Non-glycosidically linked pseudodisaccharides: Thioethers, sulfoxides, sulfones, ethers, selenoethers, and their binding to lectins

Article abstract of DOI:10.1002/ejoc.200901481

Hydrolytically stable non-glycosidically linked tail-to-tail pseudodisaccharides are linked by a single bridging atom remote from the anomeric centre of the constituent monosaccharides. Some such pseudodisaccharides with sulfur or oxy gen bridges were found to act as disaccharide mimetics in their binding to the Banana Lectin and to Concanavalin A. A versatile synthetic route to a small library of such compounds is described.

Full text of DOI:10.1002/ejoc.200901481

FULL PAPER
DOI: 10.1002/ejoc.200901481
Non-Glycosidically Linked Pseudodisaccharides: Thioethers, Sulfoxides,
Sulfones, Ethers, Selenoethers, and Their Binding to Lectins
Ian Cumpstey,*[a] Clinton Ramstadius,[a] Tashfeen Akhtar,[a] Irwin J. Goldstein,[b] and
Harry C. Winter[b]
Keywords: Carbohydrates / Pseudodisaccharides / Glycosides / Glycomimetics / Lectins / Sulfur
Hydrolytically stable non-glycosidically linked tail-to-tail
pseudodisaccharides are linked by a single bridging atom re-
mote from the anomeric centre of the constituent monosac-
gen bridges were found to act as disaccharide mimetics in
their binding to the Banana Lectin and to Concanavalin A. A
versatile synthetic route to a small library of such compounds
charides. Some such pseudodisaccharides with sulfur or oxy- is described.
Nevertheless, examples of such tail-to-tail-linked struc-
Introduction
tures have attracted some synthetic interest over the years.
Reports of the synthesis of O-,[2–5] N-,[6,7] or S-linked[5,8,9,10]
compounds have appeared sporadically. It has been pro-
posed that such pseudodisaccharides may act as disaccha-
ride mimics, but to date, no investigation of the interaction
of such molecules with carbohydrate-binding proteins ap-
pears to have been undertaken.
The key to any disaccharide mimicry of tail-to-tail
pseudodisaccharides would be that one monosaccharide
can mimic another; the two monosaccharides sharing a
ring-plane and certain structural motifs such as eq-eq-ax
orientation of hydroxy groups 2,3,4 in -fucose and 4,3,2 in
-mannose. Related mimicry has been observed before: for
example, some fucose-binding lectins (selectins) bind C-
mannosides;[11a] Nilsson has shown that galactose-binding
lectins (galectins) can bind β-mannose derivatives;[11b] Fleet
has shown that some glycosidases are inhibited by the
enantiomers of substrate mimics.[12] Also, Jenkins showed
that 3-amino-altrosides inhibit β-glucosidases and proposed
that the altrose residue binds with C-3 in the position corre-
sponding to glucose C-1.[13]
The manner in which monosaccharides may be linked by
formal condensation may be classified as follows: head-to-
head disaccharides of the trehalose or sucrose type, where
the anomeric centres of the two monosaccharides are in-
volved in the linkage; head-to-tail disaccharides, where the
anomeric centre of one monosaccharide is linked to a non-
anomeric centre of a second monosaccharide by means of
an acetal; tail-to-tail linked pseudodisaccharides where the
anomeric centre of neither of the constituent monosac-
charides is involved in the linkage (Figure 1). The first two
of these groups are very common in nature; the third is
almost unknown. In fact, only one example of such a motif
as a substructure is known;[1] a possible second example,
the All(6–6)All ether-linked structure proposed for Coyolosa,
has been discredited.[2]
Lectin inhibitors have possible applications as biological
tools and potential therapeutics, for example, in anti-ad-
hesion therapy (bacterial lectins),[14a] and against inflam-
mation (selectins)[14b] or cancer (galectins).[14c] A disaccha-
ride mimic would be expected to bind to a lectin with a
higher affinity and specificity than a monosaccharide
mimic, but having an inter-glycose linkage that is stable to
hydrolysis is one prerequisite for such ligands, if they are to
be put into an environment containing either strong acid or
glycosidases. We planned to synthesise a small library of S-
linked tail-to-tail pseudodisaccharides and to test the bind-
ing of these compounds (along with O- and Se-linked ana-
logues, as well as oxidised analogues) to the lectins, Banana
lectin (BanLec) and Concanavalin A (ConA). In this way,
Figure 1. A head-to-tail disaccharide and a tail-to-tail pseudodisac-
charide, a potential glycomimetic.
[a] Department of Organic Chemistry, Stockholm University,
Arrhenius Laboratory,
10691 Stockholm, Sweden
Fax: +46-8-15-4908
E-mail: ian.cumpstey@sjc.oxon.org
[b] Department of Biological Chemistry, University of Michigan
Medical School,
Ann Arbor, MI 48109-5606, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901481.
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I. Cumpstey et al.
FULL PAPER
we planned to test the theory that such hydrolytically stable
tail-to-tail pseudodisaccharides can act as glycomimetics in
their binding to carbohydrate-binding proteins. We report
our results from the synthesis and binding studies in this
paper.
Results and Discussion
Synthesis
Our synthesis of thioether pseudodisaccharides is based
on SN2 displacement of carbohydrate sulfonates by carbo-
hydrate thiol nucleophiles. This approach gives complete
stereocontrol in the coupling reactions with inversion of
configuration at the sulfonate-bearing carbon. The carbo-
hydrate thiols are synthesised from sulfonates by SN2 sub-
stitution with thioacetate, followed by deacetylation to re-
veal the thiol. By this stepwise approach, we may use the
same sulfonate twice to access C2-symmetric thioether
pseudodisaccharides, or use two different sulfonates to ob-
tain unsymmetrically substituted thioethers. Related ap-
proaches have been used for the synthesis of thiooligosacch-
arides; carbohydrate sulfonates have been displaced either
by thioacetate to introduce sulfur, or by an anomeric thiol
for thiodisaccharide formation.[15]
Scheme 1. Sulfonation and thioacetate formation. (i) MsCl, Et3N,
CH2Cl2, 0 °C;[27] (ii) Tf2O, py, CH2Cl2, 0 °C, r.t.; (iii) KSAc, DMF;
13, 73%; 14, 84%; 15, 84%; 16, 80%; 17, 88%; 18, 58% + elimi-
nation 19% (all yields over two steps).
We converted some partially protected carbohydrates 1–
6[16–21] to their triflates 8–12[22–26] or mesylate (7). In many
cases, heating the sulfonates with potassium thioacetate in
DMF gave a clean and high-yielding conversion to the
thioacetates 13–17 with inversion of configuration
(Scheme 1). This gave us access to gluco or manno config-
ured monosaccharides equipped for substitution at the 2-
(15 and 17), 3- (14), 4- (18), and 6- (13) positions. For the
2-substituted manno derivatives, we prepared both α- and
β-anomers 17 and 15, respectively, of the methyl glycoside.
An allose derivative 16 equipped for 3-substitution was also
prepared. For the formation of gluco thioacetate 18 from
Figure 2. Some triflates that failed to give useful yields of thioacet-
ates.
galacto triflate 12, involving an axǞeq conversion, the yield sulfides (Figure 5) and unreacted thiol or triflate could
was lower and an elimination product was also formed, pre- sometimes also be isolated. The formation of the thioethers
sumably due to the trans-diaxial relationship between pro- always proceeded with inversion of configuration. It is also
ton and leaving group in the ground-state conformation of noteworthy that essentially no difference in the efficiency of
the triflate starting material 12. In some further cases, de- the reaction between the formation of sec-sec, primary-sec
composition of the triflate was seen under the substitution and primary-primary linked thioethers was seen. This is in
reaction conditions and minimal product could be isolated marked contrast to the behaviour of reactions for the for-
(Figure 2). The effect of the structure and protecting group mation of similar N-linked structures, where the more strin-
pattern of carbohydrate triflates on the success of nucleo- gent steric and electronic demands of a secondary centre
philic displacement reactions has been noted before.[28,29]
over a primary centre (in a carbohydrate) appear to strongly
Having established routes to suitable triflates and disfavour the formation of pseudodisaccharides with sec-
thioacetates, we examined coupling (thioetherification) re- ondary amine linkages involving even just one secondary
actions to form thioether-linked pseudodisaccharides. centre.[7]
Cleavage of the thioacetates 13–17 (and 19, synthesised ear-
We also investigated a streamlined synthesis of C2-symmet-
lier,[30] Figure 3) to give thiols was achieved by treatment ric thioether pseudodisaccharides using a divalent sulfur
with sodium methoxide in methanol. After aqueous work- anion as nucleophile to dimerise a sulfonate electrophile,
up, the crude thiols were heated with the required sulfonates based on previous work for (1–1)-linked thiodisaccharide syn-
7–10 and sodium hydride at 50 °C in DMF, and major thesis.[31,32] Treatment of carbohydrate triflates with dried so-
pseudodisaccharide products 20–32 were rapidly formed dium sulfide in acetonitrile with molecular sieves gave the
(Table 1, Figure 4). Small amounts of the corresponding di- dimers in generally very good yield for those triflates that give
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Non-Glycosidically Linked Pseudodisaccharides
Figure 3. Thioacetate 19.
Table 1. Thioetherification reactions for S-pseudodisaccharide syn-
thesis.
Entry Thioacetate
[equiv.]
Sulfonate
[equiv.]
Conditions[a] Product/yield[b]
1
2
3
4
5
6
7
8
13 (1)
13 (1.5)
15 (1)
13 (1)
14 (1)
14 (1)
15 (1.5)
15 (2)
7 (1.5)
8 (1)[c]
7 (1.5)
9 (1.5)
8 (1.5)
9 (1.6)
8 (1)[c]
9 (1)
A
A
A
A
A
A
A
A
B
20/54%; 33/15%
21/81%
22/47%
22/42%
23/68%; 34/15%
24/75%
24/70%
25/73%
26/85%
Figure 5. Disulfides.
Table 2. Approach to C2-symmetric S-pseudodisaccharides.
9
13-SH (1.5)[d] 10 (1)
10
11
12
16 (1.5)
17 (1)
19 (1)
9 (1)
A
A
A
27/60%
28/94%
29/81%
8 (1.5)[c]
8 (1.6)[c]
Entry
Sulfonate
t[a]
Product/yield[b]
[a] A: Thioacetate, MeONa, MeOH then sulfonate, NaH, DMF,
50 °C; B: Thiol, sulfonate, NaH, DMF, r.t. [b] Isolated yields. [c]
Purified triflate was used. [d] The purified thiol derived from 13
was used.
1
2
3
4
5
8
17 h
3 h
3 h
3 d
1 h
23/86%
25/86%
30/90%
31/64%[c]
32/46%[d]
9
10
11
12
a clean SN2 reaction with thioacetate (i.e. 8–11), and in a
somewhat lower yield for galacto triflate 12 (Table 2). The
reaction with triflate 11 seemed rather sluggish.
[a] Conditions: Na2S (2 equiv.) MeCN, sieves 4 Å, 50 °C. [b] Iso-
lated yields. [c] Purified triflate was used. [d] Disulfide 35 (6%) and
elimination products (18%) were also isolated.
Removal of the benzyl ethers from thioether pseudodi-
saccharides 20–31 was effected by treatment with sodium in ated pseudodisaccharides 36–45 (Figure 6) were sub-
liquid ammonia; acetals were removed with acid (Table 3). sequently deprotected with sodium methoxide to give the
Following the reductive deprotection, the pseudodisaccha- free thioether pseudodisaccharides 46–57 (Figure 7). The
rides were peracetylated to facilitate purification. Peracetyl- benzoate esters were similarly removed from 32 to give de-
Figure 4. Protected thioethers.
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I. Cumpstey et al.
FULL PAPER
Table 3. Deprotection of thioether pseudodisaccharides.
Entry
Starting material
Conditions[a]
Peracetate/yield[b]
Deprotected/yield[c]
1
2
3
4
5
6
7
8
20
21
22
23
24
25
26
27
28
29
30
31
32
A (–40 °C, 10 min)
B
A (–40 °C, 10 min)
C
36/73%
–
37/64%
38/92%
–
39/61%
40/58%
41/76%
42/40%
43/68%
44/57%
45/80%
–
46/72%
47/19%[d]
48/92%
49/78%
50/38%[d]
51/97%
52/92%
53/77%
54/83%
55/75%
56/94%
57/76%
58/78%[d]
B
A (–40 °C, 10 min)
A (–78 °C, 1 h)
A (–78 °C, 30 min)
D
9
10
11
12
13
D
A (–40 °C, 5 min)
A (–78 °C, 7 min)
E
[a] A: Na, NH3(l), (T), MeOH, (t); then Ac2O, py; B: Na, NH3(l), –78 °C; then TFA (90%); C: TFA (90%); then Ac2O, NaOAc; D: Na,
NH3(l), –78 °C, MeOH, 2 min; then TFA (90%); then Ac2O, py; E: NaOMe, MeOH, 50 °C. [b] Isolated yields. [c] Isolated yields, from
peracetates unless otherwise stated. [d] Yield from respective protected starting materials (peracetates were not formed).
Figure 6. Thioether peracetates.
protected 58. The deprotection procedures worked (derived from e.g. 25, not shown) by hydrogenation over
smoothly, with the exception of those compounds bearing palladium failed. The thioether starting materials used in
both benzylic and isopropylidene protection (i.e. 21, 24, 28, these oxidations were C2-symmetric; the sulfoxides are C1-
29). Some decomposition was seen during the first step of symmetric, i.e. the C2 axis has been destroyed, but only one
deprotection of these compounds (Birch reduction condi- diastereomer is possible; the sulfone is once again C2-sym-
1
tions), which could be minimised by running the reaction metric. This is evident from the H NMR spectra of the
for very short reaction times, but the yields were not usually compounds: the C2-symmetric thioether and sulfone have
as high as for the fully benzylated or benzyl/benzylidene- only half as many signals as the C1-symmetric sulfoxide.
protected thioether pseudodisaccharides.
Examination of the 3J coupling constants in the 1H
To investigate the effect of oxidising the bridging sulfur NMR spectra across the series thioether–sulfoxide–sulfone
to the sulfoxide and sulfone oxidation levels on lectin bind- strongly suggests that oxidation of sulfur induces significant
ing, the C2-symmetric pseudodisaccharides 51, 56 and 57 conformational change in the allopyranose rings away from
4
were oxidised. Treatment with mCPBA gave sulfoxides 59, the C1 chair conformation. For example, the J1,2 coupling
61 and 63 at 0 °C and short reaction times, or sulfones 60, constant changes in the allo series: 56, 8.1 Hz; 61, 4.9 Hz
4
62 and 64 at room temp. after longer reaction times in good and 5.6 Hz; 62, 2.7 Hz. In the sulfone (only), a J2,4 cou-
yields (Scheme 2).[29] Oxidation was best carried out on the pling (1.4 Hz) is also seen. In the α (57, 63, 64) and β (51,
unprotected thioether pseudodisaccharides, as attempted 59, 60) manno series, no significant changes in the coupling
3
removal of the benzyl ether and benzylidene protection constants are seen on oxidation. In general, the JH,H cou-
from protected sulfoxide or sulfone pseudodisaccharides pling constants of the thioether pseudodisaccharides are as
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Non-Glycosidically Linked Pseudodisaccharides
Figure 7. Unprotected thioether pseudodisaccharides.
anosides also gave some decomposition and low yields
(Scheme 3). The α,α-dimer 65 could be separated from the
α,β- and β,β-compounds 66a,b (which could not be sepa-
rated) after acetylation. Deacetylation gave the deprotected
α,α-compound 67 and a mixture of the deprotected α,β and
β,β compounds 68a,b (10:1).
Scheme 2. Oxidation. (i) mCPBA, CH2Cl2, MeOH, 0 °C; 59, 99%;
61, 89%; 63, 72%; (ii) mCPBA, CH2Cl2, MeOH, 0 °CǞr.t.; 60,
77%; 62, 99%; 64, 63%.
Scheme 3. Fischer glycosylation of thioether pseudodisaccharides
and deprotection. (i) MeOH, AcCl, 65 °C; then Ac2O, py; 65, 8%;
66a,b, 10%; (ii) NaOMe, MeOH; 67, 92%; 68a,b, 99%.
expected for the 4C1 conformation of the respective contrib-
The synthesis of ether-linked pseudodisaccharides 69–73
uting monosaccharides, indicating that formation of a thio- has been described previously.[4] Two further examples 74
ether pseudodisaccharide does not appear to have a big ef- and 75 were synthesised in the same manner by alkylation
fect on the ring conformation.
of the alcohols 4 and 84 with the allo triflate 8 (Scheme 4).
Locking the anomeric position of the (S3–3)-linked glu- These compounds 69–75 were deprotected by catalytic hy-
cose dimer 49 would give information on which anomer drogenolysis (to remove benzyl ethers) or acid treatment (to
bound more strongly to the lectins. Thus we heated 49 with remove acetals) as necessary, followed by peracetylation to
HCl in methanol to form two glycosidic bonds.[33] The ini- allow purification. Peracetylated pseudodisaccharides were
tially formed mixture contained furanosides as expected, deprotected with sodium methoxide to give the free ether-
but leaving the reaction longer to equilibrate to the pyr- linked pseudodisaccharides 76–82 (Scheme 4).
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I. Cumpstey et al.
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Lectin Binding Studies
Banana lectin (BanLec) from Musa acuminata is a tetra-
mer composed of 15 kDa subunits[34] with a somewhat un-
usual carbohydrate binding specificity. It recognises 2- or
3-substituted glucose or mannose residues,[35,36] including
internal (α1Ǟ3)-linked glucose, but it will not tolerate sub-
stitution (or deoxygenation) at the 4- or 6-positions. It will,
though, bind the terminal glucose residues in (α1Ǟ6)-
branched glucans and mannans.[37] BanLec has been crys-
tallised and its X-ray structure determined with two disac-
charide ligands, Glc(β1Ǟ3)Glc and Xyl(β1Ǟ3)Man-
αMe,[38] revealing two similar sugar-binding sites.
The pseudodisaccharides [thioether-linked 46–58, 67, 68;
sulfoxide-linked 59, 61, 63; sulfone-linked 60, 62, 64; ether-
linked 76–82; and selenoether-linked 83 (Figure 8)[39]] were
assayed for binding to BanLec using isothermal titration
microcalorimetry (ITC). The results are summarised in
Table 4. Some mannose and glucose derivatives (mono- and
disaccharides) were included as standards (Table 4, Entries
1–6). The pseudodisaccharides had a range of binding affin-
ities, with many failing to bind at all. The compounds that
bound most strongly to BanLec are 2- or 3- substituted
methyl α-mannosides: MeαMan(3–3)Glc (ether 80 and
thioether 55), MeαMan(2–3)Glc (ether 78 and thioether
54), MeαMan(2–2)ManαMe (thioether 57, sulfoxide 63 and
sulfone 64). Changing between a bridging sulfur and oxy-
gen appears to have a relatively small effect on the affinity,
which may be surprising, given the differences in C–O vs.
C–S bond lengths and C–O–C vs. C–S–C bond-angles, and
in hydrogen-bond acceptor capability between oxygen and
sulfur. Wherever 2-substituted α-Man and β-Man deriva-
tives are compared (50 vs. 54; 51 vs. 57), the α derivatives
tend to bind more strongly, which is not surprising, given
BanLec’s preference for α-configured glucose and mannose
derivatives over their β anomers. We can envisage two pos-
sible binding orientations for the pseudodisaccharides. 3-
Substituted glucose and both 2- and 3-substituted mannose
bind to BanLec, and it is difficult to speculate regarding
the binding mode based on our data. Only one of these
compounds, the MeαMan(3–3)Glc ether-linked derivative
80 binds more strongly than methyl α-mannoside.
Figure 8. Selenoether 83.
For the Glc(3–3)Glc compounds, the thioether 49 binds
most strongly, the ether 76 slightly less so, and the seleno-
ether 83 does not bind at all. The glucose residues in the
unprotected pseudodisaccharides exist as mixtures of the
pyranoses, as judged by their 1H NMR spectra, α/β approx-
imately 1:1. The ether-linked α-monomethyl glycoside 81
bound more strongly than did the β compound 82. The α,α
bis-methyl glycoside 67 bound more strongly than the 10:1
mixture of α,β and β,β bis-methyl glycosides 68a,b. These
Scheme 4. Ether synthesis and deprotection. (i) 8, NaH, DMF; 74,
19%; 75, 45%; (ii) TFA (90%); 76, 83%; 77, 78%; (iii) a) TFA
(90%); b) H2, Pd (C), AcOH, H2O; c) Ac2O, pyridine; d) NaOMe,
MeOH; 78, 79%; 79, 72%; 80, 78%; 81, 66%; 82, 61%.
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Non-Glycosidically Linked Pseudodisaccharides
Table 4. Binding of pseudodisaccharides to banana lectin and Concanavalin A.[a]
Entry Compound
Structure
Binding constant Ka [–1]
BanLec
Con A
1
2
3
4
5
6
7
8
9
MeαMan
Man(α1Ǟ2)Man
Man(α1Ǟ3)Man
Glc
3-O-benzyl-Glc
3-O-methyl-Glc
Glc(3–3)Glc
Glc(S3–3)Glc
520Ϯ22
8960Ϯ280
35700Ϯ970
11000Ϯ130
372
141
269
268
76
49
83
81
82
67
68a,b
80
55
78
54
50
79
77
58
52
46
48
47
51
59
60
57
63
64
56
61
62
53
141Ϯ21
241Ϯ16
n.b.
95Ϯ2
n.b.
223Ϯ2
186Ϯ2
691Ϯ78
519Ϯ7
474Ϯ35
446Ϯ10
276
n.b.
75Ϯ2
n.b.
n.b.
n.b.
119Ϯ31
120Ϯ2
70Ϯ2
n.b.
186Ϯ2
529Ϯ42
274Ϯ17
576Ϯ34
n.b.
n.b.
n.b.
n.d.
n.d.
n.d.
n.d.
n.d.
n.b.
Glc(Se3–3)Glc
MeaGlc(3–3)Glc
MeβGlc(3–3)Glc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
MeαGlc(S3–3)GlcαMe
MeαGlc(S3–3)GlcβMe [+MeβGlc(S3–3)GlcβMe]
MeαMan(3–3)Glc
MeαMan(S3–3)Glc
MeαMan(2–3)Glc
MeαMan(S2–3)Glc
MeβMan(S2–3)Glc
MeαAlt(3–3)Glc
n.b.
7950Ϯ390
32400Ϯ600
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.b.
59300Ϯ2800
13100Ϯ142
26900Ϯ1300
n.d.
n.d.
n.d.
All(3–3)Glc
MeβGlc(S4–4)GlcβMe
MeαMan(S6–3)AllβMe
MeαMan(S6–6)ManαMe
MeαMan(S6–2)ManβMe
MeαMan(S6–3)Glc
MeβMan(S2–2)ManβMe
MeβMan(SO2–2)ManβMe
MeβMan(SO22–2)ManβMe
MeαMan(S2–2)ManαMe
MeαMan(SO2–2)ManαMe
MeαMan(SO22–2)ManαMe
MeβAll(S3–3)AllβMe
MeβAll(SO3–3)AllβMe
MeβAll(SO23–3)AllβMe
MeβMan(S2–3)AllβMe
n.d.
n.b.
Ͻ 50
n.d.
[a] n.b. = no binding; n.d. = not determined. Error values are for curve fitting of the single titration, not variance of replicates, which
were not done.
data suggest that BanLec prefers the α-Glc configuration ance of BanLec for C-6 substitution at glucose and the fact
over the β-Glc, which is consistent with the reported bind- that in the crystal structures of the complexed Glc(β1Ǟ3)
ing preferences for reducing terminal glucose.[36] Compar- Glc and Xyl(β1Ǟ3)ManαMe, 6-OH of the reducing end
ing the affinities of different 3-substituted glucose com- glucose and mannose residues are buried in the protein, it
pounds: ethers 76, 79, 77 and thioether 47, we see a wide seems likely that the 6-substituted mannose derivatives bind
range of binding, which leads us to speculate that both in the orientation with the 2-substituted Man or 3-substi-
monosaccharide residues are interacting with the protein. tuted Glc residues, respectively, in the primary binding
The thioether 49 does bind more strongly than the mono- subsite.
saccharide glucose. However, the binding affinities of these
Concanavalin A (ConA) is an extensively studied plant
pseudodisaccharides do not come up to the level of the lectin from Jack Bean (Canavalia ensiformis). The mono-
most strongly binding disaccharides, e.g. Glc(β1Ǟ3)Glc (Ka meric subunit has a molecular weight of 27 kDa, and binds
= 830 –1), Glc(β1Ǟ3)GlcαMe (Ka = 2400 –1),[36] and mono- and disaccharides with a 1:1 stoichiometry. The
even some simple 3-O-alkylglucose derivatives (Table 4, En- requirements for binding are free equatorial hydroxy groups
tries 5,6) bind more strongly to BanLec.
at C-3 and C-4, and a free hydroxy group at C-6.[40] Man-
Some thioether-linked 6-substituted mannose derivatives nose binds more strongly than glucose and GlcNAc, al-
(47, 48) bind, whereas others (46, 52) do not. Those deriva- though these two monosaccharides do bind. Man(α1Ǟ2)
tives that bind have a second monosaccharide that consist- Man binds more strongly than the other mannobioses
ently shows some binding (ManβMe 48 or Glc 47), whereas (which have binding affinities not much enhanced over
one that does not bind has a second monosaccharide that monosaccharidic mannose).[41] The crystal structure of
tends not to bind (All 52). For the (S6–6)-linked compound ConA in complex with Man(α1Ǟ2)ManαMe reveals two
46, the inter-ring linkage is, at four bonds, longer than any binding modes, one with the reducing end mannose in the
inter-ring linkage in a disaccharide. Given the non-toler- monosaccharide binding site and the non-reducing end
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1957

I. Cumpstey et al.
FULL PAPER
onance (1H) spectra were recorded with Bruker Avance II 400
(400 MHz) or 500 (500 MHz) or Varian Mercury 300 (300 MHz)
or 400 (400 MHz) spectrometers; multiplicities are quoted as sing-
let (s), broad singlet (br. s), doublet (d), doublet of doublets (dd),
triplet (t), apparent triplet (at), apparent triplet of doublets (atd),
doublet of apparent triplets (dat), quartet (q), apparent quartet
(aq), or multiplet (m). Carbon nuclear magnetic resonance (13C)
spectra were recorded with Bruker Avance II 400 (100 MHz) or 500
(125 MHz) or Varian Mercury 300 (75 MHz) or 400 (100 MHz)
spectrometers, and multiplicities were assigned by DEPT. Spectra
mannose in a second binding subsite; the other with the
non-reducing end mannose in the monosaccharide binding
site and the reducing end mannose in a third binding sub-
site.[42]
Some of the pseudodisaccharides were also tested for
binding to ConA (Table 4). Two thioether-linked pseudodi-
saccharides, MeαMan(S2–3)Glc 54 and MeαMan(S2–2)
ManαMe (57) bound with high affinity: 54 bound with sim-
ilar affinity to the best-known natural disaccharide ligand
Man(α1Ǟ2)Man, while 57 bound approximately twice as were assigned using COSY, HSQC and DEPT experiments. All
chemical shifts are quoted on the δ scale in parts per million (ppm).
Residual solvent signals were used as an internal reference. Low-
and high-resolution (HRMS) electrospray (ES) mass spectra were
recorded using a Bruker Microtof instrument. MALDI spectra
were recorded on a Bruker Biflex III spectrometer using 2Ј,4Ј,6Ј-
trihydroxyacetophenone trihydrate (THAP) as matrix. Infra-red
spectra were recorded with a Perkin–Elmer Spectrum One FT-IR
spectrometer using the thin film method on NaCl plates. Optical
rotations were measured with a Perkin–Elmer 241 polarimeter with
a path length of 1 dm; concentrations are given in g/100 mL. Thin
well. Changing the bridging group from sulfur to oxygen
(54Ǟ78) gave a fourfold loss in affinity. Oxidising the bridg-
ing sulfur in 57 to sulfoxide 63 or sulfone 64 levels also gave
some loss of affinity. Man(3–3)Glc (55, 80) or Glc(3–3)Glc
(49, 76) derivatives did not bind to ConA, as may be ex-
pected from the low binding affinities of ConA for 3-substi-
tuted carbohydrates. It is possible that the highest affinity
binder MeαMan(S2–2)ManαMe benefits from a favourable
entropy factor. Its C2 symmetry leads to double the number
of degenerate binding modes, which ought to lead to a more layer chromatography (TLC) was carried out on Merck kieselgel
sheets, pre-coated with 60F254 silica. Plates were visualised with
UV light and developed using 10% sulfuric acid, or an ammonium
molybdate (10% w/v) and cerium(IV) sulfate (2% w/v) solution in
10% sulfuric acid. Flash column chromatography was carried out
on silica gel (35–70 micron, Grace). CMAW means chloroform/
MeOH/acetic acid/water, 60:30:3:5. Acetonitrile (puriss.) was pur-
chased from Riedel-de Haën and used without purification. DMF
was from VWR (AnalaR normapur) and used without purification.
Reactions performed under hydrogen or nitrogen were maintained
by an inflated balloon.
favourable entropy of binding, although the many other un-
predictable factors contributing to the binding event may
render this contribution irrelevant.
Conclusions
Thioether-linked pseudodisaccharides are available
stereospecifically by SN2 displacement of carbohydrate
sulfonates by carbohydrate thiol nucleophiles. The reactions
can be as efficient for the formation of sec–sec linkages as
for the formation of linkages involving a primary carbon
(C-6), with the caveat that the efficiency of the SN2 dis-
placements are dependent on the individual monosaccha-
ride substrates and their protecting groups.
Some of the unprotected pseudodisaccharides with ether,
thioether, sulfoxide and sulfone linkages bound to the lec-
tins, Banana lectin and Concanavalin A. Binding to banana
lectin was in many cases similar to or worse than binding
of monosaccharides, but the very best ligands did bind to
the lectin with enhanced binding affinity over monosaccha-
rides. Binding to ConA occurred in general with much
higher affinities than to the BanLec. In this case, the best
pseudodisaccharide ligands bound with affinities similar to
or enhanced over the strongest known disaccharide ligand,
suggesting an interaction involving both halves of the
pseudodisaccharide and a mimicry of the disaccharide
binding event. The binding of the hydrolytically stable
pseudodisaccharides to lectins opens up the field to further
research. The mode of binding of these structures, the effect
of the linking heteroatom and the possibility of extending
the work to binding animal or bacterial lectins would all
now be relevant topics for investigation.
Methyl 2,3,4-Tri-O-benzyl-6-O-methylsulfonyl-α-D-mannopyranos-
ide (7): Alcohol 1[16] (600 mg, 1.30 mmol) was dissolved in CH2Cl2
(3 mL) and cooled to 0 °C under N2. Triethylamine (0.27 mL,
1.95 mmol) and mesyl chloride (0.11 mL, 1.42 mmol) were added,
and the mixture was stirred at 0 °C. After 90 min, TLC (pentane/
EtOAc, 2:1) showed the formation of a product (Rf = 0.3) and
little starting material remaining (Rf = 0.2). Further triethylamine
(0.13 mL, 1.0 mmol) and mesyl chloride (55 µL, 0.7 mmol) were
added. After a further 20 min, TLC showed the complete conver-
sion of starting material into a major product. The mixture was
diluted with CH2Cl2 (50 mL) and washed with ice-water (50 mL)
then NH4Cl (satd. aq., 50 mL). The organic phase was dried
(MgSO4), filtered, and concentrated in vacuo to give the crude mes-
ylate 7 as a pale yellow oil, which was used without further purifi-
cation. The material could be purified by column chromatography
(pentane/EtOAc, 2:1) for characterisation: colourless oil. [α]2D3
=
+42.2 (c = 1.0, in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37–
7.27 (m, 15 H, Ar-H), 4.97 (d, J = 10.8 Hz, 1 H, PhCHHЈ), 4.77
(d, J = 11.9 Hz, 1 H, PhCHHЈ), 4.71 (d, J1,2 = 1.8 Hz, 1 H, 1-H),
4.67–4.63 (m, 4 H, 2 PhCHHЈ, PhCH2), 4.53 (dd, J5,6Ј = 2.0, J6,6Ј
= 11.5 Hz, 1 H, 6Ј-H), 4.43 (dd, J5,6 = 4.4, J6,6Ј = 11.5 Hz, 1 H, 6-
H), 3.98–3.90 (m, 2 H, 3-H, 4-H), 3.80 (at, J = 2.3 Hz, 1 H, 2-H),
3.76 (m, 1 H, 5-H), 3.32 (s, 3 H, OCH3), 3.00 (s, 3 H, SO2CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 138.3, 138.2 (2 s, Ar-C),
128.6, 128.6, 128.5, 128.2, 128.0, 127.8, 127.7 (7 d, Ar-CH), 99.4
(d, C-1), 80.1, 74.7, 74.1, 70.4 (4 d, C-2, C-3, C-4, C-5), 75.4, 73.2,
72.3, 69.6 (4 t, 3 PhCH2, C-6), 55.2 (q, OCH3), 38.0 (q, SO2CH3)
ppm. MS (ES+): m/z (%) = 560 (100) [M + NH4+]. HRMS: calcd.
for C29H38NO8S [MNH4+] 560.2313; found 560.2320.
Experimental Section
General: Melting points were recorded with a Gallenkamp melting
point apparatus and are uncorrected. Proton nuclear magnetic res-
Preparation of Triflates 8–12: Alcohol 2[17] (403 mg, 1.6 mmol) was
dissolved in CH2Cl2 (14 mL) and the mixture cooled to 0 °C under
1958
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1951–1970

Non-Glycosidically Linked Pseudodisaccharides
N2. Pyridine (0.50 mL, 6.2 mmol) and triflic anhydride (0.51 mL,
3.1 mmol) were added, and the mixture was stirred at 0 °C. After
2 h, TLC (pentane/EtOAc, 1:1) showed complete conversion of the
starting material into a single product. The mixture was poured
into ice-water (100 mL) and extracted with CH2Cl2 (2ϫ50 mL).
Methyl 2-S-Acetyl-3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-thio-β-
-mannopyranoside (15): Triflate (1.15 g, 2.7 mmol), KSAc
(790 mg, 6.9 mmol) in DMF (10 mL) at room temp. for 19 h gave,
D
9
by the same procedure as described for 13 and chromatography
(pentane/EtOAc, 4:1) the thioacetate 15 (969 mg, 84%) as a pale
1
The organic extracts were dried (Na2SO4), filtered, and concen- yellow oil. [α]2D3 = –67.4 (c = 1.0, in CHCl3). H NMR (300 MHz,
trated in vacuo to give the crude triflate 8 (610 mg),[22] which was
used without further purification.
CDCl3): δ = 7.51–7.26 (m, 10 H, Ar-H), 5.57 (s, 1 H, PhCH), 4.72
(d, J = 12.4 Hz, 1 H, PhCHHЈ), 4.64–4.57 (m, 3 H, PhCHHЈ, 1-
H, 2-H), 4.30 (dd, J5,6Ј = 4.7, J6,6Ј = 10.4 Hz, 1 H, 6Ј-H), 3.94 (dd,
J2,3 = 4.4, J3,4 = 9.6 Hz, 1 H, 3-H), 3.80 (at, J = 10.3 Hz, 1 H, 6-
H), 3.66 (at, J = 9.5 Hz, 1 H, 4-H), 3.50 (s, 3 H, OCH3), 3.38 (atd,
Jat = 9.6, J5,6Ј = 4.7 Hz, 1 H, 5-H), 2.42 [s, 3 H, SC(O)CH3] ppm.
13C NMR (75 MHz, CDCl3): δ = 194.2 (s, C=O), 137.7, 137.3 (2
s, 2 Ar-C), 129.0, 128.4, 128.2, 127.7, 126.1 (5 d, Ar-CH), 101.6 (d,
PhCH), 101.4 (d, C-1), 80.2 (d, C-4), 75.3 (d, C-3), 71.7 (t, PhCH2),
68.5 (t, C-6), 67.7 (d, C-5), 57.3 (q, OCH3), 49.2 (d, C-2), 30.7 [q,
Alcohol 3[18] (1.0 g, 2.7 mmol) was converted with pyridine
(0.54 mL, 6.7 mmol) and triflic anhydride (0.55 mL, 3.4 mmol) in
CH2Cl2 (10 mL) by the same procedure as described for compound
8, into the crude triflate 9,[23] which was used without further puri-
fication, or purified by flash column chromatography (toluene/
EtOAc, 5:1, 1% Et3N).
Alcohol 4[19] (2.0 g, 5.4 mmol) was converted with pyridine
(1.08 mL, 13.4 mmol) and triflic anhydride (1.10 mL, 6.7 mmol) in
CH2Cl2 (10 mL) by the same procedure as described for compound
8, into the crude triflate 10,[24] which was used without further puri-
fication.
SC(O)CH ] ppm. IR (film): ν = 1692 (C=O) cm–1. MS (ES+): m/z
˜
3
(%) = 453 (100) [M + Na+]. HRMS: calcd. for C23H26O6SNa
[MNa+] 453.1342; found 453.1345.
Methyl 3-S-Acetyl-2-O-benzyl-4,6-O-benzylidene-3-deoxy-3-thio-β-
Alcohol 5[20] (224 mg, 0.60 mmol) was converted with pyridine
(0.29 mL, 3.6 mmol) and triflic anhydride (0.2 mL, 1.2 mmol) in
CH2Cl2 (5 mL, freshly distilled) by the same procedure as described
for compound 8 into the crude triflate 11 (318 mg)[25] as a yellow
solid, which was used without further purification.
D-allopyranoside (16): Triflate 10 (2.31 g, 5.4 mmol), KSAc (1.03 g,
9.0 mmol) in DMF (10 mL) at room temp. for 6 h gave, by the
same procedure as described for 13 and chromatography (pentane/
EtOAc, 4:1 Ǟ 2:1) followed by trituration with ether, the thioacet-
ate 16 (1.85 g, 80%) as an off-white solid, which was recrystallised;
Colourless crystals, m.p. 146–150 °C (EtOAc/pentane). [α]2D1 = –109
Alcohol 6[21] (228 mg) was converted with pyridine (0.15 mL,
1.8 mmol) and triflic anhydride (0.15 mL, 0.9 mmol) in CH2Cl2
(6 mL) by the same procedure as described for compound 8, into
the crude triflate 12,[26] which was used without further purifica-
tion.
1
(c = 1.0, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.44–7.28
(m, 10 H, Ar-H), 5.53 (s, 1 H, PhCH), 4.76 (at, J = 4.4 Hz, 1 H,
3-H), 4.72, 4.66 (2 d, J = 11.9 Hz, 2 H, PhCH2), 4.41 (d, J1,2
=
7.9 Hz, 1 H, 1-H), 4.33 (dd, J5,6Ј = 5.0, J6,6Ј = 10.5 Hz, 1 H, 6Ј-H),
3.78 (dd, J3,4 = 4.0, J4,5 = 9.3 Hz, 1 H, 4-H), 3.72 (at, J = 10.1 Hz,
1 H, 6-H), 3.65 (dd, J1,2 = 7.9, J2,3 = 4.7 Hz, 1 H, 2-H), 3.59 (m,
1 H, 5-H), 3.57 (s, 3 H, OCH3), 2.41 [s, 3 H, C(O)CH3] ppm. 13C
NMR (100 MHz, CDCl3): δ = 31.0 [q, C(O)CH3], 46.6 (d, C-3),
57.4 (q, OCH3), 66.7 (d, C-5), 69.1 (t, C-6), 72.3 (t, PhCH2), 75.6
(d, C-2), 76.7 (d, C-4), 101.1 (d, PhCH), 103.6 (d, C-1), 129.1,
128.5, 128.3, 128.1, 127.9, 126.2 (6 d, Ar-CH), 137.6, 137.2 (2 s, 2
Ar-C), 193.6 (s, C=O) ppm. MS (ES+): m/z (%) = 453 (100) [M +
Na+]. HRMS: calcd. for C23H26O6SNa [MNa+] 453.1342; found
453.1335.
Methyl
6-S-Acetyl-2,3,4-tri-O-benzyl-6-deoxy-6-thio-α-D-manno-
pyranoside (13): Crude mesylate 7 (200 mg, 0.37 mmol) was dis-
solved in DMF (2 mL). Potassium thioacetate (84 mg, 0.74 mmol)
was added, and the mixture was stirred at 90 °C. After 3 h, TLC
(pentane/EtOAc, 3:1) showed complete conversion of starting ma-
terial (Rf = 0.2) into a single product (Rf = 0.8). The reaction mix-
ture was cooled, then ether (50 mL) was added, and the mixture
washed with brine (50 mL). The aqueous phase was re-extracted
with diethyl ether (30 mL) and the combined organic extracts dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (pentane/EtOAc, 8:1) to
give the thioacetate 13 (170 mg, 88%) as a yellow oil. [α]2D3 = +35.7
Methyl 2-S-Acetyl-3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-thio-α-
D-mannopyranoside (17): Triflate 11 (206 mg, 0.48 mmol), KSAc
1
(93 mg, 0.82 mmol) in DMF (5 mL) at 90 °C, for 1 h 50 min gave,
by the same procedure as described for 13 and column chromatog-
raphy (pentane/EtOAc, 10:1 Ǟ 4:1), thioacetate 17 (148 mg, 88%)
as a yellow oil. [α]2D3 = +16 (c = 1.0, in CHCl3); δH (500 MHz,
CDCl3): δ = 7.49–7.47 (m, 2 H, Ar-H), 7.39–7.23 (m, 8 H, Ar-H),
5.58 (s, 1 H, CHPh), 4.72 (s, 1 H, H-1), 4.68, 4.63 (2 d, J = 12.2 Hz,
(c = 1.0, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.42–7.26
(m, 15 H, Ar-H), 4.96, 4.68 (2 d, J = 10.8 Hz, 2 H, PhCH2), 4.77,
4.72 (2 d, J = 12.3 Hz, 2 H, PhCH2), 4.69 (d, J1,2 = 2.0 Hz, 1 H,
1-H), 4.63 (s, 2 H, PhCH2), 3.88 (dd, J2,3 = 3.0, J3,4 = 9.0 Hz, 1 H,
3-H), 3.82–3.78 (m, 2 H, 2-H, 4-H), 3.71 (atd, Jat = 8.7, J5,6Ј
=
2.7 Hz, 1 H, 5-H), 3.60 (dd, J5,6Ј = 2.7, J6,6Ј = 13.5 Hz, 1 H, 6Ј-H),
3.31 (s, 3 H, OCH3), 3.11 (dd, J5,6 = 8.1, J6,6Ј = 13.5 Hz, 1 H, 6-
H), 2.36 [s, 3 H, SC(O)CH3] ppm. 13C NMR (75 MHz, CDCl3): δ
= 195.3 (s, C=O), 138.5, 138.4, 138.3 (3 s, 3 Ar-C), 128.5, 128.5,
128.5, 128.3, 127.9, 127.8, 127.8, 127.7, 127.7 (9 d, Ar-CH), 99.1
(d, C-1), 80.1 (d, C-3), 77.7, 74.7 (2 d, C-2, C-4), 75.3, 72.9, 72.3
(3 t, 3 PhCH2), 71.0 (d, C-5), 54.8 (q, OCH3), 31.4 (t, C-6), 30.6
2 H, PhCH2), 4.38 (d, J2,3 = 4.9 Hz, 1 H, H-2), 4.28 (dd, J2,3
4.9 Hz, J3,4 = 9.8 Hz, 1 H, H-3), 4.23 (dd, J5,6Ј = 4.4 Hz, J6,6Ј
=
=
9.9 Hz, 1 H, H-6Ј), 3.87–3.76 (m, 2 H, H-5, H-6), 3.69 (at, J =
9.5 Hz, 1 H, H-4), 3.35 (s, 3 H, OCH3), 2.39 [s, 3 H, C(O)CH3]; δC
(125 MHz, CDCl3): δ = 194.2 (s, C=O), 138.0, 137.5 (2 s, 2 Ar-C),
129.0, 128.4, 128.3, 127.7, 127.7, 126.2 (6 d, Ar-CH), 102.5 (d, C-
1), 101.7 (d, CHPh), 80.6 (d, C-4), 72.9 (d, C-3), 72.1 (t, PhCH2),
68.9 (t, C-6), 63.9 (d, C-5), 55.3 (q, OCH3), 48.2 (d, C-2), 30.8 [q,
C(O)CH ]. IR (film): ν = 1694 (C=O) cm–1. MS (ES+): m/z (%) =
[q, SC(O)CH ] ppm. IR (film): ν = 1694 (C=O) cm–1. MS (ES+):
˜
3
m/z (%) = 1067 (20) [2M + Na+], 545 (100) [M + Na+]. HRMS:
calcd. for C30H34O6S [MNa+] 545.1968; found 545.1952.
3
˜
469 (2) [M + K+] 453 (100) [M + Na+]. HRMS: calcd. for
C23H26O6SNa [MNa+] 453.1342; found 453.1322.
3-S-Acetyl-1,2:5,6-di-O-isopropylidene-3-deoxy-3-thio-α-D-gluco-
furanose (14): Triflate 8 (244 mg, 0.62 mmol), KSAc (142 mg,
1.24 mmol) in DMF (2 mL) at 90 °C for 4 h gave, by the same
procedure as described for 13 and chromatography (CH2Cl2/diethyl
ether, 49:1) the thioacetate 14 (175 mg, 84%) as a pale brown oil.[43]
Methyl 4-S-Acetyl-2,3,6-tri-O-benzoyl-4-deoxy-4-thio-β-D-glucopyr-
anoside (18): Triflate 12 (288 mg, 0.45 mmol), KSAc (103 mg,
0.90 mmol) in DMF (3 mL) at 90 °C for 50 min gave, by the same
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1959

I. Cumpstey et al.
FULL PAPER
procedure as described for 13 and chromatography (pentane/
ane/EtOAc, 5:1 Ǟ 4:1), the thioether 20 (142 mg, 47%) as a
EtOAc, 3:1) the thioacetate 18 (147 mg, 58%) as a white solid, colourless oil. [α]2D1 = +44.6 (c = 1.0, in CHCl3). 1H NMR
which was recrystallised: colourless crystals, m.p. 154–157 °C
(EtOAc/pentane). [α]2D3 = +114 (c = 1.0, in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 8.13–8.11 (m, 2 H, Ar-H), 7.95–7.89 (m, 4
(400 MHz, CDCl3): δ = 7.39–7.23 (m, 30 H, Ar-H), 4.94, 4.63 (2
d, J = 11.1 Hz, 4 H, PhCH2), 4.73, 4.69 (2 d, J = 12.4 Hz, 4 H,
PhCH2), 4.66 (d, J1,2 = 1.6 Hz, 2 H, 1-H), 4.60 (s, 4 H, PhCH2),
H, Ar-H), 7.61–7.31 (m, 9 H, Ar-H), 5.75 (at, J = 10.1 Hz, 1 H, 3- 3.85 (dd, J2,3 = 3.1, J3,4 = 9.0 Hz, 2 H, 3-H), 3.81–3.74 (m, 4 H, 2-
H), 5.44 (at, J = 8.7 Hz, 1 H, 2-H), 4.74–4.67 (m, 2 H, 1-H, 6Ј-H),
4.58 (dd, J5,6 = 4.6, J6,6Ј = 12.0 Hz, 1 H, 6-H), 4.13–4.03 (m, 2 H,
4-H, 5-H), 3.51 (s, 3 H, OCH3), 2.19 [s, 3 H, SC(O)CH3] ppm. 13C
NMR (75 MHz, CDCl3): δ = 192.7 (s, SC=O), 166.3, 165.8, 165.3
H, 4-H), 3.71 (atd, Jat = 9.0, J5,6Ј = 1.9 Hz, 2 H, 5-H), 3.29 (s, 6
H, OCH3), 3.12 (dd, J5,6Ј = 1.9, J6,6Ј = 13.4 Hz, 2 H, 6Ј-H), 2.78
(dd, J5,6 = 8.8, J6,6Ј = 13.4 Hz, 2 H, 6-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.7, 138.6, 138.5 (3 s, 6 Ar-C), 128.5,
(3 s, 3 OC=O), 133.4, 133.3, 133.2 (3 s, 3 Ar-C), 130.2, 129.9, 129.9, 128.0, 128.0, 127.9, 127.8, 127.7, 127.7 (7 d, Ar-CH), 98.9 (d, C-
129.9, 129.4, 129.0, 128.5, 128.4, 128.4 (9 d, Ar-CH), 101.9 (d, C-
1), 73.1, 73.0 (2 d, C-2, C-5), 71.9 (d, C-3), 64.0 (t, C-6), 57.0 (q,
1), 80.4 (d, C-3), 78.0 (d, C-4), 75.2, 72.8, 72.2 (3 t, 6 PhCH2), 74.8
(d, C-2), 72.7 (d, C-5), 54.8 (q, OCH3), 35.0 (t, C-6) ppm. MS
OCH ), 44.7 (d, C-4), 30.8 [q, SC(O)CH ] ppm. IR (film): ν = 1727 (ES+): m/z (%) = 949 (85) [M + Na+], 944 (100) [M + NH4+].
˜
3
3
(C=O) cm–1. MS (ES+): m/z = 582 [M + NH4+]. HRMS: calcd. for
HRMS: calcd. for C56H62O10SNa [MNa+] 949.3956; found
949.3940.
C30H32O9NS (MNH4+) 582.1792; found 582.1800.
The elimination product was also isolated: 41 mg (19%) of a yellow
oil; NMR spectroscopic data were identical to those described for
methyl 2,3,6-tri-O-benzoyl-4-deoxy-α--threo-hex-4-enopyranos-
ide.[44]
The disulfide 33 (20 mg, 15%) was isolated as a colourless oil.
1
[α]2D4 = +137 (c = 1.0, in CHCl3). H NMR (400 MHz, CDCl3): δ
= 7.37–7.21 (m, 30 H, Ar-H), 4.92, 4.57 (2 d, J = 11.2 Hz, 4 H,
PhCH2), 4.73, 4.68 (2 d, J = 12.4 Hz, 4 H, PhCH2), 4.68 (d, J1,2
=
1.5 Hz, 2 H, 1-H), 4.59 (s, 4 H, PhCH2), 3.88–3.80 (m, 4 H, 3-H,
5-H), 3.77 (at, J = 2.3 Hz, 2 H, 2-H), 3.73 (at, J = 9.2 Hz, 2 H, 4-
H), 3.31 (s, 6 H, OCH3), 3.17 (dd, J5,6Ј = 2.0, J6,6Ј = 13.4 Hz, 2 H,
6Ј-H), 2.86 (dd, J5,6 = 9.1, J6,6Ј = 13.4 Hz, 2 H, 6-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 41.6 (t, C-6), 55.0 (q, OCH3), 70.5
(d, C-5), 72.3, 72.9, 75.1 (3 t, 6 PhCH2), 74.8 (d, C-2), 77.9 (d, C-
4), 80.4 (d, C-3), 99.0 (d, C-1), 127.7, 127.8, 127.8, 128.0, 128.5 (5
d, Ar-CH), 138.4, 138.5, 138.6 (3 s, 6 Ar-C) ppm. MS (MALDI):
m/z = 998 [M + K+], 982 [M + Na+]. HRMS: calcd. for
C56H66O10NS2 (MNH4+) 976.4123; found 976.4094.
General Procedure I: Thioether Pseudodisaccharide Formation from
Thioacetates: (Table 1). The thioacetate (0.12–0.35 mmol) was dis-
solved in MeOH (1–3 mL). A solution of sodium (1.5–2 equiv.) in
MeOH (1 mL) was added, and the solution immediately degassed
and stirred at room temp. under N2. After TLC indicated complete
conversion of the starting material to a major product (typically
20–40 min), the reaction mixture was added to NH4Cl (satd. aq.,
25 mL), and extracted with CH2Cl2 (25 mL). The organic phase
was dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was dissolved in DMF, and sulfonate (usually
1.5 equiv.) was added either as a solution in DMF (total 2–3 mL)
or as a solid. The mixture was degassed under N2. Sodium hydride
(60% in oil, 2 equiv.) was added, and the mixture was stirred at
50 °C. After TLC indicated complete consumption of thiol or sul-
fonate (ca. 30 min), NH4Cl (satd. aq., 25 mL) was added, and the
mixture extracted with Et2O (2ϫ25 mL). The organic phase was
dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography to give the thioether
pseudodisaccharide.
(1,2:5,6-Di-O-isopropylidene-3-deoxy-α-
D-glucofuranos-3-yl)(methyl
2,3,4-tri-O-benzyl-6-deoxy-α- -mannopyranosid-6-yl)sulfane (21):
D
According to general procedure I, thioacetate 13 (160 mg,
0.31 mmol) and triflate 8 (82 mg, 0.20 mmol) gave, after purifica-
tion by flash chromatography (pentane/EtOAc, 5:1), the thioether
21 (123 mg, 81%) as a colourless oil. [α]2D4 = +19.3 (c = 1.0, in
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39–7.26 (m, 15 H, Ar-
H), 5.79 (d, J1,2 = 3.5 Hz, 1 H, 1II-H), 4.96, 4.64 (2 d, J = 10.8 Hz,
2 H, PhCH2), 4.79 (d, J1,2 = 3.5 Hz, 1 H, 2II-H), 4.76 (d, J =
12.4 Hz, 1 H, PhCHHЈ), 4.72–4.69 (m, 2 H, 1I-H, PhCHHЈ), 4.60
(s, 2 H, PhCH2), 4.37 (dat, J4,5 = 8.6, Jat = 5.6 Hz, 1 H, 5II-H),
4.20 (dd, J3,4 = 3.7, J4,5 = 8.6 Hz, 1 H, 4II-H), 4.10 (dd, J5,6Ј = 6.2,
J6,6Ј = 8.6 Hz, 1 H, 6ЈII-H), 3.97 (dd, J5,6 = 5.2, J6,6Ј = 8.6 Hz, 1
H, 6II-H), 3.91 (at, J = 9.0 Hz, 1 H, 4I-H), 3.86 (dd, J2,3 = 2.8, J3,4
= 9.0 Hz, 1 H, 3I-H), 3.80–3.75 (m, 2 H, 2I-H, 5I-H), 3.59 (d, J3,4
= 3.7 Hz, 1 H, 3II-H), 3.34 (s, 3 H, OCH3), 3.05 (dd, J5,6Ј = 2.4,
J6,6Ј = 13.7 Hz, 1 H, 6ЈI-H), 2.91 (dd, J5,6 = 7.4, J6,6Ј = 13.7 Hz, 1
H, 6I-H), 1.51, 1.35, 1.29, 1.27 [4 s, 12 H, 2 C(CH3)2] ppm. 13C
NMR (100 MHz, CDCl3): δ = 138.6, 138.4 (2 s, Ar-C), 128.6,
128.5, 128.1, 128.0, 127.9, 127.8 (6 d, Ar-CH), 111.9, 109.4 [2 s, 2
C(CH3)2], 105.0 (d, C-1II), 99.1 (d, C-1I), 86.2 (d, C-2II), 80.6, 80.3
(2 d, C-3I, C-4II), 77.4 (d, C-4I), 75.4, 72.9, 72.3 (3 t, 3 PhCH2),
74.7, 73.0 (2 d, C-2I, C-5I), 74.2 (d, C-5II), 67.9 (t, C-6II), 55.0 (q,
OCH3), 53.2 (d, C-3II), 34.0 (t, C-6I), 27.0, 26.9, 26.5, 25.5 (4 q, 4
CH3) ppm. MS (ES+): m/z (%) = 1467 (5) [2M + Na+], 745 (100)
[M + Na+]. HRMS: calcd. for C40H50O10SNa [MNa+] 745.3017;
found 745.2999.
General Procedure II: Pseudodisaccharide Formation by Triflate Di-
merisation with Sodium Sulfide: See Table 2; sodium sulfide nonah-
ydrate (2–4 equiv.) was dried by heating with a heat gun in air. The
crystals first melted to give a liquid, which upon further heating
lost water to give a solid pale yellow residue. Note: excessive heat-
ing of this solid leads to discolouration and is avoided. The residue
was cooled to room temp. under vacuum (water aspirator) before
use. Molecular sieves (powdered, 4 Å) were added. The triflate
(0.18–1.9 mmol) was dissolved in acetonitrile (2–6 mL) and added.
The mixture was stirred at 50 °C under N2 until TLC showed com-
plete consumption of triflate. Efficient stirring is necessary here as
the reaction mixture is heterogeneous. The mixture was then cooled
to room temp. then filtered through Celite and rinsed through with
CH2Cl2 (50 mL). The solution was washed with HCl (1 , 50 mL)
and the aqueous phase re-extracted with CH2Cl2. The combined
organic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
to give the thioether.
Bis(methyl 2,3,4-tri-O-benzyl-6-deoxy-α-
D-mannopyranosid-6-yl)-
(Methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-D-mannopyranosid-
sulfane (20) and Bis(methyl 2,3,4-Tri-O-benzyl-6-deoxy-α-
D-manno-
2-yl)(methyl 2,3,4-tri-O-benzyl-6-deoxy-α- -mannopyranosid-6-yl)-
D
pyranosid-6-yl)disulfane (33): According to general procedure I,
thioacetate 13 (149 mg, 0.29 mmol) and mesylate 7 (232 mg,
sulfane (22): According to general procedure I, thioacetate 15
(58 mg, 0.14 mmol) and mesylate 7 (110 mg, 0.20 mmol) gave, after
0.43 mmol) gave, after purification by flash chromatography (pent- purification by flash chromatography (pentane/EtOAc, 4:1), the
1960
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1951–1970

Non-Glycosidically Linked Pseudodisaccharides
thioether 22 (52 mg, 47%) as a colourless oil. [α]2D3 = –2.0 (c = 0.5,
PhCH), 4.92 (d, J = 12.4 Hz, 1 H, PhCHHЈ), 4.82–4.78 (m, 2 H,
1
in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.48–7.21 (m, 25 H, 2II-H, PhCHHЈ), 4.66 (dat, J5,6 = 6.0, Jat = 7.8 Hz, 1 H, 5II-H),
Ar-H), 5.58 (s, 1 H, PhCH), 4.93, 4.60 (2 d, J = 11.1 Hz, 2 H, 4.52 (d, J1,2 = 1.6 Hz, 1 H, 1I-H), 4.29 (dd, J5,6Ј = 4.8, J6,6Ј
=
PhCH2), 4.80–4.69 (m, 5 H, 1II-H, 2 PhCH2), 4.60 (s, 2 H, PhCH2),
4.48 (d, 1 H, 1I-H), 4.28 (dd, J5,6Ј = 4.8, J6,6Ј = 10.4 Hz, 1 H, 6ЈI-
H), 4.07 (at, J = 9.4 Hz, 1 H, 4I-H), 3.88–3.76 (m, 6 H, 2II-H, 3II-
10.4 Hz, 1 H, 6ЈI-H), 4.24 (dd, J3,4 = 3.5, J4,5 = 7.9 Hz, 1 H, 4II-
H), 4.17–4.09 (m, 2 H, 4I-H, 6ЈII-H), 3.98 (dd, J5,6 = 6.0, J6,6Ј
8.4 Hz, 1 H, 6II-H), 3.87–3.80 (m, 4 H, 2I-H, 3I-H, 6I-H, 3II-H),
=
H, 4II-H, 5II-H, 3I-H, 6I-H), 3.55 (dd, J1,2 = 1.5, J2,3 = 4.4 Hz, 1 3.51 (s, 3 H, OCH3), 3.33 (atd, Jat = 9.7, J5,6Ј = 4.8 Hz, 1 H, 5I-
H, 2I-H), 3.47, 3.34 (2 s, 6 H, 2 OCH3), 3.32–3.27 (m, 2 H, 5I-H, H), 1.49, 1.44, 1.34, 1.24 [4 s, 12 H, 2 C(CH3)2] ppm. 13C NMR
6ЈII-H), 2.98 (m, 1 H, 6II-H) ppm. 13C NMR (100 MHz, CDCl3): (100 MHz, CDCl3): δ = 138.2, 137.5 (2 s, Ar-C), 129.0, 128.5, 128.3,
δ = 138.8, 138.7, 138.5, 138.5, 137.7 (5 s, 5 Ar-C), 129.0, 128.5, 127.8, 127.6, 126.1 (6 d, Ar-CH), 111.7, 109.1 [2 s, 2 C(CH3)2],
128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.7, 126.2 (10 d, Ar-CH),
104.7 (d, C-1II), 102.6 (d, C-1I), 101.6 (d, PhCH), 86.1 (d, C-2II),
103.2 (d, C-1I), 101.6 (d, PhCH), 99.0 (d, C-1II), 80.5, 78.1, 77.2,
80.9 (d, C-4II), 80.2 (d, C-4I), 77.2 (d, C-3I), 73.8 (d, C-5II), 73.0 (t,
75.0, 72.5 (5 d, C-2II, C-3II, C-4II, C-5II, C-3I), 80.0 (d, C-4I), 75.2, PhCH2), 68.6 (t, C-6I), 67.9 (d, C-5I), 67.6 (t, C-6II), 57.2 (q,
73.0, 72.4, 72.2 (4 t, 4 PhCH2), 68.8 (t, C-6I), 67.9 (d, C-5I), 57.2, OCH3), 53.3, 52.4 (2 d, C-2I, C-3II), 26.9, 26.7, 26.3, 25.4 (4 q, 4
55.0 (2 q, 2 OCH3), 53.0 (d, C-2I), 36.1 (t, C-6II) ppm. m/z CH3) ppm. MS (MALDI): m/z = 669 [M + K+], 653 [M + Na+].
(MALDI) 874 (M + K+), 858 [M + Na+]. MS (ES+): m/z (%) =
HRMS: calcd. for C33H42O10SNa [MNa+] 653.2391; found
653.2403.
+
852 (80) [M + NH4+]. HRMS: calcd. for C49H58O10NS (MNH4
852.3776; found 852.3746.
)
Recovered triflate was also isolated (112 mg).
According to general procedure I, thioacetate 13 (70 mg,
0.13 mmol) and triflate 9 (101 mg, 0.20 mmol) gave, after purifica-
tion by flash chromatography (pentane/EtOAc, 3:1), the thioether
22 (47 mg, 42%) identical to that described above.
According to general procedure I, thioacetate 15 (133 mg,
0.31 mmol) and triflate 8 (82 mg, 0.20 mmol) gave, after purifica-
tion by flash chromatography (pentane/EtOAc, 7:2), the thioether
24 (92 mg, 70%) identical to that described above.
Bis(1,2:5,6-di-O-isopropylidene-3-deoxy-α-
ane (23) and Bis(1,2:5,6-di-O-isopropylidene-3-deoxy-α-
D
-glucofuranos-3-yl)sulf-
-glucofur-
Bis(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-D-mannopyr-
D
anosid-2-yl)sulfane (25): According to general procedure I,
thioacetate 15 (231 mg, 0.54 mmol) and triflate 9 (135 mg,
0.27 mmol) gave, after purification by flash chromatography (pen-
tane/EtOAc, 3:1), the thioether 25 (146 mg, 73%) as a colourless
oil. [α]2D1 = –131 (c = 1.0, in CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 7.52–7.26 (m, 20 H, Ar-H), 5.57 (s, 2 H, PhCH), 4.96, 4.69 (2
d, J = 12.1 Hz, 4 H, PhCH2), 4.58 (d, J1,2 = 1.1 Hz, 2 H, 1-H),
4.35 [br. s (obsd.), 2 H, 2-H], 4.34 (dd, J5,6Ј = 4.8, J6,6Ј = 10.2 Hz,
2 H, 6Ј-H), 4.05 (at, J = 9.5 Hz, 2 H, 4-H), 3.92 (at, J = 10.2 Hz,
2 H, 6-H), 3.88 (dd, J2,3 = 4.8, J3,4 = 9.7 Hz, 2 H, 3-H), 3.53 (s, 6
H, OCH3), 3.37 (atd, Jat = 9.6, J5,6Ј = 4.8 Hz, 2 H, 5-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 138.5, 137.7 (2 s, Ar-C), 128.9,
128.3, 128.3, 128.1, 127.5, 126.2 (6 d, Ar-CH), 104.0 (d, C-1), 101.5
(d, PhCH), 78.7 (d, C-4), 76.8 (d, C-3), 70.8 (t, PhCH2), 68.8 (t, C-
6), 68.2 (d, C-5), 57.0 (q, OCH3), 49.9 (d, C-2) ppm. MS (MALDI):
m/z = 781 [M + K+ ], 765 [M + Na+ ]. HRMS: calcd. for
C42H46O10SNa [MNa+] 765.2704; found 765.2674.
anos-3-yl)disulfane (34): According to general procedure I,
thioacetate 14 (41 mg, 0.12 mmol) and triflate 8 (72 mg, 0.18
mmol) gave, after purification by flash chromatography (pentane/
EtOAc, 4:1), the thioether 23 (43 mg, 68 %) as a colourless oil.
[α]2D3 = –40.9 (c = 1.0, in CHCl3). H NMR (400 MHz, CDCl3): δ
1
= 5.81 (d, J1,2 = 3.5 Hz, 2 H, 1-H), 4.82 (d, J1,2 = 3.5 Hz, 2 H, 2-
H), 4.31 (dat, J4,5 = 8.8, Jat = 5.6 Hz, 2 H, 5-H), 4.19 (dd, J3,4
=
3.7, J4,5 = 8.8 Hz, 2 H, 4-H), 4.12 (dd, J5,6Ј = 6.0, J6,6Ј = 8.6 Hz, 2
H, 6Ј-H), 3.96 (dd, J5,6 = 5.3, J6,6Ј = 8.6 Hz, 2 H, 6-H), 3.51 (d,
J3,4 = 3.7 Hz, 2 H, 3-H), 1.50, 1.42, 1.35, 1.31 (4 s, 24 H, 8 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 109.5, 112.1 [2 s, 4
C(CH3)2], 105.0 (d, C-1), 86.2 (d, C-2), 80.3 (d, C-4), 74.1 (d, C-
5), 68.0 (t, C-6), 52.8 (d, C-3), 27.0, 26.8, 26.4, 25.4 (4 q, 8 CH3)
ppm. MS (MALDI): m/z = 541 [M + Na+]. HRMS: calcd. for
C24H38O10SNa [MNa+] 541.2078; found 541.2079.
1
The disulfide 34 was isolated (5 mg, 7%)[45] as a colourless oil. H
NMR (400 MHz, CDCl3): δ = 5.92 (d, J1,2 = 3.5 Hz, 2 H, 1-H),
4.90 (d, J1,2 = 3.5 Hz, 2 H, 2-H), 4.30 (ddd, J4,5 = 8.8, J5,6 = 4.8,
J5,6Ј = 6.0 Hz, 2 H, 5-H), 4.19 (dd, J3,4 = 3.8, J4,5 = 8.8 Hz, 2 H,
4-H), 4.13 (dd, J5,6Ј = 6.0, J6,6Ј = 8.6 Hz, 2 H, 6Ј-H), 3.96 (dd, J5,6
= 4.8, J6,6Ј = 8.6 Hz, 2 H, 6-H), 3.64 (d, J3,4 = 3.8 Hz, 2 H, 3-H),
1.52, 1.43, 1.37, 1.34 (4 s, 24 H, 8 CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 112.1, 109.8, [2 s, 4 C(CH3)2], 105.2 (d, C-1), 85.7 (d,
C-2), 80.4 (d, C-4), 73.8 (d, C-5), 68.1 (t, C-6), 57.9 (d, C-3), 27.0,
26.8, 26.4, 25.2 (4 q, 8 CH3) ppm.
According to general procedure II, triflate 9 (500 mg, 1.0 mmol),
sodium sulfide (475 mg, 2.0 mmol), molecular sieves (500 mg) and
MeCN (6 mL) gave, after purification by flash chromatography
(pentane/EtOAc, 3:1, 1% Et3N), the thioether 25 (316 mg, 86%)
identical to that described above.
(Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-β-
D-allopyranosid-3-
yl)(methyl 2,3,4-tri-O-benzyl-6-deoxy-α- -mannopyranosid-6-yl)-
D
sulfane (26): According to general procedure I, thiol 13-SH (iso-
lated thiol derived from deprotection of thioacetate 13, 78 mg,
0.16 mmol) and triflate 10 (55 mg, 0.11 mmol) gave, after purifica-
tion by flash chromatography (pentane/EtOAc, 5:1), the thioether
26 (77 mg, 85%) as a colourless oil. [α]2D2 = +20.5 (c = 2.2, in
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.50–7.18 (m, 25 H, Ar-
H), 5.43 (s, 1 H, PhCH), 4.84, 4.52 (2 d, J = 11.1 Hz, 2 H, PhCH2),
4.80, 4.74 (2 d, J = 12.4 Hz, 2 H, PhCH2), 4.75 (d, J1,2 = 7.9 Hz,
1 H, 1II-H), 4.73, 4.68 (2 d, J = 12.4 Hz, 2 H, PhCH2), 4.70 (d, J1,2
= 1.5 Hz, 1 H, 1I-H), 4.59, 4.56 (2 d, J = 11.9 Hz, 2 H, PhCH2),
According to general procedure II, triflate 8 (660 mg, 1.7 mmol),
sodium sulfide (811 mg, 3.4 mmol), molecular sieves (50 mg) and
MeCN (6 mL) gave, after purification by flash chromatography
(pentane/EtOAc, 5:1, 1% Et3N), the thioether 23 (375 mg, 86%)
identical to that described above.
(Methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-
id-2-yl)(1,2:5,6-di-O-isopropylidene-3-deoxy-α- -glucofuranos-3-yl)-
sulfane (24): According to general procedure I, thioacetate 14
D-mannopyranos-
D
(123 mg, 0.34 mmol) and triflate 9 (297 mg, 0.59 mmol) gave, after 4.33 (dd, J5,6Ј = 5.2, J6,6Ј = 10.5 Hz, 1 H, 6ЈII-H), 4.01 (atd, Jat
=
purification by flash chromatography (pentane/EtOAc, 4:1 Ǟ 3:1),
9.7, J5,6Ј = 5.2 Hz, 1 H, 5II-H), 3.86 (at, J = 4.0 Hz, 1 H, 3II-H),
the thioether 24 (174 mg, 75%) as a colourless oil. [α]2D0 = –28.8 (c
3.81–3.78 (m, 2 H, 3I-H, 4I-H), 3.78–3.73 (m, 2 H, 2I-H, 5I-H), 3.68
(at, J = 10.0 Hz, 1 H, 6II-H), 3.63 (dd, J3,4 = 3.8, J4,5 = 9.3 Hz, 1
1
= 1.0, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.50–7.26 (m,
10 H, Ar-H), 5.78 (d, J1,2 = 3.5 Hz, 1 H, 1II-H), 5.61 (s, 1 H, H, 4II-H), 3.56 (s, 3 H, OCH3), 3.52 (dd, J1,2 = 7.9, J2,3 = 4.4 Hz,
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1961

I. Cumpstey et al.
FULL PAPER
1 H, 2II-H), 3.29 (dd, J5,6Ј = 1.8, J6,6Ј = 13.8 Hz, 1 H, 6ЈI-H), 3.19
(s, 3 H, OCH3), 3.01 (dd, J5,6 = 8.9, J6,6Ј = 13.8 Hz, 1 H, 6I-H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 137.5, 138.3, 138.5, 138.6,
138.8 (5 s, 5 Ar-C), 129.0, 128.4, 128.4, 128.3, 128.2, 127.9, 127.8,
(Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-
id-3-yl)(3-deoxy-1,2:5,6-di-O-isopropylidene-α-
yl)sulfane (29): According to general procedure I, thioacetate 19
(75 mg, 0.17 mmol) and triflate 8 (105 mg, 0.27 mmol) gave, after
D
-mannopyranos-
D
-glucofuranos-3-
127.8, 127.7, 127.7, 127.6, 127.5, 126.4 (13 d, Ar-CH), 102.7 (d, C- purification by flash chromatography (toluene Ǟ toluene/EtOAc,
1II), 101.6 (d, PhCH), 98.9 (d, C-1I), 80.4, 78.0 (2 d, C-3I, C-4I),
12:1), the thioether 29 (89 mg, 81%) as a colourless oil. [α]2D1
=
79.2 (d, C-4II), 77.5 (d, C-2II), 75.1, 72.9, 72.2, 72.2 (4 t, 4 PhCH2), –10.9 (c = 1.0, in CHCl3); δH (500 MHz, CDCl3): δ = 7.56–7.53
74.9 (d, C-2I), 72.3 (d, C-5I), 69.3 (t, C-6II), 64.5 (d, C-5II), 57.4, (m, 2 H, Ar-H), 7.41–7.31 (m, 8 H, Ar-H), 5.72 (d, J1,2 = 3.5 Hz,
54.7 (2 q, 2 OCH3), 50.1 (d, C-3II), 35.9 (t, C-6I) ppm. MS (ES+): 1 H, H-1II), 5.64 (s, 1 H, CHPh), 4.87 (d, J1,2 = 3.5 Hz, 1 H, H-
m/z (%) = 873 (21) [M + K+], 857 (92) [M + Na+] 852 (100) [M +
2II), 4.70 (s, 2 H, PhCH2), 4.65 (s, 1 H, H-1I), 4.40 (dat, J = 6.3 Hz,
NH4+]. HRMS: calcd. for C49H58O10SN (MNH4+) 852.3776; found Jat = 8.5 Hz, 1 H, H-5II), 4.25 (m, 1 H, H-6ЈI), 4.19–4.12 (m, 2 H,
852.3764.
H-4II, H-6ЈII), 3.97 (dd, J3,4 = 11.0 Hz, J4,5 = 8.3 Hz, 1 H, H-4I),
3.92 (dd, J5,6 = 6.3 Hz, J6,6Ј = 8.3 Hz, 1 H, H-6II), 3.85–3.79 (m, 3
H, H-2I, H-5I, H-6I), 3.65 (d, J3,4 = 3.5 Hz, 1 H, H-3II), 3.50 (dd,
J2,3 = 3.0 Hz, J3,4 = 11.0 Hz, 1 H, H-3I), 3.36 (s, 3 H, OCH3), 1.46,
1.40, 1.33, 1.11 [4 s, 12 H, 2 C(CH3)2]; δC (125 MHz, CDCl3): δ =
137.7, 137.6 (2 s, Ar-C), 128.9, 128.5, 128.3, 128.2, 128.1, 126.2 (6
d, Ar-CH), 111.8, 109.3 [2 s, 2 C(CH3)2], 104.9 (d, C-1II), 101.9 (d,
CHPh), 98.5 (d, C-1I), 86.5 (d, C-2II), 80.8 (d, C-4II), 79.9 (d, C-
2I), 79.7 (d, C-4I), 74.3 (d, C-5II), 74.1 (t, PhCH2), 69.0 (t, C-6I),
68.2 (t, C-6II), 65.7 (d, C-5I), 54.9 (q, OCH3), 53.9 (d, C-3II), 49.0
(d, C-3I), 26.8, 26.2, 25.3 [3 q, 2 C(CH3)2]. MS (ES+): m/z (%) =
669 (6) [M + K+] 653 (100) [M + Na+]. HRMS: calcd. for
C33H42O10SNa [MNa+] 653.2391; found 653.2385.
(Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-β-
yl)(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-
D
-allopyranosid-3-
D
-mannopyr-
anosid-2-yl)sulfane (27): According to general procedure I,
thioacetate 16 (150 mg, 0.35 mmol) and triflate 9 (264 mg,
0.52 mmol) gave, after purification by flash chromatography (pent-
ane/EtOAc, 4:1), the thioether 27 (150 mg, 60%) as a colourless
oil. [α]2D3 = –118 (c = 1.0, in CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 7.55–7.05 (m, 20 H, Ar-H), 5.57, 5.54 (2 s, 2 H, 2 PhCH), 4.96,
4.67 (2 d, J = 11.5 Hz, 2 H, PhCH2), 4.75–4.71 (m, 3 H, 1II-H, 3II-
H, PhCHHЈ), 4.58 (d, J1,2 = 0.9 Hz, 1 H, 1I-H), 4.52–4.42 (m, 2
H, 5II-H, 6ЈII-H), 4.38 (br. d, J2,3 = 4.9 Hz, 1 H, 2I-H), 4.32 (dd,
J5,6Ј = 4.8, J6,6Ј = 10.3 Hz, 1 H, 6ЈI-H), 4.19 (d, J = 13.0 Hz, 1 H,
PhCHHЈ), 3.94 (at, J = 9.5 Hz, 1 H, 4I-H), 3.90 (at, J = 10.2 Hz,
1 H, 6I-H), 3.81 (dd, J3,4 = 3.1, J4,5 = 8.8 Hz, 1 H, 4II-H), 3.77 (at,
J = 9.8 Hz, 1 H, 6II-H), 3.72 (dd, J2,3 = 4.9, J3,4 = 9.9 Hz, 1 H, 3I-
H), 3.59 (dd, J1,2 = 8.1, J2,3 = 4.8 Hz, 1 H, 2II-H), 3.54, 3.56 (2 s,
6 H, 2 OCH3), 3.29 (atd, Jat = 9.7, J5,6Ј = 4.8 Hz, 1 H, 5I-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.2, 138.1, 137.7, 137.6 (4 s,
4 Ar-C), 128.9, 128.5, 128.4, 128.4, 128.2, 128.0, 127.7, 127.5,
127.2, 126.2, 126.1 (11 d, Ar-CH), 104.1 (d, C-1I), 101.5, 101.4,
101.4 (3 d, 2 PhCH, C-1II), 81.2 (d, C-4II), 78.2 (d, C-4I), 76.7 (d,
C-2II), 76.3 (d, C-3I), 70.3 (t, 2 PhCH2), 69.2 (t, C-6II), 68.7 (t, C-
6I), 68.1 (d, C-5I), 63.5 (d, C-5II), 57.4, 57.0 (2 q, 2 OCH3), 49.0
(d, C-2I), 46.5 (d, C-3II) ppm. MS (ES+): m/z (%) = 1507 (10) [2M
+ Na+], 765 (100) [M + Na+]. HRMS: calcd. for C42H46O10SNa
[MNa+] 765.2704; found 765.2687.
Bis(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-β-D-allopyranos-
id-3-yl)sulfane (30): According to general procedure II, triflate 10
(500 mg, 1.0 mmol), sodium sulfide (475 mg, 2.0 mmol), molecular
sieves (500 mg) and MeCN (6 mL) gave, after purification by flash
chromatography (pentane/EtOAc, 3:1, 1% Et3N), the thioether 30
(331 mg, 90%) as a colourless oil. [α]2D1 = –112 (c = 1.0, in CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.52–7.12 (m, 20 H, Ar-H), 5.57
(s, 2 H, PhCH), 4.76, 4.24 (2 d, J = 12.2 Hz, 4 H, PhCH2), 4.72
(at, J = 4.0 Hz, 2 H, 3-H), 4.67 (d, J1,2 = 8.1 Hz, 2 H, 1-H), 4.49
(atd, Jat = 9.6, J5,6Ј = 5.4 Hz, 2 H, 5-H), 4.41 (dd, J5,6Ј = 5.4, J6,6Ј
= 10.4 Hz, 2 H, 6Ј-H), 3.79 (dd, J3,4 = 3.3, J4,5 = 9.1 Hz, 2 H, 4-
H), 3.75 (at, J = 10.3 Hz, 2 H, 6-H), 3.51 (s, 6 H, OCH3), 3.45 (dd,
J1,2 = 8.1, J2,3 = 4.8 Hz, 2 H, 2-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.8, 137.7 (2 s, 4 Ar-C), 129.0, 128.4, 128.2, 127.8,
127.4, 126.1 (6 d, Ar-CH), 101.7 (d, PhCH), 101.3 (d, C-1), 81.3
(d, C-4), 76.7 (d, C-2), 70.2 (t, PhCH2), 69.2 (t, C-6), 63.5 (d, C-
(Methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-
anosid-2-yl)(3-deoxy-1,2:5,6-di-O-isopropylidene-α- -glucofuranos-
D-mannopyr-
5), 57.5 (q, OCH3), 46.0 (d, C-3) ppm. MS (MALDI): m/z = 781 [M
D
+
+ K+], 765 [M + Na+]. HRMS: calcd. for C42H50O10SN (MNH4
760.3150; found 760.3142.
)
3-yl)sulfane (28): According to general procedure I, thioacetate 17
(217 mg, 0.50 mmol) and triflate 8 (284 mg, 0.72 mmol) gave, after
purification by flash chromatography (pentane/EtOAc, 8:1 Ǟ 5:1),
the thioether 28 (300 mg, 94%) as a colourless oil. [α]2D3 = +13.2 (c
= 1.0, in CHCl3); δH (400 MHz, CDCl3): δ = 7.50–7.48 (m, 2 H,
Ar-H), 7.40–7.24 (m, 8 H, Ar-H), 5.73 (d, J1,2 = 3.5 Hz, 1 H, H-
1II), 5.62 (s, 1 H, CHPh), 4.96 (d, J1,2 = 1.1 Hz, 1 H, H-1I), 4.92,
4.75 (2 d, J = 12.1 Hz, 2 H, PhCH2), 4.87 (d, J1,2 = 3.5 Hz, 1 H,
H-2II), 4.41 (dat, Jat = 5.9 Hz, J = 8.7 Hz, 1 H, H-5II), 4.24–4.14
(m, 4 H, H-6ЈII, H-3II or H-4II, H-5I, H-6ЈI), 4.07 (at, J = 8.9 Hz,
1 H, H-4I), 3.96 (dd, J5,6 = 5.7 Hz, J6,6Ј = 8.6 Hz, 1 H, H-6II), 3.84–
3.78 (m, 2 H, H-3I, H-6I), 3.59–3.56 (m, 2 H, H-2I, H-3II or H-4II),
3.34 (s, 3 H, OCH3), 1.48, 1.43, 1.35, 1.18 [4 s, 12 H, 2 C(CH3)2];
δC (125 MHz, CDCl3): δ = 138.6, 137.6 (2 s, 2 Ar-C), 129.0, 128.5,
128.3, 127.7, 127.7, 126.2 (6 d, 6 Ar-CH), 111.9, 109.4 [2 s, 2
C(CH3)2], 104.9 (d, C-1II), 103.2 (d, C-1I), 101.7 (d, CHPh), 86.2
(d, C-2II), 80.7 (d, C-4I), 80.6, 74.8 (2 d, C-4II, C-5I), 74.3 (d, C-
5II), 73.5 (t, PhCH2), 69.0 (t, C-6I), 68.2 (t, C-6II), 64.2 (d, C-3I),
55.3, 53.0 (2 d, C-2I, C-3II), 55.0 (q, OCH3), 27.0, 26.8, 26.3, 25.5
[4 q, 2 C(CH3)2]. MS (ES+): m/z (%) = 669 (13) [M + K+], 653
(100) [M + Na+]. HRMS: calcd. for C33H42O10SNa [MNa+]
653.2391; found 653.2386.
Bis(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-D-mannopyr-
anosid-2-yl)sulfane (31): According to general procedure II, purified
triflate 11 (141 mg, 0.28 mmol), sodium sulfide (210 mg,
0.88 mmol), molecular sieves (300 mg) and MeCN (3 mL) gave, af-
ter purification by flash chromatography (pentane/EtOAc, 10:1 Ǟ
7:1 Ǟ 5:1, 1% Et3N), the thioether 31 (66 mg, 64%) as a colourless
oil. [α]2D2 = +26.1 (c = 1.0, in CHCl3); δH (500 MHz, CDCl3): δ =
7.53–7.51 (m, 4 H, Ar-H), 7.42–7.28 (m, 16 H, Ar-H), 5.65 (s, 2 H,
PhCH), 5.04 (d, J1,2 = 1.0 Hz, 2 H, H-1), 4.92, 4.67 (2 d, J =
11.8 Hz, 4 H, PhCH2), 4.27–4.16 (m, 6 H, H-3, H-4 or H-5, H-6Ј),
3.85–3.79 (m, 4 H, H-4 or H-5, H-6), 3.53 (dd, J1,2 = 1.0 Hz, J2,3
= 4.1 Hz, 2 H, H-2), 3.19 (s, 6 H, OCH3); δC (125 MHz, CDCl3):
δ = 138.8, 137.7 (2 s, Ar-C), 129.0, 128.4, 128.3, 127.7, 127.7, 126.1
(6 d, Ar-CH), 103.1 (d, C-1), 101.6 (d, PhCH), 80.7, 75.6, 64.1 (3
d, C-3, C-4, C-5), 73.6 (t, PhCH2), 69.0 (t, C-6), 54.8 (q, OCH3),
54.2 (d, C-2). MS (ES+): m/z (%) = 781 (6) [M + K+], 765 (100)
[M + Na+]. HRMS: calcd. for C42H46O10SNa [MNa+] 765.2704;
found 765.2693.
Bis(methyl 2,3,6-tri-O-benzoyl-4-deoxy-β-D-glucopyranosid-4-yl)sul-
fane (32) and Bis(methyl 2,3,6-tri-O-benzoyl-4-deoxy-β-
D-glucopyr-
1962
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1951–1970

Non-Glycosidically Linked Pseudodisaccharides
anosid-4-yl)disulfane (35): According to general procedure II, trifl-
ate 12 (206 mg, 0.32 mmol), sodium sulfide (156 mg, 0.65 mmol),
molecular sieves (200 mg) and MeCN (4 mL) gave, after purifica-
tion by flash chromatography (two columns, pentane/EtOAc, 3:1,
1% Et3N; then CH2Cl2/Et2O, 30:1), the thioether 32 (75 mg, 46%)
as white crystals, m.p. 248–249 °C (iPrOH/CH2Cl2). [α]2D2 = +82.4
and recovery of unreacted starting material, presumably due to the
low solubility of the protected pseudodisaccharides in the NH3/
THF mixture.
Bis(methyl 6-deoxy-α-D-mannopyranosid-6-yl)sulfane (46): Follow-
ing general procedure III, benzylated pseudodisaccharide 20
(46 mg, 0.05 mmol) gave, with THF (2 mL), ammonia (ca. 10 mL),
sodium (ca. 80 mg); then acetylation and chromatography, hexa-
acetate 36 (23 mg, 73%) as a colourless oil.
1
(c = 1.0, in CHCl3). H NMR (400 MHz, CDCl3): δ = 8.01 (d, J
= 7.1 Hz, 4 H, Ar-H), 7.95 (d, J = 7.1 Hz, 4 H, Ar-H), 7.86 (d, J
= 7.1 Hz, 4 H, Ar-H), 7.58 (at, J = 7.4 Hz, 2 H, Ar-H), 7.48–7.20
(m, 16 H, Ar-H), 5.59 (dd, J2,3 = 9.3, J3,4 = 11.0 Hz, 2 H, 3-H),
5.28 (dd, J1,2 = 7.6, J2,3 = 9.3 Hz, 2 H, 2-H), 4.78 (dd, J5,6Ј = 1.9,
J6,6Ј = 11.7 Hz, 2 H, 6Ј-H), 4.60 (dd, J5,6 = 6.0, J6,6Ј = 11.7 Hz, 2
H, 6-H), 4.54 (d, J1,2 = 7.6 Hz, 2 H, 1-H), 3.85 (ddd, J4,5 = 10.2,
J5,6 = 6.0, J5,6Ј = 1.9 Hz, 2 H, 5-H), 3.33 (s, 6 H, OCH3), 3.30 (at,
J = 10.6 Hz, 2 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.0, 165.6, 165.2 (3 s, 3 C=O), 133.4, 133.4, 133.2 (3 d, Ar-CH),
129.9, 129.9, 129.8, 129.3, 128.7, 128.3 (6 s, d, Ar-C, CH), 101.6
(d, C-1), 76.0 (d, C-5), 73.0 (d, C-2), 72.5 (d, C-3), 63.8 (t, C-6),
56.7 (q, OCH3), 47.9 (d, C-4) ppm. MS (ES+): m/z (%) = 1033 (100)
[M + Na+]. HRMS: calcd. for C56H50O16SNa [MNa+] 1033.2712;
found 1033.2712.
Hexaacetate 36 (23 mg, 0.036 mmol) was dissolved in MeOH
(1.5 mL). Sodium (2 mg, 0.09 mmol) was dissolved in MeOH and
the resulting solution added to the solution of pseudodisaccharide.
The mixture was stirred at room temp. for 2 h, after which time,
TLC (EtOAc/MeOH, 9:1) showed the presence of a single compo-
nent (Rf = 0.1). Dowex resin (H+) was added, then the mixture
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (EtOAc/MeOH, 4:1) to give the un-
protected pseudodisaccharide 46 (10 mg, 72%) as a white solid.
1
[α]2D3 = +94.4 (c = 0.5, in MeOH). H NMR (400 MHz, CD3OD):
δ = 4.59 (d, J1,2 = 1.6 Hz, 2 H, 1-H), 3.77 (dd, J1,2 = 1.6, J2,3
=
3.3 Hz, 2 H, 2-H), 3.61 (dd, J3,4 = 9.2, J2,3 = 3.3 Hz, 2 H, 3-H),
3.59 (atd, J5,6Ј = 2.0, Jat = 8.7 Hz, 2 H, 5-H), 3.53 (at, J = 9.2 Hz,
2 H, 4-H), 3.40 (s, 6 H, OCH3), 3.11 (dd, J5,6Ј = 2.0, J6,6Ј = 13.7 Hz,
2 H, 6Ј-H), 2.79 (dd, J5,6 = 8.4, J6,6Ј = 13.7 Hz, 2 H, 6-H) ppm.
13C NMR (100 MHz, CD3OD): δ = 102.6 (d, C-1), 74.8 (d, C-5),
72.6 (d, C-3), 72.1 (d, C-2), 71.6 (d, C-4), 55.2 (q, OCH3), 35.8 (t,
C-6) ppm. MS (ES+): m/z (%) = 409 (100) [M + Na+]. HRMS:
calcd. for C14H26O10S [MNa+] 409.1139; found 409.1140.
An elimination product was also isolated (28 mg, 18%) identical to
that obtained in the preparation of 18.[44]
Disulfide 35 was obtained as a colourless oil (10 mg, 6%). [α]2D2
=
1
–70.6 (c = 0.5, in CHCl3). H NMR (400 MHz, CDCl3): δ = 8.16–
7.18 (m, 30 H, Ar-H), 5.65 (at, J = 10.1 Hz, 2 H, 3-H), 5.42 (at, J
= 8.7 Hz, 2 H, 2-H), 4.92 (dd, J5,6Ј = 2.2, J6,6Ј = 12.0 Hz, 2 H, 6Ј-
H), 4.38 (dd, J5,6 = 5.9, J6,6Ј = 12.0 Hz, 2 H, 6-H), 4.14 (br. s, 2 H,
1-H), 3.95 (ddd, J4,5 = 10.4, J5,6 = 5.9, J5,6Ј = 2.2 Hz, 2 H, 5-H),
3.30 [br. m (obsd.), 2 H, 4-H], 3.29 (s, 6 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.2, 165.6, 165.3 (3 s, 3 C=O), 133.6,
133.4, 133.2 (3 d, Ar-CH), 130.1, 130.0, 129.8, 129.5, 129.2, 128.7,
128.6, 128.4 (8 s, d, Ar-C, CH), 101.3 (d, C-1), 73.5 (d, C-5), 73.0
(d, C-2), 72.0 (d, C-3), 64.2 (t, C-6), 56.8 (q, OCH3), 52.4 (br. d,
C-4) ppm. MS (ES+): m/z (%) = 1065 (100) [M + Na+]. HRMS:
calcd. for C56H50O16S2Na [MNa+] 1065.2432; found 1065.2394.
(Methyl
6-deoxy-α-
D-mannopyranosid-6-yl)(3-deoxy-D-glucopyr-
anos-3-yl)sulfane
(47):
Pseudodisaccharide 21
(123 mg,
0.170 mmol) was dissolved in THF (1.5 mL) and cooled to –78 °C
under N2. NH3 (ca. 20 mL) was condensed into the flask and Na
(ca. 125 mg, 5.4 mmol) was added. The mixture turned deep blue.
After 2 min, MeOH (150 µL) was added. After a further 2 min, the
reaction was quenched by the addition of NH4Cl(s), and the mix-
ture warmed to room temp. The mixture was partitioned between
water (40 mL) and EtOAc (3ϫ30 mL). The combined organic ex-
tracts were dried (Na2SO4), filtered, and concentrated in vacuo.
TLC (EtOAc) showed the presence of a major component (Rf =
0.2). The residue was purified by flash column chromatography
(EtOAc).
General Procedure III: Deprotection by Dissolving-Metal Reduction,
Followed by Acetylation: Ammonia was condensed into a flask co-
oled to –78 °C and sodium was added. The metal quickly dissolved
to give a dark blue solution. The protected pseudodisaccharide was
dissolved in THF and added by cannula to the vigorously stirred
reducing solution. MeOH was added in some cases. The mixture
was stirred at –78 °C for a short time (typically 2–10 min), after
which time ammonium chloride (solid) was added to quench the
reaction mixture and destroy the blue colour. The cooling bath was
removed and the ammonia was allowed to evaporate and then the
residue left under vacuum.
The major component was dissolved in TFA (90%, 1 mL) and
stired at room temp. After 1 h, water (2 mL) was added, and the
mixture concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc/MeOH, 4:1), to give the unpro-
tected pseudodisaccharide 47 (12 mg, 19%) as a colourless oil
(glucose: α/β, 1:1). The α and β descriptors refer to the two pseudo-
disaccharides containing α- and β-glucose residues, respectively.
The residue was dissolved in pyridine, and Ac2O was added. The
mixture was stirred overnight, after which time, TLC (pentane/
EtOAc, 1:1) showed the presence of a major carbohydrate compo-
nent. The reaction was worked up and the residue purified by flash
column chromatography (pentane/EtOAc, 1:1, 1% Et3N) to give
the peracetate.
Selected data: 1H NMR (500 MHz, D2O): δ = 5.23 (d, J1,2
3.5 Hz, 1 H, 1IIα-H), 4.73 (s, 2 H, 1Iα-H, 1Iβ-H), 4.65 (d, J1,2
=
=
7.7 Hz, 1 H, 1IIβ-H), 3.93–3.47 (m), 3.44 (s, 6 H, 2 OCH3), 3.26
(dd, J1,2 = 7.7, J2,3 = 10.8 Hz, 1 H, 2IIβ-H), 3.20–3.17 (m, 2 H, 6ЈI-
H), 2.97–2.89 (m, 3 H, 3IIα-H, 6I-H), 2.71 (at, J = 10.2 Hz, 1 H,
3IIβ-H) ppm. 13C NMR (data from HSQC, 500 MHz, D2O): δ =
101.6 (C-1I), 97.9 (C-1IIβ), 92.2 (C-1IIα), 61.5, 61.7 (C-6IIα, C-6IIβ),
56.0 (C-3IIβ), 55.7 (OCH3), 52.5 (C-3IIα), 32.4 (C-6I) ppm. MS
(ES+): m/z (%) = 395 (100) [M + Na+]. HRMS: calcd. for
C13H24O10S [MNa+] 395.0982; found 395.0976.
Alternatively, the THF solution of protected pseudodisaccharide
was cooled to –78 °C and ammonia was condensed into the flask.
Sodium was added to the vigorously stirred solution and slowly
dissolved to give a blue colour. MeOH was added (see Table 3).
The mixture was stirred at –78 °C for a short time. Further sodium
was added if necessary to maintain the blue colour. Then ammo-
nium chloride was added to quench and the reaction mixture was
processed as described above. This procedure could give lower
product yields than the reverse addition procedure described above
(Methyl 2-deoxy-β-D-mannopyranosid-2-yl)(methyl 6-deoxy-α-D-
mannopyranosid-6-yl)sulfane (48): Following general procedure III,
benzylated pseudodisaccharide 22 (46 mg, 0.05 mmol) gave, with
THF (2 mL), ammonia (ca. 10 mL), sodium (ca. 120 mg); then
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1963

I. Cumpstey et al.
acetylation and chromatography, hexaacetate 37 (23 mg, 64%) as a trated in vacuo. TLC (EtOAc) showed the presence of a major com-
FULL PAPER
colourless oil.
ponent (Rf = 0.2). The residue was purified by flash column
chromatography (EtOAc Ǟ EtOAc/MeOH, 10:1).
Hexaacetate 37 (18 mg, 0.028 mmol) was deprotected as described
for 46 to give the unprotected pseudodisaccharide 48 (10 mg, 92%)
as a white solid. [α]2D3 = –2.8 (c = 0.5, in MeOH). 1H NMR
(400 MHz, CD3OD): δ = 4.59 (d, J1,2 = 1.6 Hz, 1 H, 1II-H), 4.58
(d, J1,2 = 1.5 Hz, 1 H, 1I-H), 3.84 (dd, J5,6Ј = 2.4, J6,6Ј = 11.9 Hz,
1 H, 6ЈI-H), 3.76 (dd, J1,2 = 1.6, J2,3 = 3.2 Hz, 1 H, 2II-H), 3.72
The major component was dissolved in TFA (90%, 2 mL) and
stirred at room temp. After 1 h, water (2 mL) was added, and the
mixture concentrated in vacuo. The residue was purified on a
Waters Sep-pak cartridge eluting with water, to give the unprotec-
ted pseudodisaccharide 50 (11 mg, 38%) as a colourless oil (gluc-
(dd, J2,3 = 4.4, J3,4 = 9.3 Hz, 1 H, 3I-H), 3.65–3.53 (m, 4 H, 3II-H, ose: α/β, 1:1). The α and β descriptors refer to the two pseudodisac-
4II-H, 5II-H, 6I-H), 3.51, 3.42 (2 s, 6 H, 2 OCH3), 3.40 [dd (obsd.), charides containing α- and β-glucose residues, respectively. 1H
J1,2 = 1.5, J2,3 = 4.4 Hz, 1 H, 2I-H], 3.37 (at, J = 9.3 Hz, 1 H, 4I- NMR (400 MHz, CD3OD): δ = 5.18 (d, J1,2 = 3.5 Hz, 1 H, 1II
-
-
α
H), 3.18 (ddd, J4,5 = 9.3, J5,6 = 6.2, J5,6Ј = 2.4 Hz, 1 H, 5I-H), 3.15
(dd, J5,6Ј = 1.8 Hz, 1 H, 6ЈII-H), 2.81 (dd, J5,6 = 8.3, J6,6Ј = 14.0 Hz,
1 H, 6II-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 103.4 (d, C-
1I), 102.7 (d, C-1II), 78.9 (d, C-5I), 75.1 (d, C-3I), 74.4 (d, C-5II),
H), 4.64 (m, 2 H, 1Iα-H, 1Iβ-H), 4.52 (d, J1,2 = 7.5 Hz, 1 H, 1II
β
I
I
H), 3.58, 3.58 (2 s, 6 H, OCH3 α, OCH3 β), 3.53–3.87 (m, 11 H,
6IIα-H, 6ЈIIα-H, 6IIβ-H, 6ЈIIβ-H, 6Iα-H, 6ЈIα-H, 6Iβ-H, 6ЈIβ-H), 3.27–
3.44 [m (obsd.), 8 H, 2Iα-H, 2Iβ-H], 3.18–3.22 (m, 2 H), 3.12 (dd,
72.4 (d, C-3II), 72.1 (d, C-2II), 71.4 (d, C-4II), 69.8 (d, C-4I), 63.0 J1,2 = 7.5, J2,3 = 10.8 Hz, 1 H, 2IIβ-H), 2.91 (at, J = 10.7 Hz, 1 H,
(t, C-6I), 57.0, 55.5 (2 q, 2 OCH3), 57.0 (d, C-2I), 37.1 (t, C-6II) 3IIα-H), 2.54 (at, J = 10.4 Hz, 1 H, 3IIβ-H) ppm. 13C NMR
ppm. MS (ES+): m/z (%) = 795 (20) [2M + Na+], 409 (100) [M
+ Na+]. HRMS: calcd. for C14H26O10S [MNa+] 409.1139; found
409.1144.
(100 MHz, CD3OD): δ = 102.6, 102.6 (2 d, C-1Iα, C-1Iβ), 99.3 (d,
C-1IIβ), 93.1 (d, C-1IIα), 80.3, 78.8, 78.8, 74.5, 74.3, 74.2, 73.9, 71.5,
70.0, 69.9, 69.3 (11 d, C-2IIα, C-2IIβ, C-4IIα, C-4IIβ, C-5IIα, C-5II
,
β
C-3Iα, C-3Iβ, C-4Iα, C-4Iβ, C-5Iα, C-5Iβ), 63.0, 62.9, 62.8 (3 t, C-
Bis(3-deoxy-D-glucopyranos-3-yl)sulfane (49): Protected pseudodi-
6IIα,C-6II
,
β
C-6Iα, C-6Iβ), 60.3 (d, C-3IIβ), 57.1 (q, OCH3 α
,
I
saccharide 23 (42 mg, 0.08 mmol) was dissolved in a mixture of
TFA (1.8 mL) and water (0.2 mL). After 1 h, water was added, and
the mixture concentrated in vacuo.
I
OCH3 β), 56.0 (d, C-3IIα), 55.3, 53.9 (2 d, C-2Iα, C-2Iβ) ppm. MS
(ES+): m/z (%) = 1139 (5) [3M + Na+], 767 (25) [2M + Na+], 395
(100) [M + Na+]. HRMS: calcd. for C13H24O10S [MNa+] 395.0982;
found 395.0984.
The residue was dissolved in Ac2O (2 mL), and sodium acetate
(3 mg) was added. The mixture was heated at 150 °C for 40 min,
then allowed to cool to room temp. The mixture was diluted with
EtOAc (25 mL), and washed with water (25 mL). The organic
phase was dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography (EtOAc/
pentane, 1:1 Ǟ EtOAc) to give the octaacetate 38 (52 mg, 92%) as
a colourless oil.
Bis(methyl 2-deoxy-β-D-mannopyranosid-2-yl)sulfane (51): Follow-
ing general procedure III, benzylated pseudodisaccharide 25
(316 mg, 0.43 mmol) gave, with THF (3 mL), ammonia (ca.
20 mL), sodium (ca. 280 mg) and MeOH (40 µL); then acetylation
and chromatography, hexaacetate 39 (167 mg, 61%) as a colourless
oil. Also starting material 25 was recovered after the reduction step
by partitioning the residue between toluene and water. Chromatog-
raphy (pentane/EtOAc, 2:1) on the organic phase gave starting ma-
terial 25 (70 mg, 22%).
Octaacetate 38 (47 mg, 0.068 mmol) was deprotected as described
for 46 to give the unprotected pseudodisaccharide 49 (19 mg, 78%)
as a white solid (α,α/α,β/β,β, 1:2:1). The and descriptors refer
α
β
Hexaacetate 39 (167 mg, 0.26 mmol) was deprotected as described
for 46 to give the unprotected pseudodisaccharide 51 (98 mg, 97%)
as a white solid. [α]2D1 = –136 (c = 1.0, in MeOH). 1H NMR
(500 MHz, D2O): δ = 4.76 (d, J1,2 = 1.3 Hz, 2 H, 1-H), 3.89 (dd,
to signals from α- and β-configured glucose residues, respectively.
1H NMR (400 MHz, CD3OD): δ = 5.16 (d, J1,2 = 3.3 Hz, 2 H, 1α-
H, 1α-H), 4.52 (d, J1,2 = 7.5 Hz, 2 H, 1β-H, 1β-H), 3.86–3.65 (m,
10 H, 5-H, 5-H, 6α-H, 6α-H, 6β-H, 6β-H, 6Јα-H, 6Јα-H, 6Јβ-H, 6Јβ-
H), 3.46 (dd, J1,2 = 3.5, J2,3 = 11.0 Hz, 1 H, 2α-H), 3.44 (dd, J1,2
= 3.5, J2,3 = 11.0 Hz, 1 H, 2α-H), 3.40–3.27 [m (obsd.), 6 H, 5-H,
5-H, 4α-H, 4α-H, 4β-H, 4β-H], 3.15 (dd, J1,2 = 7.5, J2,3 = 10.8 Hz,
1 H, 2β-H), 3.14 (dd, J1,2 = 7.5, J2,3 = 10.8 Hz, 1 H, 2β-H), 3.02
(at, 10.7 Hz, 1 H, 3α-H), 3.01 (at, J = 10.7 Hz, 1 H, 3α-H), 2.67 (at,
J = 10.5 Hz, 1 H, 3β-H), 2.65 (at, J = 10.6 Hz, 1 H, 3β-H) ppm.
13C NMR (100 MHz, CD3OD): δ = 99.3 (d, C-1β, C-1β), 93.2 (d,
C-1α, C-1α), 80.4, 80.3 (2 d, C-5, C-5), 75.2, 74.9 (2 d, C-2β, C-2β),
73.9 (d, C-5, C-5), 72.0, 72.3 (2 d, C-2α, C-2α), 70.8, 70.6, 70.1, 69.9
(4 d, C-4α, C-4α, C-4β, C-4β), 63.0 (t, C-6α, C-6α, C-6β, C-6β), 58.8,
57.1 (2 d, C-3β, C-3β), 54.8, 53.3 (2 d, C-3α, C-3α) ppm. MS (ES+):
m/z (%) = 1097 (5) [3M + Na+], 739 (30) [2M + Na+], 381 (100)
J5,6Ј = 2.2, J6,6Ј = 12.4 Hz, 2 H, 6Ј-H), 3.82 (dd, J2,3 = 4.4, J3,4
=
9.4 Hz, 2 H, 3-H), 3.68 (dd, J5,6 = 6.4, J6,6Ј = 12.4 Hz, 2 H, 6-H),
3.57 (s, 6 H, OCH3), 3.49 (dd, J1,2 = 1.3, J2,3 = 4.4 Hz, 2 H, 2-H),
3.43 (at, J = 9.6 Hz, 2 H, 4-H), 3.35 (ddd, J4,5 = 9.6, J5,6 = 6.4,
J5,6Ј = 2.2 Hz, 2 H, 5-H) ppm. 13C NMR (125 MHz, D2O): δ =
101.8 (d, C-1), 77.2 (d, C-5), 73.5 (d, C-3), 68.7 (d, C-4), 61.5 (t,
C-6), 57.7 (d, C-2), 57.4 (q, OCH3) ppm. MS (ES+): m/z (%) =
795 (92) [2M + Na+], 409 (100) [M + Na+]. HRMS: calcd. for
C28H52O20S2Na (2MNa+) 795.2386; found 795.2377.
(Methyl 3-deoxy-β-D-allopyranosid-3-yl)(methyl 6-deoxy-α-D-man-
nopyranosid-6-yl)sulfane (52): Following general procedure III, ben-
zylated pseudodisaccharide 26 (134 mg, 0.16 mmol) gave, with
[M + Na+]. HRMS: calcd. for C12H22O10S [MNa+] 381.0826; found THF (2 mL), ammonia (ca. 10 mL), sodium (ca. 140 mg), MeOH
381.0819.
(40 µL); then acetylation and chromatography, hexaacetate 40
(59 mg, 58%) as a colourless oil.
(Methyl
2-deoxy-β-D-mannopyranosid-2-yl)(3-deoxy-D-glucopyr-
anos-3-yl)sulfane (50): Pseudodisaccharide 24 (49 mg, 0.077 mmol)
was dissolved in THF (2 mL) and cooled to –78 °C under N2. NH3
(ca. 10 mL) was condensed into the flask and Na (ca. 75 mg,
3.2 mmol) was added. The mixture turned deep blue. After 1 h
Hexaacetate 40 (59 mg, 0.092 mmol) was deprotected as described
for 46 to give the unprotected pseudodisaccharide 52 (33 mg, 92%)
as a white solid. [α]2D3 = +42.2 (c = 1.0, in MeOH). 1H NMR
(500 MHz, D2O): δ = 4.73 (d, 1 H, 1I-H), 4.50 (d, J1,2 = 8.0 Hz, 1
H, 1II-H), 3.93 (dd, J1,2 = 1.5, J2,3 = 3.2 Hz, 1 H, 2I-H), 3.90–3.86
(m, 2 H, 6ЈII-H), 3.76–3.60 (m, 7 H, 2II-H, 3II-H, 6II-H, 3I-H, 5I-
20 min, the reaction was quenched by the addition of NH4Cl(s)
,
and the mixture warmed to room temp. The mixture was parti-
tioned between water (50 mL) and EtOAc (5ϫ25 mL). The com-
bined organic extracts were dried (Na2SO4), filtered, and concen-
H), 3.53, 3.44 (2 s, 6 H, 2 OCH3), 3.18 (dd, J5,6Ј = 2.2, J6,6Ј
=
13.8 Hz, 1 H, 6ЈI-H), 2.94 (dd, J5,6 = 8.1, J6,6Ј = 13.8 Hz, 1 H, 6I-
1964
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1951–1970

Non-Glycosidically Linked Pseudodisaccharides
H) ppm. 13C NMR (125 MHz, D2O): δ = 102.4 (d, C-1II), 101.6 refer to the two pseudodisaccharides containing α- and β-glucose
1
(d, C-1I), 76.1, 72.7, 70.9, 70.8, 70.5, 70.0, 67.4 (7 d, C-2II, C-4II, residues, respectively: H NMR (400 MHz, D2O): δ = 5.21 (d, J1,2
C-5II, C-2I, C-3I, C-4I, C-5I), 61.6 (t, C-6II), 57.6, 55.6 (2 q, 2 = 3.5 Hz, 1 H, 1IIα-H), 5.09–5.08 (m, 2 H, 1Iα-H, 1Iβ-H), 4.64 (d,
OCH3), 56.8 (d, C-3II), 36.8 (t, C-6I) ppm. MS (ES+): m/z (%) =
795 (10) [2M + Na+], 409 (100) [M + Na+]. HRMS: calcd. for
C28H52O20S2Na (2MNa+) 795.2386; found 795.2386; calcd. for
C14H26O10SNa [MNa+] 409.1128; found 409.1139.
J1,2 = 7.7 Hz, 1 H, 1IIβ-H), 4.10–4.07 (m, 2 H), 3.89–3.68 (m, 9 H,
6Iα-H, 6IIα-H, 6Iβ-H, 6IIβ-H, 6ЈIα-H, 6ЈIIα-H, 6ЈIβ-H, 6ЈIIβ-H), 3.62–
3.48 (m, 6 H, 2IIα-H), 3.44–3.36 (m, 7 H, 2Iα-H, 2Iβ-H, 4IIα-H, 4II
-
β
H, OCH3), 3.33 (s, 3 H, OCH3), 3.25 (dd, J1,2 = 7.7, J2,3 = 10.8 Hz,
1 H, 2IIβ-H), 2.97 (at, J = 10.9 Hz, 1 H, 3IIα-H), 2.75 (at, J =
10.5 Hz, 1 H, 3IIβ-H) ppm. 13C NMR (125 MHz, D2O): δ = 102.1,
102.0 (2 d, C-1Iα, C-1Iβ), 97.1 (d, C-1IIβ), 91.4 (d, C-1IIα), 78.3, 72.3,
70.5, 69.8, 69.7 (5 d), 73.0 (d, C-2IIβ), 72.8 (d, C-2IIα), 68.7, 68.4 (2
d, C-4IIα, C-4IIβ), 67.8 (d), 61.0, 60.8, 60.7 (3 t, C-6Iα, C-6IIα, C-6Iβ,
C-6IIβ), 57.3 (d, C-3IIβ), 54.8 (q, 2 OCH3), 54.0 (C-3IIα), 52.3, 52.4
(2 d, C-2Iα, C-2Iβ) ppm. MS (ES+): m/z (%) = 395 (100) [M + Na+].
HRMS: calcd. for C13H24O10SNa [M + Na+] 395.0982; found
395.0970.
(Methyl 3-deoxy-β-D-allopyranosid-3-yl)(methyl 2-deoxy-β-D-man-
nopyranosid-2-yl)sulfane (53): Following general procedure III, ben-
zylated pseudodisaccharide 27 (118 mg, 0.16 mmol) gave, with
THF (2 mL), ammonia (ca. 10 mL), sodium (ca. 120 mg), MeOH
(40 µL); then acetylation and chromatography, hexaacetate 41
(77 mg, 76%) as a colourless oil.
Hexaacetate 41 (77 mg, 0.12 mmol) was deprotected as described
for 46 to give the unprotected pseudodisaccharide 53 (36 mg, 77%)
as a white solid. [α]2D3 = –86.6 (c = 1.0, in MeOH). 1H NMR
(Methyl
3-deoxy-α-D-mannopyranosid-3-yl)(3-deoxy-D-glucopyr-
(500 MHz, D2O): δ = 4.77 [m (obsd.), 1 H, 1I-H], 4.46 (d, J1,2
=
anos-3-yl)sulfane (55): Thioether 29 (52 mg, 0.08 mmol) was dis-
solved in THF (3 mL) under Ar and cooled to –78 °C. Ammonia
(ca. 15 mL) was condensed into the reaction flask and MeOH
(30 µL, 1.7 mmol) and sodium (42 mg, 1.8 mmol) were added. Af-
ter approximately 10 s, the reaction mixture turned dark blue. After
a further 2 min, the reaction was quenched by the addition of
NH4Cl (105 mg, 3 mmol) and left to warm to room temp. The
crude residue was purified by column chromatography (EtOAc),
yielding the triol as a colourless oil (28 mg, 75%).
7.9 Hz, 1 H, 1II-H), 3.92–3.86 (m, 4 H, 6ЈII-H, 6ЈI-H), 3.72–3.62
(m, 5 H, 2II-H, 3II-H, 6II-H, 6I-H), 3.58, 3.53 (2 s, 6 H, 2 OCH3),
3.50–3.46 (m, 2 H, 4-H, 2I-H), 3.37 (ddd, J = 2.3, J = 6.4, J =
9.6 Hz, 1 H, 5-H) ppm. 13C NMR (125 MHz, D2O): δ = 102.5 (d,
C-1II), 101.7 (d, C-1I), 77.3, 76.2, 73.3, 70.8, 68.6, 67.5, 68.6 (6 d,
C-2II, C-4II, C-5II, C-3I, C-4I, C-5I), 61.5, 61.5 (2 t, C-6II, C-6I),
59.0 (d, C-3II), 58.5 (d, C-2I), 57.5, 57.4 (2 q, 2 OCH3) ppm. MS
(ES+): m/z (%) = 795 (35) [2M + Na+], 409 (100) [M + Na+].
HRMS: calcd. for C14H26O10SNa [MNa+] 409.1128; found
409.1143.
A solution of 90% aqueous trifluoroacetic acid (1.5 mL TFA and
0.16 mL H2O) was added to the triol (17 mg, 0.04 mmol). After
25 min, the reaction mixture was diluted with H2O (5 mL) and con-
centrated in vacuo in order to remove the TFA. TLC (EtOAc/
MeOH, 10:1) indicated the complete consumption of starting mate-
rial (Rf = 0.5) and the formation of two major products (Rf =
0.2 and 0.1). The remaining water was removed by repeated co-
evaporation with toluene and the resulting residue was dried under
high vacuum for 1 h.
(Methyl
2-deoxy-α-D-mannopyranosid-2-yl)(3-deoxy-D-glucopyr-
anos-3-yl)sulfane (54): Thioether 28 (134 mg, 0.21 mmol) was dis-
solved in THF (3 mL) under Ar and cooled to –78 °C. Ammonia
(ca. 20 mL) was condensed into the reaction flask and MeOH
(70 µL, 1.70 mmol) and sodium (67 mg, 2.9 mmol) were added. Af-
ter a few minutes, the reaction mixture turned dark blue. After
2 min, the reaction was quenched by addition of NH4Cl (160 mg,
3 mmol) and left to warm to room temp. for the ammonia to evapo-
rate. The crude residue was purified by column chromatography
(EtOAc), to give the triol as a colourless oil (82 mg, 85%).
The residue was dissolved in pyridine (1 mL) and Ac2O (1 mL),
and after 16 h, TLC (pentane/EtOAc, 1:2) indicated the formation
of a major product (Rf = 0.3). The reaction mixture was diluted
with EtOAc (20 mL) and washed with 1  HCl (3ϫ20 mL). The
combined aqueous phases were extracted with EtOAc (2ϫ20 mL).
The combined organic phases were then washed with NaHCO3
(satd. aq., 3ϫ20 mL). The combined aqueous phases were ex-
tracted with EtOAc (2ϫ20 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was purified by column chromatography (pentane/EtOAc, 1:1
Ǟ 1:2) to give heptaacetate 43 (23 mg; α/β, 1:1; 91%) as a colour-
less oil.
A mixture of TFA (2 mL) and water (0.23 mL) was added to the
triol (36 mg, 0.08 mmol). After 4 min, the reaction mixture was di-
luted with H2O (10 mL) and concentrated in vacuo. TLC (EtOAc/
MeOH, 10:1) indicated the complete consumption of starting mate-
rial (Rf = 0.5) and the formation of at least two major products
(Rf = 0.2 and 0). The remaining water was removed by repeated
co-evaporation with toluene and the residue was dried under high
vacuum for 45 min.
The residue was dissolved in pyridine (3 mL) and Ac2O (1.5 mL),
and after 13 h, TLC (toluene/EtOAc, 2:1) indicated the formation
of two major products (Rf = 0.4 and 0.3). The reaction mixture
was diluted with EtOAc (20 mL) and washed with HCl (1 ,
3ϫ20 mL). The combined aqueous phases were extracted with
EtOAc (2ϫ20 mL). The combined organic phases were then
washed with NaHCO3 (satd. aqueous, 3ϫ20 mL). The combined
aqueous phases were extracted with EtOAc (2ϫ20 mL). The com-
bined organic phases were then dried (Na2SO4), filtered, and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (pentane/EtOAc, 2:1 Ǟ 1:1) to give heptaacetate 42 (25 mg,
α/β 1:1; 47%) as a colourless oil.
Heptaacetate 43 (23 mg, 0.03 mmol) was deprotected as described
for 46 and the crude product purified by column chromatography
(EtOAc/MeOH, 5:1) to give the unprotected pseudodisaccharide 55
(10 mg; α/β, 1:1.4, 75%) as a white solid; The and descriptors
α
β
refer to the two pseudodisaccharides containing α- and β-glucose
1
residues, respectively. H NMR (400 MHz, D2O): δ = 5.21 (d, J1,2
= 3.5 Hz, 1 H, 1IIα-H), 4.71 (m, 2 H, 1Iα-H, 1Iβ-H), 4.64 (d, J1,2
=
7.6 Hz, 1 H, 1IIβ-H), 4.03–4.02 (m, 2 H, 2Iα-H, 2Iβ-H), 3.89–3.57
(m, 14 H, 2IIα-H, 4Iα-H, 4Iβ-H, 5Iα-H, 5Iβ-H, 5IIα-H or 5IIβ-H, 6Iα-
H, 6IIα-H, 6Iβ-H, 6IIβ-H, 6ЈIα-H, 6ЈIIα-H, 6ЈIβ-H, 6ЈIIβ-H), 3.50 (m,
1 H, 5IIα-H or 5IIβ-H), 3.41–3.33 (m, 8 H, 2 OCH3, 4IIα-H, 4IIβ-H),
3.26 (dd, J1,2 = 7.6, J2,3 = 10.8 Hz, 1 H, 2IIβ-H), 3.21–3.17 (m, 2
H, 3Iα-H, 3Iβ-H), 3.04 (at, J = 10.6 Hz, 1 H, 3IIα-H), 2.81 (at, J =
10.6 Hz, 1 H, 3IIβ-H) ppm. 13C NMR (125 MHz, D2O): δ = 99.9
(d, C-1Iα, C-1Iβ), 97.1 (d, C-1IIβ), 91.4 (d, C-1IIα), 78.4 (d, C-5IIα or
Heptaacetate 42 (19 mg, 0.03 mmol) was deprotected as described
for 46 and the crude product purified by column chromatography
(EtOAc/MeOH, 4:1) to give the unprotected pseudodisaccharide 54
(9 mg; α/β, 1:1; 83%) as a white solid; The and descriptors
α
β
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1965

I. Cumpstey et al.
FULL PAPER
C-5IIβ), 73.6, 72.3, 70.7, 66.5, 66.4 (5 d), 73.2 (d, C-2IIβ), 71.0, 70.9 Bis(methyl 2-deoxy-β-
D
-mannopyranosid-2-yl) Sulfoxide (59): The
(2 d, C-2Iα, C-2Iβ), 68.9, 68.5 (2 d, C-4IIα, C-4IIβ), 61.2, 61.0, 60.9 thioether 51 (25 mg, 0.064 mmol) was dissolved in a mixture of
(3 t, C-6Iα, C-6IIα, C-6Iβ, C-6IIβ), 55.8 (d, C-3IIβ), 54.6 (q, 2 OCH3), CH2Cl2 (0.5 mL) and MeOH (2 mL) and cooled to 0 °C. mCPBA
52.2 (d, C-3IIα), 50.9, 50.6 (2 d, C-3Iα, C-3Iβ) ppm. MS (ES+): m/z
(70%, 32 mg, 0.13 mmol) was added, and it dissolved slowly. The
(%) = 395 (100) [M + Na+]. HRMS: calcd. for C13H24O10SNa [M mixture was stirred at 0 °C for 45 min, after which time TLC
+ Na+] 395.0982; found 395.0974.
Bis(methyl 3-deoxy-β- -allopyranosid-3-yl)sulfane (56): Following
(CMAW) showed complete conversion of the starting material (Rf
= 0.3) into a single product (Rf = 0.2). Ethanethiol (10 mL) was
added, then the mixture was concentrated in vacuo. The residue
was purified by flash column chromatography (CMAW) to give the
sulfoxide 59 (26 mg, 99%) as a colourless oil. [α]2D3 = –96.9 (c = 1.0,
D
general procedure III, benzylated pseudodisaccharide 30 (692 mg,
0.93 mmol) gave, with THF (6 mL), ammonia (ca. 30 mL), sodium
(ca. 280 mg), MeOH (72 µL); then acetylation and chromatog-
raphy, hexaacetate 44 (337 mg, 57%) as colourless crystals.
1
in MeOH). H NMR (500 MHz, D2O): δ = 5.08 (d, J1,2 = 2.8 Hz,
1 H, 1II-H), 4.91 (d, J1,2 = 2.2 Hz, 1 H, 1I-H), 4.49 (dd, J1,2 = 2.2,
J2,3 = 4.8 Hz, 1 H, 2I-H), 4.22 (dd, J2,3 = 4.8, J3,4 = 8.8 Hz, 1 H, 3I-
H), 4.16 (dd, J2,3 = 5.5, J3,4 = 8.0 Hz, 1 H, 3II-H), 4.09 [m (obsd.), 1
H, 2II-H], 4.07 (at, J = 8.6 Hz, 1 H, 4I-H), 3.98 (dd, J5,6Ј = 2.8,
J6,6Ј = 12.1 Hz, 1 H, 6ЈI-H), 3.96 (dd, J5,6Ј = 3.3, J6,6Ј = 12.0 Hz, 1
H, 6ЈII-H), 3.87 (at, J = 7.8 Hz, 1 H, 4II-H), 3.82–3.86 (m, 2 H, 6I-
H, 6II-H), 3.66 (ddd, J4,5 = 7.7, J5,6 = 6.9, J5,6Ј = 3.3 Hz, 1 H, 5II-
H), 3.58 (s, 3 H, OCH3), 3.57 (m, 1 H, 5I-H), 3.52 (s, 3 H, OCH3)
ppm. 13C NMR (125 MHz, D2O): δ = 100.2 (d, C-1II), 99.8 (d, C-
1I), 77.2 (d, C-5I), 76.8 (d, C-5II), 73.2 (d, C-3I), 69.7 (d, C-3II),
68.1 (d, C-4II), 67.3 (d, C-4I), 61.4, 61.2 (2 t, C-6I, C-6II), 61.0 (d,
C-2II), 59.5 (d, C-2I), 56.9, 56.8 (2 q, 2 OCH3) ppm. MS (ES+): m/z
(%) = 827 (8) [2M + Na+], 425 (100) [M + Na+]. HRMS: calcd.
for C14H26O11SNa [MNa+] 425.1088; found 425.1090.
Hexaacetate 44 (337 mg, 0.53 mmol) was deprotected as described
for 46 to give the unprotected pseudodisaccharide 56 (192 mg,
1
94%) as a white solid. [α]2D3 = –28.1 (c = 1.0, in MeOH). H NMR
(500 MHz, D2O): δ = 4.40 (d, J1,2 = 8.1 Hz, 2 H, 1-H), 3.82–3.77
(m, 4 H, 4-H, 6Ј-H), 3.64–3.60 (m, 6 H, 2-H, 5-H, 6-H), 3.56 (at,
J = 4.3 Hz, 2 H, 3-H), 3.46 (s, 6 H, OCH3) ppm. 13C NMR
(125 MHz, D2O): δ = 101.9 (d, C-1), 75.6 (d, C-5), 70.2 (d, C-2),
66.9 (d, C-4), 60.8 (t, C-6), 59.4 (d, C-3), 57.0 (q, OCH3) ppm. MS
(ES+): m/z (%) = 1181 (4) [3M + Na+], 795 (23) [2M + Na+], 409
(100) [M + Na+]. HRMS: calcd. for C14H26O10SNa [MNa+]
409.1139; found 409.1150.
Bis(methyl 2-deoxy-α-D-mannopyranosid-2-yl)sulfane (57): Follow-
ing general procedure III, benzylated pseudodisaccharide 31
(77 mg, 0.10 mmol) gave, with THF (2.5 mL), ammonia (ca.
35 mL), sodium (52 mg), MeOH (35 µL); then acetylation and
chromatography, column chromatography (pentane/EtOAc, 2:1 Ǟ
1:1, 1% Et3N), hexaacetate 45 (53 mg, 80%) as an off-white solid.
Bis(methyl 2-deoxy-β-D-mannopyranosid-2-yl) Sulfone (60): The
thioether 51 (18 mg, 0.042 mmol) was dissolved in a mixture of
CH2Cl2 (0.5 mL) and MeOH (2 mL) and cooled to 0 °C. mCPBA
(70%, 46 mg, 0.19 mmol) was added. The mixture was then stirred
at room temp. for 6 h, after which time TLC (CMAW) showed
complete conversion of the starting material (Rf = 0.3) into a single
product (Rf = 0.2). The mixture was concentrated in vacuo and
the residue was purified by flash column chromatography (EtOAc/
MeOH, 10:1) to give the sulfone 60 (15 mg, 77%) as a white solid.
Hexaacetate 45 (31 mg, 0.05 mmol) was deprotected as described
for 46 and purified by column chromatography (EtOAc/MeOH,
5:1) to yield the unprotected pseudodisaccharide 57 (14 mg, 76%)
as a white solid. [α]2D1 = +49.8 (c = 1.0, in MeOH). 1H NMR
(500 MHz, D2O): δ = 5.08 (br. s, 2 H, 1-H), 4.10 (dd, J2,3 = 4.8,
J3,4 = 9.4 Hz, 2 H, 3-H), 3.85 (dd, J5,6Ј = 2.2, J6,6Ј = 12.3 Hz, 2 H,
6Ј-H), 3.74 (dd, J5,6 = 5.5, J6,6Ј = 12.3 Hz, 2 H, 6-H), 3.62–3.52 (m,
1
[α]2D3 = –33.2 (c = 0.5, in MeOH). H NMR (500 MHz, D2O): δ =
5.04 (d, J1,2 = 2.4 Hz, 2 H, 1-H), 4.58 (dd, J1,2 = 2.4, J2,3 = 4.6 Hz,
2 H, 2-H), 4.24 (dd, J2,3 = 4.6, J3,4 = 8.2 Hz, 2 H, 3-H), 4.09 (at,
J = 7.9 Hz, 2 H, 4-H), 3.99 (dd, J5,6Ј = 3.2, J6,6Ј = 12.2 Hz, 2 H,
6Ј-H), 3.90 (dd, J5,6 = 6.9, J6,6Ј = 12.2 Hz, 2 H, 6-H), 3.65 (atd,
J5,6Ј = 3.2, Jat = 7.2 Hz, 2 H, 5-H), 3.60 (s, 6 H, OCH3) ppm. 13C
NMR (125 MHz, D2O): δ = 99.1 (d, C-1), 77.2 (d, C-5), 70.4 (d,
C-3), 66.8 (d, C-4), 65.1 (d, C-2), 60.9 (t, C-6), 56.7 (q, OCH3)
ppm. MS (ES+): m/z (%) = 859 (12) [2M + Na+], 441 (100) [M +
Na+]. HRMS: calcd. for C14H26O12SNa [MNa+] 441.1037; found
441.1050.
4 H, 4-H, 5-H), 3.39 (s, 6 H, OCH3), 3.34 (dd, J1,2 = 1.1, J2,3
=
4.8 Hz, 2 H, 2-H) ppm. 13C NMR (125 MHz, D2O): δ = 101.5 (d,
C-1), 72.9 (d, C-5), 69.5 (d, C-3), 67.5 (d, C-4), 60.7 (t, C-6), 54.8
(q, OCH3), 54.2 (d, C-2) ppm. MS (ES+): m/z (%) = 795 (48) [2M
+ Na+], 409 (100) [M + Na+]. HRMS: calcd. for C28H52O20S2Na
(2MNa+) 795.2386; found 795.2382; calcd. for C14H26O10SNa
[MNa+] 409.1139; found 409.1122.
Bis(methyl 4-deoxy-β-D-glucopyranosid-4-yl)sulfane (58): Sodium
(6 mg, 0.23 mmol) was dissolved in MeOH (3 mL). This solution
was added to a suspension of hexabenzoate 32 (40 mg, 0.04 mmol)
in MeOH (3 mL) and BuOH (1.5 mL). The mixture was heated at
50 °C for 22 h, after which time, Dowex resin (H+) was added, the
mixture was filtered, and the filtrate concentrated in vacuo. The
residue was purified by flash column chromatography (CHCl3/
MeOH, 3:1) followed by purification on Sep-Pak eluting with water
Bis(methyl 3-deoxy-β-D-allopyranosid-3-yl) Sulfoxide (61): The thio-
ether 56 (28 mg, 0.073 mmol) was dissolved in a mixture of CH2Cl2
(0.5 mL) and MeOH (2 mL) and cooled to 0 °C. mCPBA (70%,
36 mg, 0.15 mmol) was added, and it dissolved slowly. The mixture
was stirred at 0 °C for 45 min, after which time TLC (CMAW)
showed complete conversion of the starting material (Rf = 0.8) into
a single product (Rf = 0.7). Ethanethiol (20 mL) was added, then
Ǟ water/MeOH, 8:2 to give the unprotected pseudodisaccharide
1
58 (12 mg, 78%) as a white solid. H NMR (500 MHz, D2O): δ = the mixture was concentrated in vacuo. The residue was purified
4.33 (d, J1,2 = 8.2 Hz, 2 H, 1-H), 4.14 (dd, J5,6Ј = 2.0, J6,6Ј
12.3 Hz, 2 H, 6Ј-H), 3.95 (dd, J5,6 = 5.4, J6,6Ј = 12.3 Hz, 2 H, 6-
H), 3.56 [m (obsd.), 2 H, 5-H], 3.55 (s, 6 H, OCH3), 3.50 (dd, J2,3
=
by flash column chromatography (CMAW) to give the sulfoxide 61
(26 mg, 89%) as a colourless oil. [α]2D3 = –50.5 (c = 1.0, in MeOH).
1H NMR (500 MHz, D2O): δ = 5.04 (d, J1,2 = 5.6 Hz, 1 H, 1II-H),
= 9.0, J3,4 = 10.4 Hz, 2 H, 3-H), 3.27 (dd, J1,2 = 8.2, J2,3 = 9.0 Hz, 4.80 (d, J1,2 = 4.9 Hz, 1 H, 1I-H), 4.25 (at, J = 4.2 Hz, 1 H, 4I-H),
2 H, 2-H), 2.84 (at, J = 10.7 Hz, 2 H, 4-H) ppm. 13C NMR 4.20 (aq, J = 5.4 Hz, 1 H, 5I-H), 4.11–4.03 (m, 3 H, 3I-H, 2II-H,
(125 MHz, D2O): δ = 103.6 (d, C-1), 77.2 (d, C-5), 75.9 (d, C-3),
74.7 (d, C-2), 62.2 (t, C-6), 57.7 (q, OCH3), 48.7 (d, C-4) ppm. MS
(ES+): m/z (%) = 1181 (40) [3M + Na+], 795 (100) [2M + Na+],
409 (90) [M + Na+]. HRMS: calcd. for C14H26O10S [MNa+]
409.1139; found 409.1151.
4II-H), 3.98–3.94 (m, 2 H, 3II-H, 5II-H), 3.90 (at, J = 4.4 Hz, 1 H,
2I-H), 3.78 (dd, J5,6Ј = 4.7, J6,6Ј = 12.1 Hz, 1 H, 6ЈII-H), 3.73 (dd,
J5,6Ј = 5.3, J6,6Ј = 12.0 Hz, 1 H, 6ЈI-H), 3.69–3.64 (m, 2 H, 6I-H,
6II-H), 3.46, 3.45 (2 s, 6 H, 2 OCH3) ppm. 13C NMR (125 MHz,
D2O): δ = 102.4 (d, C-1I), 102.1 (d, C-1II), 79.4 (d, C-5I), 78.1 (d,
1966
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1951–1970

Non-Glycosidically Linked Pseudodisaccharides
C-5II), 69.3 (d, C-2II), 67.9 (d, C-2I), 65.9 (d, C-4I), 65.7 (d, C-4II), (dd, J5,6 = 6.5, J6,6Ј = 12.2 Hz, 2 H, 6-H), 3.69 (ddd, J4,5 = 9.3, J5,6
62.0, 61.9 (2 t, C-6I, C-6II), 59.2 (d, C-3II), 58.0 (d, C-3I), 57.3, 57.2
= 6.5, J5,6Ј = 2.0 Hz, 2 H, 5-H), 3.43 (s, 6 H, OCH3) ppm. 13C
(2 q, 2 OCH3) ppm. MS (ES+): m/z (%) = 425 (100) [M + Na+]. NMR (125 MHz, D2O): δ = 95.0 (d, C-1), 73.1 (d, C-5), 68.9 (d,
HRMS: calcd. for C14H26O11SNa [MNa+] 425.1088; found C-3), 68.2 (d, C-2), 66.6 (d, C-4), 61.0 (t, C-6), 55.3 (q, OCH3)
425.1079.
ppm. MS (ES+): m/z (%) = 441 (100) [M + Na+]. HRMS: calcd.
for C14H26O12SNa [MNa+] 441.1037; found 441.1053.
Bis(methyl 3-deoxy-β-D-allopyranosid-3-yl) Sulfone (62): The thio-
ether 56 (20 mg, 0.052 mmol) was dissolved in a mixture of CH2Cl2
(0.5 mL) and MeOH (2 mL) and cooled to 0 °C. mCPBA (70%,
50 mg, 0.20 mmol) was added. The mixture was then stirred at
room temp. for 4 h, after which time TLC (CMAW) showed com-
plete conversion of the starting material (Rf = 0.8) into a single
product (Rf = 0.9). The mixture was concentrated in vacuo and
the residue was purified by flash column chromatography (EtOAc/
MeOH, 10:1) to give the sulfone 62 (22 mg, 99%) as a white solid.
Bis(methyl 3-deoxy-α-D-glucopyranosid-3-yl)sulfane (67): MeOH
(5 mL) was cooled to 0 °C and AcCl (75 µL) was added. This solu-
tion was added to the pseudodisaccharide 49 (190 mg, 0.53 mmol),
and the mixture heated at 65 °C. After 3 d, Et3N (1.5 mL) was
added, and the solvents removed in vacuo.
The residue was dissolved in a mixture of pyridine (2 mL) and ace-
tic anhydride (2 mL) and stirred at room temp. After 24 h, the mix-
ture was concentrated in vacuo and the residue purified by flash
column chromatography (EtOAc/pentane, 2:1) to give first the α,α
diglycoside 65 (27 mg, 8%) as a colourless oil; then a mixture of
the α,β diglycoside and β,β diglycoside 66a,b (34 mg, 10%) as a
colourless oil (α,β/β,β ≈ 10:1).
1
[α]2D3 = –68.3 (c = 1.0, in MeOH). H NMR (500 MHz, D2O): δ =
4.85 (d, J1,2 = 2.7 Hz, 2 H, 1-H), 4.54 (atd, J2,4 = 1.4, Jat = 2.5 Hz,
2 H, 4-H), 4.33 (atd, J2,4 = 1.4, Jat = 2.7 Hz, 2 H, 2-H), 4.13 (at, J
= 2.7 Hz, 2 H, 3-H), 4.09 (dat, J4,5 = 2.3, Jat = 6.7 Hz, 2 H, 5-H),
3.76 (dd, J5,6Ј = 6.3, J6,6Ј = 11.7 Hz, 2 H, 6Ј-H), 3.73 (dd, J5,6
=
7.1, J6,6Ј = 11.7 Hz, 2 H, 6-H), 3.48 (s, 6 H, OCH3) ppm. 13C NMR
(125 MHz, D2O): δ = 102.9 (d, C-1), 81.1 (d, C-5), 67.2 (d, C-2),
65.4 (d, C-4), 62.2 (t, C-6), 61.3 (d, C-3), 56.8 (q, OCH3) ppm.
MS (ES+): m/z (%) = 441 (100) [M + Na+]. HRMS: calcd. for
C14H26O12SNa [MNa+] 441.1037; found 441.1053.
The hexaacetate 65 (27 mg, 0.042 mmol) was dissolved in MeOH
(1.5 mL). Sodium (3 mg, 0.13 mmol) was dissolved in MeOH
(1.5 mL), and the resulting solution added to the solution of carbo-
hydrate. The mixture was stirred at room temp. and after 2 h, TLC
(EtOAc/MeOH, 5:1) showed the presence of a single component
(Rf = 0.2). Silica was added to the reaction mixture, then the sol-
vent was removed in vacuo and the residue purified by flash col-
umn chromatography (EtOAc/MeOH, 5:1) to give the unprotected
pseudodisaccharide 67 (15 mg, 92%) as a white solid. [α]2D3 = +174
(J2,4 value obtained from a sine-bell window function.)
Bis(methyl 2-deoxy-α-D-mannopyranosid-2-yl) Sulfoxide (63): Thio-
ether 57 (14 mg, 0.04 mmol) was dissolved in MeOH (1.5 mL) and
CH2Cl2 (0.5 mL) and cooled to 0 °C. mCPBA (70%, 10 mg,
0.04 mmol) was added and after 1 h, TLC (EtOAc/MeOH, 3:1)
indicated the complete consumption of starting material (Rf = 0.3)
and the formation of a major product (Rf = 0.2). The reaction
was quenched by addition of ethanethiol (10 µL) and the reaction
mixture concentrated concentrated in vacuo. The resulting crude
residue was purified twice by column chromatography; first
(CHCl3/MeOH/AcOH/H2O, 60:30:3:5) and then (EtOAc/MeOH,
1
(c = 0.5, in MeOH). H NMR (500 MHz, D2O): δ = 4.84 (d, J1,2
= 3.6 Hz, 2 H, 1-H), 3.86 (dd, J5,6Ј = 2.3, J6,6Ј = 12.2 Hz, 2 H, 6Ј-
H), 3.76 (dd, J5,6 = 5.4, J6,6Ј = 12.2 Hz, 2 H, 6-H), 3.69 (ddd, J4,5
= 9.6, J5,6 = 5.4, J5,6Ј = 2.3 Hz, 2 H, 5-H), 3.63 (dd, J1,2 = 3.6, J2,3
= 11.1 Hz, 2 H, 2-H), 3.42 (s, 6 H, OCH3), 3.42 [m (obsd.), 2 H,
4-H], 3.01 (at, J = 10.8 Hz, 2 H, 3-H) ppm. 13C NMR (125 MHz,
D2O): δ = 99.1 (d, C-1), 73.0 (d, C-5), 70.5 (d, C-2), 68.7 (d, C-4),
61.4 (t, C-6), 55.4 (q, OCH3), 52.2 (d, C-3) ppm. MS (ES+): m/z
(%) = 795 (10) [2M + Na+], 409 (100) [M + Na+]. HRMS: calcd.
for C14H26O10SNa [MNa+] 409.1139; found 409.1140.
5:1) to yield sulfoxide 63 (11 mg, 72%) as a white powder. [α]2D3
=
+41.0 (c = 0.8, in MeOH). 1H NMR (500 MHz, D2O): δ = 5.18 (d,
J1,2 = 1.2 Hz, 1 H, 1I-H), 5.15 (d, J1,2 = 2.6 Hz, 1 H, 1II-H), 4.40
(dd, J2,3 = 5.2, J3,4 = 7.8 Hz, 1 H, 3II-H), 4.36 (dd, J1,2 = 1.2, J3,4
= 7.8 Hz, 1 H, 2I-H), 4.28 (dd, J3,4 = 7.8, J3,4 = 9.3 Hz, 1 H, 3I-
H), 4.09 (dd, J3,4 = 7.8, J4,5 = 9.1 Hz, 1 H, 4II-H), 3.90–3.93 (m, 2
H, 6ЈI-H, 6ЈII-H), 3.69–3.86 (m, 6 H, 5II-H, 5I-H, 6I-H, 6II-H, 2II-
H, 4I-H), 3.46, 3.44 (2 s, 6 H, 2 OCH3) ppm. 13C NMR (125 MHz,
D2O): δ = 98.3 (d, C-1II), 96.1 (d, C-1I), 73.0, 72.5 (2 d, C-5I, C-
5II), 71.0 (d, C-3II), 69.2 (d, C-3I), 67.6 (d, C-4II), 67.5 (d, C-4I),
63.6 (d, C-2II), 62.0 (d, C-2I), 61.4, 60.8 (2 t, C-6I, C-6II), 55.2, 55.1
(2 q, 2 OCH3) ppm. MS (ES+): m/z (%) = 425 (100) [M + Na+].
HRMS: calcd. for C14H26O11SNa [MNa+] 425.1088; found
425.1097.
(Methyl 3-deoxy-α-
D
-glucopyranosid-3-yl)(methyl 3-deoxy-β-
D-gluco-
pyranosid-3-yl)sulfane and Bis(methyl 3-deoxy-β-D-glucopyranosid-
3-yl)sulfane (68a,b): The hexaacetates 66a,b (30 mg, 0.047 mmol)
were deprotected as described for 67, to give the unprotected
pseudodisaccharides 68a,b (18 mg, 99%) as a white solid (α,β/β,β
ca. 10:1). Selected data for α,β compound: The and descriptors
α
β
refer to signals from α- and β-configured glucose residues, respec-
1
tively. H NMR (500 MHz, D2O): δ = 4.84 (d, J1,2 = 3.6 Hz, 1 H,
1α-H), 4.42 (d, J1,2 = 7.8 Hz, 1 H, 1β-H), 3.92 (dd, J5,6Ј = 2.3, J6,6Ј
= 12.3 Hz, 1 H, 6Јβ-H), 3.86 (dd, J5,6Ј = 2.3, J6,6Ј = 12.3 Hz, 1 H,
6Јα-H), 3.71–3.78 (m, 2 H, 6α-H, 6β-H), 3.69 (m, 1 H, 5α-H), 3.63
(dd, J1,2 = 3.6, J2,3 = 11.2 Hz, 1 H, 2α-H), 3.57 (s, 3 H, OCH3),
3.54 (m, 1 H, 5β-H), 3.44 (s, 3 H, OCH3), 3.40–3.47 (m, 2 H, 4α-
H, 4β-H), 3.30 (dd, J1,2 = 7.8, J2,3 = 10.8 Hz, 1 H, 2β-H), 3.02 (at,
J = 10.8 Hz, 1 H, 3α-H), 2.83 (at, J = 10.6 Hz, 1 H, 3β-H) ppm.
13C NMR (125 MHz, D2O): δ = 104.8 (d, C-1β), 99.1 (d, C-1α),
78.8 (d, C-5β), 73.0 (d, C-5α), 72.5 (d, C-2β), 70.4 (d, C-2α), 68.8,
69.2 (2 d, C-4α, C-4β), 61.6 (t, C-6β), 61.4 (t, C-6α), 57.7 (q, OCH3),
55.4, 55.4 (d, q, C-3β, OCH3), 52.9 (d, C-3α) ppm. Selected data
for the β,β compound: 1H NMR (500 MHz, D2O): δ = 4.43 (d, J1,2
= 7.8 Hz, 1 H, 1-H), 2.84 (at, J = 10.6 Hz, 1 H, 3-H) ppm. 13C
Bis(methyl 2-deoxy-α-D-mannopyranosid-2-yl) Sulfone (64): Thio-
ether 57 (13 mg, 0.03 mmol) was dissolved in MeOH (1.5 mL) and
CH2Cl2 (1 mL) and mCPBA (70%, 25 mg, 0.10 mmol) was added.
After 6 h 30 min, TLC (EtOAc/MeOH, 3:1) indicated the complete
consumption of starting material (Rf = 0.3) and the formation of
a major product (Rf = 0.4). The reaction mixture was concentrated
in vacuo and the resulting residue was purified twice by column
chromatography; first (EtOAc/MeOH, 5:1) and then (CMAW) to
yield sulfone 64 (9 mg, 63%) as a white powder. [α]2D3 = +32.0 (c =
0.8, in MeOH). 1H NMR (500 MHz, D2O): δ = 5.45 (d, J1,2
=
1.3 Hz, 2 H, 1-H), 4.43 (dd, J1,2 = 1.3, J2,3 = 5.7 Hz, 2 H, 2-H), NMR (125 MHz, D2O): δ = 55.8 (d, C-3) ppm. MS (ES+): m/z (%)
4.29 (dd, J2,3 = 5.7, J3,4 = 9.0 Hz, 2 H, 3-H), 4.10 (at, J = 9.2 Hz, = 795 (25) [2M + Na+], 409 (100) [M + Na+]. HRMS: calcd. for
2 H, 4-H), 3.89 (dd, J5,6Ј = 2.0, J6,6Ј = 12.2 Hz, 2 H, 6Ј-H), 3.76
C14H26O10SNa [MNa+] 409.1139; found 409.1138.
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1967

I. Cumpstey et al.
FULL PAPER
Methyl 3-O-(1,2:5,6-Di-O-isopropylidene-3-deoxy-α-
D
-glucofuranos- [4 q, 2 C(CH3)2] ppm. MS (ES+): m/z (%) = 1251 (15) [2M + Na+],
3-yl)-4,6-O-benzylidene-2-O-benzyl-α-
D-glucopyranoside
(74):
637 (100) [M + Na+]. HRMS: calcd. for C33H42O11Na [MNa+]
637.2619; found 637.2590.
Alcohol 84 (113 mg, 0.30 mmol) and triflate 8 (180 mg, 0.46 mmol)
were dissolved in DMF (3 mL). Sodium hydride (60% in oil, 24 mg,
0.60 mmol) was added, and the mixture was stirred under N2. After
30 min, TLC (pentane/EtOAc, 2:1) showed complete consumption
of triflate (Rf = 0.8), some alcohol remaining (Rf = 0.5) and the
formation of product (Rf = 0.7) as well as more polar compounds.
The reaction mixture was added to brine (50 mL) and extracted
with Et2O (2ϫ50 mL). The organic phase was dried (Na2SO4), fil-
tered, and concentrated in vacuo. The residue was purified by flash
column chromatography (pentane/EtOAc, 3:1) to give the pseudo-
disaccharide 74 (36 mg, 19%) as a colourless oil. [α]2D1 = –9.2 (c =
1.0, in CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.48–7.29 (m, 10
H, Ar-H), 5.61 (d, J1,2 = 3.7 Hz, 1 H, 1II-H), 5.50 (s, 1 H, PhCH),
4.88, 4.59 (2 d, J = 12.1 Hz, 2 H, PhCH2), 4.77 (d, J1,2 = 3.7 Hz,
1 H, 2II-H), 4.47 (d, J1,2 = 3.7 Hz, 1 H, 1I-H), 4.43 (m, 1 H, 5II-
Bis(3-deoxy-D-glucopyranos-3-yl) Ether (76): The protected pseudo-
disaccharide 69 (223 mg, 0.44 mmol) was dissolved in a mixture of
TFA (3 mL) and water (0.3 mL) and stirred at room temp. After
2 h, water (3 mL) was added, and the mixture concentrated in
vacuo. The residue was purified by flash column chromatography
(CHCl3/MeOH, 4:1) to give the deprotected compounds 76
(126 mg, 83%) as a white solid. Mixture of three compounds: α,α;
α,β; β,β. The and descriptors refer to signals from α- and β-
α
β
configured glucose residues, respectively. Partial data 1H NMR
(500 MHz, D2O): δ = 5.25 (d, J1,2 = 3.7 Hz, 1 H, 1α-H), 4.69 (d,
J1,2 = 7.9 Hz, 1 H, 1β-H), 4.68 (d, J1,2 = 7.9 Hz, 1 H, 1β-H) ppm.
13C NMR (125 MHz, D2O): δ = 96.5, 96.5 (2 d, 2 C-1β), 92.6, 92.6
(2 d, 2 C-1α), 88.4, 88.2 (2 d), 85.7, 85.6 (2 d), 61.2, 61.0 (2 t, C-6)
ppm. MS (ES+): m/z (%) = 1049 (5) [3M + Na+], 707 (30) [2M +
Na+], 365 (100) [M + Na+]. HRMS: calcd. for C12H22O11Na
[MNa+] 365.1054; found 365.1046.
H), 4.38 (d, J3,4 = 2.8 Hz, 1 H, 3II-H), 4.24 (dd, J5,6Ј = 4.8, J6,6Ј
=
10.2 Hz, 1 H, 6ЈI-H), 4.11 (dd, J3,4 = 2.8, J4,5 = 7.6 Hz, 1 H, 4II-
H), 4.06 (dd, J5,6Ј = 6.3, J6,6Ј = 8.6 Hz, 1 H, 6ЈII-H), 4.02–3.98 (m,
2 H, 3I-H, 6II-H), 3.81 (atd, Jat = 10.0, J5,6Ј = 4.8 Hz, 1 H, 5I-H),
3.68 (at, J = 10.3 Hz, 1 H, 6I-H), 3.48 (dd, J1,2 = 3.7, J2,3 = 9.2 Hz,
1 H, 2I-H), 3.43 (at, J = 9.5 Hz, 1 H, 4I-H), 3.34 (s, 3 H, OCH3),
1.44, 1.34, 1.29, 1.12 [4 s, 12 H, 2 C(CH3)2] ppm. 13C NMR
(125 MHz, CDCl3): δ = 138.5, 137.3 (2 s, 2 Ar-C), 129.3, 128.6,
128.4, 128.2, 128.1, 126.0 (6 d, Ar-CH), 111.5, 109.1 [2 s, 2
C(CH3)2], 105.1 (d, C-1II), 101.7 (d, PhCH), 99.1 (d, C-1I), 83.0 (d,
C-3II), 82.5 (d, C-2II), 81.2 (d, C-4II), 80.5 (d, C-2I), 80.1 (d, C-4I),
76.6 (d, C-3I), 74.1 (t, PhCH2), 72.3 (d, C-5II), 69.1 (t, C-6I), 67.4
(t, C-6II), 62.5 (d, C-5I), 55.5 (q, OCH3), 26.8, 26.8, 25.9, 25.7 [4
q, 2 C(CH3)2] ppm. MS (ES+): m/z (%) = 1251 (10) [2M + Na+],
637 (100) [M + Na+]. HRMS: calcd. for C33H42O11Na [MNa+]
637.2619; found 637.2593.
3-O-(3-Deoxy-D-allopyranos-3-yl)-D-glucopyranose (77): Unsym-
metrical pseudodisaccharide 70 (153 mg, 0.30 mmol) was depro-
tected with 90% TFA in an analogous manner to that described
for 76 to give the deprotected compounds 77 (81 mg, 78%) as a
colourless solid. Predominantly a mixture of two compounds:
Glcpα,Allpβ and GlcpβAllpβ, approx 1:1. Smaller trace amounts
of other allose configurations could be seen in 1H NMR spectrum.
Partial data. The and descriptors refer to signals from α- and
α
β
β-configured monosaccharide residues, respectively. 1H NMR
(500 MHz, D2O): δ = 5.25 (d, J1,2 = 3.1 Hz, 1 H, 1IIα-H), 4.93 (d,
J1,2 = 8.2 Hz, 1 H, 1Iβ-H), 4.92 (d, J1,2 = 8.3 Hz, 1 H, 1Iβ-H), 4.69
(d, J1,2 = 7.9 Hz, 1 H, 1IIβ-H) ppm. 13C NMR (125 MHz, D2O): δ
= 95.9 (d, C-1IIβ), 94.2, 94.2 (2 d, 2 C-1Iβ), 92.1 (d, C-1IIα), 87.6,
85.0 (2 d), 83.4, 83.2 (2 d), 61.2, 60.8, 60.7 (3 t, C-6) ppm. MS
(ES+): m/z (%) = 707 (20) [2M + Na+], 365 (100) [M + Na+].
HRMS: calcd. for C12H22O11Na [MNa+] 365.1054; found
365.1046.
Methyl 3-O-(1,2:5,6-Di-O-isopropylidene-3-deoxy-α-
D-glucofuranos-
3-yl)-4,6-O-benzylidene-2-O-benzyl-β- -glucopyranoside
D
(75):
Alcohol 4 (63 mg, 0.17 mmol) and triflate 8 (100 mg, 0.26 mmol)
were dissolved in DMF (2 mL). Sodium hydride (60% in oil, 14 mg,
0.34 mmol) was added, and the mixture was stirred under N2. After
1 h, TLC (pentane/EtOAc, 3:1) showed complete consumption of
triflate (Rf = 0.7), some alcohol remaining (Rf = 0.5) and the for-
mation of product (Rf = 0.6) as well as more polar compounds.
Further triflate 8 (45 mg, 0.11 mmol) was added, along with further
NaH (14 mg, 0.34 mmol). After a further 1 h, the reaction mixture
was added to brine (50 mL) and extracted with Et2O (2ϫ50 mL).
The organic phase was dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy (pentane/EtOAc, 4:1) to give the pseudodisaccharide 75
(47 mg, 45%) as a colourless oil. [α]2D2 = –20.7 (c = 1.0, in CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.50–7.28 (m, 10 H, Ar-H), 5.65
(d, J1,2 = 3.6 Hz, 1 H, 1II-H), 5.53 (s, 1 H, PhCH), 4.88, 4.84 (2 d,
J = 10.5 Hz, 2 H, PhCH2), 4.79 (d, J1,2 = 3.6 Hz, 1 H, 2II-H), 4.42–
4.35 (m, 4 H, 1I-H, 6ЈI-H, 3II-H, 5II-H), 4.07 (dd, J = 2.9, J =
8.1 Hz, 1 H, 4II-H), 4.04 (dd, J5,6Ј = 6.3, J6,6Ј = 8.6 Hz, 1 H, 6ЈII-
H), 3.96 (dd, J5,6 = 6.0, J6,6Ј = 8.6 Hz, 1 H, 6II-H), 3.76 (at, J =
10.2 Hz, 1 H, 6I-H), 3.74 (at, J = 9.0 Hz, 1 H, 3I-H or 4I-H), 3.56
(s, 3 H, OCH3), 3.52 (at, J = 9.4 Hz, 1 H, 3I-H or 4I-H), 3.44–3.38
(m, 2 H, 2I-H, 5I-H), 1.46, 1.25, 1.21, 1.12 [4 s, 12 H, 2 C(CH3)2]
Methyl 2-O-(3-Deoxy-D-glucopyranos-3-yl)-α-D-mannopyranoside
(78): The protected compound 71 (110 mg, 0.18 mmol) was dis-
solved in a mixture of TFA (1.4 mL) and water (0.15 mL), and the
mixture was stirred at room temp. in air. After 20 min, water (5 mL)
was added and the mixture was concentrated in vacuo. Toluene was
then added and the mixture concentrated in vacuo.
The resulting residue was dissolved in a mixture of water (1.5 mL)
and AcOH (0.1 mL), and Pd (10% on C, 10 mg) was added. The
mixture was degassed and stirred under H2. After 20 h, TLC
(EtOAc/MeOH, 4:1) showed a single product (Rf = 0.1). The mix-
ture was filtered through Celite and concentrated in vacuo.
The residue was dissolved in a mixture of acetic anhydride (1 mL)
and pyridine (1 mL), and stirred at room temp. After 17 h, the mix-
ture was added to HCl (1 , 25 mL) and extracted with CH2Cl2
(25 mL). The organic phase was washed with NaHCO3 (satd. aq.
25 mL), then dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography (pen-
tane/EtOAc, 1:3) to give the heptaacetate (94 mg, 81%) as a colour-
less oil.
ppm. 13C NMR (100 MHz, CDCl3): δ = 138.8, 137.2 (2 s, 2 Ar-C), The heptaacetate was deacetylated with NaOMe in MeOH and
129.3, 128.4, 128.4, 127.9, 127.7, 126.0 (6 d, Ar-CH), 111.6, 109.1
purified by flash column chromatography (CMAW) to give the free
[2 s, 2 C(CH3)2], 105.7 (d, C-1I), 105.1 (d, C-1II), 101.5 (d, PhCH), pseudodisaccharide 78 (50 mg, 79%) as a colourless oil; mixture of
83.1, 82.8, 82.6 (3 d, C-2I, C-2II, C-3II), 81.3 (d, C-4II), 79.5, 79.5 two compounds (α/β, 1:1). The and descriptors refer to signals
α
β
(2 d, C-3I, C-4I), 74.9 (t, PhCH2), 72.0 (d, C-5II), 68.8 (t, C-6I), from α- and β-configured glucose residues, respectively. Partial data
67.5 (t, C-6II), 66.2 (d, C-5I), 57.6 (q, OCH3), 26.8, 26.8, 25.9, 25.5
1H NMR (500 MHz, D2O): δ = 5.26 (d, J1,2 = 3.5 Hz, 1 H, 1II
-
α
1968
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1951–1970

Non-Glycosidically Linked Pseudodisaccharides
H), 5.01 (d, J1,2 = 1.5 Hz, 1 H, 1I-H), 5.00 (d, J1,2 = 1.5 Hz, 1 H,
TLC (EtOAc/MeOH, 4:1) showed a single product (Rf = 0.2). The
1I-H), 4.68 (d, J1,2 = 7.9 Hz, 1 H, 1IIβ-H), 3.44, 3.43 (2 s, 6 H, 2 mixture was filtered through Celite and concentrated in vacuo.
OCH3) ppm. 13C NMR (125 MHz, D2O): δ = 100.0, 99.8 (2 d, C-
The residue was dissolved in a mixture of acetic anhydride (1 mL)
1I), 95.9 (d, C-1IIβ), 91.9 (d, C-1IIα), 60.9, 60.7, 60.5 (3 t, C-6), 54.9
and pyridine (1 mL), and stirred at room temp. After 17 h, the mix-
ture was added to HCl (1 , 50 mL) and extracted with EtOAc
(q, OCH3) ppm. MS (ES+): m/z (%) = 735 (15) [2M + Na+], 379
(100) [M + Na+]. HRMS: calcd. for C13H24O11Na [MNa+]
(50 mL). The organic phase was washed with NaHCO3 (satd. aq.
379.1211; found 379.1200.
30 mL), then dried (Na2SO4), filtered, and concentrated in vacuo.
Methyl
3-O-(3-Deoxy-D-glucopyranos-3-yl)-α-D-altropyranoside
The residue was purified by flash column chromatography
(pentane/EtOAc, 2:1) to give the heptaacetate (44 mg, 87%) as a
colourless oil, α:β, 1:1.2.
(79): According to the method described for 78, protected pseudo-
disaccharide 72 (60 mg, 0.098 mmol) was converted to its hepta-
acetate, and then deacetylated with NaOMe in MeOH and purified
by flash column chromatography (CMAW) to give the free pseudo-
disaccharide 79 (25 mg, 72%); mixture of two compounds (α/β,
1:1). The and descriptors refer to signals from α- and β-config-
The heptaacetate (28 mg, 0.043 mmol) was dissolved in a mixture
of MeOH (3 mL) and aqueous ammonia (1.5 mL) and stirred at
room temp. After 90 min, the mixture was concentrated in vacuo.
The residue was purified by Sep-Pak eluting with water, and freeze-
α
β
ured glucose residues, respectively. Partial data. 1H NMR
(400 MHz, D2O): δ = 5.24 (d, J1,2 = 3.6 Hz, 1 H, 1IIα-H), 4.69 (br.
s, 2 H, 1I-H), 4.67 (d, J1,2 = 8.0 Hz, 1 H, 1IIβ-H), 3.42 (s, 6 H, 2
OCH3) ppm. 13C NMR (100 MHz, D2O): δ = 100.8 (d, C-1I), 95.6
(d, C-1IIβ), 91.8 (d, C-1IIα), 60.9, 60.5, 60.3 (3 t, C-6), 55.4 (q,
OCH3) ppm. MS (ES+): m/z (%) = 1091 (5) [3M + Na+], 735 (25)
[2M + Na+], 379 (100) [M + Na+]. HRMS: calcd. for C13H24O11Na
[MNa+] 379.1211; found 379.1203.
dried to give the deprotected compound 82 (11 mg, 70%); The
α
and β descriptors refer to signals from α- and β-configured glucose
1
residues, respectively. Partial data. H NMR (500 MHz, D2O): δ =
5.24 (d, J1,2 = 3.8 Hz, 1 H, 1IIα-H), 4.67 (d, J1,2 = 7.9 Hz, 1 H, 1II
-
β
H), 4.43 (d, J1,2 = 8.0 Hz, 1 H, 1I-H), 4.42 (d, J1,2 = 8.0 Hz, 1 H,
1I-H), 3.41 (s, 6 H, 2 OCH3) ppm. 13C NMR (data from HSQC,
500 MHz, D2O): δ = 104.0 (C-1I), 96.6 (C-1IIβ), 92.8 (C-1IIα) ppm.
MS (ES+): m/z (%) = 735 (10) [2M + Na+], 379 (100) [M + Na+].
HRMS: calcd. for C13H24O11Na [MNa+] 379.1211; found
379.1208.
Methyl 3-O-(3-Deoxy-D-glucopyranos-3-yl)-α-D-mannopyranoside
(80): According to the method described for 78, protected pseudo-
disaccharide 73 (289 mg, 0.47 mmol) was converted to its hepta-
acetate (238 mg, 78%); this was deacetylated with NaOMe in
MeOH and purified by flash column chromatography (CMAW) to
give the free pseudodisaccharide 80 (130 mg, 78%); mixture of two
compounds (α/β, 1:1). The α and β descriptors refer to signals from
Lectin Binding Studies: Banana lectin was prepared from over-ripe
bananas by previously published methods[34,46] or modifications
thereof.[47] Concanavalin A was available from previous studies. Li-
gands other than the pseudodisaccharides described herein were
available from previous studies, or were purchased from Sigma (St.
Louis, MO) or from V-Labs, Inc. (Covington, LA). Lectins and
ligands were dissolved in PBS (10 m sodium phosphate buffer, pH
7.2, 150 m in NaCl, 0.2 m in CaCl2, and 0.04% NaN3). Binding
was determined by isothermal titration calorimetry using a Micro-
Cal VP-ITC calorimeter (Micro-Cal, Northampton, MA, USA) at
25 °C. Data were analysed using Origin ver. 7 software supplied
with the instrument. The lectin in PBS, generally at approx. 0.2 m
in subunits, was titrated with ligand, usually at 20–30 m in the
same buffer. Concentrations and titration volumes were adjusted
so that the titration proceeded to at least a 10-fold excess of ligand
at the expected stoichiometry. Nevertheless, especially for BanLec,
the relatively low binding constants (Ka Ͻ 1000 –1) precluded ob-
taining full saturation or a definite sigmoidal titration curve from
which a definitive stoichiometry can be obtained. In such cases, the
stoichiometry (n) was fixed at 1 for curve-fitting to determine Ka;
n values between about 0.5 and 2–3 had little effect on the Ka value
obtained. However, other thermodynamic parameters, such as mo-
lar enthalpy and entropy of binding cannot be determined accu-
rately, so no attempt was made to assess the effects of ligand struc-
ture on these parameters.
1
α- and β-configured glucose residues, respectively. Partial data. H
NMR (500 MHz, D2O): δ = 5.24 (d, J1,2 = 2.6 Hz, 1 H, 1IIα-H),
4.80 [m (obsd.), 2 H, 1I-H], 4.67 (d, J1,2 = 7.9 Hz, 1 H, 1IIβ-H),
3.41, 3.41 (2 s, 6 H, 2 OCH3) ppm. 13C NMR (125 MHz, D2O): δ
= 101.3 (d, C-1I), 96.1 (d, C-1IIβ), 92.3 (d, C-1IIα), 61.3, 61.1, 61.0
(3 t, C-6), 55.2 (q, OCH3) ppm. MS (ES+): m/z (%) = 1091 (10)
[3M + Na+], 735 (80) [2M + Na+], 379 (100) [M + Na+]. HRMS:
calcd. for C13H24O11Na [MNa+] 379.1211; found 379.1194.
Methyl
3-O-(3-Deoxy-D-glucopyranos-3-yl)-α-D-glucopyranoside
(81): Protected 74 (36 mg, 0.059 mmol) was converted into the hep-
taacetate (31 mg, 81%), a colourless oil, in an identical manner as
described for 75 below (α/β, 1:1.4).
The heptaacetate (31 mg, 0.048 mmol) was converted into the de-
protected compound 81 (14 mg, 81%) in an identical manner as
described for 82. The and descriptors refer to signals from α-
α
β
and β-configured glucose residues, respectively. Partial data. 1H
NMR (500 MHz, D2O): δ = 5.24 (d, J1,2 = 3.7 Hz, 1 H, 1IIα-H),
4.83 (d, J1,2 = 3.7 Hz, 2 H, 1I-H), 4.68 (d, J1,2 = 8.0 Hz, 1 H, 1II
-
β
H), 3.55 (s, 6 H, 2 OCH3) ppm. 13C NMR (data from HSQC,
500 MHz, D2O): δ = 100.0 (C-1I), 96.6 (C-1IIβ), 92.7 (C-1IIα) ppm.
MS (ES+): m/z (%) = 1091 (5) [3M + Na+], 735 (30) [2M + Na+],
379 (100) [M + Na+]. HRMS: calcd. for C13H24O11Na [MNa+]
379.1211; found 379.1225.
Supporting Information (see also the footnote on the first page of
this article): Characterisation data for peracetylated derivatives and
1
copies of the H and 13C spectra for new compounds.
Methyl
3-O-(3-Deoxy-D-glucopyranos-3-yl)-β-D-glucopyranoside
(82): The protected compound 75 (48 mg, 0.078 mmol) was dis-
solved in a mixture of TFA (1.4 mL) and water (0.15 mL), and the
mixture was stirred at room temp. in air. After 30 min, water (5 mL)
was added and the mixture was concentrated in vacuo. Toluene was
then added and the mixture concentrated in vacuo.
Acknowledgments
I. C. is grateful to the Swedish Research council (Vetenskapsrådet)
and Carl Tryggers Stiftelse for financial support and to Stockholm
University for an Ivar Bendixson stipend. We thank Prof. Ray Trie-
vel of the Biological Chemistry Dept., University of Michigan, for
permission to use an isothermal titration calorimeter.
The resulting residue was dissolved in a mixture of MeOH (1 mL),
water (1 mL) and AcOH (0.1 mL), and Pd (10% on C, 10 mg) was
added. The mixture was degassed and stirred under H2. After 20 h,
Eur. J. Org. Chem. 2010, 1951–1970
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1969

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