Regioselective polymethylation of α-(1 → 4)-linked mannopyranose oligosaccharides

Article abstract of DOI:10.1021/jo4001299

An approach has been developed of the regioselective methylation of α-(1 → 4)-linked mannopyranose oligosaccharides via a four-step methodology. The key reaction involved n-Bu₂SnCl₂-mediated activation of cis-diols. By tuning protecting groups on the substrates, multiple cis-diols in the substrates were functionalized in a consistent and regioselective manner. Using optimized substrates and reaction conditions, regioselective methylation of di-, tri-, and tetrasaccharide substrates proceeded in isolated yields per cis-diol of 95, 88 and 79%, respectively. The methodology was also applied to functionalize trans-diols in α-cyclodextrin.

Full text of DOI:10.1021/jo4001299

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Article
Regioselective Polymethylation of alpha-(1--
4)-linked Mannopyranose Oligosaccharides
>
Li Xia, and Todd L. Lowary
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4001299 • Publication Date (Web): 13 Mar 2013
Downloaded from http://pubs.acs.org on March 16, 2013
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Regioselective Polymethylation of α-(1→4)-linked
Mannopyranose Oligosaccharides
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Li Xia and Todd L. Lowary*
Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Gunning–
Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada
Email: tlowary@ualberta.ca
OBn
OH
OBn
OH
1
. nꢀBu SnCl , TsCl, DIPEA
2 2
2. NaH, MeI
3. HCl, MeOH
O
OBn
OH
O
OBn
OH
TrO
HO
HO
MeO
4
. Mg, MeOH
O
OBn
OH
O
OBn
OH
O
O
HO
MeO
n
n
O
Selective alkylation
O
bulky
O
O
HO
n = 0-2
MeO
n = 0-2
substituent
OC H
OC H
8 17
8
17
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Abstract
An approach has been developed of the regioselective methylation of αꢀ(1→4)ꢀlinked
mannopyranose oligosaccharides via a fourꢀstep methodology. The key reaction involved n-
Bu SnCl ꢀmediated activation of cisꢀdiols. By tuning protecting groups on the substrates,
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multiple cisꢀdiols in the substrates were functionalized in a consistent and regioselective manner.
Using optimized substrates and reaction conditions regioselective methylation of diꢀ, triꢀ and
tetrasaccharide substrates proceeded in isolated yields per cisꢀdiol of 95%, 88% and 79%,
respectively. The methodology was also applied to functionalize transꢀdiols in αꢀcyclodextrin.
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Introduction
Total synthesis plays an important role in providing compounds that can be used for
understanding the biological role of complex organic molecules, both naturuallyꢀoccurring and
synthetic. However, this approach is generally laborious and timeꢀconsuming. To overcome this
problem, semisynthetic approaches can provide a more rapid solution by using readily available
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1
ꢀ2
compound skeletons as templates. For example, a recent example of semiꢀsynthesis was the
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installation of a trifluoromethyl moiety onto the drug Lipitor, via direct C–H functionalization.
Although appealing, direct and selective functionalization of carbohydrates, particularly
glycans more complicated than monosaccharides, is difficult. Although it is often possible to
exploit steric differences to selectively functionalize primary over secondary carbohydrate
4
ꢀ5
alcohols, differentiating secondary hydroxyl groups on oligosaccharides is challenging.
Regioselective acylations have been successfully carried out directly on unprotected
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7
disaccharides, e.g., sucrose 1 and lactose 2 (Figure 1), using organotin reagents. However,
further functionalization of these molecules is often difficult, as the introduced acyl groups are
baseꢀlabile and thus prone to migrate under the basic conditions typically used in alkylation
8
reactions. In another example, sulfate groups have been introduced onto unprotected
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oligosaccharides, however, in low yield, e.g., xylose trisaccharide 3 (Figure 1).
On the other hand, regioselective alkylation reactions appear to be more challenging to
carry out on oligosaccharides. Indeed, we were surprised to discover that there are only limited
10,† 11 12
examples of regioselective alkylation of unprotected oligosaccharides, e.g., 4, 5, 6 (Figure
1). The regioselectivities of the reactions leading to 4 and 5 were achieved by deprotonating the
†
Although 4 is not an oligosaccharide, it is classified as such here given its structural similarity
to a disaccharide.
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most acidic hydroxyl groups with strong bases; lactoside 6 was obtained via the organotinꢀ
mediated selective activation of vicinal diols.
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Figure 1. Examples of regioselective acylation, sulfation or alkylation of oligosaccharides.
During studies of the αꢀ(1→4)ꢀmannosyltransferase involved in the biosynthesis of 3ꢀOꢀ
1
3
methylꢀmannose polysaccharides (MMPs), we had the need to access a panel of αꢀ(1→4)ꢀ
linked mannopyranose oligosaccharides with or without methyl groups (A and B, Figure 2).
Although these analogs are structurally similar, traditional routes for their synthesis require
different building blocks, and/or multiple functional group interconversions on oligosaccharides.
For example, to obtain tetrasaccharides of both analogs (n = 2 for both A and B), 15 steps are
required for A and 24 steps for B in Figure 2. We were therefore interested to determine if it was
possible to access B via functionalization of A. We report here our studies towards achieving this
goal.
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Conventional route to A
Conventional route to B
OH
O
OH
O
HO
HO
HO
HO
HO
HO
OH
OMe
5
steps
3
steps
8 steps
6 steps
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OAc
O
Ph
O
OAc
O
OBz
O
OBn
O
O
AcO
AcO
MeO
BnO
AcO
MeO
BnO
HO
AcO
MeO
STol
STol
STol
OC H
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17
1
0 steps (n = 2)
7
steps (n = 2)
OH
OH
OH
OH
O
OH
HO
MeO
O
OH
HO
HO
OH
O
OH
O
OH
OH
OH
O
O
HO
MeO
n
Selective methylation
n
OH
O
O
O
O
HO
MeO
?
OC H
OC H
8 17
8
17
B (n = 0–12)
A (n = 0–12)
Figure 2. Conventional methods to synthesize analogs A and B and the approach developed here.
Results and discussion
Initial attempts to regioselectively alkylate α-(1→4)-linked mannopyranose
oligosaccharides
We first studied the selective methylation of αꢀ(1→4)ꢀlinked mannopyranose diꢀ and
trisaccharides. These substrates were synthesized from pyranone 7, which was obtained in two
14
steps by treatment of (R)ꢀ2ꢀ(benzyloxy)ꢀ1ꢀ(furanꢀ2ꢀyl)ethanol with Nꢀbromosuccinimide
1
5
followed by reaction with diꢀtertꢀbutyl dicarbonate. With 7 in hand, use of the Pdꢀcatalyzed
1
6
iterative glycosylation methodology developed by O’Doherty and coworkers (Scheme 1)
provided diene 10 and triene 11. Exhaustive dihydroxylation of the double bonds in 10 and 11
provided the desired disaccharide 12 and trisaccharide 13 in excellent overall yields. The high
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diasteroselectivity observed in these reactions is consistent with previous report.
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OBn
OBn
OBn
n-octanol, Pd (dba) , PPh ,
NaBH , CeCl •7H O,
2
3
3
4
3
2
O
O
CH Cl , 4Å molecular seives
2
2
MeOH
O
O
O
HO
96%
88%
OBoc
OC
8
H
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OC H
8 17
8
7
9
OBn
OBn
OH
O
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0
OBn
OH
HO
1. 7, Pd (dba) , PPh , CH Cl ,
O
OBn
OsO , NMO,
4
tꢀBuOH-acetone
2
3
3
2
2
HO
HO
4
Å molecular seives, 85%
O
O
O
O
HO
2. NaBH , CeCl •7H O,
MeOH, 91%
80%
4
3
2
OC H
8 17
1
0
OC H
8
17
12
1. 7, Pd (dba) , PPh , CH Cl ,
2 3 3 2 2
4Å molecular seives, 95%
2
. NaBH , CeCl •7H O,
4
3
2
MeOH, 85%
OBn
OBn
OH
O
OBn
HO
O
OBn
OH
HO
OsO , NMO,
tꢀBuOH-acetone
4
HO
O
OBn
O
O
OBn
O
HO
OH
O
O
75%
O
O
HO
11
1
3
OC H
8
17
OC H
8
17
Scheme 1. Synthesis of disaccharide 12 and trisaccharide 13.
We began by investigating the possibility of direct introduction of two alkyl groups onto
disaccharide 12, at Oꢀ3 and Oꢀ3′ positions. Because nꢀBu SnO is well known to selectively
2
17
activate the equatorial hydroxyl groups of cisꢀdiols via a cyclic stannylene acetal, we
anticipated that using two equivalents of this reagent would result in formation of a bisꢀ
‡
17ꢀ20
coordinated intermediate 14 from disaccharide 12 (Table 1).
Subsequent addition of the
alkylating reagent would lead to the formation of the diꢀsubstituted product 12a (Table 1), with
alkylation at both equatorial positions (Oꢀ3 and Oꢀ3′).
‡
It should be appreciated that stannylene acetals of carbohydrate diols typically adopt structureꢀ
1
7ꢀ20
dependent higherꢀorder oligomers (e.g., dimers, pentamers) in solution.
The depiction of 14
as a monomer is a simplified representation of the intermediate, because, if indeed it is formed,
its oligomeric structure in solution has not been investigated and is therefore unknown.
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a
Table 1. Direct regioselective alkylation of disaccharide 12.
Bu
Bu
OBn
Sn
O
Bu
Bu
O
OBn
HO
Sn
OBn
OH
O
O
O
O
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12
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E+
O
O
OBn
OH
HO
MeO
OC H
8
17
E+ 14
bis-coordinated intermediate
O
OBn
2'
OH
O
MeO
O
OBn
OC H
HO
HO
3'
2
8
17
1
2a
1. n-Bu
SnO, toluene, reflux
OH
2
O
O
OBn
OH
OBn
2
. nꢀBu NI, MeI, additive, T
HO
4
OH
3
OC H
8
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O
OBn
O
OBn
OH
1
2
HO
HO
MeO
MeO
OMe
O
O
O
O
HO
HO
OC H
OC H
8 17
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17
1
2b
12c
b
Products distribution (NMR yield )
monosubstituted
15% mixture
Recovered
T
Entry
Additive
(
°C)
disubstituted
12
80%
28%
ꢀ
1
2
3
40
70
40
ꢀ
ꢀ
< 5%
12a (19%), 12b (3%)
12c (35%), 15% other isomers
CsF
12a (29%), 12b (45%), 26% other isomers
ꢀ
a. Reaction conditions: 12 (1 equiv.), nꢀBu SnO (2 equiv.), nꢀBu NI (2 equiv.), MeI (20 equiv.), additive (4 equiv.),
2
4
toluene (0.01 M);
1
b. Yields were obtained by integration of anomeric protons of the products observed in crude H NMR spectrum.
To explore this possibility, disaccharide 12 was heated at reflux in toluene with two
equivalents of nꢀBu SnO and then treated with methyl iodide at various temperatures (Table 1).
2
1
Formation of products was monitored by H NMR spectroscopy of the crude reaction mixtures,
and the yield was determined by integrating the anomeric protons in the newly formed products.
Three major products were observed: two disubstituted regioisomers (12a and 12b) as well as a
monosubstituted derivative, 12c. When the alkylation was performed at 40 °C (entry 1, Table 1),
8
0% of starting material 12 remained. Raising the reaction temperature to 70 °C increased the
amount of dimethylated products, 12a (19%) and 12b (3%). However, the reaction was
incomplete and a number of monomethylated products were produced (entry 2, Table 1).
Addition of CsF drove the reaction to completion with the formation of exclusively dimethylated
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products (entry 3, Table 1). However, the desired regioisomer 12a was formed in only 29%
yield, while the major product was the undesired isomer 12b in 45% yield. The remaining mass
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balance was the other dimethylated isomers, based upon H NMR analysis of the crude reaction
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mixtures. The structures of 12a, 12b and 12c were assigned unambiguously after isolation of the
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corresponding products and characterization by H NMR spectroscopy along with H– H COSY
experiments. Regioisomers 12a and 12b were distinguished by comparison of the ring protons
adjacent to the alkylated hydroxyl groups. Chemical shifts of Hꢀ2, Hꢀ2′, Hꢀ3 and Hꢀ3′ of 12 are
between 3.94–3.59 ppm. After alkylation Hꢀ3 and Hꢀ3′ of 12a are significantly upfieldꢀshifted to
3
.46 and 3.33 ppm, respectively, while Hꢀ2 and Hꢀ2′ slightly downfieldꢀshifted to 4.00 and 4.08
ppm, respectively. This result indicated 12a is Oꢀ3, Oꢀ3′ꢀalkylated. In 12b, Hꢀ2 and Hꢀ3′ are
upfield shifted to 3.37 and 3.33 ppm, indicating substitution taking place at 2ꢀOH and 3′ꢀOH
positions. For the major monoalkylated adduct, 12c, only the signal for Hꢀ3′ was deshielded.
Despite the rather modest results obtained with disaccharide 12 as the substrate, we
applied the nꢀBu SnOꢀmediated alkylation conditions to trisaccharide 13 (Scheme 2). With this
2
substrate, triꢀsubstitution took place predominantly. No starting material was detected after the
reaction; however, a minimum of five regioisomers were observed. The desired 3, 3′, 3′′ꢀ
trisubstituted 13a was isolated as the major product but it accounted only for 41% of all the
products. Two other identified isomers were: Oꢀ3, Oꢀ2′, Oꢀ3′′ triꢀOꢀmethylated 13b and Oꢀ2, Oꢀ
3
′, Oꢀ3′′ triꢀOꢀmethylated 13c. The structures of the products were established as described
above for the reactions with disaccharide 12.
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Scheme 2. Direct regioselective alkylation of 13.
These studies suggest that the degree of alkylation of carbohydrate polyol systems can be
controlled with nꢀBu SnOꢀcoordination. However, consistent regioselectivity was difficult to
2
achieve with substrates such as disaccharide 12 and trisaccharide 13. We therefore decided to
explore if regioselectivity could be improved for acylation reactions. We first tested acylation of
disaccharide 12. Because nꢀBu SnOꢀmediated acylation of cisꢀdiols usually activates the
2
17
equatorial hydroxyl group, we expected to see predominant Oꢀ3, Oꢀ3′ꢀdisubstitution of 12.
Regioselective acylation of disaccharide 12
Regioselective acylation of 12 was explored using BzCl at room temperature after
heating the substrate at reflux with a tin reagent (2 equiv nꢀBu SnO or 1.5 equiv (nꢀBu Sn) O) in
2
3
2
toluene. Of the two reagents used, nꢀBu SnO gave only trace amounts of disubstituted products.
2
Isolation was not attempted due to the low yield. In contrast, when (nꢀBu Sn) O was used, diꢀOꢀ
3
2
benzoylated products were obtained exclusively (method A, Scheme 3). In addition, only two of
the four possible regioisomers were produced. Unexpectedly, the anticipated 3,3′ꢀdisubstituted
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5a was only formed as a minor product (21%, NMR yield). Instead, 15b, in which Oꢀ2 and Oꢀ3′
were benzoylated, was the major product, and was produced in a 79% yield as observed from the
1
H NMR spectrum of the crude reaction mixture. This regiochemistry was supported by the
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significant downfield shift of Hꢀ2 and Hꢀ3′ in the H NMR spectrum for 15b compared to that
for 12. In addition to the method described above, which involved an excess of tin reagent, the
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reaction was also performed with a catalytic amount of nꢀBu SnO (method B, Scheme 3).
2
However, this catalytic method also produced the 3,3′ꢀdisubstituted product 15a in a low yield
(25%, NMR yield). The major product of this reaction was 2,3′ꢀdisubstituted 15b, which was
obtained in 60% yield; The remaining 15% were other unidentified disubstituted isomers.
OBn
OBn
OH
O
OH
O
Method A:
nꢀBu Sn) O (1.5 equiv.), HO
OBn
OBz
OBn
OH
HO
BzO
3'
(
2
3
2
BzO
toluene, reflux then BzCl
O
3'
O
O
O
12
HO
BzO
3
Method B:
OC H
8 17
nꢀBu SnO (20 mol%),
OC H
8 17
2
1
5b
15a
1% (method A)
Et N, BzCl
3
7
6
9% (method A)
0% (method B)
2
2
5% (method B)
Scheme 3. Regioselective acylation of 12.
Before trying more acylation conditions, we considered the origin of the regioselectivity.
Noticeably, the two diols of 12 (2′,3′ꢀcisꢀdiol and 2,3ꢀcisꢀdiol) were alkylated with different
regioselectivity to produce 15b as the major product using either method A or method B
(Scheme 3). The diol at the nonꢀreducing moiety (2′,3′ꢀcisꢀdiol) underwent substitution
preferentially at the equatorial 3′ꢀOH group. In contrast, the diol at the reducing end residue (2,3ꢀ
cisꢀdiol) showed the opposite selectivity, resulting in preferential functionalization of the axial 2ꢀ
OH group.
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This latter result is inconsistent with many reported tinꢀmediated reactions in which
functionalization of the equatorial hydroxyl group of cisꢀdiols on sixꢀmembered rings is
1
7
preferential. For example, benzoylation of 16, when carried out in the presence of nꢀBu SnO,
2
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23
produced only 16b with substitution at the equatorial hydroxyl group (Figure 3). More recently
2
4
25
developed methods, using either borinic acid derivatives or Me SnCl , also give the same
2
2
selectivity with cisꢀdiols. Nevertheless, it should be noted that examples giving different
regioselectivity have been previously reported in the case of mannose. As examples, 16–19,
2
3,26ꢀ28
when reacted under the same conditions resulted in different regioselectivities (Figure 3).
These compounds differ only in the protecting groups, suggesting that these substituents play an
important role in controlling the regioselectivity.
2
OH
2
OBz
2
OH
O
R O
R O
R O
1
) n-Bu SnO
2
1
O
1
O
1
R O
R O
R O
HO
HO
BzO
2
) BzCl
OMe
OMe
OMe
a
b
1
2
1
1
1
6: R = H, R = Trityl resin
none
major
9-41%
32%
98%
minor
43-67%
63%
1
2
7: R , R = benzylidene
1
2
8: R , R = Bn
1
2
19: R = Bn, R = per-benzoyl Manp αꢀ(1→6)
23,26ꢀ28
Figure 3. Regioselective acylation of 2,3ꢀcisꢀdiol of mannose residues.
To rationalize the selectivity of the acylation reaction of 12, we compared the steric
environment of the two diols. We postulated that the selectivity of the diol at the reducing end
(
2,3ꢀcisꢀdiol) was influenced by the bulky mannose substituent at Oꢀ4, which rendered Oꢀ3 less
accessible for reaction than Oꢀ2 (Figure 4A). On the other hand, the diol at the nonꢀreducing end
of 12 (2′,3′ꢀcisꢀdiol) is not hindered and the acylation occurs on the equatorial Oꢀ3′ position
preferentially. This rationale also explains the regioselectivity trends observed in 16–19 (Figure
2
3
3). With no substituent at Oꢀ4, benzoylation occurred exclusively at Oꢀ3 to give 16b. However,
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
26
27
28
the presence of any substituent at Oꢀ4 (17, 18, or 19 ) decreased the regioselectivity and
significant amounts of Oꢀ2 substitution was also observed. Therefore, we hypothesized that
introducing a bulky substituent at Oꢀ4′ of disaccharide 12 would reverse the selectivity at the
nonꢀreducing residue diol, and give an enhanced yield of the Oꢀ2 and Oꢀ2′ diꢀOꢀacylated
products (Figure 4B).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A)
Bu
B)
bulky substitution
bulky substitution
Bu
OBn
OBn
OH
Sn
OBn
OH
O
Bu
Bu
E+
O
OBn
OBz
O
OBn
HO
BzO
HO
Sn
O
OBn
OH
O
O
RO
O
O
HO
O
O
E+
HO
5b
O
OO
O
OC H
8 17
HO
OC H
1
8
17
more accessible
less accessible
OC H
8
17
less accessible
Figure 4. Rationale for the observed regioselectivity of the benzoylation of 12 with nꢀBu SnO.
2
Substrate modification and optimization of regioselective acylation conditions
To test this hypothesis, a disaccharide modified at Oꢀ4′ with a tꢀbutyldimethylsilyl (TBS)
group (21, Scheme 4) was synthesized. The TBS group was introduced by treating alcohol 10
with TBSOTf and the resulting product, 20, was then dihydroxylated with OsO to provide 21 in
4
9
1% yield overall yield. With 21 in hand, the regioselective acylation reaction was examined.
We investigated three reported catalytic methods for regioselective acylation of diols, including
25
22
two tin reagents, Me SnCl2 and nꢀBu SnO, as well as a borinic acid derivative
2
2
24
Ph BOCH CH NH . All these methods were reported to efficiently catalyze the regioselective
2
2
2
2
acylation of monosaccharides, but their application to oligosaccharide systems had not been
investigated.
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OBn
OBn
OH
4
'
O
OBn
OBn
OH
O
RO
TBSO
HO
OsO , NMO
4
O
O
O
O
91 %
HO
TBSOTf
,6-lutidine
OC H
8 17
1
0: R = H
20: R = TBS
21
OC H
8 17
2
99%
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Preparation of TBSꢀmodified disaccharide 21.
When 21 was treated with 2.4 equivalents BzCl (1.2 equiv per diol) in the presence of 20
mol% Me SnCl , nꢀBu SnO or Ph BOCH CH NH (10 mol% per diol), both tin reagents gave
2
2
2
2
2
2
2
satisfactory conversions (entries 1 and 2, Table 2). However, the use of Ph BOCH CH NH led
2
2
2
2
only to ~10% conversion of 21 (entry 3, Table 2). Using of Me SnCl gave 60% of a mixture of
2
2
monoꢀOꢀbenzoylated products and 40% of diꢀOꢀbenzoylated products (entry 1). Of the
disubstituted products, 22% was the expected 2,2′ꢀdiꢀOꢀbenzoylated 21a and 18% was the 3,2′ꢀ
1
diꢀOꢀbenzoylated isomer 21d as determined by H NMR spectroscopy. The other two isomers,
21b and 21c, were not detected. With nꢀBu SnO, three diꢀOꢀbenzoylated products were formed:
2
6
3% of the desired 21a, 9% of 21c and 16% of 21d (entry 2). These results support our
hypothesis that a bulky substituent at Oꢀ4′ of 21 alters the regioselectivity of the nonꢀreducing
end diol to favor substitution at Oꢀ2′.
The regioselectivity employing nꢀBu SnO (21a:21d = 3.9:1) was better than with
2
Me SnCl (21a:21d = 1.2:1), suggesting that the size of the alkyl group in the catalyst also
2
2
influence acylation regioselectivity. Indeed, replacing Me SnCl with the more hindered nꢀ
2
2
Bu SnCl gave 21a as the only observed disubstituted isomer (entry 4, Table 2). However, 57%
2
2
of the monobenzoylated products remained when this catalyst was used. When the nꢀBu SnCl –
2
2
catalyzed reaction of 21 was repeated with 10 equivalents of BzCl, (5 equiv per diol), an 87%
yield of 21a was produced (entry 5, Table 2). However, when the same amount of BzCl was
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
employed in reactions using nꢀBu SnO, mainly tribenzoylated products were produced (entry 6,
2
Table 2).
a
Table 2. Regioselective benzoylation of 21 with different catalysts.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Products distribution (NMR yield)
Recoverd
Entry BzCl amount
Conditions
disubstituted
monosubstituted
21
21a 21b 21c 21d
1
2
3
4
5
6
2.4 equiv
2.4 equiv
2.4 equiv
2.4 equiv
10 equiv
10 equiv
Me SnCl , DIPEA, THF
22
63
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
9
ꢀ
18
16
ꢀ
60
ꢀ
ꢀ
ꢀ
2
2
nꢀBu SnO, Et N, CH Cl
2
2
3
2
Ph BOCH CH NH , CH CN
<10
57
ꢀ
90
-
2
2
2
2
3
nꢀBu SnCl , DIPEA, THF
43
87
ꢀ
ꢀ
2
2
nꢀBu SnCl , DIPEA, THF
6
7
ꢀ
2
2
nꢀBu SnO, Et N, CH Cl
2
tribenzoylated products observed
2
3
2
a
Reaction conditions: 21 (1 equiv., 0.1 M), catalyst (20 mol%), base (4 equiv. for entry 1–4, 10 equiv. for entry 5–
6
,), BzCl (2.4–10 equiv.), room temperature, 3 h.
Encouraged by the success of these preliminary studies, the regioselective benzoylation
of 21 catalyzed by nꢀBu SnCl was optimized using various solvents (Table 3). In all solvents, a
2
2
similar trend in the regioselectivity (21a >> 21c, 21d > 21b) was observed, with the exception of
pyridine, where the substrate formed a mixture of products containing more than two benzoyl
groups. Among all the solvents tested, THF gave the least amount of undesired isomers (entry 1).
Lowering the temperature to 0 °C did not improve the selectivity but, as expected, slowed the
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reaction (entry 6). Thus, future reactions employed THF as the solvent and were carried out at
room temperature.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Table 3. Solvent optimization for regioselective benzoylation of 21.
Product distribution (%)
Entry Solvent
T (°C)
Disubstituted
Monosubstituted
2
1a
21b
21c
21d
7
1
2
3
4
5
6
THF
RT
RT
87
ꢀ
ꢀ
ꢀ
ꢀ
6
ꢀ
ꢀ
CH Cl2
68
61
76
10
20
28
12
2
MeCN
RT
< 4
Et O
2
RT
12
ꢀ
Pyridine
THF
RT
overbenzoylation
8
0 °C
66
ꢀ
7
19
a
Reaction conditions: 21 (1 equiv.0.1 M), nꢀBu SnCl (20 mol%), DIPEA (10 equiv.), BzCl (10 equiv.), 3 h.
2
2
Next, we tested the optimized method with other acylating reagents (Table 4). The
relatively unhindered acylation reagent AcCl gave no regioselectivity (entry 1). The bulky PivCl
produced a single disubstituted isomer 22a with the expected 2,2′ꢀdisubstitution; however, 51%
of the monoꢀ2ꢀOꢀpivaloyated product remained, as well as 36% of starting material 21 (entry 2).
Replacing BzCl with pꢀTsCl gave the expected diꢀOꢀtosylated product 23a in excellent yield and
regioselectivity (entry 3), although the equivalents of TsCl and reaction time had to be increased
to drive the reaction to completion. When tosylation was performed with 15 equivalents of TsCl
for 24 hours, 89% of 23a was observed (entry 4).
Having established that the introduction of a stericallyꢀdemanding protecting group on Oꢀ
4′ of 21 successfully switched the regioselectivity of the nonꢀreducing end residue, we next
introduced a trityl substituent onto substrate instead of a TBS group (disaccharide 24, Table 4).
This compound was found to be a better substrate than 21. Regioselective tosylation of 24
efficiently furnished a 91% isolated yield of the desired 25a (entry 5, Table 4). Only a trace
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
amount of other isomers was produced from this reaction. Based on these results and for reasons
discussed in greater detail below, we shifted our focus to tosylation reactions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 4. Protecting group scope of regioselective acylation.
Products (NMR yield)
disubstituted monosubstituted
Unreacted
starting material
Entry
Substrate
RCl (amount)
1
2
3
4
5
AcCl (2.4 equiv)
PivCl (10 equiv)
TsCl (10 equiv)
TsCl (15 equiv)
TsCl (10 equiv)
trace
> 80%
10%
36%
trace
ꢀ
22a (13%)
51%
1
2
1 (R = TBS)
23a (62%)
31%
23a (89%), 23d (11%)
25a (96%), 25d (4%)
ꢀ
ꢀ
1
24 (R = Tr)
ꢀ
a
Reaction conditions: substrate (1 equiv., 0.1 M), nꢀBu SnCl (20 mol%), DIPEA (10 equiv.), RCl (2.4–15 equiv.),
2
2
room temperature, 24h.
Application to tri- and tetrasaccharides substrates
With a set of optimized conditions developed, the methodology was applied to more
challenging substrates: trisaccharide 26 and tetrasaccharide 27, which were obtained from their
corresponding triene 11 and tetraene 28, respectively (Scheme 5). Considering that regioselective
acylation of each diol generates two possible regioisomers, trisaccharide 26, with three diol pairs,
would have eight possible triꢀOꢀsulfonylated isomers and tetrasaccharide 27 would have 16
possible products. When 26 and 27 were subjected to the optimized regioselective sulfonation
conditions, the desired trisubstituted product 26a and tetrasubstituted product 27a were obtained
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as the major regioisomers in both cases, in 69% and 38% isolated yields, respectively. In both
cases, these products were the major regioisomers. Although the isolated yield of the desired
regioisomers dropped when the substrates used went from the disaccharide to the tetrasaccharide,
the efficiency of the regioselectivity is still remarkable. Tosylation of disaccharide 24 produced a
91% yield of 25a, corresponding to a 95% sulfonylation selectivity for each diol pair. In the case
of the reaction with trisaccharide 26, a 69% yield of 26a corresponds to an 88% selectivity for
each diol pair. For the reaction with tetrasaccharide 27, a 38% yield is equivalent to sulfonylating
each diol with 79% selectivity.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Regioselective modification of trisaccharide 26 and tetrasaccharide 27.
Subsequent functionalization of oligosaccharide by alkylation
After successfully introducing multiple protecting groups onto the diꢀ, triꢀ and
tetrasaccharides with good regioselectivity, the ability to further functionalize these compounds
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was investigated. Attempts to methylate 21a using NaH as base resulted in benzoyl group
migration (condition a, Scheme 6A), a common problem during alkylation under basic
8
conditions. The use of milder bases such as Ag O and Ag CO failed to prevent acyl migration
2
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29ꢀ30
(
condition b, Scheme 6A).
proved unsuccessful (conditions c and d, Scheme 6A).
To overcome this acyl migration problem, the substrates with the sulfonyl groups were
In addition, methylation of 21a using CH N and MeOTf also
2 2
3
1ꢀ32
3
3
used. As expected, the tosyl groups of 23a were stable to alkylation with NaH and MeI.
However, in addition to the desired product 29, an unexpected byproduct, 30 (Scheme 6B),
presumably resulting from intramolecular silyl group migration under the basic reaction
conditions, was formed. The use of an alternative substrate with a baseꢀstable trityl group on Oꢀ
4
′ (25a) avoided this problem, giving the desired diꢀOꢀmethyl disaccharide 31. The trityl group
in 31 was easily removed using HCl in methanol to give 32 in 83% yield over the two steps.
3
4
Finally, the tosyl groups of 32 were cleaved with magnesium in methanol at reflux. Subsequent
hydrogenolysis removed the remaining benzyl groups, furnishing partially methlated
disaccharide 33 (Scheme 6C).
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20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
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37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6
.
Attempted methylation with disaccharides 21a, 23a and 25a.
Following this approach, the methylated trisaccharide 36 and tetrasaccharide 37 were
obtained three steps from 26a and 27a, in 41% and 70% overall yields, respectively (Scheme 7).
Scheme 7. Methylation of trisaccharide 26a and tetrasaccharide 27a.
Application to α-cyclodextrin
To explore the generality of the methodology, it was applied to αꢀcyclodextrin. Chemical
modifications of cyclodextrins are of significant interest and have been widely used to tune their
3
5
physical properties. However, methods to selectively functionalize the secondary face of these
cyclic oligosaccharides are still limited. In particular, derivatives that are functionalized at Oꢀ3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
36
positions are difficult to prepare. Noticing of the similarity between the αꢀ(1→4)ꢀlinked
mannose oligosaccharides described above and the αꢀ(1→4)ꢀlinked glucopyranose residues
present in αꢀcyclodextrin, we envisioned our methodology might be able to provide the 3ꢀOꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
7
alkylated analogs. As expected, the TBSꢀprotected αꢀcyclodextrin 38 underwent tosylation
with high regioselectivity (Scheme 8). The expected fully 2ꢀOꢀtosylated product 39 was obtained
in 77% isolated yield. Of the other byproducts produced from this reaction, the major one,
isolated in 5% yield, had five of the residues exclusively tosylated at Oꢀ2. After protection of all
the Oꢀ2 positions of cyclodextrin, methyl groups were installed quantitatively onto Oꢀ3 of 39 to
give 40. This substrate has transꢀ instead of cisꢀdiols, which suggested the approach does not
§
require a cisꢀdiol. This methodology thus provides a new method for the selective
functionalization of cyclodextrins.
Scheme 8. Regioselective functionalization of αꢀcyclodextrin.
Conclusion
In conclusion, we demonstrate here a method that can be used to regioselectively
functionalize multiple hydroxyl groups in oligosaccharides. Key to the development of this
approach was the realization that the regioselectivity of organotinꢀmediated acylation and
§
17ꢀ20
Stannyleneꢀacetal intermediates of transꢀdiols, in particular αꢀglucopyranosides, have been described.
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sulfonation of diols can be altered by tuning the size of protecting groups on the substrate.
Although such effects can, in retrospect, be identified in previous examples of such
23,26ꢀ28
functionalizations,
carried out previously.
rational optimization of these steric effects appears not to have been
10
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The focus of this paper has been on the selective methylation of cisꢀdiols in αꢀ(1→4)ꢀ
linked mannopyranose oligomers, which are an interesting class of lipidꢀbinding
3
8ꢀ40
oligosaccharides.
When coupled with O’Doherty’s palladiumꢀcatalyzed pyranone
1
6
glycosylation methodology, we consider this approach to be a viable alternative to more
traditional approaches to these targets, which rely on the preparation of a number of selectively
1
3,41ꢀ47
protected monosaccharides derivatives.
We also provide examples showing that the
method is effective for selectively functionalizing not only cisꢀdiols but also transꢀdiols (in αꢀ
cyclodextrin) and further work in applying this method to other oligosaccharide systems is
ongoing. In particular, the stereochemistry at Cꢀ1 and Cꢀ4, and the identity of the protecting
group at Oꢀ6, may influence the selectivity of the process. We note that during the preparation of
this manuscript a similar method, also employing nꢀBu SnCl as the catalyst, was reported for the
2
2
4
8
regioselective monosulfonylation of an unprotected disaccharide by Muramatsu. The major
difference is that whereas Muramatsu aimed to protect only one of the hydroxyl groups of an
oligosaccharide, our approach targets simultaneous functionalization of multiple hydroxyl groups.
Experimental section
General experimental methods: All reagents were purchased from commercial sources and
were used without further purification unless noted. All reactions were carried out under a
positive pressure of argon or nitrogen at room temperature unless specified and were monitored
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by TLC on silica gel 60ꢀF254 (0.25 mm). Visualization of the reaction components was achieved
using UV fluorescence (254 nm) and/or by charring with acidified anisaldehyde solution in
ethanol. Organic solvents were evaporated under reduced pressure and the products were
purified by column chromatography on silica gel (230–400 mesh). Optical rotations were
measured in a microcell (10 cm, 1 mL) at ambient temperature and are in units of
0
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degree⋅mL/(g⋅dm). H NMR spectra were recorded at 500 MHz or 600 MHz and chemical shifts
are referenced to residual CHCl (7.26 ppm, CDCl ), CHDCl (5.32 ppm, CD Cl ), or CHD OD
3
3
2
2
2
2
13
(
3.30 ppm, CD OD). C NMR spectra were recorded at 125 MHz and chemical shifts are
3
referenced to CDCl (77.0 ppm) or CD Cl (53.8 ppm). Reported splitting patterns are
3
2
2
abbreviated as s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, app = apparent.
1
1
Assignments of NMR spectra were based on twoꢀdimensional experiments ( H– H COSY,
HSQC, and HMBC) and stereochemistry of the anomeric centers of the pyranose rings were
1
confirmed by measuring J
via coupled HSQC experiments. High resolution ESIꢀMS
Cꢀ1,Hꢀ1
spectra (timeꢀofꢀflight analyzer) were recorded on samples suspended in THF or CH OH and
3
with added NaCl. Low resolution MALDIꢀMS (timeꢀofꢀflight analyzer) used 2,5ꢀ
dihydroxybenzoic acid (DHB) as matrix.
(2R,6R)-6-((benzyloxy)methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl tert-butyl carbonate (7):
1
5
A reported method was used for the synthesis of 7. To a stirring iceꢀcold solution of (R)ꢀ2ꢀ
1
4
(
benzyloxy)ꢀ1ꢀ(furanꢀ2ꢀyl)ethanol (2.9 g, 13.2 mmol) in mixed THF and H O (21 mL, THF–
2
H O 4:1) was add NaHCO •3H O (2.3 g, 26.5 mmol) and NaOAc (1.1 g, 13.2 mmol). Nꢀ
2
3
2
bromosuccinimide (2.4 g, 13.2 mmol) was added and the resulting yellow solution was stirred at
°C for 1.5 h. The reaction mixture was concentrated to remove THF and then extracted with
CH Cl . After washing with saturated aqueous NaHCO and brine, the organic layer was dried
0
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over Na SO and concentrated to afford a yellow liquid (3.4 g). This yellow liquid (1.5 g, 5.7
2
4
mmol) was then dissolved in CH Cl (8 mL) and cooled to −78 °C. Diꢀtꢀbutyl dicarbonate (1.5 g,
2
2
6.8 mmol) was added into this solution followed by 4ꢀdimethylaminopyridine (70.8 mg, 0.6
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60
mmol). The solution was stirred for 1 h while warming to room temperature. The resulting black
solution was concentrated and the crude residue was purified by chromatography (hexane–
EtOAc 9:1) to afford α isomer 7 (919.4 mg, 48% over two steps) as a pale yellow syrup. This
reaction also produced the β isomer (212.1 mg, 11%) as yellow syrup. The following data are for
α isomer 7 only. R 0.57 (hexane–EtOAc 3:1); [α] = −72.2 (c 3.0, CHCl ); IR: 1751.6 (C=O),
f
D
3
1
1
702.3 (Boc C=O); H NMR (500 MHz, CDCl ) δ 7.39–7.27 (m, 5H, Ar), 6.94 (dd, J = 10.3, 3.7
3
Hz, 1H, Hꢀ2), 6.48 (d, J = 3.7 Hz, 1H, Hꢀ1), 6.28 (d, J = 10.3 Hz, 1H, Hꢀ3), 4.72 (dd, J = 4.4, 2.7
Hz, 1H, Hꢀ5), 4.60 (s, 2H, 2 × OCH Ph), 3.97 (dd, J = 10.9, 4.4 Hz, 1H, Hꢀ6a), 3.92 (dd, J =
2
1
3
10.9, 2.6 Hz, 1H, Hꢀ6b), 1.54 (s, 9H, Boc); C NMR (126 MHz, CDCl ) δ 193.0 (Cꢀ4), 151.7
3
(Boc C=O), 141.4 (Cꢀ2), 137.8 (Ar), 129.1 (Cꢀ3), 128.4 (2C, Ar), 127.7 (2C, Ar), 127.7 (Ar),
8
9.2 (Cꢀ1), 83.7 (Boc tꢀBu), 76.4 (Cꢀ5), 73.7 (OCH Ph), 68.5 (Cꢀ6), 27.7 (Boc tꢀBu); HRMS
2
+
(
ESI) calcd C H O [M+Na] 357.1309, found 357.1311.
1
8
22
6
(
2R,6S)-2-((benzyloxy)methyl)-6-(octyloxy)-2H-pyran-3(6H)-one (8): A solution of CH Cl (3
2 2
mL) containing 7 (352.9 mg, 1.1 mmol) and 1ꢀoctanol (0.5 mL, 3.2 mmol) with 4 Å molecular
sieves was stirred at room temperature for 0.5 before 2.5 mol%
tris(dibenzylideneacetone)dipalladium(0) Pd (dba) (26.8 mg, 0.03 mmol) and 10 mol%
h
2
3
triphenylphosphine PPh (28.0 mg, 0.12 mmol) were added. After stirring for 1.5 h, the resulting
3
purple solution was concentrated and the resulting residue was purified by chromatography
(hexane–EtOAc 15:1) to afford 8 (351.4 mg, 96%) as a colorless liquid. R 0.59 (hexane–EtOAc
f
1
3
:1); [α] = −32.7 (c 0.9, CHCl ); H NMR (500 MHz, CDCl ) δ 7.39–7.26 (m, 5H, Ar), 6.91 (dd,
D
3
3
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J = 10.2, 3.5 Hz, 1H, Hꢀ2), 6.15 (d, J = 10.3 Hz, 1H, Hꢀ3), 5.33 (d, J = 3.5 Hz, 1H, Hꢀ1), 4.65–
4.60 (m, 3H, Hꢀ5, 2 × OCH Ph), 3.95 (dd, J = 10.8, 4.8 Hz, 1H, Hꢀ6a), 3.92 (dd, J = 10.9, 3.0 Hz,
2
1H, Hꢀ6b), 3.88 (dt, J = 9.6, 6.8 Hz, 1H, octyl OCH ), 3.62 (dt, J = 9.6, 6.6 Hz, 1H, octyl OCH ),
2 2
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3
4
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0
1
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4
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8
9
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.70–1.59 (m, 2H, octyl OCH CH ), 1.44–1.21 (m, 10H, octyl CH ), 0.90 (t, J = 7.0 Hz, 3H,
2
2
2
13
octyl CH ); C NMR (126 MHz, CDCl ) δ 194.4 (Cꢀ4), 144.1 (Cꢀ2), 138.0 (Ar), 128.3 (2C, Ar),
3
3
127.8 (Ar), 127.6 (3C, Ar (2C), Cꢀ3), 93.2 (Cꢀ1), 74.5 (Cꢀ5), 73.7 (OCH Ph), 69.7 (octyl OCH ),
2 2
6
8.7 (Cꢀ6), 31.8, 29.7, 29.4, 29.3, 26.2, 22.7 (6C, octyl CH ), 14.1 (octyl CH ); HRMS (ESI)
2
3
+
calcd C H O [M+Na] 369.2036, found 369.2040.
2
1
30
4
(2R,3S,6S)-2-((benzyloxy)methyl)-6-(octyloxy)-3,6-dihydro-2H-pyran-3-ol (9): To a solution
of ketone 8 (343.0 mg, 1.1 mmol) in methanol (2.5 mL) at −78 °C was added NaBH (42.3 mg,
4
1
.1 mmol) and CeCl •7H O (392.7 mg, 1.1 mmol). The solution was stirred overnight while
3 2
warming to room temperature. The mixture was concentrated to remove the methanol and then
the residue was redissolved in CH Cl . After washing with water and brine, the organic layer was
2
2
dried over Na SO , and then concentrated. The resulting residue was purified by chromatography
2
4
(hexane–EtOAc 6:1) to afford alcohol 9 (307.3 mg, 88%) as a colorless syrup. R 0.35 (hexane–
f
1
EtOAc 3:1); [α] = +20.0 (c 0.8, CHCl ); H NMR (500 MHz, CDCl ) δ 7.40–7.27 (m, 5H, Ar),
D
3
3
5.94 (d, J = 10.2 Hz, 1H, Hꢀ3), 5.76 (ddd, J = 10.2, 2.7, 2.2 Hz, 1H, Hꢀ2), 4.99 (d, J = 2.6 Hz, 1H,
Hꢀ1), 4.65 (d, J = 12.0 Hz, 1H, OCH Ph), 4.61 (d, J = 12.0 Hz, 1H, OCH Ph), 4.23 (dddd, J =
2
2
9.2, 5.6, 3.5, 1.8 Hz, 1H, Hꢀ4), 3.89–3.83 (m, 1H, Hꢀ5), 3.82–3.75 (m, 2H, Hꢀ6a, octyl OCH2),
3
.72 (dd, J = 10.0, 4.9 Hz, 1H, Hꢀ6b), 3.50 (dt, J = 9.6, 6.6 Hz, 1H, octyl OCH ), 2.67 (d, J = 5.9
2
Hz, 1H, OHꢀ4), 1.67–1.55 (m, 2H, octyl OCH CH ), 1.43–1.22 (m, 10H, octyl CH ), 0.91 (t, J =
2
2
2
13
7
.0 Hz, 3H, octyl CH ); C NMR (126 MHz, CDCl ) δ 137.9 (Ar), 133.0 (Cꢀ3), 128.5 (2C, Ar),
3 3
1
27.8 (Ar), 127.7 (2C, Ar), 126.2 (Cꢀ2), 94.3 (Cꢀ1), 73.7 (OCH Ph), 70.7 (Cꢀ6), 70.0 (Cꢀ5), 68.8
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(
octyl OCH ), 65.6 (Cꢀ4), 31.9, 29.8, 29.4, 29.3, 26.2, 22.7 (6C, octyl CH ), 14.1 (octyl CH );
2
2
3
+
HRMS (ESI) calcd C H O [M+Na] 371.2193, found 371.2189.
21 32
4
(2R,3S,6S)-2-((benzyloxy)methyl)-6-(((2R,3S,6S)-2-((benzyloxy)methyl)-6-(octyloxy)-3,6-
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dihydro-2H-pyran-3-yl)oxy)-3,6-dihydro-2H-pyran-3-ol (10): The reaction was performed as
described for the synthesis of 8, with alcohol 9 (611.8 mg, 1.8 mmol) and donor 7 (818.5 mg, 2.6
mmol) in the presence of Pd (dba) (41.8 mg, 0.05 mmol) and PPh (60.0 mg, 0.23 mmol) in
2
3
3
CH Cl (6 mL). The crude residue was purified by chromatography (hexane–EtOAc 7:1) to
2
2
afford a ketone (842.1 mg, 85%) as a colorless syrup. This ketone was then reduced as described
for 9, with NaBH (68.6 mg, 1.8 mmol) and CeCl •7H O (656.2 mg, 1.8 mmol) in methanol (6
4
3
2
mL). Chromatographic purification of the crude reaction mixture (hexane–EtOAc 6:1) furnished
alcohol 10 (770.3 mg, 91%) as a colorless syrup. R 0.38 (hexane–EtOAc 2:1); [α] = +35.3 (c
f
D
1
0
3
2
.9, CHCl ); H NMR (500 MHz, CDCl ) δ 7.40–7.24 (m, 10H, Ar), 6.05 (d, J = 10.3 Hz, 1H, Hꢀ
3
3
), 5.97 (d, J = 10.2 Hz, 1H, Hꢀ3′), 5.84 (ddd, J = 10.3, 2.7, 1.8 Hz, 1H, Hꢀ2), 5.68 (ddd, J = 10.2,
.4, 2.4 Hz, 1H, Hꢀ2′), 5.20 (d, J = 2.4 Hz, 1H, Hꢀ1′), 5.03 (d, J = 2.1 Hz, 1H, Hꢀ1), 4.62–4.41
(
m, 5H, Hꢀ4, 4 × OCH Ph), 4.26 (dddd, J = 10.3, 3.4, 3.4, 1.7 Hz, 1H, Hꢀ4′), 4.01 (ddd, J = 9.4,
2
3.6, 3.6 Hz, 1H, Hꢀ5), 3.81 (dt, J = 9.5, 6.8 Hz, 1H, octyl OCH ), 3.77–3.73 (m, 2H, Hꢀ6a, Hꢀ6b),
2
3
6
2
.73–3.68 (m, 1H, Hꢀ5′), 3.66 (dd, J = 9.6, 4.3 Hz, 1H, Hꢀ6a′), 3.55 (dd, J = 9.6, 5.7 Hz, 1H, Hꢀ
b′), 3.50 (dt, J = 9.5, 6.6 Hz, 1H, octyl OCH ), 2.33 (d, J = 4.9 Hz, 1H, OHꢀ4′), 1.67–1.57 (m,
2
13
H, octyl OCH CH ), 1.40–1.21 (m, 10H, octyl CH ), 0.90 (t, J = 7.0 Hz, 3H, octyl CH ); C
2
2
2
3
NMR (126 MHz, CDCl ) δ 138.5, 137.6 (2C, Ar), 133.2 (Cꢀ3′), 129.3 (Cꢀ3), 128.5 (2C, Ar),
3
128.3 (2C, Ar), 127.9 (Ar), 127.8 (2C, Ar), 127.4 (3C, Ar), 127.3 (Cꢀ2), 125.8 (Cꢀ2′), 94.3 (Cꢀ1),
9
1.1 (Cꢀ1′), 73.7, 73.21 (2C, 2 × OCH Ph), 70.6 (Cꢀ6′), 69.9 (Cꢀ5′), 69.7 (Cꢀ6), 69.1 (Cꢀ5), 68.7
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(
octyl OCH ), 67.3 (Cꢀ4), 66.0 (Cꢀ4′), 31.9, 29.8, 29.4, 29.3, 26.3, 22.7 (6C, octyl CH ), 14.1
2
2
+
(octyl CH ); HRMS (ESI) calcd C H O [M+Na] 589.3136, found 589.3136.
3
34 46
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(
2R,3S,6S)-2-((benzyloxy)methyl)-6-(((2R,3S,6S)-2-((benzyloxy)methyl)-6-(((2R,3S,6S)-2-
(benzyloxy)methyl)-6-(octyloxy)-3,6-dihydro-2H-pyran-3-yl)oxy)-3,6-dihydro-2H-pyran-3-
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(
yl)oxy)-3,6-dihydro-2H-pyran-3-ol (11): The reaction was performed as described for the
synthesis of 8, with alcohol 10 (978.0 mg, 1.73 mmol) and donor 7 (1.02 g, 3.05 mmol) in the
presence of Pd (dba) (69.0 mg, 0.08 mmol) and PPh (80.0 mg, 0.31 mmol) in CH Cl (22 mL).
2
3
3
2
2
The crude residue was purified by chromatography (hexane–EtOAc 9:1) to afford a ketone (1.28
1
g, 95%) as a pale yellow syrup. [α] = +5.1 (c 0.6, CHCl ); H NMR (500 MHz, CDCl ) δ 7.38–
D
3
3
7
.21 (m, 15H, Ar), 6.83 (dd, J = 10.2, 3.5 Hz, 1H, Hꢀ2′′), 6.18 (d, J = 10.3 Hz, 1H, Hꢀ3′′), 6.11 (d,
J = 10.3 Hz, 1H, Hꢀ3′), 6.05 (d, J = 10.3 Hz, 1H, Hꢀ3), 5.85 (ddd, J = 10.3, 2.7, 1.8 Hz, 1H, Hꢀ2),
5
.78 (ddd, J = 10.3, 2.7, 1.9 Hz, 1H, Hꢀ2′), 5.57 (d, J = 3.5 Hz, 1H, Hꢀ1′′), 5.27 (d, J = 2.1 Hz,
H, Hꢀ1′), 5.03 (d, J = 2.2 Hz, 1H, Hꢀ1), 4.63 (dd, J = 9.3, 1.3 Hz, 1H, Hꢀ4′), 4.60–4.37 (m, 8H,
1
Hꢀ4, Hꢀ5′′, 6 × OCH Ph), 4.02 (ddd, J = 9.3, 5.6, 1.8 Hz, 1H, Hꢀ5), 3.85–3.75 (m, 4H, Hꢀ5′, Hꢀ6a,
2
Hꢀ6a′′, octyl OCH ), 3.71 (dd, J = 10.9, 5.7 Hz, 1H, Hꢀ6b), 3.63–3.58 (m, 2H, Hꢀ6a′, Hꢀ6b′′),
2
3.54 (dd, J = 10.8, 1.7 Hz, 1H, Hꢀ6b′), 3.50 (dt, J = 9.5, 6.6 Hz, 1H, octyl OCH ), 1.66–1.57 (m,
2
13
2
H, octyl OCH CH ), 1.41–1.22 (m, 10H, octyl CH ), 0.90 (t, J = 7.0 Hz, 3H, octyl CH ); C
2
2
2
3
NMR (126 MHz, CDCl ) δ 194.0 (Cꢀ4′′), 143.6 (Cꢀ2′′), 138.5, 138.0, 137.8 (3C, Ar), 129.2 (2C,
3
Cꢀ3, Cꢀ3′), 128.3 (2C, Ar), 128.3 (2C, Ar), 128.3 (2C, Ar), 128.2 (Cꢀ3′′), 127.7 (2C, Ar), 127.6
(2C, Ar), 127.6 (2C, Ar), 127.4 (4C, 3 × Ar, Cꢀ2), 127.3 (Cꢀ2′), 94.2 (Cꢀ1), 91.4 (Cꢀ1′), 90.0 (Cꢀ
1
6
′′), 75.0 (Cꢀ5′′), 73.7, 73.5, 73.2 (3C, 3 × OCH Ph), 69.9 (Cꢀ6), 69.7 (Cꢀ5′), 69.1 (Cꢀ5), 69.0 (Cꢀ
2
′), 68.7 (octyl OCH ), 68.5 (Cꢀ6′′), 67.5 (Cꢀ4), 67.4 (Cꢀ4′), 31.9, 29.8, 29.4, 29.3, 26.3, 22.7 (6C,
2
+
octyl CH ), 14.1 (octyl CH ); HRMS (ESI) calcd C H O [M+Na] 805.3922, found 805.3915.
2
3
47 58 10
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9
This ketone (208.9 mg, 0.21 mmol) was then reduced as described for 9, with NaBH (8.0 mg,
4
0
.21 mmol) and CeCl •7H O (80.2 mg, 0.21 mmol) in methanol (2.5 mL). Chromatographic
3 2
purification of the crude reaction mixture (hexane–EtOAc 3:1) furnished alcohol 11 (177.2 mg,
10
11
12
13
14
15
16
17
18
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20
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55
56
57
58
59
60
1
8
5%) as a colorless syrup. R 0.30 (hexane–EtOAc 3:1); [α] = +35.6 (c 0.8, CHCl ); H NMR
f
D
3
(500 MHz, CDCl ) δ 7.38–7.23 (m, 15H, Ar), 6.07 (d, J = 10.1 Hz, 1H, Hꢀ3′), 6.05 (d, J = 9.3 Hz,
3
1
H, Hꢀ3), 5.99 (d, J = 10.2 Hz, 1H, Hꢀ3′′), 5.84 (ddd, J = 10.3, 2.7, 1.8 Hz, 1H, Hꢀ2), 5.74 (ddd,
J = 10.3, 2.7, 1.9 Hz, 1H, Hꢀ2′), 5.70 (ddd, J = 10.2, 2.7, 2.3 Hz, 1H, Hꢀ2′′), 5.25 (d, J = 2.0 Hz,
1H, Hꢀ1′), 5.20 (d, J = 2.4 Hz, 1H, Hꢀ1′′), 5.03 (d, J = 2.1 Hz, 1H, Hꢀ1), 4.60–4.39 (m, 8H, Hꢀ4,
Hꢀ4′, 3 × OCH Ph), 4.27 (ddd, J = 8.6, 4.4, 1.7 Hz, 1H, Hꢀ4′′), 4.02 (ddd, J = 9.2, 6.0, 1.7 Hz, 1H,
2
Hꢀ5), 3.88–3.76 (m, 3H, Hꢀ5′, Hꢀ6a, octyl OCH ), 3.74–3.62 (m, 4H, Hꢀ5′′, Hꢀ6a, Hꢀ6a′, Hꢀ6a′′),
2
3
.60 (dd, J = 10.8, 2.0 Hz, 1H, Hꢀ6b′), 3.55–3.46 (m, 2H, Hꢀ6b′′, octyl OCH ), 2.41 (d, J = 4.6
2
Hz, 1H, OHꢀ4′′), 1.67–1.55 (m, 2H, octyl OCH CH ), 1.40–1.20 (m, 10H, octyl CH ), 0.90 (t, J
2
2
2
1
3
= 7.0 Hz, 3H, octyl CH ); C NMR (126 MHz, CDCl ) δ 138.5, 138.4, 137.6 (3C, 3 × Ar), 133.3
3
3
(
Cꢀ3′′), 129.9, 129.3 (2C, Cꢀ3, Cꢀ3′), 128.5 (2C, Ar), 128.3 (2C, Ar), 128.3 (2C, Ar), 127.9 (Ar),
127.8 (2C, Ar), 127.4 (3C, Ar), 127.4 (2C, Ar), 127.4 (Ar), 127.3 (Cꢀ2), 126.7 (Cꢀ2′), 125.7 (Cꢀ
′′), 94.2 (Cꢀ1), 91.3 (Cꢀ1′), 91.0 (Cꢀ1′′), 73.7, 73.4, 73.2 (3C, 3 × OCH Ph), 70.7 (Cꢀ6′′), 69.9
2
2
(
Cꢀ6), 69.8 (2C, Cꢀ5′, Cꢀ5′′), 69.2 (Cꢀ6′), 69.1 (Cꢀ5), 68.7 (octyl OCH ), 67.5 (Cꢀ4), 66.7 (Cꢀ4′),
2
6
6.1 (Cꢀ4′′), 31.9, 29.8, 29.4, 29.3, 26.3, 22.7 (6C, octyl CH ), 14.1 (octyl CH ); HRMS (ESI)
2 3
+
calcd C H O [M+Na] 807.4079, found 807.4070.
4
7
60 10
Octyl 6-O-benzyl-α-
solution of 10 (561.8 mg, 0.97 mmol) in tꢀbutanol and acetone (4 mL, v/v 1:1) was added OsO4
2.5 wt.% in tꢀbutanol, 250 uL, 0.02 mmol) and Nꢀmethylꢀmorpholine Nꢀoxide (NMO, 50% w/v
in water, 0.3 mL). After stirring at room temperature overnight, saturated aqueous Na SO3
D
-mannopyranosyl-(1→4)-6-O-benzyl-α-D-mannopyranoside (12): To a
(
2
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6
solution was added. The mixture was concentrated to remove tꢀbutanol and then the residue was
extracted with CH Cl three times. The combined organic layer was concentrated and the resultig
2
2
residue was purifed by chromatography (CH Cl –methanol 15:1) to afford 12 (492.3 mg, 80%)
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
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9
0
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8
9
0
1
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3
4
5
6
7
8
9
0
1
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3
4
5
6
7
8
9
0
1
as a pale yellow syrup. R 0.14 (CH Cl –methanol 15:1); [α] = +59.5 (c 1.2, methanol); H
f
2
2
D
NMR (498 MHz, CD OD) δ 7.34–7.20 (m, 10H, Ar), 5.22 (d, J = 1.8 Hz, 1H, Hꢀ1′), 4.69 (d, J =
3
1
.6 Hz, 1H, Hꢀ1), 4.53–4.41 (m, 4H, 4 × OCH Ph), 3.94 (dd, J = 3.1, 1.9 Hz, 1H, Hꢀ2′), 3.83–
2
3.59 (m, 12H, Hꢀ2, Hꢀ3, Hꢀ3′, Hꢀ4, Hꢀ4′, Hꢀ5, Hꢀ5′, 2 × Hꢀ6, 2 × Hꢀ6′, octyl OCH ), 3.39 (dt, J =
2
9
.6, 6.4 Hz, 1H, octyl OCH ), 1.61–1.52 (m, 2H, octyl OCH CH ), 1.38–1.21 (m, 10H, octyl
2 2 2
1
3
CH ), 0.88 (t, J = 7.0 Hz, 3H, octyl CH ); C NMR (125 MHz, CD OD) δ 139.8, 139.7 (2C, Ar),
2
3
3
129.3 (2C, Ar), 129.3 (2C, Ar), 129.0 (2C, Ar), 128.9 (2C, Ar), 128.6 (Ar), 128.6 (Ar), 103.4 (Cꢀ
1
1
1
′, J
= 171.4 Hz), 101.4 (Cꢀ1, J
= 167.0 Hz), 76.6 (Cꢀ4), 74.6, 74.4 (2C, 2 ×
Cꢀ1,Hꢀ1
Cꢀ1,Hꢀ1
OCH Ph), 74.4, 73.2, 72.7, 72.5, 72.2, 72.1 (6C, Cꢀ2, Cꢀ2′, Cꢀ3, Cꢀ3′, Cꢀ5, Cꢀ5′), 71.4, 71.4 (2C,
2
Cꢀ6, Cꢀ6′), 68.8 (octyl OCH ), 68.7 (Cꢀ4′), 33.0, 30.6, 30.4, 30.4, 27.3, 23.7 (6C, octyl CH ),
2
2
+
1
4.5 (octyl CH ); HRMS (ESI) calcd C H O [M+Na] 657.3245, found 657.3239.
3 34 50 11
Synthesis of octyl 6-O-benzyl-3-O-methyl-α-
D
-mannopyranosyl-(1→4)-6-O-benzyl-3-O-
methyl-α-D-mannopyranoside (12a), octyl 6-O-benzyl-3-O-methyl-α-
D
-mannopyranosyl-
(1→4)-6-O-benzyl-2-O-methyl-α-D-mannopyranoside (12b) and octyl 6-O-benzyl-3-O-
methyl-α- -mannopyranosyl-(1→4)-6-O-benzyl-α-D-mannopyranoside (12c): Compound 12
D
(
0.01–0.04 mmol, 1 equiv.) and nꢀBu SnO (2 equiv.) were heated at reflux in toluene (0.01 M)
2
overnight. The resulting yellowlish solution was cooled to room teperature before MeI (20
equiv.), t-Bu NI (2 equiv.) and CsF (none for entry 1 and 2, 4 equiv. for entry 3) were added.
4
The mixture was stirred at designated temperature (see Table 1) overnight before concentrated.
The crude products were then purifed by chromatography (CH Cl –methanol 30:1 to 20:1) to
2
2
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afford an inseparable mixture of 12a and 12b as a yellow syrup, as well as separable 12c as a
yellow syrup. R 0.51 for 12a and 12b, 0.43 for 12c (CH Cl –methanol 12:1);
f
2
2
Octyl
6-O-benzyl-3-O-methyl-α- -mannopyranosyl-(1→4)-6-O-benzyl-3-O-methyl-α-D-
D
10
11
12
13
14
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1
mannopyranoside (12a): H NMR (600 MHz, CD OD) δ 7.39–7.18 (m, 10H, Ar), 5.16 (d, J =
3
1
.9 Hz, 1H, Hꢀ1′), 4.76 (d, J = 1.8 Hz, 1H, Hꢀ1), 4.53–4.40 (m, 4H, 4 × OCH Ph), 4.08 (dd, J =
2
3
.1, 2.1 Hz, 1H, Hꢀ2′), 4.00 (dd, J = 3.2, 1.9 Hz, 1H, Hꢀ2), 3.87–3.55 (m, 9H, Hꢀ4, Hꢀ4′, Hꢀ5, Hꢀ
5′, 4 × Hꢀ6, octyl OCH ), 3.46 (dd, J = 9.2, 3.3 Hz, 1H, Hꢀ3), 3.45 (s, 3H, OMe), 3.43–3.40 (m,
2
1
H, octyl OCH ), 3.41 (s, 3H, OMe), 3.33 (dd, J = 9.3, 3.1 Hz, 1H, Hꢀ3′), 1.62–1.55 (m, 2H,
2
octyl OCH CH ), 1.40–1.21 (m, 10H, octyl CH ), 0.84 (t, J = 7.5 Hz, 3H, octyl CH ); HRMS
2
2
2
3
+
(
ESI) calcd C H O [M+Na] 685.3558, found 685.3555.
36 54 11
Octyl
6-O-benzyl-3-O-methyl-α-
D
-mannopyranosyl-(1→4)-6-O-benzyl-2-O-methyl-α-D-
1
mannopyranoside (12b): H NMR (600 MHz, CD OD) δ 7.39–7.18 (m, 10H, Ar), 5.24 (d, J =
3
1
.9 Hz, 1H, Hꢀ1′), 4.87 (d, J = 1.6 Hz, 1H, Hꢀ1), 4.53–4.40 (m, 4H, 4 × OCH Ph), 4.16 (dd, J =
2
3.0, 2.1 Hz, 1H, Hꢀ2′), 3.87–3.55 (m, 10H, Hꢀ3, Hꢀ4, Hꢀ4′, Hꢀ5, Hꢀ5′, 4 × Hꢀ6, octyl OCH ), 3.44
2
(
s, 3H, OMe), 3.44 (s, 3H, OMe), 3.43–3.40 (m, 1H, octyl OCH ), 3.37 (dd, J = 3.5, 1.7 Hz, 1H,
2
Hꢀ2), 3.33 (dd, J = 9.3, 3.1 Hz, 1H, Hꢀ3′), 1.62–1.55 (m, 2H, octyl OCH CH ), 1.40–1.21 (m,
2
2
+
1
0H, octyl CH ), 0.84 (t, J = 7.5 Hz, 3H, octyl CH ); HRMS (ESI) calcd C H O [M+Na]
2
3
36 54 11
6
85.3558, found 685.3555;
Octyl
6-O-benzyl-3-O-methyl-α- -mannopyranosyl-(1→4)-6-O-benzyl-α-D-
D
1
mannopyranoside (12c): H NMR (600 MHz, CD OD) δ 7.36–7.19 (m, 10H, Ar), 5.25 (d, J =
3
2.0 Hz, 1H, Hꢀ1′), 4.70 (d, J = 1.6 Hz, 1H, Hꢀ1), 4.54–4.40 (m, 4H, 2 × OCH Ph), 4.17 (dd, J =
2
3
.0, 2.1 Hz, 1H, Hꢀ2′), 3.85–3.60 (m, 11H, Hꢀ2, Hꢀ3, Hꢀ4, Hꢀ4′, Hꢀ5, Hꢀ5′, 4 × Hꢀ6, octyl OCH2),
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