26,
30.07, ꢁ3.89, ꢁ5.57. MS (ES, Na+): m/z (relative intensity) 706.1
(100). HRMS (M+Na+) calcd for C34H41NO7SeSiNa, 706.1715; found
706.1723.
4.7. Octyl 2-deoxy-2-phthalimido-6-O-t-butyldimethylsilyl-b-D-
glucopyranoside 19
To a stirred solution of compound 18 (150 mg, 0.36 mmol) in
1.5 mL of DMF were added imidazole (72 mg, 1.07 mmol) and
TBS–Cl (67 mg, 0.44 mmol). After 39 h, the reaction mixture was
diluted with 10 mL of EtOAc and washed with 10 mL of H2O and
saturated NaCl solution. The organic extract was dried with
Na2SO4, filtered, and the filtrate concentrated. The crude product
was purified using a short silica gel plug (EtOAc) to afford 19
(140 mg, 74%) as a colorless oil. 1H NMR (CDCl3) d 7.82 (m, 2H,
Pht), 7.69 (m, 2H, Pht), 5.17 (d, 1H, J = 8.4 Hz, H1), 4.32 (dd, 1H,
J = 8.1 Hz, H4), 4.08 (dd, 1H, J = 8.5, 3.5 Hz, H2), 3.97 (dd, 1H,
J = 10.3, 5.0 Hz, H3), 3.87 (m, 1H, H5), 3.75 (m, 1H, –CH2-octyl),
3.73 (br s, 1H, –OH), 3.59 (m, 1H, H6), 3.51 (m, 1H, H6), 3.37 (m,
1H, –CH2-octyl), 2.89 (d, 1H, J = 3.6 Hz, –OH), 1.23 (br s, 2H, CH2-oc-
tyl), 1.16–1.00 (br s, 13H, CH2-octyl), 0.98–0.78 (s, 12H, tBu, CH3-
octyl), 0.07 (s, 6H, Me). 13C NMR (CDCl3) d 168.28, 134.63,
133.33, 131.74, 123.96, 122.62, 98.78, 97.51, 75.81, 74.66, 74.14,
73.00, 72.17, 71.04, 69.64, 65.06, 56.70, 55.56, 30.25, 29.25,
28.23, 26.32, 25.32, 22.55, 21.52, 18.18, 14.50, 13.51, ꢁ5.04,
ꢁ5.99. MS (ES, Na+): m/z (relative intensity) 558.2 (100). HRMS
(M+Na+) calcd for C28H45NO7Na, 558.2863; found 558.2869.
4.5. Octyl 3-O-[(benzyloxy)methyl]-2,6-dideoxy-2-
phthalamido-6-phenylseleno-b-D-glucopyranoside 17a
To a stirred solution of 16a (1.90 g, 2.42 mmol) in 100 mL of
THF/MeOH (1:1) was added 0.5 M NaOMe solution (0.28 mL,
5.32 mmol). Two additional portions (0.28 mL, 5.32 mmol) of the
NaOMe solution were added after 17 h and 23 h. After 45 h, the
reaction mixture was quenched with 2.0 g of Dowex 50 W H+ form
resin (2.1 meq/mL) and stirred gently for 30 min. The mixture was
filtered and the filtrate concentrated. The resulting oil was purified
by flash column chromatography (hexanes/EtOAc, 3:1) to afford
17a as a colorless oil (1.47 g, 89%). 1H NMR (CDCl3) d 7.71 (d, 2H,
NPht), 7.60 (m, 2H, NPht), 7.14 (m, 5H, SePh), 7.08 (m, 3H, ArH of
BOM), 7.00 (m, 2H, ArH of BOM), 5.07 (d, 1H, J = 8.3 Hz, H1), 4.74
(d, 1H, J = 7.1 Hz, O–CH2-Ph/Bn), 4.58 (d, 1H, J = 7.1 Hz, O–CH2-
Ph/Bn), 4.50 (d, 1H, J = 12.0 Hz, –OH), 4.33 (s, 2H, O–CH2–O-Bn),
4.25 (d, 1H, J = 10.8 Hz, H4), 4.18 (dd, 1H, J = 8.3 Hz, H3), 3.69–
3.62 (dd, 2H, H2/CH2-octyl), 3.49–3.42 (dd, 2H, H5/CH2-octyl),
3.31 (m, 1H, J = 13.2, 6.6 Hz,H6), 3.11 (m, 1H, J = 12.8, 8.3 Hz, H6),
1.32–1.31 (br s, 2H, CH2-octyl), 1.16–0.97 (br s, 10H, CH2-octyl),
0.88 (t, 3H, CH3-octyl). 13C NMR (CDCl3) d 171.00, 136.30, 133.93,
132.03, 131.52, 130.99, 128.87, 128.41, 127.92, 127.72, 126.45,
123.47, 123.01, 98.11, 96.06, 82.53, 75.46, 74.00, 70.31, 69.50,
60.26, 55.15, 31.54, 31.47, 29.68, 29.01, 25.70, 22.53, 22.48,
20.92, 14.09, 13.95. MS (ES, Na+): m/z (relative intensity) 704.2
(100). HRMS (M+Na+) calcd for C36H43NO7SeNa, 704.2102; found
704.2103.
4.8. Octyl 2-deoxy-2-phthalimido-3-O-acetyl-4,6-O-
benzylidene-b-D-glucopyranoside 21
Compound 20 (2.25 g, 2.45 mmol) was dissolved in 10 mL of
Ac2O and 10 mL of pyridine. After 19 h, the reaction mixture was
diluted to 75 mL of EtOAc and washed with 50 mL of saturated
CuSO4, H2O, saturated NaHCO3, and saturated NaCl solutions. The
organic extract was dried with Na2SO4, filtered, and the filtrate
concentrated. The crude product was purified by flash column
chromatography (hexanes/EtOAc, 3:1) to afford 21 (1.12 g, 83%)
as a colorless oil: 1H NMR (CDCl3) d 7.81 (br s, 2H, NPht), 7.66
(br s, 2H, NPht), 7.43 (br s, 2H, Ph), 7.30 (br s, 3H, Ph), 5.89 (d,
1H, J = 9.8 Hz, H4), 5.51 (s, 1H, benzylidene), 5.43 (d, 1H,
J = 8.4 Hz, H1), 4.37 (d, 1H, J = 10.2, 4.1 Hz, H3), 4.29 (dd, 1H,
J = 9.1 Hz, H2), 3.83–3.74 (m, 3H, H6/H6/H5), 3.71 (m, 1H, CH2-oc-
tyl), 3.42 (m, 1H, CH2-octyl), 2.04 (s, 3H, OAc), 1.93 (s, 3H, NHAc),
1.58–1.55 (br s, 2H, CH2-octyl), 1.28–1.21 (br s, 10H, CH2-octyl),
0.85 (s, 3H, CH3-octyl). 13C NMR (CDCl3) d 170.03, 136.99, 134.28,
134.14, 128.14, 126.22, 123.44, 101.49, 98.65, 79.28, 77.50, 77.25,
76.99, 70.13, 69.76, 68.59, 66.18, 55.39, 31.55, 29.19, 29.14,
29.10, 29.01, 25.70, 22.50, 20.47, 14.01. MS (ES, Na+): m/z (relative
intensity) 574.2 (100). HRMS (M+Na+) calcd for C31H37NO8Na,
574.2417; found 574.2415.
4.6. t-Butyldimethylsilyl-3-O-[(benzyloxy)methyl]-2,6-dideoxy-
2-phthalamido-6-phenylseleno-b-D-glucopyranoside 17b
To a stirred solution of 16b (270 mg, 0.34 mmol) in 10 mL of
THF/MeOH (1:1) was added 1 M NaOMe solution (0.35 mL,
0.35 mmol). After 6 h, the reaction mixture was quenched with
750 mg of Dowex 50 W H+ form resin (2.1 meq/mL) and stirred
gently for 15 min. The mixture was filtered and the filtrate concen-
trated. The resulting oil was purified by flash column chromatogra-
phy (hexanes/EtOAc, 3:1) to afford 17b as a colorless oil (200 mg,
87%): 1H NMR (CDCl3) d 7.89 (d, 2H, NPht), 7.79 (m, 2H, NPht),
7.62 (m, 2H, SePh), 7.37–2.28 (m, 8H, SePh/ArH of BOM), 5.42 (d,
1H, J = 7.8 Hz, H1), 4.93 (d, 1H, J = 6.0 Hz, O–CH2-Ph/Bn), 4.73 (d,
2H, O–CH2-Ph/Bn/O–CH2–O-Bn), 4.33 (s, 1H, O–CH2–O-Bn), 4.47
(d, 1H, J = 1.4 Hz, –OH), 4.40 (d, 1H, J = 10.9, 8.0 Hz, H3), 4.31 (dd,
1H, J = 10.8, 7.8 Hz, H2), 3.79 (dd, 1H, J = 9.0, 2.4 Hz, H4), 3.62 (m,
2H, J = 5,7, 3.0, 2.0 Hz, H5/H6), 3.24 (m, 1H, J = 12.6, 8.8 Hz, H6),
4.9. Octyl 2-deoxy-2-phthalimido-3-O-acetyl-6-O-t-
butyldimethylsilyl-b-D-glucopyranoside 22
Compound 21 (1.10 g, 1.99 mmol) was suspended in 50 mL of
AcOH/H2O (1:1) and heated to 100 °C. After 4.5 h, the reaction mix-
ture was cooled and concentrated. The crude product was diluted
in 75 mL of EtOAc and washed with 50 mL of saturated NaHCO3
and saturated NaCl solutions. The organic extract was dried with
Na2SO4, filtered, and the filtrate concentrated to afford the diol
(890 mg) as a colorless oil and taken on without any purification.

790
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
A portion of the crude diol (100 mg) was dissolved in 2.0 mL of
DMF, to which TBS–Cl (40 mg, 0.27 mmol) and imidazole (44 mg,
0.65 mmol) were added. After 20 h, the DMF was concentrated.
The crude product was diluted to 20 mL of EtOAc and washed with
10 mL of H2O and saturated NaCl solution. The organic extract was
dried with Na2SO4, filtered, and the filtrate concentrated. The crude
product was purified using a short silica gel plug (EtOAc) to afford
22 (105 mg, 81%, two steps) as a colorless oil: 1H NMR (CDCl3) d
7.86 (br s, 2H, NPht), 7.74 (br s, 2H, NPht), 5.65 (d, 1H, J = 10.6,
8.9 Hz, H4), 5.35 (d, 1H, J = 8.5 Hz, H1), 4.21 (dd, 1H, J = 10.6,
8.5 Hz, H3), 3.97–3.83 (m, 2H, H5/H2), 3.78 (m, 2H, H6/H6), 3.61
(m, 1H, CH2-octyl), 3.42 (m, 1H, CH2-octyl), 2.94 (d, J = 4.9 Hz,
OH), 2.04 (s, 3H, OAc), 1.93 (s, 3H, NHAc), 1.58–1.55 (br s, 2H,
CH2-octyl), 1.28–1.21 (br s, 10H, CH2-octyl), 0.85 (s, 3H, CH3-octyl).
13C NMR (CDCl3) d 171.40, 170.32, 168.18, 167.78, 134.18, 134.11,
133.87, 131.37, 123.47, 123.41, 123.30, 98.09, 97.46, 76.23, 75.37,
73.77, 70.30, 70.07, 69.25, 69.04, 60.35, 55.42, 31.60, 29.29,
29.09, 25.87, 25.60, 22.52, 20.66, 17.94, 14.13. MS (ES, Na+): m/z
(relative intensity) calcd for C30H47NO8Na, 512.3; found 512.3
(100).
gentle vacuum, the tube sealed and heated to 100 °C. After 41 h,
the reaction mixture was cooled, the tube opened and the reaction
mixture concentrated and placed under vacuum for 6.5 h to afford
the free isolactosamine (10 mg) as a colorless oil. The crude prod-
uct, immediately taken on to the next step without any purifica-
tion, was dissolved in 1.0 mL of pyridine and 1.0 mL of Ac2O.
After 18.5 h, the reaction mixture was diluted with 5 mL EtOAc
and washed with 5 mL of saturated CuSO4, H2O, saturated NaHCO3,
and saturated NaCl solutions. The organic extract was dried with
Na2SO4, filtered, and the filtrate concentrated. The resulting light
yellow oil was purified using preparative thin layer chromatogra-
phy (hexanes/EtOAc, 1:1) to afford 31 (8 mg, 41%, three steps) as
a colorless oil: 1H NMR (CDCl3) d 5.65 (d, 1H, J = 7.1 Hz, NH), 5.33
(d, 1H, J = 3.3 Hz, H40), 5.06 (dd, 1H, J = 10.3, 7.9 Hz, H20), 4.98–
4.91 (m, 3H, H1/H3/H30), 4.56–4.52 (m, 2H, H4/H10), 4.13–4.06
(m, 4H, H2/H50/H60/H60), 3.87–3.81 (m, 2H, H6/H6), 3.66 (m, 1H,
H5), 3.46 (m, 1H, CH2-octyl), 3.13 (m, 1H, CH2-octyl, 2.14 (s, 3H,
OAc), 2.09 (s, 3H, OAc), 2.03 (s, 3H, OAc), 2.00 (s, 3H, OAc), 1.96
(s, 3H, NHAc), 1.55 (br s, 3H, CH2-octyl), 1.25 (br s, 9H, CH2-octyl),
0.85 (t, 3H, CH3-octyl). 13C NMR (CDCl3) d 170.73, 170.37, 170.27,
169.50, 168.90, 100.49, 98.96, 71.75, 71.03, 70.62, 70.05, 69.47,
69.11, 66.90, 62.55, 61.04, 60.35, 58.23, 53.37, 31.77, 29.44,
29.28, 25.87, 23.62, 22.60, 20.80, 20.61, 14.03. MS (ES, Na+): m/z
(relative intensity) 770.1 (100). HRMS (M+Na+) calcd for
C34H53NO17Na, 770.3229; found 770.3211.
4.10. Octyl 2-deoxy-2-phthalimido-3-O-(2,3,4,6-tetra-O-acetyl-
b-D
-galactopyranosyl)-4,6-O-benzylidene-b-
D-glucopyranoside
28
To a stirred solution of acceptor 20 (600 mg, 1.22 mmol) and
donor 23 (X = OC(NH)CCl3) (684 mg, 1.34 mmol) in 20 mL of
CH2Cl2 at ꢁ20 °C were added 1.0 g 3 Å molecular sieves and freshly
4.12. Octyl 2-deoxy-2-acetamido-3-O-b-D-galactopyranosyl-b-D-
glucopyranoside 3
distilled TMS-OTf (50 lL, 0.30 mmol). The reaction mixture was al-
lowed to warm to 0 °C for 3 h and then to room temperature. After
24 h, the reaction mixture was quenched with 0.05 mL of NEt3 and
filtered. The filtrate was washed with 20 mL of saturated NaHCO3
and saturated NaCl solutions. The organic extract was dried with
Na2SO4, filtered, and the filtrate concentrated. The crude oil was
purified using flash column chromatography (hexanes/EtOAc,
2:1) to afford 28 (840 mg, 83%) as a colorless foam: 1H NMR
(CDCl3) d 7.88 (s, 2H, Pht), 7.77 (s, 2H, Pht), 7.49 (s, 2H, Ph), 7.38
(s, 3H, Ph), 5.58 (s, 1H, benzylidene), 5.19 (d, 1H, J = 3.1 Hz, H40),
5.14 (d, 1H, J = 8.5 Hz, H1), 4.99 (dd, 1H, J = 10.3, 8.0 Hz, H20),
4.76–4.71 (m, 2H, H3/H30), 4.55 (d, 1H, J = 8.0 Hz, H10), 4.37 (dd,
1H, J = 10.5, 4.8 Hz, H4), 4.30 (dd, 1H, J = 10.4, 8.6 Hz, H2), 4.03
(dd, 1H, J = 11.0, 8.3 Hz, H60), 3.86 (m, 1H, H60), 3.82–3.77 (m, 3H,
H6/H6/CH2-octyl), 3.63 (m, 1H, H5), 3.49 (m, 1H, H50), 3.38 (m,
1H, CH2-octyl), 2.08 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.98 (s, 3H,
OAc), 1.92 (s, 3H, OAc), 1.26–1.13 (br s, 3H, CH2-octyl), 1.03–0.96
(br s, 9H, CH2-octyl), 0.82 (t, 3H, CH3-octyl). 13C NMR (CDCl3) d
170.23, 170.01, 169.98, 168.82, 137.05, 134.18, 129.22, 128.31,
126.00, 101.43, 100.48, 98.74, 81.08, 75.69, 70.99, 70.28, 70.01,
69.19, 68.74, 66.63, 66.31, 60.76, 56.38, 31.60, 29.20, 29.03,
29.01, 25.70, 22.53, 20.56, 20.49, 20.39, 20.06, 14.15, 13.99. MS
(ES, Na+): m/z (relative intensity) 861.9 (100). HRMS (M+Na+) calcd
for C43H53NO16Na, 862.3262; found 862.3259.
To a stirred solution of 31 (5 mg, 6.7
THF (1:1) was added 0.5 M NaOMe solution (28
l
mol) in 0.5 mL of MeOH/
L, 54 mol). After
l
l
4 d, the reaction mixture was quenched with 0.050 g of Dowex
50 W H+ form resin (2.1 meq/mL) and stirred gently for 20 min.
The mixture was filtered and the filtrate concentrated. The result-
ing white powder was purified using a short silica gel plug with
CHCl3/MeOH (4:1) to afford 3 (3 mg, 90%) as a white powder: 1H
NMR (D2O) d 4.40 (d, 1H, J = 7.7 Hz, H1), 4.29 (d, 1H, J = 7.7 Hz,
H10), 3.79–3.74 (m, 3H, H20/H3/H30), 3.67–3.62 (m, 6H, H40/H4/
H2/H5/H60/H60), 3.57–3.43 (m, 2H, H6/H6), 3.41–3.34 (m, 3H,
H5/-CH2-octyl), 1.90 (s, 3H, NHAc), 1.40 (br s, 3H, CH2-octyl),
1.14 (br s, 9H, CH2-octyl), 0.72 (t, 3H, CH3-octyl). 13C NMR (D2O)
d 174.48, 103.51, 100.87, 82.49, 75.35, 75.27, 72.49, 70.68, 70.59,
68.75, 68.53, 61.01, 60.77, 54.62, 31.08, 28.55, 28.47, 28.32,
25.07, 22.27, 22.00, 13.37. MS (ES, Na+): m/z (relative intensity)
518.3 (100). HRMS (M+Na+) calcd for C22H41NO11Na, 518.2577;
found 518.2576.
4.13. Octyl 2-deoxy-2-phthalamido-3-O-(2,3,4,6-tetra-O-acetyl-
D-galactopyranosyl)-4-O-benzoyl-6-phenylseleno-b-D-
glucopyranoside 29
b-
To a stirred solution of 28 (700 mg, 0.83 mmol) in 35 mL of CCl4
were added NBS (160 mg, 0.92 mmol) and BaCO3 (483 mg,
2.45 mmol). The reaction mixture was heated to reflux and after
a few minutes it turned to an orange color. As the reaction mixture
progressed, it became white. After 45 min, the reaction was cooled,
filtered, and the filtrated concentrated. The crude product was dis-
solved in 50 mL of CH2Cl2 and washed with 25 mL of H2O three
times and once with 25 mL of saturated NaCl solution. The organic
extract was dried with Na2SO4, filtered and the filtrate concen-
trated to yield the bromide (750 mg) as a white powder and taken
on without any purification: 1H NMR (CDCl3) d 8.04 (m, 2H, Bz),
7.85 (d, 2H, NPht), 7.77 (m, 2H, NPht), 7.57 (m, 2H, Bz), 7.44 (m,
3H, Bz), 5.14 (m, 1H, H3), 5.11 (d, 1H, J = 8.5 Hz, H1), 4.97 (d, 1H,
J = 4.2 Hz, H40), 4.83 (dd, 1H, J = 10.5, 3.7 Hz, H30), 4.54 (dd, 1H,
J = 10.5, 3.5 Hz, H20), 4.32 (m, 1H, H50), 4.18 (d, 1H, J = 7.8 Hz,
4.11. Octyl 2-deoxy-2-acetamido-3-O-(2,3,4,6-tetra-O-acetyl)-b-
D-galactopyranosyl-4,6-O-diacetyl-b-D-glucopyranoside 31
A solution of 28 (22 mg, 26 mol) in 1.0 mL AcOH/H2O (1:1)
l
was heated to reflux. After 2 h, the reaction mixture was cooled
and concentrated. The crude reaction mixture was diluted with
30 mL of EtOAc and washed with 20 mL of saturated NaHCO3 and
saturated NaCl solutions. The organic extract was dried with
Na2SO4, filtered, and the filtrate concentrated. The crude product
was purified with a short silica gel plug (EtOAc) to afford the diol
(20 mg) as a colorless oil. To a stirred solution of this diol in
0.5 mL of EtOH in
(0.11 mL, 2.40 mmol). The reaction mixture was placed under a
a
Schlenk tube was added H2NNH2ꢀH2O

T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
791
H10), 4.09 (dd, 1H, J = 4.1 Hz, H2), 3.94 (m, 1H, H4), 3.77 (m, 1H,
CH2-octyl), 3.53 (m, 2H, H60/H60), 3.49–3.31 (m, 4H, H5/H6/H6/
CH2-octyl), 2.09–1.75 (s, 12H, OAc), 1.41 (br s, 3H, CH2-octyl),
1.14–0.98 (br s, 9H, CH2-octyl), 0.80 (t, 3H, CH3-octyl). 13C NMR
(CDCl3) d 169.92, 168.88, 164.58, 134.40, 133.32, 131.32, 129.91,
129.68, 128.25, 123.44, 100.09, 97.84, 74.64, 73.68, 72.43, 71.05,
70.65, 70.13, 66.77, 68.76, 66.09, 60.03, 55.54, 53.30, 31.46,
31.15, 28.99, 28.89, 25.58, 22.40, 20.22, 13.87. MS (ES, Na+): m/z
(relative intensity) calcd for C43H52NO16BrNa, 940.2; found 940.2
(100).
69.87, 69.39, 66.92, 61.05, 60.36, 58.39, 31.79, 29.50, 29.44,
29.29, 25.89, 23.57, 22.61, 20.99, 20.89, 20.77, 20.60, 20.49,
14.15. MS (ES, Na+): m/z (relative intensity) 868.2 (100). HRMS
(M+Na+) calcd for C38H55NO17SeNa, 868.2635; found 868.2645.
4.15. Octyl 2-deoxy-2-phthalamido-4-O-(2,3,4,6-tetra-O-acetyl-
b-D-galactopyranosyl)-3-O-acetyl-6-O-t-butyldimethylsilyl-b-D-
glucopyranoside 32
To a stirred solution of donor 23 (1.0 g, 2.0 mmol) and acceptor
19 (650 mg, 0.19 mmol) in 75 mL of CH2Cl2 was added 0.25 g 3 Å
molecular sieves. The reaction mixture was refluxed for 1 h and
To a stirred solution of the bromide (750 mg) in 30 mL of THF
were added NEt3 (0.37 mL, 2.69 mmol), PhSeH (0.24 mL,
2.45 mmol), and Bu4NI (75 mg, 0.20 mmol). The reaction mixture
was brought to reflux at 65 °C. After 16 h, the reaction was cooled
and diluted to 100 mL of CH2Cl2 and washed with 100 mL of satu-
rated NaHCO3, H2O, and saturated NaCl solutions. The organic ex-
tract was dried with Na2SO4, filtered and the filtrate
concentrated. The resulting yellow oil was purified using flash col-
umn chromatography (hexanes/EtOAc, 2:1) to afford 29 (700 mg,
84%, two steps) as a colorless oil: 1H NMR (CDCl3) d 8.03 (m, 2H,
Bz), 7.87 (d, 2H, NPht), 7.79 (m, 2H, NPht), 7.58 (m, 2H, Bz), 7.46
(m, 4H, Bz/SePh), 7.19 (m, 2H, SePh), 5.23 (m, 1H, H30), 5.07 (d,
1H, J = 8.5 Hz, H1), 5.00 (d, 1H, J = 2.9 Hz, H40), 4.86 (dd, 1H,
J = 10.3, 7.8 Hz, H20), 4.79 (dd, 1H, J = 10.7, 8.9 Hz, H3), 4.56 (m,
1H, H50), 4.34 (dd, 1H, J = 10.7, 8.5 Hz, H2), 4.09 (d, 1H, J = 7.8 Hz,
H10), 3.94 (m, 1H, H4), 3.72 (m, 2H, H60/H60), 3.52 (m, 1H, H5),
3.44 (m, 1H, H6), 3.33 (m, 2H, CH2-octyl), 3.13 (m, 1H, H6), 2.08
(s, 3H, OAc), 2.04 (s, 3H, OAc), 1.95 (s, 3H, OAc), 1.87 (s, 3H,
OAc), 1.27–1.17 (br s, 3H, CH2-octyl), 1.06–1.00 (br s, 9H, CH2-oc-
tyl), 0.83 (t, 3H, CH3-octyl). 13C NMR (CDCl3) d 170.12, 170.04,
169.97, 169.00, 164.76, 134.49, 133.32, 132.19, 129.74, 128.99,
128.32, 126.79, 123.52, 100.23, 97.91, 74.97, 74.21, 70.81, 70.13,
69.65, 68.84, 66.18, 60.08, 55.74, 31.61, 29.05, 25.73, 22.56,
20.58, 20.36, 20.29, 14.03. MS (ES, Na+): m/z (relative intensity)
1018.2 (100). HRMS (M+Na+) calcd for C49H57NO16SeNa,
1018.2740; found 1018.2745.
then cooled to ꢁ50 °C and freshly distilled TMS-OTf (35
lL,
0.19 mmol) was added. After 15 min, the reaction mixture was
quenched with 0.1 mL of NEt3 and filtered. The filtrate was washed
with 20 mL of saturated NaHCO3 and saturated NaCl solutions. The
organic extract was dried with Na2SO4, filtered and the filtrate con-
centrated to provide the desired product containing a free 3-hydro-
xyl group (590 mg, 56%). This product was dissolved in 10 mL of
pyridine and 10 mL of Ac2O. After 20 h, the reaction mixture was
diluted to 50 mL of EtOAc and washed with 50 mL of saturated
CuSO4, H2O, saturated NaHCO3, and saturated NaCl solutions. The
organic extract was dried with Na2SO4, filtered, and the filtrate
concentrated. The crude oil was purified using flash column chro-
matography (hexanes/EtOAc, 2:1) to afford 32 (210 mg, 34%, two
steps) as a colorless oil/solid: 1H NMR (CDCl3) d 7.79 (br s, 2H,
Pht), 7.69 (s, 2H, Pht), 5.67 (dd, 1H, J = 10.7, 9.0 Hz, H30), 5.31 (d,
1H, J = 3.1 Hz, H40), 5.26 (d, 1H, J = 8.4 Hz, H1), 5.07 (dd, 1H,
J = 10.3, 8.0 Hz, H20), 4.91 (dd, 1H, J = 10.4, 3.5 Hz, H3), 4.69 (d,
1H, J = 7.9 Hz, H10), 4.13–4.02 (m, 4H, H4/H2/H6/H6), 3.94–3.89
(m, 2H, H60/H60), 3.84 (m, 1H, H2), 3.81 (m, 1H, H50), 3.71 (m,
1H, CH2-octyl), 3.47 (m, 1H, Hz, H5), 3.36 (m, 1H, CH2-octyl),
2.13–1.86 (s, 18H, NHAc, OAc), 1.67 (br s, 2H, CH2-octyl), 1.24–
1.00 (br s, 12H, CH2-octyl), 0.87 (s, 12H, tBu, CH3-octyl), 0.06 (s,
6H, Me). 13C NMR (CDCl3) d 171.08, 170.30, 170.17, 170.08,
170.05, 168.85, 167.93, 167.93, 167.57, 134.11, 133.94, 131.33,
123.38, 100.32, 97.61, 75.13, 75.08, 71.10, 70.96, 70.49, 69.40,
69.13, 68.67, 66.79, 66.35, 61.02, 60.95, 60.31, 54.99, 31.57,
29.23, 29.04, 25.84, 25.79, 22.50, 20.96, 20.66, 20.57, 20.49,
18.24, 14.11, 13.97, ꢁ4.97, ꢁ5.33. MS (ES, Na+): m/z (relative inten-
sity) 930.3 (100). HRMS (M+Na+) calcd for C38H65NO17SiNa,
930.3919; found 930.3926.
4.14. Octyl 2-deoxy-2-acetamido-3-O-(2,3,4,6-tetra-O-acetyl-b-
D
-galactopyranosyl)-4-O-acetyl-6-phenylseleno-b-D-
glucopyranoside 30
To a stirred solution of 29 (45 mg, 45 lmol) in 1.0 mL of EtOH in
a Schlenk tube was added H2NNH2ꢀH2O (0.19 mL, 4.070 mmol). The
reaction mixture was placed under a gentle vacuum, the tube
sealed and heated to 100 °C. After 18.5 h, the reaction mixture
was cooled, the tube opened, and the reaction mixture concen-
trated and placed under vacuum for 6 h to afford the free isolactos-
amine (40 mg) as a colorless oil. The product, which was taken on
to the next step without any purification, was dissolved in 3.0 mL
of pyridine and 3.0 mL of Ac2O. After 20.5 h, the reaction mixture
was diluted with 10 mL of EtOAc and washed with 10 mL of satu-
rated CuSO4, H2O, saturated NaHCO3, and saturated NaCl solutions.
The organic extract was dried with Na2SO4, filtered, and the filtrate
concentrated. The resulting light yellow oil was purified using pre-
parative thin layer chromatography (hexanes/EtOAc, 1:4) to afford
30 (29 mg, 76%, two steps) as a colorless oil/solid: 1H NMR (CDCl3)
d 7.48 (m, 3H, SePh), 7.26 (m, 2H, SePh), 5.89 (d, 1H, J = 7.1 Hz, NH),
5.33 (d, 1H, J = 2.5 Hz, H40), 5.04 (dd, 1H, J = 10.1 Hz, H20), 4.96–
4.90 (m, 2H, H30/H1), 4.80 (dd, 1H, J = 9.1 Hz, H3), 4.55–4.48 (m,
3H, H10/H4/H50), 3.86 (dd, 1H, J = 12.9, 6.4 Hz, H60), 3.66 (dd, 1H,
J = 8.9, 6.1 Hz, H60), 3.74 (m, 1H, H2), 3.42 (m, 1H, CH2-octyl),
3.12 (m, 1H, CH2-octyl), 3.03–2.97 (m, 3H, H5/H6/H6), 2.16 (s,
3H, OAc), 2.13 (br s, 15H, OAc/NHAc), 1.52 (br s, 3H, CH2-octyl),
1.25 (br s, 9H, CH2-octyl), 0.86 (t, 3H, CH3-octyl). 13C NMR (CDCl3)
d 175.13, 171.13, 170.88, 170.39, 170.18, 170.11, 169.67, 169.01,
132.57, 129.01, 126.91, 100.53, 98.78, 73.73, 73.04, 71.06, 70.54,
4.16. Octyl 2-deoxy-2-acetamido-4-O-(2,3,4,6-tetra-O-acetyl-b-
D-galactopyranosyl)-3,6-O-acetyl-b-D-glucopyranoside 36
To a stirred solution of 32 (100 mg, 0.12 mmol) in 4.0 mL of
EtOH in
Schlenk tube was added H2NNH2ꢀH2O (0.53 mL,
a
10.40 mmol). The reaction mixture was placed under a gentle vac-
uum, the tube sealed and heated to 100 °C. After 15 h, the reaction
mixture was cooled, the tube opened, and the reaction mixture
concentrated and placed under vacuum for 6 h to afford the free
lactosamine (26 mg) as a colorless oil. The product was taken on
to the next step without any purification. The crude product was
dissolved in 3 mL of pyridine and 3 mL of Ac2O. After 30 h, the reac-
tion mixture was diluted with 20 mL of EtOAc and washed with
20 mL of saturated CuSO4, H2O, saturated NaHCO3, and saturated
NaCl solutions. The organic extract was dried with Na2SO4, filtered,
and the filtrate concentrated. The resulting yellow oil was purified
using flash column chromatography (hexanes/EtOAc, 1:1) to afford
36 (60 mg, 70%, two steps) as a colorless oil/solid: 1H NMR (CDCl3)
d 5.63 (d, 1H, N-H), 5.35 (d, 1H, H40), 5.23 (dd, 1H, J = 10.2 Hz, H20),
5.19 (m, 1H, H3), 5.04 (dd, 1H, J = 10.8, 7.8 Hz, H30), 4.82 (dd, 1H,
J = 9.6 Hz, H4), 4.57 (d, 1H, J = 8.3 Hz, H1), 4.53 (dd, 1H, H2), 4.42
(d, 1H, J = 7.4 Hz, H10), 4.10 (dd, 1H, H60), 4.00 (m, 1H, H60), 3.83–
3.73 (m, 3H, H6/H6/CH2-octyl), 3.64 (m, 1H, H5), 3.57 (m, 1H, Hz,

792
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
H50), 3.40 (m, 1H, CH2-octyl), 2.07–1.88 (s, 21H, NHAc, OAc), 1.53–
1.51 (br s, 3H, CH2-octyl), 1.30–1.10 (br s, 9H, CH2-octyl), 0.85 (t,
3H, CH3-octyl). MS (ES, Na+): m/z (relative intensity) 770.3 (100).
HRMS (M+Na+) calcd for C32H53NO17Na, 770.3211; found
770.3220.
d 7.83 (br s, 2H, Pht), 7.71 (m, 2H, Pht), 7.57 (m, 2H, SePh), 7.27
(m, 3H, SePh), 5.71 (dd, 1H, J = 10.6, 8.0 Hz, H20), 5.33 (d,
J = 8.4 Hz, H1), 5.27 (d, 1H, J = 3.4 Hz, H40), 5.07 (dd, 1H, J = 10.4,
8.4 Hz, H2), 4.81 (dd, 1H, J = 10.4, 3.5 Hz, H30), 4.46 (d, 1H,
J = 8.0 Hz, H10), 4.20 (dd, 1H, J = 10.6, 8.5 Hz, H3), 4.08 (m, 2H,
H60/H60), 3.83 (m, 2H, H4/H50), 3.75 (m, 1H, H5), 3.71 (m, 1H,
CH2-octyl), 3.43 (d, 1H, J = 12.4, 2.4 Hz, H6), 3.37 (m, 1H, CH2-oc-
tyl), 3.14 (d, 1H, J = 12.3, 6.7 Hz, H6), 2.14–1.90 (s, 18H, NHAc,
OAc), 1.41 (br s, 3H, CH2-octyl), 1.24–1.03 (m, 9H, CH2-octyl),
0.82 (t, 3H, CH3-octyl). 13C NMR (CDCl3) d 170.35, 170.18, 170.03,
169.84, 168.92, 132.93, 129.24, 127.27, 101.01, 97.79, 80.16,
74.13, 71.06, 70.92, 70.53, 69.91, 69.16, 66.61, 60.78, 55.14,
53.41, 31.64, 29.39, 29.22, 25.79, 22.58, 20.63, 20.57, 20.51,
14.04, 13.62. MS (ES, Na+): m/z (relative intensity) 956.2 (100).
HRMS (M+Na+) calcd for C44H55NO16SeNa, 956.2584; found
956.2607.
4.17. Octyl 2-deoxy-2-acetamido-4-O-b-D-galactopyranosyl-b-D-
glucopyranoside 4
To a stirred solution of 36 (55 mg, 74 lmol) in 3.0 mL of MeOH
was added NaOMe powder (8.6 mg, 0.16 mmol). After 3 d, the reac-
tion mixture was quenched with 0.10 g of Dowex 50 W H+ form re-
sin (2.1 meq/mL) and stirred gently for 20 min. The mixture was
filtered and the filtrate concentrated. The resulting white powder
was purified using a short silica gel plug (CHCl3/MeOH, 4:1) to af-
ford 4 (15 mg, 41%) as a white powder: 1H NMR (D2O) d 4.70–4.60
(m, 2H, H1/H10), 3.95–3.92 (m, 3H, H20/H3/H30), 3.79 (m, 6H, H40/
H4/H2/H50/H60/H60), 3.54–3.45 (m, 5H, H6/H6/H5/-CH2-octyl),
2.07 (s, 3H, NHAc), 1.63 (br s, 3H, CH2-octyl), 1.32 (br s, 9H, CH2-oc-
tyl), 0.89 (t, 3H, CH3-octyl). 13C NMR (D2O) d 133.86, 126.09,
101.71, 75.14, 72.53, 71.75, 70.86, 70.70, 68.86, 66.01, 62.66,
60.98, 56.79, 47.68, 31.10, 28.37, 25.25, 25.07, 22.00, 21.87,
19.95, 13.38. MS (ES, Na+): m/z (relative intensity) 518.2 (100).
HRMS (M+Na+) calcd for C22H41NO11Na, 518.2577; found
518.2582.
4.20. Octyl 2-deoxy-2-acetamido-4-O-(2,3,4,6-tetra-O-acetyl-b-
D-galactopyranosyl)-3-O-acetyl-6-phenylseleno-b-D-
glucopyranoside 35
To a stirred solution of 34 (50 mg, 53 lmol) in 1 mL of EtOH in a
Schlenk tube was added H2NNH2ꢀH2O (0.23 mL, 4.82 mmol). The
reaction mixture was placed under a gentle vacuum, the tube
sealed, and heated to 100 °C. After 15 h, the reaction mixture was
cooled, the tube opened, and the reaction mixture concentrated
and placed under vacuum for 6 h to afford the free amine as an
oil/solid. The product, which was taken on to the next step without
any purification, was dissolved in 1.0 mL of pyridine and 1.0 mL of
Ac2O. After 17.5 h, the reaction mixture was diluted with 10 mL of
EtOAc and washed with 10 mL of saturated CuSO4, H2O, saturated
NaHCO3, and saturated NaCl solutions. The organic extract was
dried with Na2SO4, filtered, and the filtrate concentrated. The
resulting light yellow oil was purified using flash column chroma-
tography (hexanes/EtOAc, 1:2) to afford 35 (40 mg, 88%, two steps)
as a colorless oil/solid: 1H NMR (CDCl3) d 7.58 (m, 3H, SePh), 7.35
(m, 2H, SePh), 5.60 (d, 1H, J = 9.5 Hz, NH), 5.29 (d, 1H, H40), 5.04
(dd, 1H, J = 9.0 Hz, H20), 4.82 (dd, 1H, J = 10.4, 3.3, Hz, H30), 4.42
(d, 1H, J = 7.5 Hz, H10), 4.37 (d, 1H, J = 8.0 Hz, H1), 4.08 (m, 2H,
H60/H60), 4.04 (m, 1H, H50), 3.81 (m, 1H, H3), 3.78–3.72 (m, 3H,
H4/H2/H5), 3.64 (m, 1H, CH2-octyl), 3.38 (m, 2H, H6/H6), 3.14
(m, 1H, CH2-octyl), 2.17 (s, 3H, OAc), 2.13–1.91 (br s, 15H, OAc/
NHAc), 1.52 (br s, 3H, CH2-octyl), 1.25 (br s, 9H, CH2-octyl), 0.87
(t, 3H, CH3-octyl). 13C NMR (CDCl3) d 170.67, 170.03, 169.21,
133.48, 132.19, 130.24, 129.19, 128.60, 127.95, 126.67, 100.44,
100.16, 74.77, 73.66, 72.88, 71.19, 70.19, 69.69, 68.45, 67.25,
66.05, 60.87, 53.73, 52.58, 29.39, 25.90, 23.75, 22.73, 21.36,
21.14, 21.02, 20.32, 20.10, 19.99. MS (ES, Na+): m/z (relative inten-
sity) 868.3 (100). HRMS (M+Na+) calcd for C38H55NO17SeNa,
868.2635; found 868.2671.
4.18. Octyl 2-deoxy-2-phthalamido-4-O-(2,3,4,6-tetra-O-acetyl-
b-D
-galactopyranosyl)-3-O-acetyl-b-
D-glucopyranoside 33
To a stirred 0 °C solution of 32 (220 mg, 0.24 mmol) in 8.0 mL of
CH3CN and pyridine (1.0 mL) in a Nalgene bottle was added 1.0 mL
HFꢀpyridine. The reaction mixture was allowed to warm to room
temperature. After 2.5 h, the reaction mixture was diluted to
25 mL of CH2Cl2 and washed with 25 mL of saturated CuSO4,
H2O, saturated NaHCO3, and saturated NaCl solutions. The organic
extract was dried with Na2SO4, filtered, and the filtrated concen-
trated. The crude oil was purified using a short silica gel plug
(EtOAc) to afford 33 (180 mg, 92%) as a colorless oil: 1H NMR
(CDCl3) d 7.80 (br s, 2H, Pht), 7.76 (s, 2H, Pht), 5.47 (m, 1H, H30),
5.36 (d, J = 8.3 Hz, H1), 5.32 (d, 1H, H40), 5.28 (m, 2H, H3/H20),
5.11 (m, 1H, H3), 4.99 (m, 1H, H4), 4.66 (d, 1H, J = 7.7 Hz, H10),
4.16 (dd, 1H, J = 10.0 Hz, H2), 4.10–3.98 (m, 3H, H6/H6/CH2-octyl),
3.94–3.88 (m, 2H, H60/H60), 3.78 (m, 2H, H5/H50), 3.58 (m, 1H, CH2-
octyl), 3.40 (d, 1H, J = 8.0 Hz, –OH), 2.12–1.89 (s, 18H, NHAc, OAc),
1.67 (br s, 2H, CH2-octyl), 1.24–1.12 (m, 10H, CH2-octyl), 0.80 (t,
3H, CH3-octyl). 13C NMR (CDCl3) d 170.35, 170.21, 170.11, 169.87,
169.21, 167.97, 134.27, 132.65, 123.56, 100.97, 98.11, 75.61,
74.68, 71.36, 70.97, 70.48, 70.26, 69.21, 66.69, 60.76, 60.50,
55.03, 53.40, 31.59, 29.22, 29.06, 25.75, 22.54, 20.69, 20.64,
20.60, 20.58, 20.52, 14.01, 13.60. MS (ES, Na+): m/z (relative inten-
sity) 816.3 (100). HRMS (M+Na+) calcd for C38H50NO17Na,
816.3055; found 816.3079.
4.21. Octyl 2,6-dideoxy-2-acetamido-3-O-(2,3,4,6-tetra-O-
acetyl-b-
D-galactopyranosyl)-4-O-acetyl-5,6-dehydro-b-D-
4.19. Octyl 2,6-dideoxy-2-phthalamido 4-O-(2,3,4,6-tetra-O-
glucopyranoside 37
acetyl-b-D-galactopyranosyl)-3-O-acetyl-6-phenylseleno-b-D-
glucopyranoside 34
To a stirred solution of 30 (90 mg, 0.10 mmol) in 1.75 mL of
MeOH/H2O (6:1) were added NaHCO3 (10 mg, 0.12 mmol) and
NaIO4 (34 mg, 0.16 mmol). A white precipitate formed during the
course of the reaction. After 2 h, the reaction mixture was filtered
and the filtrate concentrated to leave the H2O. The filtrate had 5 mL
of H2O added and the aqueous extract was washed three times
with 5 mL of EtOAc. The combined organic extracts were washed
with 10 mL of saturated NaCl solution and dried with Na2SO4, fil-
tered, and the filtrate concentrated. The crude product (55 mg), a
mixture of selenoxides and olefin, was taken on without purifica-
tion. Under an argon atmosphere, the crude product was dissolved
To a stirred ꢁ20 °C solution of 33 (30 mg, 37
lmol) in 0.10 mL
of CH2Cl2 were added N-PSP (22 mg, 75 lmol) and PBu3 (18 lL,
75 lmol). The reaction mixture was warmed to 0 °C and the tem-
perature maintained at 0 °C. After 41 h, the reaction mixture was
diluted to 5 mL of CH2Cl2 and washed with 5 mL of H2O and satu-
rated NaCl solution. The organic extract was dried with Na2SO4, fil-
tered, and the filtrated concentrated. The crude oil was purified
using preparative thin layer chromatography (hexanes/EtOAc,
2:1) to afford 34 (14 mg, 40%) as a colorless oil: 1H NMR (CDCl3)

T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
793
in 5.0 mL DHP and heated at reflux temperature. After 50 min,
NMR analysis indicated a partial loss of O-acetyl groups. Therefore,
Ac2O (2 mL) and pyridine (2 mL) were added to re-acetylate the
free hydroxyl groups. Standard workup resulted in a crude product
that was purified using flash column chromatography (hexanes/
EtOAc, 1:1) to afford 37 (46 mg, 63%) as a white oil/solid: 1H
NMR (CDCl3) d 6.03 (d, 1H, J = 9.8 Hz, N-H), 5.88 (d, 1H, J = 8.1 Hz,
H1), 5.64 (m, 1H, H3), 5.37 (d, 1H, J = 3.2 Hz, H40), 5.14 (dd, 1H,
J = 10.3, 8.0 Hz, H20), 5.01 (dd, 1H, J = 10.4, 3.4 Hz, H30), 4.92 (dd,
2H, J = 3.1 Hz, H6/H6), 4.81 (d, 1H, J = 7.9 Hz, H10), 4.65 (m, 1H,
H4), 4.43–4.40 (m, 3H, J = 6.5 Hz, H50/H60/H60), 3.92 (m, 1H, H2),
3.78 (m, 1H, CH2-octyl), 3.45 (m, 1H, CH2-octyl), 2.10 (s, 3H,
OAc), 2.07–1.98 (br s, 15H, OAc/NHAc), 1.55 (br s, 3H, CH2-octyl),
1.19 (br s, 9H, CH2-octyl), 0.85 (t, 3H, CH3-octyl). 13C NMR (CDCl3)
d 171.12, 170.37, 170.27, 170.06, 169.54, 169.09, 168.88, 150.88,
145.59, 121.66, 99.74, 95.28, 77.91, 70.98, 70.59, 69.84, 68.96,
68.62, 66.95, 66.42, 60.96, 60.34, 52.72, 31.77, 29.22, 29.13,
25.87, 23.97, 23.30, 22.58, 21.00, 20.93, 20.72, 20.64, 20.60,
20.53, 14.14, 14.05. MS (ES, Na+): m/z (relative intensity) 710.3
(100). HRMS (M+Na+) calcd for C32H49NO15Na, 710.3000; found
710.2993.
H20), 5.31 (d, 1H, H1), 5.02 (m, 1H, H3), 4.44 (d, 1H, H10), 4.30
(m, 1H, H4), 4.18 (m, 1H, H50), 3.75 (m, 2H, Hz, H60/H60), 3.43 (m,
1H, H2), 3.43 (m, 1H, CH2-octyl), 3.13 (m, 1H, CH2-octyl), 2.78 (d,
1H, H6), 2.53 (d, 1H, H6), 2.12–1.69 (br s, 18H, OAc/NHAc), 1.62
(br s, 3H, CH2-octyl), 1.25 (br s, 9H, CH2-octyl), 0.90 (t, 3H, CH3-oc-
tyl). 13C NMR (C6D6) d 170.61, 170.44, 170.23, 78.43, 71.66, 69.93,
69.58, 68.09, 67.64, 63.07, 61.58, 33.56, 32.55, 30.44, 30.17, 30.05,
26.65, 26.54, 23.39, 21.20, 21.12, 21.02, 20.64, 20.41, 20.28, 20.21,
14.67, ꢁ1.71. MS (ESI) m/z (relative intensity): 726.3 ([M+Na]+),
100).
4.24. Octyl 2-deoxy-2-acetamido-4-O-(2,3,4,6-tetra-O-acetyl-b-
D-galactopyranosyl)-3-O-acetyl-5,6-epoxy-b-D-glucopyranoside
40
To a stirred 0 °C solution of 39 (11 mg, 16 lmol) in 2.0 mL of
CH2Cl2 was added DMDO (approximately 8 mL). After 1 h, the reac-
tion mixture was dried with Na2SO4, filtered, and the filtrate was
concentrated to afford 40 (11 mg, 92%) as a colorless oil: 1H NMR
(C6D6) d 6.37 (d, 1H, J = 9.7 Hz, N-H), 5.60 (m, 1H, H3), 5.49 (d,
1H, J = 3.0 Hz, H40), 5.27 (d, 1H, J = 8.7 Hz, H1), 5.25 (dd, 1H,
J = 10.6, 3.4 Hz, H30), 4.82 (dd, 1H, J = 2.8 Hz, H20), 4.79 (m, 1H,
H50), 4.74 (d, 1H, J = 7.9 Hz, H10), 4.12 (m, 2H, Hz, H60/H60), 3.85
(m, 1H, H4), 3.54 (m, 1H, CH2-octyl), 3.36 (m, 1H, H2), 3.18 (m,
1H, CH2-octyl), 2.82 (d, 1H, J = 4.7 Hz, H6), 2.43 (d, 1H, J = 4.7 Hz,
H6), 2.01–1.61 (br s, 18H, OAc/NHAc), 1.53 (br s, 3H, CH2-octyl),
1.28 (br s, 9H, CH2-octyl), 0.91 (t, 3H, CH3-octyl). 13C NMR (C6D6)
d 171.06, 170.41, 170.00, 169.56, 169.22, 103.69, 101.62, 79.06,
74.08, 71.96, 71.49, 71.08, 69.91, 69.73, 67.49, 61.45, 51.45,
49.24, 32.51, 30.11, 30.06, 30.01, 26.64, 23.39, 23.20, 21.04,
20.76, 20.56, 20.48, 20.23, 14.67, ꢁ1.73. MS (ESI) m/z (relative
intensity): 726.3 ([M+Na+] 100).
4.22. Octyl 2,6-dideoxy-2-acetamido-4-O-(2,3,4,6-tetra-O-
acetyl-b-D-galactopyranosyl)-3-O-acetyl-5,6-dehydro-b-D-
glucopyranoside 39
To a stirred solution of 35 (40 mg, 50
H2O (6:1) were added NaHCO3 (5 mg, 58
l
l
mol) in 7.0 mL of MeOH/
mol) and NaIO4 (17 mg,
mol). A white precipitate formed during the course of the reac-
80
l
tion. After 2.5 h, the reaction mixture was filtered and the filtrate
concentrated to leave the H2O. The filtrate had 5.0 mL of H2O added
and the aqueous extract was washed three times with 5.0 mL of
EtOAc. The combined organic extracts were washed with 10 mL
of saturated NaCl solution and dried with Na2SO4, filtered, and
the filtrate concentrated. The resulting mixture of olefin and selen-
oxides (31 mg) was taken on without any purification, dissolved in
3.0 mL of DHP, and heated to reflux at 100 °C. After 45 min, the
reaction mixture was cooled and diluted with 5.0 mL of CH2Cl2
and washed with 5.0 mL of H2O, saturated NaHCO3, and saturated
NaCl solutions. The organic extract was dried with Na2SO4, filtered
and, the filtrate concentrated. The crude product was purified
using flash column chromatography (hexanes/EtOAc, 1:1) to afford
39 (12 mg, 40%, two steps) as a colorless oil: 1H NMR (CDCl3) d 6.55
(d, 1H, J = 9.6 Hz, N-H), 5.37 (d, 1H, J = 3.0 Hz, H40), 5.29 (d, 1H, H1),
5.20 (dd, 1H, J = 8.0 Hz, H20), 5.06 (dd, 1H, J = 10.5, 3.4 Hz, H30), 4.92
(s, 1H, H60), 4.88 (s, 1H, H60), 4.68 (s, 1H, H6), 4.63 (s, 1H, H6), 4.54
(d, 1H, J = 7.9 Hz, H10), 4.30 (m, 1H, H4), 4.21 (dd, 1H, J = 4.9 Hz,
H3), 4.13 (m, 1H, H50), 3.89 (m, 1H, H2), 3.75 (m, 1H, CH2-octyl),
3.36 (m, 1H, CH2-octyl), 2.17 (s, 3H, OAc), 2.09–1.96 (br s, 15H,
OAc/NHAc), 1.53 (br s, 3H, CH2-octyl), 1.35 (br s, 9H, CH2-octyl),
0.86 (t, 3H, CH3-octyl). 13C NMR (CDCl3) d 171.13, 170.17, 170.09,
169.95, 169.33, 149.46, 103.87, 101.85, 97.76, 73.29, 70.86, 70.28,
69.44, 68.59, 68.05, 66.57, 60.88, 46.82, 31.82, 29.42, 29.32,
29.29, 26.10, 22.88, 22.63, 21.04, 20.85, 20.64, 14.18. MS (ES,
Na+): m/z (relative intensity) 710.3 (100). HRMS (M+Na+) calcd
for C32H49NO15Na, 710.3000; found 710.3006.
4.25. Octyl 2-deoxy-2-acetamido-3-O-b-D-galactopyranosyl-5-
fluoro-b- -glucopyranoside 1
D
To a ꢁ78 °C stirred solution of 38 (18 mg, 25
lmol) in 1.0 mL of
CH2Cl2 was added HFꢀpyridine (10 L). After 1.75 h, the reaction
l
mixture was quenched with 0.01 mL of NEt3 and the resulting light
yellow solution was diluted to 5 mL of CH2Cl2 and washed with
5 mL of H2O and saturated NaCl solution. The organic extract was
dried with Na2SO4, filtered, and the filtrate concentrated to afford
the (5-F) glycoside (30 mg) which was taken on without any puri-
fication. NH3 was bubbled through a stirred methanolic solution
(2 mL) of the resulting (5-F) glycoside at 0 °C. After 10 min, the
flask was sealed and warmed to room temperature. After 1.5 h,
the solvent and NH3 were removed with a stream of nitrogen.
The resulting product was purified using preparative thin layer
chromatography (EtOAc/MeOH, 5:1) to afford 1 (3 mg, 23% two
steps) as a white powder: 1H NMR (D2O) d 3.92 (m, 1H, H1),
3.76–3.58 (d, 4H, H10/H20/H3/H30), 3.42–3.28 (m, 6H, H40/H4/H2/
H50/H60/H60), 3.41–3.34 (m, 2H, –CH2-octyl), 2.19–2.06 (m, 2H,
H6/H6), 1.86 (s, 3H, NHAc), 1.48 (br s, 3H, CH2-octyl), 1.29 (br s,
9H, CH2-octyl), 0.91 (t, 3H, CH3-octyl). 13C NMR (D2O) d 174.73,
105.84, 90.69, 77.37, 72.32, 69.80, 61.53, 60.38, 55.56, 46.61,
40.64, 35.13, 29.38, 25.71, 21.58, 10.79. 19F NMR (D2O) d 89.6.
MS (ES, Na+): m/z (relative intensity) calcd for; found 536.2
(100). HRMS (M+Na+) calcd for C22H40NO11FNa, 536.2483; found
536.2457.
4.23. Octyl 2-deoxy-2-acetamido-3-O-(2,3,4,6-tetra-O-acetyl-b-
D
-galactopyranosyl)-4-O-acetyl-5,6-epoxy-b-D-glucopyranoside
38
4.26. Octyl 2-deoxy-2-acetamido-4-O-b-D-galactopyranosyl-5-
To a stirred 0 °C solution of 37 (45 mg, 65
lmol) in 2.0 mL of
fluoro-b- -glucopyranoside 2
D
CH2Cl2 was added DMDO (approximately 8 mL). After 13 h, the
reaction mixture was dried with Na2SO4, filtered, and the filtrate
was concentrated to afford 38 (44 mg, 95%) as a colorless oil: 1H
NMR (C6D6) d 5.78 (m, 1H, H30), 5.56 (d, 1H, H40), 5.50 (dd, 1H,
To a ꢁ78 °C stirred solution of 7d (11 mg, 15
lmol) in 1.0 mL of
CH2Cl2 was added HFꢀpyridine (0.01 mL). After 2 h, the reaction
mixture was quenched with 0.01 mL of NEt3 and the resulting light

794
T. L. Hagena, J. K. Coward / Tetrahedron: Asymmetry 20 (2009) 781–794
yellow solution was washed with 5 mL of H2O and saturated NaCl
solution. The organic extract was dried with Na2SO4, filtered, and
the filtrate concentrated to afford the (5-F) glycoside (20 mg) and
taken on without any purification. NH3 was bubbled through a stir-
red methanolic solution (2 mL) of the resulting (5-F) glycoside at
0 °C. After 10 min, the flask was sealed and warmed to room tem-
perature. After 1.5 h, the solvent and NH3 were removed with a
stream of nitrogen. The resulting product was purified using flash
column chromatography (EtOAc/MeOH, 5:1) to afford 2 (3 mg, 37%
two steps) as a white powder: 1H NMR (D2O) d 4.12 (d, 1H,
J = 7.1 Hz, H1), 3.91 (m, 1H, H10), 3.73–3.57 (m, 3H, H20/H3/H30),
3.44–2.93 (m, 8H, H40/H4/H2/H50/H60/H60/-CH2-octyl), 2.00–1.95
(m, 2H, H6/H6), 2.00 (s, 3H, NHAc), 1.47 (br s, 3H, CH2-octyl),
1.32 (br s, 9H, CH2-octyl), 0.84 (t, 3H, CH3-octyl). 13C NMR (D2O)
d 173.64, 103.26, 90.68, 75.41, 72.49, 71.01, 69.31, 68.61, 61.94,
61.06, 56.48, 42.26, 31.11, 28.49, 25.05, 22.03, 21.31, 13.42,
10.55. 19F NMR (D2O) d 69.5. MS (ES, Na+): m/z (relative intensity)
calcd for; found 536.2 (100). HRMS (M+Na+) calcd for C22H40NO11F-
Na, 536.2483; found 536.2485.
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T.H. is the recipient of a Merit Fellowship from the Horace H.
Rackham School of Graduate Studies, University of Michigan. This
research was supported, in part, by the College of Pharmacy and
the Department of Chemistry, University of Michigan. We grate-
fully acknowledge the contributions of Esther Joo to this research.
We also thank Julia Silveira, a participant in the National Science
Foundation program, Research Experience for Undergraduates
(REU) for her contributions to this research.