Synthesis of trisaccharides by hetero-diels-alder welding of two monosaccharide units

Article abstract of DOI:10.1002/ejoc.201200277

A new strategy for the synthesis of di- and trisaccharides based on the de novo synthesis of the linking saccharide unit is presented. In this strategy, functionalized monosaccharide building blocks already incorporating the glycosidic linkages are welded together using a metal-catalyzed hetero-Diels-Alder (HDA) reaction to generate a new monosaccharide unit between them. The highest yields and selectivities in the HDA reaction were obtained by using chiral Schiff base chromium complexes. Disaccharide products were accessible by reaction of Danishefsky's diene with acetyl- and benzyl-protected galactoside aldehydes. For the synthesis of trisaccharide products, acetyl-protected glucose or galactose-derived dienes were fused with monosaccharide-derived aldehydes using chromium catalysts for the HDA reaction. The desired trisaccharide products were obtained in moderate to good yields with excellent stereoselectivity. The central pyranulose-ring generated in the process possessed an L-cis-enulose configuration according to NMR spectroscopy and modeling studies. 1 + 1 equals 3! The hetero-Diels-Alder union of two functionalized monosaccharide building blocks - one bearing an aldehyde and the other a readily accessible diene moiety - affords functionalized trisaccharide structures in moderate to good yields and excellent stereoselectivities when β-anomers of the aldehydes are used. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200277

Job/Unit: O20277
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Date: 11-06-12 15:42:57
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FULL PAPER
DOI: 10.1002/ejoc.201200277
Synthesis of Trisaccharides by Hetero-Diels–Alder Welding of Two
Monosaccharide Units
Jatta A. Himanen[a] and Petri M. Pihko*[a]
Keywords: Synthetic methods / Cycloaddition / Carbohydrates / Chromium
A new strategy for the synthesis of di- and trisaccharides
based on the de novo synthesis of the linking saccharide unit
is presented. In this strategy, functionalized monosaccharide
building blocks already incorporating the glycosidic linkages
are welded together using a metal-catalyzed hetero-Diels–
Alder (HDA) reaction to generate a new monosaccharide unit
between them. The highest yields and selectivities in the
HDA reaction were obtained by using chiral Schiff base chro-
mium complexes. Disaccharide products were accessible by
reaction of Danishefsky’s diene with acetyl- and benzyl-pro-
tected galactoside aldehydes. For the synthesis of trisac-
charide products, acetyl-protected glucose or galactose-de-
rived dienes were fused with monosaccharide-derived alde-
hydes using chromium catalysts for the HDA reaction. The
desired trisaccharide products were obtained in moderate to
good yields with excellent stereoselectivity. The central
pyranulose-ring generated in the process possessed an L-cis-
enulose configuration according to NMR spectroscopy and
modeling studies.
Introduction
Oligosaccharides form functionally and structurally the
most diverse organic molecular group in Nature. Because
of their roles in biological recognition and regulation pro-
cesses, oligosaccharides have become the focus of intense
synthetic efforts. The chemical synthesis of oligosaccharides
normally relies on the coupling of separate existing mono-
saccharide parts through the formation of the glycosidic
bond. However, this method often suffers from laborious
protection strategies and difficulties with controlling the
stereochemistry and position of the glycosidic linkage.[1]
An alternative strategy is to construct the monosac-
charide linchpin between two smaller saccharide building
blocks through the direct de novo synthesis of the central
monosaccharide unit (Scheme 1). The advantage of such a
strategy is that in the coupling step there is no need to con-
trol the stereochemistry and the position of glycosidic link-
ages because they have been preset in the pre-functionalized
building blocks. Furthermore, there is no need for differen-
tial protection of the different hydroxy groups of the sub-
units, and consequently fewer protection and final depro-
tection steps would be needed. This strategy might enable
easier access to nonnatural and 13C-labeled oligosaccha-
rides.
Scheme 1. De novo saccharide welding.
In this paper, we present our results for the construction
of di- and trisaccharides based on a de novo saccharide
linchpin construction. The functionalized monosaccharide
units, already including the glycosidic linkages, are welded
together using the hetero-Diels–Alder reaction (HDA) to
generate the central monosaccharide unit (Scheme 2).[2] Pre-
viously, the HDA reaction has been used almost exclusively
for the synthesis of different monosaccharides[3] or unnatu-
ral disaccharides.[4] In this study, the aim was to extend the
HDA strategy to the construction of more complex oligo-
saccharide units by using starting materials that already in-
corporate glycosylated carbohydrate building blocks both
at the diene and the dienophile.
[a] Department of Chemistry, University of Jyväskylä,
P. O. B. 35, 40014 JYU, Finland
Results and Discussion
Fax: +358-14-260-2501
The basic idea behind this work is presented in Scheme 2.
Starting from common glycosylated aldehyde precursor 1,
both di- and trisaccharide products can be accessed by
E-mail: Petri.Pihko@jyu.fi
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200277.
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J. A. Himanen, P. M. Pihko
FULL PAPER
Scheme 2. A hetero-Diels–Alder strategy for the de novo synthesis of oligosaccharides.
using the HDA reaction with a suitable diene. The disac- 25.[6] The synthesis started with preparation of peracetyl-
charide products can be obtained from Danishefsky’s or ated galacto-, gluco- and mannopyranosides 11, 12 and 23
Rawal’s diene 2 or 3 with aldehydes 1. Furthermore, this (Schemes 3 and 4).[7] The glycosylation reaction of allyl
method can be expanded to trisaccharide synthesis by using alcohol led to the pyranoside 13, 14 and 24 in moderate
a more complex pyranoside part containing diene 4. In yields.[8,9] The alkene functionality was then oxidatively
both cases, the HDA products can easily be transformed cleaved (by using OsO4 and then NaIO4) to give aldehydes
into different trisaccharides 6 and tetrasaccharides 8.[3b,5] 15, 16 and 25 in good yields over two steps.[6b,10,11]
We initiated the work with the construction of the aldehyde
building blocks.
In the case of benzyl- and tert-butyldimethylsilyl-(TBS-)
protected monosaccharide derivatives, the protective groups
were modified after the allylation step (Scheme 3). Deacetyl-
ation of allyl tetra-O-acetylgalactopyranoside (13) under
Zemplén conditions afforded allyl β-d-galactopyranoside
Synthesis of the Building Blocks: Aldehyde Dienophiles
The synthesis of monosaccharide aldehyde dienophiles (17).[12] Treatment of 17 with benzyl chloride (BnCl) and
15, 16 and 25 was carried out according to a method de- NaH afforded allyl tetra-O-benzyl-β-galactopyranoside
scribed previously for the synthesis of mannose aldehyde (18).[13] For the TBS-protection, a two-stage silylation, first
Scheme 3. Synthesis of galacto- and glucopyranoside dienophiles. Reagents and conditions: (i) NaOAc, acetic anhydride, 100 °C, 11 (α/β
= 1:97, 47%), 12 (α/β = 1:3, 80%); (ii) allyl alcohol, BF3·OEt2, molecular sieves (4 Å), CH2Cl2, 0 °C to room temp., 13 (pure β, 61%),
14 (pure β, 52%); (iii) OsO4, N-methylmorpholine-N-oxide (NMO), tBuOH/THF/H2O, room temp.; (iv) NaIO4, Na2CO3, THF, pH 7
buffer, 0 °C, 15 (88%), 16 (92%), 19 (94%), 21 (86%); (v) NaOMe/MeOH, room temp.; (vi) DOWEX-50WX8 (H+ form) ion exchange
resin, room temp., 17 (71%); (vii) BnCl, NaH, 115–130 °C, 18 (40%); (viii) TBSCl, imidazole, I2, MeCN-DMF; (ix) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 °C to room temp., 20 (71%).
2
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Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
ate. Other catalysts gave lower selectivities. The low yields
were mainly attributed to the pyranone-formation step be-
cause intermediate 32 was obtained with good conversion
as determined by NMR spectroscopy (Ͼ 70%). Increasing
the amount of AcCl, or use of alternative conditions [tri-
fluoroacetic acid (TFA), chloroacetic acid], also failed. An-
other reason for the low yields was the partial decomposi-
tion of diene 3. Even though a higher yield was obtained
with excess of aldehyde 15 (Table 1, Entry 7), this was not
an economical option because of the more laborious syn-
thesis of 15. Consequently, this approach was abandoned.
Scheme 4. Synthesis of mannopyranoside dienophile. Reagents and
conditions: (i) NaOAc, acetic anhydride, 100 °C, 23 (α/β = 5:1,
quant.); (ii) allyl alcohol, BF3·OEt2, molecular sieves (4 Å),
CH2Cl2, 0 °C to room temp., 24 (pure α, 35%); (iii) OsO4, NMO,
tBuOH/THF/H2O, room temp.; (iv) NaIO4, Na2CO3, THF, pH 7
buffer, 0 °C, 25 (93%).
Table 1. HDA reaction of acetyl-protected galactose-derived alde-
hyde 15 with Rawal’s diene 3.
with tert-butyldimethylsilyl chloride (TBSCl) followed by
completion of the silylation with tert-butyldimethylsilyl tri-
fluoromethanesulfonate (TBSOTf), afforded the desired tet-
rasilylated galactopyranoside 20.[14,15] The alkene function-
ality was cleaved to give aldehydes 19 and 21 in good yields
over two steps. The α-anomer of acetyl-protected galactose
aldehyde 15α was prepared according to methods described
in the literature (Scheme 3).[7,16] In addition to the fully
functionalized pyranoside aldehydes we also prepared a
model dienophile 28 (Scheme 5).[17]
Scheme 5. Synthesis of the model dienophile. Reagents and condi-
tions: (i) iPr2NEt, Bu4NI, benzyl chloromethyl ether (BOMCl),
THF, 0 °C to room temp., 27 (78%); (ii) O3, CH2Cl2/MeOH, then
Me2S, –78 °C, 28 (83%).
Synthesis of Disaccharide Products
In our de novo saccharide welding strategy, the stereo-
selective HDA reaction is the key step to construct the cen-
tral monosaccharide unit. We began the HDA reaction
studies with the synthesis of disaccharide products. In ini-
tial screens, Rawal’s diene 3 was employed owing to its high
reactivity.[18] Consequently, we anticipated that only very
mild activation, such as a hydrogen-bond donor catalyst,
would be required for catalysis. Previously, the Rawal group
had demonstrated the efficiency of both TADDOL-type[19]
and BAMOL-type[20] catalysts in HDA reactions with sim-
ple aldehydes and 3.
Table 1 summarizes the results obtained with 3 and ga-
lactose-derived aldehyde 15. In a control reaction without
catalyst, 15 did not exhibit any stereochemical bias and as
such a chiral catalyst was needed (Table 1, Entry 1). This
fact could be used to our advantage because, in principle,
we could access both l- and d-configured monosaccharide
units. Although moderate selectivities were obtained with
TADDOL catalysts 29a–29c when the reaction was carried
Entry Catalyst
Temp.
[°C]
Time
[h]
Yield[a]
[%]
dr (d/l)[b]
1
2
3
4
5
6
7
8
–
–20
–78
–40
120
72
20
23
16
16
18
25
25
20
20
trace
trace
10
51
29
50:50
n.d.
29a
29a
29a
29b
29c
29d
30a[e]
30b[e]
31a
31b
63:37
80:20
71:29
80:20
58:42
67:33
63:37
64:36
45:55
–20[c]
–20[c]
–20[c]
–20[c]
–20[c]
–20[c]
–20[c]
–20[c]
35
68[d]
15
9
10
11
60
trace
trace
[a] Yield of isolated product. [b] Determined by 1H NMR spec-
troscopy after purification. Absolute stereochemistry of the B ring
was assigned by analogy with the literature precedents.[21–23] In
cases where a non-optimal catalyst combination is described, the
dr of the product was not determined accurately and therefore not
detected (n.d.). [c] The reaction was started at –78 °C and warmed
to –20 °C for the reported reaction time. [d] 200 mol-% of aldehyde
out at –20 °C, the yields of the products were only moder- 15 used. [e] Catalyst loading 40 mol-%.
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The next diene in our tests was the less reactive diene
2.[24] Previously, several groups have reported asymmetric
catalytic HDA reaction of 2 with a variety of aromatic and
aliphatic aldehydes to give corresponding dihydropyr-
anones.[25] For example, chiral bisoxazoline(BOX)-cop-
per(II),[26] BINOL-titanium (IV)[27] and tetradentate salen Figure 1. Possible binding modes of a Lewis-acidic metal catalyst
Schiff base chromium(III) complexes[22] are employed for
to aldehydes 28 and 15.
asymmetric HDA reactions in good to excellent enantio-
selectivity. Other metal and chiral ligand combinations have
Table 2 summarizes the results obtained with 2 and
also been used successfully in this HDA reaction.[28] With model aldehyde 28. Although high selectivities were ob-
less nucleophilic dienes, the chiral-indanol-based Schiff base tained with BINOL-titanium complexes (ligands 35a and
chromium(III) complexes, pioneered by Jacobsen, have 35b), the yields of the products were only moderate
been very popular.[29]
(Table 2, Entries 7 and 8).[30] Different BOX-copper(II) as
In general, 2 and related dienes typically require Lewis well as BINOL-zinc and BINOL-magnesium complexes
acid activation for the heterodienophile. Preliminary screens gave lower selectivities. However, the use of salen-chromium
with aldehyde 15, diene 2, and Lewis acids, such as ZnCl2, complex (ligand 36a) turned out to be promising consider-
MgBr2, La(OTf)3, Yb(OTf)3 or Sc(OTf)3 resulted in prod- ing both stereoselectivity and yield of the reaction (Table 2,
uct formation, but without any selectivity, pointing to the Entries 11 and 12).
need of a chiral catalyst. However, the Lewis acids could
With the results of the preliminary catalyst screening at
theoretically bind to the multifunctionalized aldehydes in hand, optimization was continued by using acetyl protected
several sites, so we decided to study the feasibility of dif- galactose-derived aldehyde 15 (Table 3). The use of BI-
ferent chiral catalysts by using an achiral model aldehyde NOL-titanium complexes (ligands 35a and 35b) afforded a
28 containing an acetal unit (Figure 1).
good level of stereoselectivity, but the yields were low
Table 2. HDA reaction of model aldehyde 28 with Danishefsky’s diene 2.
Entry
Metal
Anion
Ligand
Solvent
T [°C]
t [h]
Yield[a] [%]
er (d/l)[b]
1
2
3
4
5
6
7
8
Zn2+[c]
Cl–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
Et2O
room temp.
–20 Ǟ 0[d]
–20 Ǟ 0[d]
–20 Ǟ 0[d]
0
room temp.
0
1
138
138
138
41
4
1
1
43
47
17
22
69
32
40
n.d.
42
37
23
19
70
41
70
31
50:50
38:62
54:46
42:58
62:38
51:49
5:95
95: 5
65:35
68:32
14:86
39:61
Cu2+
OTf–
OTf–
OTf–
OTf–
OTf–
OiPr–
OiPr–
34a
34b
34c
34d
34d
35a
35b
35a
35a
36a
36a
Cu2+
Cu2+
Cu2+
Cu2+
Ti4+[e]
Ti4+[e]
ZnEt2
MgBu2
Cr3+ [g]
Cr3+ [g]
0
9
room temp.[f]
room temp.[f]
–20[h]
10
11
12
–
BF4
SbF6
–
Et2O
–20
[a] The isolated product. In cases where a non-optimal catalyst combination is described, the yield of product was not determined
accurately and therefore not reported (n.d.). [b] Determined by HPLC after purification [IPA:hexane 10%, 0.7 mL/min, λ = 254 nm, tR
(d-isomer) = 38 min and tR (l-isomer) = 45 min]. Absolute stereochemistry of the newly formed ring was assigned by analogy with
literature precedents.[21–23] [c] Catalyst loading 20 mol-%. [d] Reaction stirred for 96 h at –20 °C and 42 h at 0 °C. [e] Catalyst loading
20 mol-%. [f] Reaction was stirred at 0 °C for 20 h, then transferred to room temp. [g] Catalyst loading 5 mol-%. [h] The reaction was
started at –40 °C and warmed to –20 °C overnight.
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Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
Table 3. HDA reaction of Ac-protected galactoside derivative 15 with Danishefsky’s diene 2.
Entry
Metal
Anion
Ligand MX (+ Ligand) [%] Solvent
T [°C]
Time [h]
Yield[a] [%]
dr (d/l)[b]
1
2
3
4
5
6
7
8
Zn2+
Zn2+
Mg2+
Mg2+
Zn2+
Ti4+
Cl–
–
–
–
–
34b
35a
35b
35b
35b
38
36a
36a
36b
36b
120
120
120
120
40
20
20
10
10
10
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
toluene
toluene
toluene
toluene
toluene
Et2O
room temp.
room temp.
room temp.
–78
room temp.
0
0
0
10 min
0.5
0.5
24
24
1
1
17
17
137
18.5
41
18.5
45
76
35
35
n.d.
20
33
50:50
50:50
45:55
67:33
50:50
18:82
92:8
50:50
50:50
55:45
59:41
70:30
78:22
81:19
Br–
Br–
Br–
Br–
iPrO–
iPrO–
Ti4+
37
ZnEt2
ZniPr2
ZnEt2
Cr3+
n.d.
n.d.
n.d.
59
52
59
9
0
10
11
12
13
14
0[c]
–20
–44
–20
–20
Cl–
–
Cr3+
BF4
5
5
5
Et2O
Et2O
Et2O
Cr3+
Cl–
Cr3+
BF4
27
–
[a] The isolated product. In cases where a non-optimal catalyst combination is described, the yield of product was not determined
accurately and therefore not reported (n.d.). [b] Determined by 1H NMR spectroscopy after purification. Absolute stereochemistry of
the B ring was assigned by analogy with literature precedents.[21–23] [c] Reaction stirred for 65 h at 0 °C and 72 h at room temp.
(Table 3, Entries 6 and 7). The salen–chromium complexes tion. Interestingly, both ligand enantiomers led to the same
(ligand 36a and 36b) turned out to be better choices with diastereomer of product (Table 3, Entries 11 and 13). Al-
respect to both the stereoselectivity and the yield of reac- though the tetrafluoroborate counter anion gave better
Table 4. HDA reaction of Bn-protected galactoside derivative 19 with Danishefsky’s diene 2.
Entry
M
Anion
Ligand
MX (+ Ligand) [mol-%]
Solvent
T [°C]
Time [h]
Yield[a] [%]
dr (d/l)[b]
1
2
3
4
5
6
7
Ti4+
Ti4+
Cr3+
Cr3+
Cr3+
Cr3+
Cr3+
iPrO–
iPrO–
Cl–
35a
35b
36a
36b
36b
39a
39b
20
20
5
5
5
1
1
toluene
toluene
Et2O
Et2O
Et2O
Et2O
Et2O
0
0
–20
–20
–20
–20
–20
2.5
2.5
18.5
18.5
45
43.5
43.5
49
30
48
54
59
54
59
16:84
89:11
61: 39
81:19
88:12
19:81
94:6
Cl–
–
BF4
Cl–
Cl–
[a] The isolated product. [b] Determined by 1H NMR spectroscopy after purification. Absolute stereochemistry of the B ring was assigned
by analogy with the literature precedents.[21–23]
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selectivities (Table 3, Entries 12 and 14), the chloride com- The use of tridentate indanol-type chromium complexes (li-
plex turned out to be a more reproducible and stable cata- gands 39a and 39b) gave the highest level of stereoselectivity
lyst.
(Table 4, Entries 6 and 7). Moreover, in this case, enantio-
In addition to the acetyl-protected aldehyde, a more lipo- meric catalysts resulted in the formation of two different
philic benzyl-protected galactose-derived aldehyde 19 was diastereomers of the products. Unfortunately, the yields of
also studied, owing to concerns of Lewis-acid-mediated the reactions were still moderate.
acetyl deprotection. The optimum conditions of Table 3
were selected, and the results are summarized in Table 4.
Synthesis of Saccharide Dienes
To expand the de novo saccharide welding to the synthe-
sis of trisaccharide products, more complex dienes incorpo-
Scheme 6. Synthesis of saccharide dienes. Reagents and conditions:
(i) RuCl3·H2O, CH2Cl2/MeCN/H2O/HOAc, room temp., 42
(quant), 43 (95%); (ii) oxalyl chloride, DMF (cat), CH2Cl2, 0 °C to
room temp.; (iii) ethyl vinyl ether, iPrNEt2, MeCN, NaIO4, 0 °C to
70 °C, 44 (74%), 45 (80%); (iv) TBSOTf, Et3N, CH2Cl2, 0 °C to
room temp., 46 (56%), 47 (40%).
1
Figure 2. H NMR spectroscopy coupling constants and chemical
shifts of cyclobutanones 48 and 49.
Table 5. Synthesis of cyclobutanones 49, 44 and 45.
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Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
rating the monosaccharide unit were needed. We decided to ketenes through treatment of the derived acid chlorides
use Scheeren’s methodology for their synthesis,[31] because with Et3N. The intermediate was subjected to [2+2] cyclo-
a similar method has been described for the synthesis of addition with ethyl vinyl ether. In our initial attempts, these
diene 49.[4,32]
conditions afforded the intermediate cyclobutanones 44 and
The synthesis of dienes 46 and 47 was initiated by the 45 in variable yields (24–58%, see Table 5, Entries 5 and 7),
preparation of allyl tetra-O-acetylated β-d-galacto- and β- comparable with results given in the literature.[31,34]
d-glucopyranosides 13 and 14 as described in Scheme 2 and
Owing to the low and variable yields, we optimized the
the oxidation of the pendant alkene functionalities to the cyclobutane synthesis using phenoxyacetic acid. Among the
corresponding carboxylic acids in Scheme 6.[33] The carbox- conditions screened (Table 5, Entries 1–4), the use of
ylic acids were then transformed into the corresponding iPr2NEt as the base afforded the desired model cyclobutane
Table 6. Reaction of monosaccharide aldehydes 15, 16, 19 and 25 with the galactose-derived diene 46.
[a] Catalyst loading 5–9 mol-%. [b] Yield of isolated product. [c] Determined by 1H NMR spectroscopy after purification. [d] Catalyst
loading 12 mol-%.
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49 reproducibly and in higher yield (60%, Table 5, Entry 4, Synthesis of Trisaccharide Products
93:7 trans/cis ratio). Evidence for the trans-configuration of
the major product is summarized in Figure 2.[31,35,36]
As discussed in the introduction, the HDA strategy can
The iPr2NEt conditions were then employed with mono- be also be expanded to allow the synthesis of trisaccharides
saccharide acids 42 and 43 affording cyclobutanoses 44 and by using the pyranoside building blocks containing diene 4.
45 in good yields (74% and 80% respectively, Table 5, En- In initial screens we used acetyl-protected glucose or
tries 6 and 8). In both cases, a complex mixture of dia- galactose derived dienes 46 and 47 with monosaccharide
stereomers was formed. Fortunately, the stereochemistry of aldehyde derivatives 15, 16, 19, 21 and 25. The results are
isolated cyclobutanones 44 and 45 had no effect on the next summarized in Tables 6 and 7. The reaction did not proceed
step, because the treatment of those with an excess of Et3N at all without any catalyst and only slow decomposition of
converted them completely to the trans-isomers (as evi- diene was observed (after 6 d). With catalytic MgBr2·OEt2,
denced by Aben and Scheeren).[31] The compounds were the yields were moderate (47–57%), but a mixture of dia-
not isolated, but allowed to undergo ring opening by adding stereomers was formed.
TBSOTf.[25] The pyranoside dienes 46 and 47 were obtained
With the screening results obtained for the disaccharide
in moderate yields (56% and 40%, respectively, system, further screens were carried out using the CrIII cata-
Scheme 6).[37] Because the final ring opening is a concerted lysts. (Table 2, ligands 39a and 39b).[38] Significantly, re-
and conrotary process, only the trans,trans-isomers of the gardless of the catalyst configuration, single diastereomers
diene products were eventually formed.[31]
of the trisaccharide products were obtained with both acet-
Table 7. Reaction of monosaccharide aldehydes 15, 16 and 19 with the glucose-derived diene 47.
1
[a] Catalyst loading 6–9 mol-%. [b] Yield of isolated product. [c] Determined by H NMR spectroscopy after purification. [d] 200 mol-%
of aldehyde 15 was used. [e] Catalyst loading 15 mol-%. [f] CH2Cl2 used as a co-solvent.
8
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Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
Figure 3. NMR spectroscopic and computational evidence [energies calculated at the DFT (6-311G**/B3LYP) level of theory] for the
configuration of 56.
Figure 4. Further NMR spectroscopic evidence for the configuration of 54 and 50. Other trisaccharides have been assigned by analogy.
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J. A. Himanen, P. M. Pihko
FULL PAPER
yl- and benzyl-protected β-galacto- and β-glucopyranoside- to allow comparison with products having known stereo-
derived aldehydes 15, 16 and 19 (Scheme 2). The highest chemistry. Unfortunately, the desired products could not be
yields were obtained in the reaction of Ac-protected obtained, mainly due to the relatively low reactivity of the
galactoside-derived aldehyde 15 with glucoside diene 47 ulose-type acceptor.[36] The stereochemistry of the products
1
(Table 7, Entries 1 and 2). On the other hand, tetrasilylated was therefore assigned through extensive H NMR NOE
aldehyde 21 failed to undergo the desired reaction.
and NOESY experiments. (Figure 3 and Figure 4).[36] For
1
Attempts at further improvement of the yields by raising product 56, which displayed the cleanest separation of H
the temperature, prolonging the reaction time, changing the NMR signals, a more complete conformational analysis
counterion (ClǞSbF6) or slow addition of the components was carried out by a combination of Monte Carlo confor-
were unsuccessful. However, increasing the amount of cata- mational search using initially force field (MMFFs) meth-
lyst did improve the yield slightly. The reaction of acetyl- ods, followed by DFT (6-311G**/B3LYP) methods for fur-
protected glucopyranoside aldehyde 16 with acetyl-pro- ther optimization and energy calculations.[36] Both d and l
tected glucopyranoside diene 46 the yields of 56 with 6 mol- isomers and both conformers of the linking B-ring (4-O-
% and 15 mol-% catalyst loadings were 45 and 51%, respec- axial and 4-O-equatorial) were examined (Figure 3). Of the
tively. Therefore, in further screens higher catalyst loadings minimum energy structures thus obtained, the only one that
(9–15 mol-%) were used.
clearly matches the NMR spectroscopic data is the l isomer
Because both chiral catalysts afforded the same trisac- having an axial 4-O substituent. In this case, the distance
charide diastereomers with high dr, we also screened an between HB4 and HA2 was short enough to explain the ob-
1
achiral catalyst based on ligand 40 (see Table 4). Com- served H NMR NOE enhancements and the correspond-
pound 40·CrCl was synthesized according to a modified lit- ing NOESY cross-peaks. For the l isomer, this 4-O-axial
erature procedure.[28] When this catalyst was employed in conformation was also more stable than 4-O-equatorial
the HDA reaction of galactopyranoside aldehyde 15 and conformation by 20.7 kcal/mol.
galactopyranoside diene 46, we again obtained the same
Taken together, the evidence points towards an l-cis con-
product diastereomer 50. However, the yield of 50 was figuration in the newly generated B ring.[40] The configura-
lower (≈ 30%) and the reactions were sluggish. Although tions of the other products 50–55 have been assigned by
the use of a chiral catalyst was not essential for the dia- analogy. The coupling constants of the B4 proton in all
stereoselectivity of HDA reaction, the higher reactivity of other products 50–55[37] were virtually identical and for the
the chiral catalysts necessitated their use in this process.
products 54 and 50 similar NOE enhancements were ob-
We also checked the influence of the anomeric center of served (Figure 4).
aldehyde 15 on the reactivity and stereoselectivity. These
studies were initially conducted with acetyl protected α-ga-
lactopyranoside derived aldehyde 15α (Scheme 2). 15α
turned out to be much more unreactive than its β-anomer.
The catalyst with ligand 39a was more efficient in this con-
text, but the highest yield of the corresponding trisac-
charide product was significantly lower than in the case of
the corresponding β anomer 15 (i.e. with diene 47, the α-
anomer afforded a 16% yield, and the β-anomer a 68%
yield). In the case of the corresponding mannopyranoside,
the α-anomer 25 was also not an optimal substrate for
HDA reaction because products were formed as a mixture
of diastereomers. With glucopyranoside diene 47 the yields
were low (15 and 7% for ligands 39a and 39b, respectively),
but with galactopyranoside diene 46, somewhat higher
yields were obtained (Table 6, Entries 7 and 8).
Conclusions
The Cr-catalyzed hetero-Diels–Alder protocol provides a
viable strategy for a selective saccharide welding between
two different saccharide units, producing galactal-type 4,6-
linked trisaccharides. The HDA protocol appears to toler-
ate different protective groups provided they are not too
bulky. The reaction is diastereoselective and fully preserves
the glycosidic linkage already present in the precursor units.
Interestingly, an l-configured enulose linking-unit is stereo-
selectively generated in the welding process.
Experimental Section
In the major products 50–56, the relative stereochemistry
of the central ulose ring (B-ring) formed in the HDA reac-
General Methods: All reactions were carried out under an argon
atmosphere in flame-dried glassware. The reaction temperatures re-
tion can be confirmed by 1H NMR spectroscopy. Compari- fer to the temperatures of the cooling or warming baths. When
needed, non-aqueous reagents were transferred under argon by
using a syringe or cannula and dried prior to use. Acetonitrile,
dichloromethane, diethyl ether, tetrahydrofuran (THF) and toluene
were obtained by passing deoxygenated solvents through activated
alumina columns (MBraun SPS-800 Series solvent purification sys-
tem). DMF was distilled from molecular sieves (4 Å). Et3N,
iPr2NEt and 2,6-lutidine were distilled from CaH2. Other solvents
and reagents were used as received. TBSOTf was prepared with
Corey’s procedure.[41] Analytical TLC was performed using Merck
silica gel F254 (230–400 mesh) plates and analyzed by UV light or
son with the literature data for related enulose rings indi-
cates that the H4–H5 coupling constant (JH4-H5) of the
trans-isomer is larger (10.4–13.2 Hz) than that of the cis-
isomer (0.6–6.0 Hz; see Tables 6 and 7).[39] For products 50–
56, the B-ring showed JH4-H5 = 1.4 Hz to 1.9 Hz, indicating
cis configuration (galacto stereochemistry).
In order to completely assign the absolute stereochemis-
try, we initially attempted the traditional synthesis of the
trisaccharide product by using bromide or trichloroacetim-
idate donors and the corresponding galactal-derived enones by staining upon heating with vanillin solution (6 g of vanillin,
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Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
5 mL of concd. H2SO4, 3 mL of glacial acetic acid, 250 mL of
EtOH). For silica gel chromatography, the flash chromatography
technique was used, with Merck silica gel 60 (230–400 mesh) and
p.a. grade solvents.
H), 4.25–4.08 (m, 3 H), 3.88 (dt, J = 6.6, 1.1 Hz, 1 H), 3.63 (dd, J
= 9.4, 7.1 Hz, 1 H), 3.57 (dd, J = 9.4, 7.1 Hz, 1 H), 2.92 (ddd, J =
17.7, 8.2, 2.4 Hz, 1 H), 2.75 (ddd, J = 17.7, 7.0, 3.7 Hz, 1 H), 2.15
(s, 3 H), 2.06 (s, 3 H) 2.04 (s, 3 H) 1.97 (s, 3 H), 1.25 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): First eluting isomer δ =
201.6, 170.3, 170.1, 170.0, 169.7, 100.7, 91.1, 70.9, 70.7, 70.2, 68.5,
66.8, 65.7, 61.1, 45.8, 20.7, 20.6 (2 C), 20.5, 15.1 ppm. Second elut-
ing isomer δ = 200.0, 170.3, 170.2, 170.0, 169.3, 99.0, 91.4, 70.9 (2
C), 70.7, 68.6, 66.9, 65.8, 61.4, 44.7, 20.7, 20.6 (2 C), 20.5,
15.1 ppm. HRMS (ESI+): calcd. for C20H28O12·Na 483.1478; found
483.1476, Δ = –0.4 ppm.
The 1H NMR and 13C NMR spectra were recorded in CDCl3,
CD3CN or CD3OD on Bruker Avance 500, 400 or 250 spectrome-
ters. The chemical shifts are reported in ppm relative to the residual
CHCl3 (δ = 7.26 ppm), CHD2CN δ (δ = 1.94 ppm) or CHD2OD
(δ = 3.31 ppm) for 1H NMR and the solvent peaks CDCl3 (δ =
77.0 ppm), CD3CN (δ = 1.32 ppm) or CD3OD (δ = 49.0 ppm) for
the 13C NMR spectra. The enantiomeric ratios (er) of the products
were determined by HPLC in comparison to the racemic samples
using Waters 501 pump and Waters 486 detector. Melting points
were determined in open capillaries by using either a Gallenkamp
melting point Apparatus or a Bibbly Stuart Scientific (SMP3) melt-
ing point Apparatus. IR spectra were recorded with either a Per-
kin–Elmer Spectrum One FT-IR spectrometer or a Bruker Optics
Tensor 27 FT-IR spectrometer. Optical rotations were obtained
with a Perkin–Elmer 343 polarimeter. High-resolution mass spec-
trometric data was recorded with a Micromass (ESI-TOF) spec-
trometer.
3-Ethoxy-2-phenoxycyclobutanone (49): Compound 49 was pre-
pared according to the general procedure. The crude produce was
purified by using flash chromatography (20% EtOAc/hexanes) to
1
give a tan oil (800 mg, 89%). H NMR spectroscopic data showed
a 93:7 ratio of the trans- and cis-diastereomers, respectively. For
the major trans-isomer: Rf (50% EtOAc/hexanes) = 0.60. IR (film):
ν = 2978, 2929, 2894, 1798, 1598, 1591, 1495, 1242, 1226, 1119,
˜
1
1104, 1026 cm–1. H NMR (500 MHz, CDCl3): δ = 7.30 (dd, J =
8.7, 7.4 Hz, 2 H), 7.06 (dd, J = 8.7, 0.9 Hz, 2 H), 7.02 (tt, J = 7.4,
0.9 Hz, 1 H), 5.28 (ddd, J = 5.4, 3.7, 2.5 Hz, 1 H), 4.31 (ddd, J =
8.0, 7.2, 5.4 Hz, 1 H), 3.65 (dd, J = 7.0, 2.5 Hz, 1 H), 3.62 (dd, J
= 7.0, 2.5 Hz, 1 H), 3.09 (ddd, J = 17.6, 8.0, 2.5 Hz, 1 H), 2.95
(ddd, J = 17.6, 7.2, 3.7 Hz, 1 H), 1.28 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 200.8, 157.2, 129.5 (2 C), 122.2,
115.7 (2 C), 91.0, 70.5, 66.0, 45.8, 15.1 ppm. HRMS (ESI+): calcd.
for C12H14O3Na 229.0841; found 229.0835, Δ = –2.4 ppm. For
minor cis-isomer: Rf (50% EtOAc/hexanes) = 0.48. 1H NMR
(250 MHz, CDCl3): δ = 7.30 (dd, J = 9.2, 8.0 Hz, 2 H), 7.06–6.98
(m, 3 H), 5.17 (ddd, J = 6.1, 4.3, 1.8 Hz, 1 H), 4.53 (app. td, J =
6.1, 2.1 Hz, 1 H), 3.65 (dd, J = 7.0, 2.5 Hz, 1 H), 3.62 (dd, J = 7.0,
2.5 Hz, 1 H), 3.16 (ddd, J = 17.7, 6.3, 4.3 Hz, 1 H), 2.81 (app. dt,
J = 17.7, 1.8 Hz, 1 H), 1.28 (t, J = 7.0 Hz, 3 H) ppm. HRMS
(ESI–): calcd. for C12H14O3H 207.1021; found 207.1017, Δ =
–2.2 ppm.
Typical Procedure for Cyclobutanone Formation
2-Ethoxy-4-oxocyclobutyl 2,3,4,6-Tetra-O-acetyl-β-galactopyranos-
ide (44): To a stirred solution of acetyl protected galactopyranoside
acid 42 (1.68 g, 4.14 mmol, 100 mol-%) in CH2Cl2 (20 mL) at room
temp. was added DMF (0.10 mL, 94 mg, 1.29 mmol, 30 mol-%).
The solution was cooled to 0 °C and oxalyl chloride (1.44 mL,
2.15 g, 16.6 mmol, 400 mol-%) was added over 10 min. Gas forma-
tion was observed. The reaction mixture was stirred for 20 min at
0 °C and then at room temp. for 2 h 10 min after which it was
concentrated in vacuo. Toluene (20 mL) and CH2Cl2 (20 mL) were
added, and the resulting solution was again concentrated. This pro-
cedure was repeated twice while maintaining the mixture under ar-
gon at all times. To the residue was added MeCN (8 mL) and the
reaction mixture was cooled to 0 °C. A mixture of ethyl vinyl ether
(0.90 mL, 680 mg, 9.36 mmol, 230 mol-%) and iPrNEt2 (0.87 mL,
643 mg, 4.97 mmol, 120 mol-%) in MeCN (1 mL) was added drop-
wise over a period of 10 min, during which time the mixture turned
cloudy. The mixture was stirred for 5 min, and then heated to
70 °C. Stirring was continued for 30 min. During this time, the mix-
ture turned first orange and then darker brown. The reaction mix-
ture was allowed to cool to room temp. and then concentrated in
vacuo. The residue was suspended in Et2O (15 mL), filtered
through Celite and washed with Et2O (2ϫ15 mL + 5 mL). The
filtrate was concentrated, and purification of the residue by flash
chromatography (initially 50% EtOAc/hexanes, finally 80% EtOAc/
2-Ethoxy-4-oxocyclobutyl 2,3,4,6-Tetra-O-acetyl-β-glucopyranoside
(45): Compound 45 was prepared according to the general pro-
1
cedure as a yellowish foam (1.52 g, 80%). H NMR spectroscopic
data showed a mixture of two diastereomers, which were both as-
sumed to possess the trans-configuration. Rf (80% EtOAc/hexanes)
= 0.51 (first eluting isomer), 0.48 (second eluting isomer). IR (film):
ν = 3062, 2977, 2941, 2897, 1751, 1628, 1435, 1370, 1225,
˜
1
1042 cm–1. H NMR (500 MHz, CDCl3): First eluting isomer δ =
5.16 (app. t, J = 9.5 Hz, 1 H), 5.03 (dd, J = 10.0, 9.6 Hz, 1 H), 4.95
(dd, J = 9.6, 8.0 Hz, 1 H), 4.86 (ddd, J = 5.3, 3.7, 2.5 Hz, 1 H),
4.76 (d, J = 8.0 Hz, 1 H), 4.19 (dd, J = 12.3, 4.6 Hz, 1 H), 4.14–
hexanes) afforded cyclobutanone 44 (1.74 g, 74%) as a yellowish 4.10 (m, 2 H), 3.68 (ddd, J = 10.0, 4.6, 2.7 Hz, 1 H), 3.62 (dd, J =
1
foam. H NMR spectroscopic data showed a mixture of two dia-
stereomers, which both were assumed to possess the trans-configu-
ration. Rf (50% EtOAc/hexanes) = 0.21 (first eluting isomer), 0.18
9.5, 7.0 Hz, 1 H), 3.54 (dd, J = 9.5, 7.0 Hz, 1 H), 2.90 (ddd, J =
17.6, 8.2, 2.5 Hz, 1 H), 2.79 (ddd, J = 17.6, 7.3, 3.7 Hz, 1 H), 2.03
(s, 3 H), 2.00 (s, 3 H) 1.97 (s, 3 H) 1.95 (s, 3 H), 1.19 (t, J = 7.0 Hz,
3 H) ppm. Second eluting isomer δ = 5.16 (app. t, J = 9.4 Hz, 1
H), 5.03 (dd, J = 10.0, 9.5 Hz, 1 H), 4.97 (dd, J = 9.5, 8.0 Hz, 1
H), 4.85 (ddd, J = 5.5, 3.8, 2.4 Hz, 1 H), 4.82 (d, J = 8.0 Hz, 1 H),
4.21–4.13 (m, 3 H), 3.64 (ddd, J = 10.0, 5.0, 2.8 Hz, 1 H), 3.60 (dd,
J = 9.5, 7.0 Hz, 1 H), 3.54 (dd, J = 9.5, 7.0 Hz, 1 H), 2.90 (ddd, J
(second eluting isomer). IR (film): ν = 3483, 2979, 2938, 1791,
˜
1750, 1371, 1225, 1079, 1061 cm–1. 1H NMR (400 MHz, CDCl3):
First eluting isomer δ = 5.39 (dd, J = 3.4, 1.1 Hz, 1 H), 5.20 (dd,
1 H, J = 10.5 Hz, 8.0 Hz), 5.01 (dd, 1 H, J = 10.5 Hz, 3.4 Hz), 4.90
(ddd, 1 H, J = 5.3 Hz, 3.5 Hz, 2.3 Hz), 4.73 (d, 1 H, J = 8.0 Hz),
4.13 (d, 1 H, J = 6.6 Hz), 4.20–4.14 (m, 2 H), 3.91 (dt, 1 H, J = = 17.7, 8.2, 2.4 Hz, 1 H), 2.72 (ddd, J = 17.7, 6.9, 3.8 Hz, 1 H),
6.6 Hz, 1.1 Hz), 3.67–3.56 (m, 2 H), 2.95 (ddd, 1 H, J = 17.6 Hz, 2.05 (s, 3 H), 2.02 (s, 3 H) 1.99 (s, 3 H) 1.96 (s, 3 H), 1.22 (t, J =
8.0 Hz, 2.3 Hz), 2.83 (ddd, 1 H, J = 17.6 Hz, 7.4 Hz, 3.5 Hz), 2.14
(s, 3 H), 2.07 (s, 3 H) 2.04 (s, 3 H) 1.97 (s, 3 H), 1.24 (t, 3 H, J = mer δ = 201.3, 170.3, 169.9, 169.3, 169.2, 99.8, 90.8, 72.5, 72.0,
7.0 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): First eluting iso-
7.0 Hz) ppm. Second eluting isomer: δ = 5.37 (dd, J = 3.5, 1.1 Hz,
1 H), 5.21 (dd, J = 10.4, 8.0 Hz, 1 H), 5.00 (dd, J = 10.4, 3.5 Hz,
1 H), 4.88 (ddd, J = 5.7, 3.5, 2.3 Hz, 1 H), 4.75 (d, J = 8.0 Hz, 1
71.0, 70.1, 68.2, 65.6, 61.7, 45.7, 20.53, 20.49, 20.4 (2C), 15.0 ppm.
Second eluting isomer δ = 200.1, 170.4, 170.0, 169.3, 169.1, 98.1,
91.0, 72.7, 71.9, 71.1, 70.9, 68.3, 65.7, 61.8, 44.7, 20.6, 20.5, 20.4
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(2 C), 15.0 ppm. HRMS (ESI+): calcd. for C20H28O12·Na 483.1478;
found 483.1486, Δ = 1.7 ppm.
(3ϫ4 mL). The combined organic phases were washed with brine
(3 mL), dried with Na2SO4 and concentrated in vacuo. Purification
of the residue by flash chromatography (initially 60% EtOAc/hex-
anes, finally 80% EtOAc/hexanes) afforded 33 as a yellowish oil
(41 g, 37%). 1H NMR showed a 92:8 ratio of the d and l dia-
stereomers, respectively.
Typical Procedure for Dienyl Pyranoside Formation[31]
(1Z,3E)-2-(tert-Butyl-dimethylsilanyloxy)-4-ethoxy-1,3-butadienyl
2,3,4,6-Tetra-O-acetyl-β-galactopyranoside (46): To a stirred solu-
tion of the galactopyranoside 44 (1.07 g, 2.33 mmol, 100 mol-%) in
CH2Cl2 (20 mL) at 0 °C was added Et3N (1.33 mL, 0.966 g,
9.55 mmol, 410 mol-%), followed by the addition of TBSOTf
(1.07 mL, 1.32 g, 4.66 mmol, 200 mol-%) over 5 min. The reaction
mixture was yellowish, but became slowly reddish. After 15 min,
the reaction mixture was warmed to room temp. and stirred for a
further 45 min. Et3N (5.0 mL) and satd. aq. NaHCO3 (20 mL) were
added, the phases were separated and the organic phase was
washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4
and concentrated. Purification of the residue by flash chromatog-
raphy (initially 30% EtOAc/hexanes containing 2 vol.-% Et3N, fi-
nally 40 % EtOAc/hexanes containing 2 vol.-% Et3N) afforded
diene 46 as a yellowish solid (752 mg, 56%). Rf (50% EtOAc/hex-
Typical Procedure for the HDA Reaction of Aldehydes 15, 19 and
28 with Danishefsky’s Diene 2 by Using Schiff Base Chromium Com-
plexes (Ligands 36a, 36b, 39a and 39b): Catalyst complexes were
synthesized according to the literature.[29a] To a stirred solution of
aldehyde (0.091 mmol, 100 mol) 39b-CrCl complex (0.7 mg,
0.01 mmol, 2 mol-%) and crushed molecular sieves (4 Å, 30 mg) in
Et2O (0.2 mL) at –20 °C was added diene 2 (22 μL, 18 mg,
0.10 mmol, 110 mol-%). The mixture was stirred for 43.5 h, then
TFA (0. 30 μL, 45 mg, 0.392 mmol, 430 mol-%) in Et2O (1.0 mL)
was added. The reaction mixture was stirred for an additional 3 h
and then quenched by adding satd. aq. NaHCO3 (3 mL). Et2O
(3 mL) was added and phases were separated. The aq. phase was
extracted with Et2O (3ϫ4 mL) and the combined organic phases
were washed with brine (3 mL), dried with Na2SO4 and concen-
trated in vacuo. Purification of the residue by flash chromatography
afforded the desired product.
anes) = 0.54. [α]D = +86.1 (c = 1.00, CH Cl ). IR (film): ν = 2956,
˜
2
2
2932, 2887, 2859, 1753, 1627, 1370, 1250, 1221, 1079 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 6.65 (d, J = 12.3 Hz, 1 H), 5.70 (s,
1 H), 5.36 (app. d, J = 3.1 Hz, 1 H), 5.27 (dd, J = 10.2, 8.0 Hz, 1
H), 5.17 (d, J = 12.3 Hz, 1 H), 5.00 (dd, J = 10.2, 3.4 Hz, 1 H),
4.67 (d, J = 8.0 Hz, 1 H), 4.16–4.09 (m, 2 H), 3.92 (td, J = 6.7,
0.8 Hz, 1 H), 3.74 (q, J = 7.1 Hz, 2 H), 2.14 (s, 3 H), 2.03 (s, 3 H),
2.01 (s, 3 H), 1.96 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.94 (s, 9 H),
0.13 (s, 6 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.3, 170.13,
170.05, 169.0, 146.8, 134.9, 125.4, 101.4, 100.4, 71.3, 70.9, 68.5,
66.9, 65.5, 61.1, 25.9 (3 C), 20.7, 20.6 (2 C) 20.5, 18.4, 14.7, –4.37,
–4.43 ppm. HRMS (ESI+): calcd. for C26H42O12SiNa 597.2343;
found 597.2347, Δ = 0.7 ppm.
2-(Benzyloxymethyloxymethyl)-2,3-dihydro-4H-pyran-4-one (37):
Compound 37 was prepared according to the general procedure by
using BINOL titanium complex (ligands 36a) and purified by using
flash chromatography (gradient of 30% to 40% EtOAc/hexanes) to
give a yellow oil (35 mg, 23%). The isolated material was deter-
mined to be a 5:95 ratio of the d and l enantiomers, respectively,
by chiral HPLC analysis [Daicel Chiralpak OD, IPA:hex 10 %,
0.7 mL/min, λ = 254 nm, tR(first eluting D enantiomer) = 38 min,
tR(second eluting L enantiomer) = 45 min]. Rf (50% EtOAc/hex-
anes) = 0.31. IR (film): ν = 3064, 3032, 2935, 2888, 1723, 1678,
˜
(1Z,3E)-2-(tert-Butyl-dimethylsilanyloxy)-4-ethoxy-1,3-butadienyl
2,3,4,6-Tetra-O-acetyl-β-glucopyranoside (47): Compound 47 was
prepared according to the general procedure. As a yellowish solid
(535 mg, 40%). Rf (50% EtOAc/hexanes) = 0.68; m.p. 113–115 °C.
1595, 1455, 1406, 1283, 1226, 1169, 1110, 1044, 1027 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 7.39–7.29 (m, 6 H), 5.432 (dd, J =
6.0, 1.1 Hz, 1 H), 4.84 (d, J = 6.8 Hz, 1 H), 4.82 (d, J = 6.8 Hz, 1
H), 4.63 (s, 2 H), 4.58 (dddd, J = 14.0, 7.1, 3.6, 3.6 Hz, 1 H), 3.85
(dd, J = 11.2, 3.6 Hz, 1 H), 3.80 (dd, J = 11.2, 5.4 Hz, 1 H), 2.72
(dd, J = 16.7, 14.0 Hz, 1 H), 2.40 (ddd, J = 16.7, 3.6, 1.1 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.6, 162.6, 137.3,
128.3 (2 C), 127.70 (2 C), 127.67, 106.9, 94.6, 77.9, 69.5, 68.1,
38.0 ppm. HRMS (ESI+): calcd. for C14H16O4H 249.1127, found
249.1122, Δ = –2.0 ppm.
[α]D = +35.2 (c = 1.00, CH Cl ). IR (film): ν = 2957, 2932, 2859,
˜
2
2
1759, 1637, 1366, 1222, 1164, 1127, 1069, 1042 cm–1 1H NMR
.
(250 MHz, CDCl3): δ = 6.65 (d, J = 12.2 Hz, 1 H), 5.71 (s, 1 H),
5.23–5.04 (m, 4 H), 4.71 (d, J = 7.6 Hz, 1 H), 4.24 (dd, J = 12.3,
4.5 Hz, 1 H), 4.14 (dd, J = 12.3, 2.6 Hz, 1 H), 3.74 (q, J = 7.0 Hz,
1 H), 3.75–3.68 (m, 1 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3 H),
1.99 (s, 3 H), 1.27 (t, J = 7.0 Hz, 3 H), 0.94 (s, 9 H), 0.13 (s, 3 H),
0.12 (s, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 170.4, 170.0,
169.1, 168.9, 146.7, 134.7, 125.4, 101.2, 99.8, 73.0, 71.9, 71.0, 67.9,
65.4, 61.6, 25.8 (3 C), 20.50, 20.48, 20.4 (2 C), 18.3, 14.6, –4.48,
–4.53 ppm. HRMS (ESI+): calcd. for C26H42O12SiNa 575.2524;
found 575.2529, Δ = 0.9 ppm.
(2,3-Dihydro-4-oxo-4H-pyran-2-yl)methyl 2,3,4,6-Tetra-O-acetyl-β-
D-galactopyranoside (33): Compound 33 was prepared according to
the general procedure by using BINOL titanium complex (ligands
1
35b) as a yellow oil (41 g, 37%). H NMR showed a 92:8 ratio of
the d and l diastereomers, respectively. Rf (50% EtOAc/hexanes)
Typical Procedures for the HDA Reaction of Aldehydes 15, 19 and
28 with Danishefsky’s Diene 2 by Using BINOL Titanium Com-
plexes (Ligands 35a and 35b): A mixture of Ti(OiPr)4 (1 m in
CH2Cl2, 51 μL, 14.3 mg, 0.051 mmol, 21 mol-%), BINOL 35b
(16.2 mg, 0.057 mmol, 24 mol-%) and crushed molecular sieves
(4 Å, 100 mg) in toluene (0.8 mL) was stirred at 40 °C for 1 h, then
allowed to cool to room temp. and a solution of acetyl-protected
galactospyranoside aldehyde 15 (94 mg, 0.24 mmol, 100 mol-%) in
toluene (1.0 mL) was added. The mixture was cooled to 0 °C and
diene 2 (66 μL, 66 mg, 0.38 mmol, 160 mol-%) was added dropwise.
The mixture was stirred for 50 min, then TFA (0.03 μL, 45 mg,
0.39 mmol, 160 mol-%) in toluene (1.0 mL) was added. Stirring was
continued for an additional 2 h, after which the reaction was
quenched by adding satd. aq. NaHCO3 (3 mL). The phases were
separated and the aqueous phase was extracted with CH2Cl2
= 0.09 (l diastereomer), 0.06 (d diastereomer). IR (film): ν = 3062,
˜
2937, 2856, 1751, 1676, 1663, 1596, 1407, 1371, 1227, 1176, 1075,
1
1049 cm–1. H NMR (400 MHz, CDCl3) l diastereomer: δ = 7.34
(d, J = 6.0 Hz, 1 H), 5.42 (dd, J = 6.0, 1.1 Hz, 1 H), 5.40 (dd, J =
3.4, 1.0 Hz, 1 H), 5.23 (dd, J = 10.5, 8.0 Hz, 1 H), 5.03 (dd, J =
10.5, 3.4 Hz, 1 H), 4.60–4.54 (m, 1 H), 4.56 (d, J = 8.0 Hz, 1 H),
4.19 (dd, J = 11.2, 6.6 Hz, 1 H), 4.13 (dd, J = 11.2, 6.7 Hz, 1 H),
4.04 (dd, J = 11.4, 4.4 Hz, 1 H), 3.92 (ddd, J = 6.7, 6.6, 1.0 Hz, 1
H), 3.85 (dd, J = 11.4, 4.0 Hz, 1 H), 2.73 (dd, J = 16.7, 14.2 Hz, 1
H), 2.43 (ddd, J = 16.7, 3.6, 1.1 Hz, 1 H), 2.16 (s, 3 H), 2.05 (s, 3
H), 2.05 (s, 3 H), 1.99 (s, 3 H) ppm. d diastereomer: δ = 7.35 (d, J
= 6.0 Hz, 1 H), 5.43 (dd, J = 6.0, 1.1 Hz, 1 H), 5.40 (dd, J = 3.4,
1.0 Hz, 1 H), 5.24 (dd, J = 10.4, 8.0 Hz, 1 H), 5.03 (dd, J = 10.4,
3.4 Hz, 1 H), 4.59 (app. ddd, J = 14.0, 6.0, 3.4 Hz, 1 H), 4.55 (d, J
= 8.0 Hz, 1 H), 4.19 (dd, J = 11.3, 6.6 Hz, 1 H), 4.13 (dd, J = 11.3,
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20277
/KAP1
Date: 11-06-12 15:42:57
Pages: 17
Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
6.6 Hz, 1 H), 4.09 (dd, J = 11.4, 3.4 Hz, 1 H), 3.92 (td, J = 6.6, chromatography (initially 60% EtOAc/hexanes, finally 70% EtOAc/
1.0 Hz, 1 H), 3.79 (dd, J = 11.4, 6.0 Hz, 1 H), 2.65 (dd, J = 16.8,
14.0 Hz, 1 H), 2.39 (ddd, J = 16.8, 3.4, 1.1 Hz, 1 H), 2.16 (s, 3 H),
2.06 (s, 3 H), 2.05 (s, 3 H), 1.99 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3) l diastereomer δ = 191.7, 170.3, 170.2, 170.1, 169.3, 162.5,
107.2, 101.4, 77.7, 70.8, 70.7, 69.5, 68.5, 66.9, 61.2, 38.0, 20.7,
20.62, 20.61, 20.5 ppm: d diastereomer δ = 191.4, 170.3, 170.2,
170.1, 169.3, 162.6, 107.2, 101.4, 77.8, 70.9, 70.7, 70.0, 68.5, 66.9,
61.2, 37.9, 20.7, 20.62, 20.60, 20.5 ppm. HRMS (ESI+): calcd. for
hexanes) afforded the product.
4,6-Di-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-1,5-an-
hydro-2-deoxy-L-threo-hex-1-en-3-ulose (50): Compound 50 was
prepared according to the general procedure as a yellow oil (48 mg,
44%). Rf (80% EtOAc/hexanes) = 0.35. [α]D = +19.8 (c = 1.00,
CH Cl ). IR (film): ν = 3064, 2982, 2940, 1751, 1688, 1599, 1371,
˜
2
2
1227, 1175, 1078, 1061 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.30 (dd, J1-HB, 2-HB = 6.1, J1-HB, 5-HB = 0.5 Hz, 1 H, 1-HB), 5.40
(dd, J1-HB, 2-HB = 6.1, J2-HB, 4-HB = 1.6 Hz, 1 H, 2-HB), 5.37 (dd, J
= 3.4, 1.0 Hz, 1 H), 5.34 (dd, J = 3.5, 1.0 Hz, 1 H), 5.18 (dd,
J2-HC, 3-HC = 10.2, J1-HC, 2-HC = 8.1 Hz, 1 H, 2-HC), 5.16 (dd,
J2-HA, 3-HA = 10.4, J1-HA, 2-HA = 8.0 Hz, 1 H, 1 H, 2-HA), 5.02 (dd,
J = 10.2, 3.5 Hz, 1 H), 5.00 (dd, J = 10.4, 3.4 Hz, 1 H), 4.62 (d,
J1-HC, 2-HC = 8.1 Hz, 1 H, 1-HC), 4.49 (d, J1-HA, 2-HA = 8.0 Hz, 1
H, 1-HA), 4.48 (ddd, J5-HB, 6-HB = 7.7, J5-HB, 6-HB = 5.8, J5-HB, 4-HB
= 1.8 Hz, 1 H, 5-HB) 4.13–4.02 (m, 4 H, 2ϫ6-HA, 2ϫ6-HC, 6-
HB), 4.04 (dd, J = 6.6, 4.3 Hz, 1 H), 3.95 (dd, J6-HB, 6-HB = 10.8,
J5-HB, 6-HB = 5.8 Hz, 1 H, 6-HB), 3.90 (app. td, J = 6.9, 1.0 Hz, 1
H), 3.87 (app. t, J2-HB, 4-HB, 5-HB = 1.8 Hz, 1 H, 4-HB), 3.86 (app.
td, J = 6.6, 1.0 Hz, 1 H), 2.17 (s, 3 H), 2.11 (s, 3 H), 2.07 (s, 3 H),
2.050 (s, 3 H),2.048 (s, 3 H), 2.01 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 188.2, 170.4, 170.22,
170.15, 170.1, 170.0, 169.9, 169.4, 169.1, 161.8, 105.7, 102.0, 10.8,
79.0, 75.7, 71.1, 71.0, 70.8, 70.7, 68.9, 68.7, 67.0, 66.9, 66.3, 61.3,
60.9, 20.68, 20.65 (2 C), 20.61, 20.57, 20.52, 20.47, 20.45 ppm.
HRMS (ESI+): cald. for C34H44O22Na 827.2222, found 827.2248,
Δ = 3.2 ppm.
C
20H26O12Na 481.1322, found 481.1331 (l diastereomer), Δ =
–1.9 ppm, 481.1321, Δ = –0.1 ppm (d diastereomer).
(2,3-Dihydro-4-oxo-4H-pyran-2-yl)methyl 2,3,4,6-Tetra-O-benzyl-β-
D-galactopyranoside (41): Compound 41 was prepared according to
the general procedure by using Schiff base chromium complex (li-
1
gand 39b) as a yellow oil (35 mg, 59%). H NMR showed a 94:6
ratio of the d and l diastereomers, respectively. Rf (50% EtOAc/
hexanes) = 0.31 (l diastereomer), 0.28 (d diastereomer). IR (film):
ν = 3088, 3063, 3031, 2920, 2872, 1723, 1677, 1596, 1454, 1364,
˜
1
1276, 1099, 1071, 1028 cm–1. H NMR (500 MHz, CDCl3) l dia-
stereomer: δ = 7.37–7.26 (m, 21 H), 5.38 (dd, J = 6.0, 1.1 Hz, 1 H),
4.95 (d, J = 11.6 Hz, 1 H), 4.89 (d, J = 10.9 Hz, 1 H), 4.79 (d, J =
10.9 Hz, 1 H), 4.75 (d, J = 10.7 Hz, 1 H), 4.73 (d, J = 10.7 Hz, 1
H), 4.63 (d, J = 11.6 Hz, 1 H), 4.57 (app. dq, J = 14.3, 4.0 Hz, 1
H), 4.46 (d, J = 11.9 Hz, 1 H), 4.43 (d, J = 11.9 Hz, 1 H), 4.42 (d,
J = 7.7 Hz, 1 H), 4.07 (dd, J = 11.3, 4.5 Hz, 1 H), 3.90 (d, J =
2.9 Hz, 1 H), 3.85 (dd, J = 9.8, 7.7 Hz, 1 H), 3.82 (dd, J = 11.3,
4.0 Hz, 1 H), 3.60–3.53 (m, 3 H), 3.54 (dd, J = 9.8, 2.9 Hz, 1 H),
2.78 (dd, J = 16.9, 14.3 Hz, 1 H), 2.44 (ddd, J = 16.9, 3.5, 1.1 Hz,
1 H) ppm. d diastereomer: δ = 7.38–7.25 (m, 21 H), 5.41 (dd, J =
6.0, 1.0 Hz, 1 H), 4.95 (d, J = 11.6 Hz, 1 H), 4.90 (d, J = 10.8 Hz,
1 H), 4.78 (d, J = 10.8 Hz, 1 H), 4.77 (d, J = 11.8 Hz, 1 H), 4.73
(d, J = 11.8 Hz, 1 H), 4.62 (d, J = 11.6 Hz, 1 H), 4.62 (m, 1 H),
4.45 (d, J = 11.7 Hz, 1 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.41 (d, J =
7.7 Hz, 1 H), 4.07 (dd, J = 11.2, 3.2 Hz, 1 H), 3.90 (d, J = 2.9 Hz,
1 H), 3.85 (dd, J = 9.7, 7.7 Hz, 1 H), 3.79 (dd, J = 11.2, 6.6 Hz, 1
H), 3.59–3.55 (m, 3 H), 3.53 (dd, J = 9.7, 2.9 Hz, 1 H), 2.63 (dd,
J = 16.8, 14.0 Hz, 1 H), 2.41 (ddd, J = 16.8, 3.7, 1.0 Hz, 1 H) ppm.
13C NMR (126 MHz, CDCl3) l diastereomer: δ = –191.9, 162.7,
138.6, 138.5, 138.4, 137.9, 128.42 (2 C), 128.36 (2 C), 128.33 (2 C),
128.28 (2 C), 128.2 (2 C), 128.1, 128.0 (2 C), 127.84 (2 C), 127.8,
127.6 (2 C), 127.5 (2 C), 107.1, 104.1, 82.2, 79.3, 78.0, 75.2, 74.6,
73.7, 73.6, 73.5, 73.1, 69.9, 68.9, 38.5 ppm. d diastereomer: δ =
191.5, 162.7, 138.63, 138.55, 138.4, 137.9, 128.44 (2 C), 128.38 (2
C), 128.33 (2 C), 128.30 (2 C), 128.2 (2 C), 128.1 (2 C), 127.9 (2
C), 127.8, 127.62 (2 C), 127.60, 127.5 (2 C), 107.1, 104.3, 82.2, 79.3,
78.3, 75.2, 74.6, 73.7, 73.6, 73.5, 73.1, 70.5, 68.9, 38.3 ppm. HRMS
(ESI+): cald. for C40H42O8Na 673.2777, found 673.2803, Δ =
–4.9 ppm (l diastereomer), 673.2770, Δ = –1.1 ppm (d dia-
stereomer).
4-O-(2,3,4,6-Tetra-O-acetyl-β-
D-galactopyranosyl)-6-O-(2,3,4,6-
tetra-O-benzyl-β- -galactopyranosyl)-1,5-anhydro-2-deoxy-D-
D
threo-hex-1-en-3-ulose (51): Compound 51 was prepared according
to the general procedure and purified by using flash chromatog-
raphy (gradient of 50% to 60% EtOAc/hexanes) to give a yellow
oil (32 mg, 41%). Rf (50% EtOAc/hexanes) = 0.24. [α]D = +16.5 (c
= 1.00, CH Cl ). IR (film): ν = 3064, 3031, 2926, 2871, 1771, 1686,
˜
2
2
1598, 1454, 1369, 1224, 1076 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.34–7.25 (m, 21 H) 5.36 (dd, J = 6.1, 1.6 Hz, 1 H), 5.30 (dd,
J = 3.5, 1.0 Hz, 1 H), 5.16 (dd, J = 10.4, 8.0 Hz, 1 H), 4.93 (dd, J
= 10.4, 3.5 Hz, 1 H), 4.92 (d, J = 11.5 Hz, 1 H), 4.83 (d, J =
11.1 Hz, 1 H), 4.79 (d, J = 11.1 Hz, 1 H), 4.71 (s, 2 H), 4.61 (d, J
= 11.5 Hz, 1 H), 4.50 (d, J = 8.1 Hz, 1 H), 4.47 (ddd, J = 8.3, 5.6,
1.7 Hz, 1 H), 4.43 (d, J = 11.8 Hz, 1 H) 4.38 (d, J = 11.8 Hz, 1 H),
4.31 (d, J = 7.7 Hz, 1 H), 4.07 (dd, J = 10.4, 5.6 Hz, 1 H), 4.03 (s,
1 H), 4.01 (s, 1 H), 3.93 (dd, J = 10.4, 8.3 Hz, 1 H), 3.89 (d, J =
2.9 Hz, 1 H), 3.86 (app. t, J = 1.7 Hz, 1 H), 3.80 (dd, J = 9.7,
7.7 Hz, 1 H), 3.68 (td, J = 6.4, 1.0 Hz, 1 H), 3.55–3.51 (m, 3 H),
3.49 (dd, J = 9.7, 2.9 Hz, 1 H), 2.10 (s, 3 H), 2.08 (s, 3 H), 1.97 (s,
3 H), 1.95 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.5,
170.4, 170.2, 169.9, 169.3, 162.0, 138.4, 138.3, 138.1, 137.7, 128.4
(2 C), 128.35 (4 C), 128.33 (3 C), 128.2 (2 C), 127.84 (3 C), 127.79
(2 C), 127.6 (2 C), 127.5 (2 C), 105.4, 104.1, 100.8, 82.1, 79.11,
79.07, 77.2, 75.9, 75.2, 74.5, 73.6, 73.5, 73.1, 72.8, 70.8, 68.73,
68.67, 66.9, 65.6, 60.8, 20.72, 20.66, 20.6, 20.5 ppm. HRMS (ESI+):
calcd. for C54H60O18Na 1019.3677, found 1019.3647, Δ =
–2.9 ppm.
General Method for the HDA Reaction of Aldehydes 15, 16, 19, 21
and 25 with Saccharide Dienes 46 and 47: To a stirred solution of
aldehyde (0.077 mmol, 100 mol-%), 39a-CrCl complex (2.7 mg,
0.006 mmol, 6 mol-%) and crushed molecular sieves (4 Å, 47 mg)
in CH2Cl2 (0.2 mL) at room temp. was added diene (0.091 mmol,
120 mol-%) in CH2Cl2 (0.2 mL). The reaction mixture was stirred
for 18 h. TFA (0.03 mL, 45 mg, 0.392 mmol, 510 mol-%) in CH2Cl2
(1.0 mL) was then added and the reaction mixture was stirred for
further 2 h before being quenched by adding satd. aq. NaHCO3
(3 mL). CH2Cl2 (3 mL) was added and the phases were separated.
The aq. phase was extracted with CH2Cl2 (3ϫ4 mL) and the com-
bined organic phases were washed with brine (3 mL), dried with
Na2SO4 and concentrated. Purification of the residue by flash
4-O-(2,3,4,6-Tetra-O-acetyl-β-
D
-galactopyranosyl)-6-O-(2,3,4,6-
-threo-
tetra-O-acetyl-β- -glucopyranosyl)-1,5-anhydro-2-deoxy-
D
D
hex-1-en-3-ulose (52): Compound 52 was prepared according to the
general procedure as a yellow oil (41 mg, 39%). Rf (80% EtOAc/
hexanes) = 0.32. [α]D = +8.32 (c = 1.00, CH Cl ). IR (film): ν =
˜
2
2
3064, 2960, 1753, 1688, 1599, 1371, 1229, 1173, 1061 cm–1
.
1H
NMR (500 MHz, CDCl3): δ = 7.31 (dd, J1-HB, 2-HB = 6.1,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13

Job/Unit: O20277
/KAP1
Date: 11-06-12 15:42:57
Pages: 17
J. A. Himanen, P. M. Pihko
FULL PAPER
J1-HB, 5-HB = 0.5 Hz, 1 H, 1-HB), 5.40 (dd, J1-HB, 2-HB = 6.1,
J1-HA, 2-HA = 7.9 Hz, 1 H, 1-HA), 4.23 (dd, J6-HC, 6-HC = 12.3,
J2-HB, 4-HB = 1.6 Hz, 1 H, 2-HB), 5.35 (dd, J3-HC, 4-HC = 3.5, J5-HC, 6-HC = 5.5 Hz, 1 H, 6-HC), 4.14–4.10 (m, 2 H, 2ϫ6-HA),
J4-HC, 5-HC = 1.1 Hz, 1 H, 4-HC), 5.19 (app. t, J3-HA, 4-HA, 5-HA
9.6 Hz, 1 H, 3-HA), 5.18 (dd, J2-HC, 3-HC = 10.4, J1-HC, 2-HC
8.1 Hz, 1 H, 2-HC), 5.06 (app. t, J3-HA, 4-HA, 5-HA = 9.6 Hz, 1 H, 1
H, 4-HA), 5.02 (dd, J2-HC, 3-HC = 10.4, J3-HC, 4-HC = 3.5 Hz, 1 H, 3-
HC), 4.98 (dd, J2-HA, 3-HA = 9.6, J1-HA, 2-HA = 7.9 Hz, 1 H, 2-HA),
=
=
4.031 (dd, J6-HC, 6-HC = 12.3, J5-HC, 6-HC = 2.5 Hz, 1 H, 6-HC), 4.030
(dd, J6-HB, 6-HB = 10.7, J5-HB, 6-HB = 7.9 Hz, 1 H, 6-HB), 3.96 (dd,
J6-HB, 6-HB = 10.7, J5-HB, 6-HB = 5.5 Hz, 1 H, 6-HB), 3.91 (td,
J5-HA, 6-HA = 6.4, J4-HA, 5-HA = 1.1 Hz, 1 H, 5-HA), 3.88 (app. t,
J2-HB, 4-HB, 5-HB = 1.8 Hz, 1 H, 4-HB), 3.67 (ddd, J4-HC, 5-HC = 10.1,
J5-HC, 6-HC = 5.5, J5-HC, 6-HC = 2.5 Hz, 1 H, 5-HC), 2.18 (s, 3 H),
2.11 (s, 3 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H), 2.01 (s, 3
4.62 (d, J1-HC, 2-HC = 8.1 Hz, 1 H, 1-HC), 4.55 (d, J1-HA, 2-HA
7.9 Hz, 1 H, 1-HA), 4.51 (ddd, J5-HB, 6-HB = 7.9, J5-HB, 6-HB = 5.9,
=
J5-HB, 4-HB = 1.7 Hz, 1 H, 5-HB), 4.18 (s, 1 H, 6-HA), 4.17 (d, J = H), 1.99 (s, 3 H), 1.98 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
2.0 Hz, 1 H, 6-HA), 4.10–4.03 (m, 2 H, 6-HC), 4.04 (dd, J6-HB, 6-HB δ = 188.2, 170.6, 170.3, 170.14, 170.09, 170.0, 169.4, 169.2 (2 C),
= 10.8, J5-HB, 6-HB = 7.9 Hz, 1 H, 6-HB), 3.96 (dd, J6-HB, 6-HB
10.8, J5-HB, 6-HB = 5.9 Hz, 1 H, 6-HB), 3.86 (app. td, J5-HC, 6-HC
6.6, J4-HC, 5-HC = 1.1 Hz, 1 H, 5-HC), 3.83 (app. t, J2-HB, 4-HB, 5-HB
= 1.7 Hz, 1 H, 4-HB), 3.71 (ddd, J4-HA, 5-HA = 10.0, J5-HA, 6-HA
=
=
105.7, 102.0, 100.3, 79.0, 75.6, 72.8, 72.0, 71.3, 71.1, 70.7, 68.7,
68.7, 68.4, 66.9, 66.2, 61.6, 61.3, 20.8, 20.7, 20.64, 20.55 (4 C),
20.49 ppm. HRMS (ESI+): calcd. for C34H44O22Na 827.2222,
found 827.2253, Δ = 3.8 ppm.
=
4.5, J5-HA, 6-HA = 3.4 Hz, 1 H, 5-HA), 2.12 (s, 3 H), 2.08 (s, 3 H),
2.06 (s, 3 H), 2.055 (s, 3 H), 2.049 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3
H), 1.97 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 188.1,
170.5, 170.4, 170.2, 170.1, 169.9, 169.5, 169.3, 169.1, 161.8, 105.7,
101.5, 100.8, 79.0, 75.7, 72.6, 72.1, 71.3, 71.1, 70.8, 70.0, 68.3, 67.1,
66.5, 61.8, 61.0, 20.7 (2 C), 20.6 (3 C), 20.5 (3 C) ppm. HRMS
(ESI+): calcd. for C34H44O22Na 827.2222, found 827.2240, Δ =
2.2 ppm.
4-O-(2,3,4,6-Tetra-O-acetyl-β-
D
-glucopyranosyl)-6-O-(2,3,4,6-tetra-
-threo-hex-1-
O-benzyl-β- -galactopyranosyl)-1,5-anhydro-2-deoxy-
D
D
en-3-ulose (55): Compound 55 was prepared according to the gene-
ral procedure and purified using flash chromatography (gradient of
40% to 50% EtOAc/hexanes) to give a yellow oil (46 mg, 32%). Rf
(50% EtOAc/hexanes) = 0.15. [α]D = +163.5 (c = 2.00, CH2Cl2).
IR (film): ν = 3031, 3007, 2938, 2874, 1754, 1688, 1598, 1454, 1368,
˜
1229, 1158, 1056 cm–1. 1H NMR (500 MHz, CDCl3): δ = –7.34–
7.25 (m, 21 H) 5.36 (dd, J = 6.1, 1.7 Hz, 1 H), 5.12 (app. t, J =
9.5 Hz, 1 H), 4.97 (app. t, J = 9.5 Hz, 1 H), 4.96 (dd, J = 9.5,
8.1 Hz, 1 H), 4.92 (d, J = 11.5 Hz, 1 H), 4.82 (d, J = 11.2 Hz, 1
H), 4.79 (d, J = 11.2 Hz, 1 H), 4.71 (s, 2 H), 4.60 (d, J = 11.5 Hz,
1 H), 4.52 (d, J = 8.1 Hz, 1 H), 4.46 (ddd, J = 8.5, 5.7, 1.6 Hz, 1
H), 4.43 (d, J = 11.9 Hz, 1 H) 4.39 (d, J = 11.9 Hz, 1 H), 4.30 (d,
J = 7.7 Hz, 1 H), 4.18 (dd, J = 12.3, 5.5 Hz, 1 H), 4.07 (dd, J =
10.4, 5.7 Hz, 1 H), 3.96 (dd, J = 12.3, 2.3 Hz, 1 H), 3.91 (dd, J =
10.4, 8.5 Hz, 1 H), 3.89 (d, J = 2.8 Hz, 1 H), 3.85 (app. t, J =
1.6 Hz, 1 H), 3.80 (dd, J = 9.7, 7.7 Hz, 1 H), 3.55–351 (m, 3 H),
3.50–3.46 (m, 1 H), 3.49 (dd, J = 9.6, 2.8 Hz, 1 H), 2.10 (s, 3 H),
2.09 (s, 3 H), 1.98 (s, 3 H), 1.94 (s, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 188.5, 170.6, 170.1, 169.4, 169.2, 162.0, 138.5, 138.4,
4-O-(2,3,4,6-Tetra-O-acetyl-β-
D
-galactopyranosyl)-6-O-(2,3,4,6-
-threo-
tetra-O-acetyl-α- -mannopyranosyl)-1,5-anhydro-2-deoxy-
D
D
hex-1-en-3-ulose (53): Compound 53 was prepared according to the
general procedure and purified by using flash chromatography
(60% EtOAc/hexanes was used) to give a yellow oil (37 mg, 48%).
For major diastereomer: Rf (50% EtOAc/hexanes) = 0.34. [α]D
=
+37.6 (c = 1.00, CH Cl ). IR (film): ν = 2959, 2940, 1750, 1687,
˜
2
2
1599, 1370, 1226, 1139, 1079, 1049 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 7.37 (d, J = 6.1 Hz, 1 H), 5.44 (dd, J = 6.1, 1.4 Hz, 1
H), 5.35 (dd, J = 3.5, 0.9 Hz, 1 H), 5.31–5.26 (m, 3 H), 5.18 (dd,
J = 10.4, 8.1 Hz, 1 H), 4.99 (dd, J = 10.4, 3.5 Hz, 1 H), 4.90 (d, J
= 1.5 Hz, 1 H), 4.63 (d, J = 8.1 Hz, 1 H), 4.52 (app. ddd, J = 6.0,
3.3, 1.9 Hz, 1 H), 4.27 (dd, J = 12.2, 5.2 Hz, 1 H), 4.14–4.01 (m, 4
H), 3.97 (ddd, J = 8.4, 5.2, 2.6 Hz, 1 H), 3.86–3.83 (m, 2 H), 3.81 138.1, 137.8, 128.40 (2 C), 128.39 (2 C), 128.37 (2 C), 128.3 (2 C),
(t, J = 1.9 Hz, 1 H), 2.16 (s, 3 H), 2.13 (s, 3 H), 2.09 (s, 3 H), 2.082 128.2 (2 C), 127.84 (2 C), 127.83 (2 C), 127.80, 127.67, 127.65 (2
(s, 3 H), 2.075 (s, 3 H), 2.04 (s, 3 H), 1.99 (s, 3 H), 1.97 (s, 3 H) ppm. C), 127.6 (2 C), 105.4, 104.2, 100.3, 82.2, 79.1, 75.9, 75.3, 74.6,
13C NMR (126 MHz, CDCl3): δ = 187.6, 170.5, 170.4, 170.2, 73.7, 73.5, 73.2, 72.9, 71.8, 71.1, 69.9, 68.8, 68.5, 67.2, 65.9, 61.5,
169.90, 169.87, 169.8, 169.6, 169.2, 162.3, 105.5, 100.8, 98.5, 79.7,
20.7, 20.63, 20.58, 20.5 ppm. HRMS (ESI+ ): calcd. for
76.6, 71.3, 70.8, 69.2, 69.1, 68.76, 68.76, 67.0, 66.3, 66.2, 62.6, 61.0, C54H60O18Na 1019.3677, found 1019.3652, Δ = –2.5 ppm.
20.8, 20.71, 20.66 (2 C), 20.62, 20.60 (2 C), 20.5 ppm. HRMS
4,6-Di-O-(2,3,4,6-tetra-O-acetyl-β-
D-glucopyranosyl)-1,5-anhydro-
(ESI+): calcd. for C34H44O22Na 827.2222, found 827.2213, Δ =
–1.1 ppm. For minor diastereomer: Rf (50 % EtOAc/hexanes) =
0.37. HRMS (ESI+): calcd. for C34H44O22Na 827.2222, found
827.2183, Δ = –4.7 ppm.
2-deoxy- -threo-hex-1-en-3-ulose (56): Compound 56 was prepared
L
according to the general procedure as a yellow oil (37 mg, 51%).
Rf (80% EtOAc/hexanes) = 0.33. [α]D = +4.84 (c = 1.00, CH2Cl2).
IR (film): ν = 3063, 2961, 1755, 1688, 1599, 1370, 1227, 1171,
˜
4-O-(2,3,4,6-Tetra-O-acetyl-β-
O-acetyl-β- -galactopyranosyl)-1,5-anhydro-2-deoxy-
en-3-ulose (54): Compound 54 was prepared according to the gene-
D
-glucopyranosyl)-6-O-(2,3,4,6-tetra-
1040 cm– 1 1 H NMR (500 MHz, CDCl3 ): δ = –7.29 (dd,
.
D
D-threo-hex-1-
J1-HB, 2-HB = 6.1, J1-HB, 5-HB = 0.6 Hz, 1 H, 1-HB), 5.41 (dd,
J1-HB, 2-HB = 6.1, J2-HB, 4-HB = 1.7 Hz, 1 H, 2-HB), 5.185 (app. t, J
ral procedure as a yellow oil (42 mg, 68%). Rf (80% EtOAc/hex- = 9.5 Hz, 1 H), 5.183 (app. t, J = 9.5 Hz, 1 H), 5.05 (app. t,
anes) = 0.40. [α]D = +14.2 (c = 1.00, CH Cl ). IR (film): ν = 3064, J3 - H A , 4 - H A , 5 - H A = 10. 0 Hz, 1 H, 4-H A ) , 5 . 0 1 ( ap p. t,
˜
2
2
2960, 2892, 1753, 1688, 1599, 1371, 1228, 1174, 1058 cm–1
.
1H J3-HC, 4-HC, 5-HC = 9.5 Hz, 1 H, 4-HC), 4.99 (dd, J2-HC, 3-HC = 9.5,
J1-HC, 2-HC = 8.1 Hz, 1 H, 2-HC), 4.97 (dd, J2-HA, 3-HA = 9.5,
NMR (500 MHz, CDCl3): δ = 7.31 (dd, J1-HB, 2-HB = 6.1,
J1-HB, 5-HB = 0.6 Hz, 1 H, 1-HB), 5.42 (dd, J1-HB, 2-HB = 6.1, J1-HA, 2-HA = 7.9 Hz, 1 H, 2-HA), 4.66 (d, J1-HC, 2-HC = 8.1 Hz, 1
J2-HB, 4-HB = 1.7 Hz, 1 H, 2-HB), 5.38 (dd, J3-HA, 4-HA = 3.5,
H, 1-HC), 4.43 (d, J1-HA, 2-HA = 7.9 Hz, 1 H, 1-HA), 4.50 (ddd,
J5-HB, 6-HB = 8.0, J5-HB, 6-HB = 6.0, J5-HB, 4-HB = 1.5 Hz, 1 H, 5-HB),
4.22 (dd, J6-HC, 6-HC = 12.2, J5-HC, 6-HC = 5.5 Hz, 1 H, 6-HC), 4.18
J4-HA, 5-HA = 1.1 Hz, 1 H, 4-HA), 5.19 (app. t, J2-HC, 3-HC, 4-HC
9.5 Hz, 1 H, 3-HC), 5.17 (dd, J2-HA, 3-HA = 10.5, J1-HA, 2-HA
=
=
7.9 Hz, 1 H, 2-HA), 5.01 (app. t, J3-HC, 4-HC, 5-HC = 9.5 Hz, 1 H, 1 (d, J5-HA, 6-HA = 3.9 Hz, 2 H, 2ϫ6-HA) 4.021 (dd, J5-HC, 6-HC
H, 4-HC), 5.00 (dd, J2-HA, 3-HA = 10.5, J3-HA, 4-HA = 3.5 Hz, 1 H, 12.2, J6-HC, 6-HC = 2.2 Hz, 1 H, 6-HC), 4.016 (dd, J6-HB, 6-HB = 10.7,
3-HA), 4.99 (dd, J2-HC, 3-HC = 9.5, J1-HC, 2-HC = 8.1 Hz, 1 H, 2-HC), J5-HB, 6-HB = 8.6 Hz, 1 H, 6-HB), 3.96 (dd, J = 10.7, 6.0 Hz, 1 H,
4.68 (d, J1-HC, 2-HC = 8.1 Hz, 1 H, 1-HC), 4.49 (ddd, J5-HB, 6-HB 6-HB), 3.83 (app. t, J2-HB, 4-HB, 5-HB = 1.5 Hz, 1 H, 4-HB), 3.71 (app.
7.9, J5-HB, 6-HB = 5.5, J4-HB, 5-HB = 1.8 Hz, 1 H, 5-HB), 4.48 (d, dt, J4-HA, 5-HA, 6-HA = 10.1, J5-HA, 6-HA = 3.9 Hz, 1 H, 5-HA), 3.66
=
=
14
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Pages: 17
Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
form of peracetylated glucopyranosides 12 turned out to be
(ddd, J4-HC, 5-HC = 10.1, J5-HC, 6-HC = 5.5, J5-HC, 6-HC = 2.4 Hz, 1
H, 5-HC), 2.11 (s, 3 H), 2.060 (s, 3 H), 2.055 (s, 3 H), 2.04 (s, 3 H),
2.02 (s, 3 H), 2.002 (s, 3 H), 1.998 (s, 3 H), 1.99 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 188.0, 170.6, 170.5, 170.12, 170.05,
169.4, 169.28, 169.26, 169.1, 161.8, 105.7, 101.4, 100.3, 78.9, 75.6,
72.8, 72.6, 72.1, 72.0, 71.3, 71.2, 68.4, 68.3, 66.3, 61.8, 61.6, 20.7,
20.59 (2 C), 20.56, 20.54 (2 C), 20.51 (2 C) ppm. HRMS (ESI+):
calcd. for C34H44O22Na 827.2222, found 827.2215, Δ = –0.8 ppm.
unreactive in these reaction conditions.
[9] T. Mori, K. Hatano, K. Matsuoka, Y. Esumi, E. J. Tooned,
Tetrahedron 2005, 61, 2751–2760.
[10] The purity of allyl pyranoside staring materials 13, 14 and 24
was important, because the aldehyde product could not be
purified without a dramatic decrease in yields.
[11] a) V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett.
1976, 17, 1973–1976; b) J. M. J. Tronchet, M. Zsely, M. Geof-
froy, Carbohydr. Res. 1995, 275, 245–258.
[12] a) G. Zemplén, Ber. Dtsch. Chem. Ges. 1926, 1254–1266; b) G.
Zemplén, E. Pacsu, Ber. Dtsch. Chem. Ges. 1929, 62, 1613–
1617; c) Y. A. Lin, J. M. Chalker, B. G. Davis, J. Am. Chem.
Soc. 2010, 132, 16805–16811.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the synthesis of aldehydes 15, 16, 19,
21, 25 and 28, HDA reactions with Rawal’s and Danishesky’s
dienes, the attempted traditional synthesis of the trisaccharide
product, details on the assignment of stereochemistry of cylobut-
anone 49 and absolute stereochemistry of trisaccharide products
[13]
[14]
W. Kinzy, R. R. Schmidt, Carbohydr. Res. 1987, 164, 265–276.
TBS-protection was first attempted with TBSCl alone as the
silylating agent, but only incomplete silylated products were
obtained. The yields of trisilylated and disilylated products
were 45% and 42%, respectively, the latter being a mixture of
two regioisomers. Complete silylation was achieved by treating
the mixture of the incomplete silylated products with TBSOTf
and tetrasilylated galactopyranoside 20 was obtained in 71%
overall yield over two steps; see the Supporting Information
for details.
a) E. J. Corey, H. Cho, C. Rucker, D. H. Hua, Tetrahedron Lett.
1981, 22, 3455–3458; b) A. Bartoszewicz, M. Kalek, J. Nilsson,
R. Hiresova, J. Stawinski, Synlett 2008, 1, 37–40; c) A. G. Bar-
rett, J. C. Beall, C. B. Braddock, K. Flack, V. C. Gibson, M. M.
Salter, J. Org. Chem. 2000, 65, 6508–6514.
1
50–56, and computational details as well as copies of H and 13C
NMR spectra of aldehydes, cyclobutanones, dienes and di- and tri-
saccharide products.
Acknowledgments
Financial support has been provided by the Academy of Finland
(project numbers 107453, 217221 and 139046), the National Grad-
uate School of Organic Chemistry and Chemical Biology
(GSOCCB) and grants from Danisco, the Emil Aaltonen Founda-
tion, and the Finnish Cultural Foundation. We thank Dr. Jari
Koivisto (Aalto University), Mr. Reijo Kauppinen (Jyväskylä) and
Mr. Esa Haapaniemi (Jyväskylä) for assistance with NMR experi-
ments. We also thank Mr. Antti Piisola (University of Jyväskylä)
for assistance with the proofreading.
[15]
[16]
[17]
E. A. Talley, M. D. Vale, E. Yanovsky, J. Am. Chem. Soc. 1945,
67, 2037–2039.
a) W. H. Pearson, A. Aponick, Org. Lett. 2006, 8, 1661–1664;
b) L. Banfi, G. Guanti, M. Rasparini, Eur. J. Org. Chem. 2003,
7, 1319–1336.
[18]
[19]
S. A. Kozmin, V. H. Rawal, J. Org. Chem. 1997, 62, 5252–5253.
a) Y. Huang, A. K. Unni, A. N. Thadani, V. H. Rawal, Nature
2003, 424, 146; b) D. J. Harriman, G. J. Deslongchamps, J.
Mol. Model. 2006, 12, 793–797.
A. K. Unni, N. Takenaka, H. Yamamoto, V. H. Rawal, J. Am.
Chem. Soc. 2005, 127, 1336–1337.
a) G. E. Keck, X.-Y. Li, D. Krishnamurthy, J. Org. Chem. 1995,
60, 5998–5999; b) S. Matsukawa, K. Mikami, Tetrahedron:
Asymmetry 1997, 8, 815–816.
[1] For reviews of function and synthesis of sugars, see: a) A.
Varki, Glycobiology 1993, 3, 97–130; b) R. A. Dwek, Chem.
Rev. 1996, 96, 683–720; c) K. M. Koeller, C. H. Wong, Chem.
Rev. 2000, 100, 4465–4493; d) A. Varki, R. J. Cummings, J. D.
Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart,
M. E. Etzler, Essentials of Glycobiology, Cold Spring Harbor
Laboratory Press, New York, 2009, pp. 1–46, 513–632; e) R. V.
Stick, S. J. Williams, Carbohydrates – The Essential Molecules
of Life, Elsevier Ltd., Great Britain, 2009, pp. 133–219, 413–
442.
[2] For reviews of asymmetric hetero-Diels–Alder reactions of
carbonyl compounds, see: a) K. A. Jørgensen, Angew. Chem.
2000, 112, 3702–3733; Angew. Chem. Int. Ed. 2000, 39, 3558–
3588; b) H. Pellissier, Tetrahedron 2009, 65, 2839–2877.
[3] For a review of on the HDA method in the synthesis of carbo-
hydrate derivatives, see: a) H. M. I. Osborn, D. Coisson, Mini-
Rev. Org. Chem. 2004, 1, 41–54; for precedents in the synthesis
of monosaccharides, see, for example: b) S. Danishefsky, J. F.
Kervin Jr., S. Kobayashi, J. Am. Chem. Soc. 1982, 104, 358–
360; c) D. J. Danishefsky, C. J. Maring, J. Am. Chem. Soc. 1985,
107, 1269–1274.
[4] R. P. C. Cousins, R. G. Pritchard, C. M. Raynor, M. Smith,
R. J. Stoodley, Tetrahedron Lett. 2002, 43, 489–492.
[5] a) S. J. Danishefsky, Aldrichim. Acta 1986, 19, 59–68; for a re-
view of the use of glycals as glycosyl donors, see: b) S. J. Dani-
shefsky, M. T. Bilodeau, Angew. Chem. 1996, 108, 1482–1522;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1380–1419.
[6] a) J.-P. Utille, B. Priem, Carbohydr. Res. 2000, 329, 431–439; b)
A. Hietanen, F. S. Ekholm, R. Leino, L. T. Kanerva, Eur. J.
Org. Chem. 2010, 36, 6974–6980.
[7] a) M. L. Wolfrom, A. Thompson, Methods Carbohydr. Chem.
1963, 211–215; b) A. I Vogel, S. B. Furniss, Vogel’s Textbook
of Practical Organic Chemistry, 5th ed., pp. 645–646, Longman
Scientific & Technical, London, New York 1989.
[20]
[21]
[22]
[23]
S. E. Schaus, J. Brånalt, E. N. Jacobsen, J. Org. Chem. 1998,
63, 403–405.
a) A. Bhattacharjee, J. K. De Brabander, Tetrahedron Lett.
2000, 41, 8069–8073; b) U. Majumder, J. M. Cox, H. W. B.
Johnson, J. D. Rainier, Chem. Eur. J. 2006, 12, 1736–1746.
S. J. Danishefsky, T. Kitahara, J. Am. Chem. Soc. 1974, 96,
7807–7808.
For reviews of the HDA reaction by using Danishefsky’s diene,
see: a) S. Danishefsky, Acc. Chem. Res. 1981, 14, 400–406; b)
S. J. Danishefsky, M. P. DeNinno, Angew. Chem. 1987, 99, 15–
23; Angew. Chem. Int. Ed. Engl. 1987, 26, 15–23.
A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron Lett.
1997, 38, 2427–2430.
a) G. E. Keck, X.-Y. Li, D. Krishnamurthy, J. Org. Chem. 1995,
60, 5998–5999; b) S. Matsukawa, K. Mikami, Tetrahedron:
Asymmetry 1997, 8, 815–816.
a) A. Togni, Organometallics 1990, 9, 3106–3113; b) Q. Gao,
T. Maruyama, M. Mouri, H. Yamamoto, J. Org. Chem. 1992,
57, 1951–1952.
[24]
[25]
[26]
[27]
[28]
[29]
a) A. G. Dossetter, T. F. Jamison, E. N. Jacobsen, Angew.
Chem. 1999, 111, 2549–2552; Angew. Chem. Int. Ed. 1999, 38,
2398–2400; b) K. Gademann, D. E. Chavez, E. N. Jacobsen,
Angew. Chem. 2002, 114, 3185–3187; Angew. Chem. Int. Ed.
2002, 41, 3059–3061; c) D. E. Chavez, E. N. Jacobsen, Org.
Synth. 2005, 82, 34–38.
[30]
[8] In the glycosylation step promoted by BF3·OEt2, the formation
of unidentified side products lowered the yields. Also the α-
The reason for the low yield of this reaction was the partial
decomposition of diene 2 under the reaction conditions.
Eur. J. Org. Chem. 0000, 0–0
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Pages: 17
J. A. Himanen, P. M. Pihko
FULL PAPER
[31] W. Aben, R. Scheeren, J. Chem. Soc. Perkin Trans. 1 1979,
3132–3138.
methane was used because of solubility problems of the dienes
in diethyl ether.
[39] a) S. Czernecki, K. Vijayakumaran, G. Ville, J. Org. Chem.
1986, 51, 5472–5475; b) A. Kirschning, J. Org. Chem. 1995, 60,
1228–1232; c) T. Fujiwara, M. Hayashi, J. Org. Chem. 2008,
73, 9161–9163.
[40] In the case of disaccharides (Table 4), the enantiomeric ligands
39a and 39b afforded products of opposite stereochemistry in
the newly formed B ring. However, we believe that it is the
stereochemical bias of the C ring diene (perhaps in combina-
tion with the A ring aldehyde) that dictates the stereochemical
outcome in the case of trisaccharides, because the enantiomeric
ligands 39a and 39b both afforded the same trisaccharide prod-
uct. As such, we believe that the stereochemical outcome from
the disaccharide experiments cannot be used to predict the
stereochemistry of the trisaccharide products.
[32] Danishefsky and co-workers have also described a method for
accessing 1,3,4-trioxygenated 1,3-dienes, but the method suffers
from low Z/E stereoselectivities, see ref.[3b,c]
.
[33] P. H. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org.
Chem. 1981, 46, 3936–3938.
[34] a) W. D. Wulff, W. E. Bauta, R. W. Kaesler, P. J. Lankford,
R. A. Miller, C. K. Murray, D. C. Yang, J. Am. Chem. Soc.
1990, 112, 3642–3659; b) L. F. Tietze, C. Güntner, K. M. Ger-
icke, I. Schuberth, G. Bunkoczi, Eur. J. Org. Chem. 2005, 2459–
2467.
[35] L. A. Paquette, L. M. Leichter, J. Am. Chem. Soc. 1970, 92,
1766–1768.
[36] See Supporting Information for details.
[37] Purification of the dienes 46 and 47 by flash chromatography
lowered the yields significantly even though base in the eluent
(Et3N) and very short columns were used.
[38] The yield and stereoselectivity of the reaction in dichlorometh-
ane and in diethyl ether were equivalent. However, dichloro-
[41] E. J. Corey, H. Cho, C. Rücker, D. H. Hua, Tetrahedron Lett.
1981, 22, 3455–3458.
Received: March 6, 2012
Published Online: ᭿
16
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Date: 11-06-12 15:42:57
Pages: 17
Synthesis of Trisaccharides by Hetero-Diels–Alder Welding
Trisaccharide Welding
1 + 1 equals 3! The hetero-Diels–Alder un-
ion of two functionalized monosaccharide
building blocks one bearing an aldehyde
and the other a readily accessible diene
moiety affords functionalized trisaccharide
structures in moderate to good yields and
excellent stereoselectivities when β-ano-
mers of the aldehydes are used.
J. A. Himanen, P. M. Pihko* .......... 1–16
Synthesis of Trisaccharides by Hetero-
Diels–Alder Welding of Two Monosac-
charide Units
Keywords: Synthetic methods / Cycload-
dition / Carbohydrates / Chromium
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