2-Allylphenyl glycosides as complementary building blocks for oligosaccharide and glycoconjugate synthesis

Article abstract of DOI:10.3762/bjoc.8.66

The O-allylphenyl (AP) anomeric moiety was investigated as a new leaving group that can be activated for chemical glycosylation under a variety of conditions, through both direct and remote pathways. Differentiation between the two activation pathways was achieved in a mechanistic study. The orthogonal-type activation of the AP moiety along with common thioglycosides allows for the execution of efficient oligosaccharide assembly.

Full text of DOI:10.3762/bjoc.8.66

2-Allylphenyl glycosides as complementary building
blocks for oligosaccharide and
glycoconjugate synthesis
Hemali D. Premathilake and Alexei V. Demchenko*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 597–605.
Department of Chemistry and Biochemistry, University of Missouri –
St. Louis, One University Boulevard, St. Louis, MO 63121, USA
doi:10.3762/bjoc.8.66
Received: 06 February 2012
Accepted: 23 March 2012
Published: 18 April 2012
Email:
Alexei V. Demchenko* - demchenkoa@umsl.edu
* Corresponding author
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
Keywords:
carbohydrates; glycosylation; leaving group; oligosaccharides;
orthogonal strategy; selective activation
Guest Editor: T. K. Lindhorst
© 2012 Premathilake and Demchenko; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The O-allylphenyl (AP) anomeric moiety was investigated as a new leaving group that can be activated for chemical glycosylation
under a variety of conditions, through both direct and remote pathways. Differentiation between the two activation pathways was
achieved in a mechanistic study. The orthogonal-type activation of the AP moiety along with common thioglycosides allows for the
execution of efficient oligosaccharide assembly.
Introduction
Current knowledge about the key roles of carbohydrates is still stimulating for major scientific efforts in the field of modern
limited. However, thanks to the explosive growth of the field of glycosciences. The traditional chemical synthesis of oligo-
glycobiology in recent years, we have already learned that saccharides is lengthy because it involves multiple manipula-
carbohydrates are involved in a broad range of vital biological tions of protecting and/or leaving groups between glycosylation
processes (e.g., fertilization, anti-inflammation, immuno- steps [5]. Many advanced strategies that shorten the oligo-
response, joint lubrication, antigenic determination) [1]. Carbo- saccharide assembly by minimizing or even eliminating
hydrates are also involved in many harmful processes (e.g., additional manipulations between coupling steps, are based
bacterial and viral infections, development of tumors, metas- either on chemoselective or on selective activation of leaving
tasis, tissue rejection, congenital disorders). The fact that many groups [6]. The use of selective activation [7] offers more
of these processes are directly associated with the pathogenesis flexibility than that of the chemoselective activation which
of deadly diseases, including AIDS, cancer, pneumonia, relies on the nature of the protecting groups [8], and Ogawa’s
septicemia, hepatitis and malaria [2-4], has been particularly orthogonal strategy is conceptually the most attractive approach
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Beilstein J. Org. Chem. 2012, 8, 597–605.
Scheme 1: Orthogonal strategy introduced by Ogawa et al.
that has been developed to date [9-12]. This technique implies ible approach for oligosaccharide synthesis. Concomitantly with
the use of two orthogonal leaving groups, LGa and LGb, the our studies, Hung et al. came up with essentially the same idea
selective activation of which can be reiterated to give stream- and reported the synthesis of AP mannosides and their acti-
lined access to oligosaccharides (Scheme 1).
vation for O-mannosylation in the presence of ICl/AgOTf [27].
Yet, the orthogonal strategy remains underdeveloped, with too The following considerations driving our efforts were of par-
few examples to become universally applicable. Only Ogawa’s ticular relevance. First, chemists have been making aryl glyco-
S-phenyl (SPh) versus fluoride [9,10,13] and our thioimidate- sides for some 130 years [28], and many excellent protocols for
based approaches [14-16] are known. A very promising orthog- their synthesis are available [29]. We determined that AP glyco-
onality was shown for O-pentenyl versus O-propargyl glyco- sides can be readily obtained from the corresponding peracetate
sides by Hotha et al. [17] and for S-glycosyl O-methyl phenyl- by using inexpensive 2-allylphenol ($ 35/100 g, Aldrich) in the
carbamothioate (SNea) versus thioglycosides/thioimidates by us presence of BF3·Et2O. For instance, acetylated AP β-D-gluco-
[18], but still their applicability to multistep synthesis remains pyranoside was obtained in 92% yield. Second, we anticipated
to be proven. Working to expand this concept, our group that the same promoters used for O-pentenyl activation [30] can
reported a related, albeit less flexible, semiorthogonal approach also activate the AP leaving group. However, since AP glyco-
with the use of S-ethyl and O-pentenyl leaving groups [19], sides bear structural features of both aryl and pentenyl glyco-
which was later extended to fluoride/O-pentenyl combination sides, they should offer a more versatile activation profile than
by Fraser-Reid and Lopez [20]. Oxygen- [21] and sulfur-based either class of the leaving group. Our working hypothesis is that
[22] leaving groups fit into many expeditious strategies for activation of the AP leaving group with I+ takes place by the
oligosaccharide synthesis [6]. However, suitable reaction condi- formation of an epi-iodonium ion, which is then opened with
tions for the orthogonal activation of these two classes of the anomeric oxygen, similarly to that known for O-pentenyl
leaving groups are yet to be found. Commonly, O-glycosides glycosides [30]. It is possible that the activation of the AP
are too stable to be used as effective glycosyl donors [21]. Pent- leaving group can also be achieved with TMSOTf or BF3·Et2O
4-enyl O-glycosides introduced by Fraser-Reid are unique in via the direct anomeric activation pathway, which was expected
this category of leaving groups, because they can be glycosi- to become the key feature of the AP-mediated glycosylation
dated under mild conditions by using I+ generated in situ. Also approach in comparison to that of both O-pentenyl or thioglyco-
this method has its limitations since I+ can also activate thiogly- sides. As a result, this pathway may offer a suitable platform for
cosides. Indeed, only the semiorthogonality of the O-pentenyl developing a fully orthogonal approach in combination with
and SEt leaving groups could be established [19]. Additionally, thioglycosides.
4-pentenol is rather expensive ($ 323/50 g, Aldrich), and
although O-pentenyl can be introduced from the anomeric To pursue this methodology we obtained a range of differently
acetate directly, the most economical synthesis includes a three- protected AP glucosides, including perbenzylated 1a, perben-
step protocol, with halide, orthoester, and the rearrangement of zoylated 1b, and derivative 1c equipped with the superarming
the latter to glycoside.
protecting-group pattern (2-O-benzoyl-3,4,6-tri-O-benzyl) [31].
For comparison, we also obtained the AP donor 1d of the
D-galacto series. With glycosyl donors 1a–d in hand, we began
Results and Discussion
As a part of the ongoing research effort to develop versatile evaluating their applicability to chemical glycosylation using a
building blocks, we present herein the development of a new range of standard glycosyl acceptors 2–5 [18]. Encouragingly,
ortho-allylphenyl (AP) leaving group. In line with other efforts the reaction of glycosyl donor 1a with the primary glycosyl
[23-26], the AP group was specifically designed to address the acceptor 2 in the presence of TMSOTf was completed within
drawbacks of O-pentenyl glycosides and to create a more flex- 15 min and provided the corresponding disaccharide 6a in 82%
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Beilstein J. Org. Chem. 2012, 8, 597–605.
yield (Table 1, entry 1). As expected, when a control experi- exploring its orthogonality to thioglycosides. This is because
ment was set up with MeOTf, no glycosylation of 2 took place thioglycosides show a completely opposite reactivity trend,
(Table 1, entry 2). The fact that the AP group in 1a can be acti- namely no reaction with TMSOTf and smooth glycosylation
vated with TMSOTf, but not with MeOTf, offers a basis for with MeOTf [32].
Table 1: Glycosylation of AP glycosyl donors 1a–d.
entry
donor + acceptor
conditionsa
time
product (yield, α/β ratio)
1
1a + 2
1a + 2
1a + 2
1a + 2
1a + 3
1a + 4
1a + 5
1b + 2
1b + 2
1b + 2
1b + 2
1b + 5
1c + 2
1c + 2
1c + 2
1c + 2
1d + 2
1d + 3
1d + 4
1d + 5
TMSOTf, rt
15 min
24 h
6a (82%, 2.7/1)
no reaction
2
MeOTf, rt
3
NIS/TMSOTf, 0 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
MeOTf, rt
40 min
15 min
4 h
6a (80%, 1.4/1)
6a (90%, 1/1.5)
7a (73%, 1.2/1)
8a (82%, 1.0/1)
9a (72%, 1/1.3)
no reaction
4
5
6
30 min
3 h
7
8
24 h
9
TMSOTf, rt
24 h
no reaction
10
11
12
13
14
15
16
17
18
19
20
NIS/TMSOTf, 0 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
MeOTf, rt
6 h
6b (77%, β only)
6b (71%, β only)
9b (78%, β only)
no reaction
2 h
3 h
24 h
TMSOTf, −20 °C
NIS/TMSOTf, 0 °C
NIS/TfOH, −20 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
NIS/TfOH, 0 °C
2.5 h
10 min
15 min
15 min
4 h
6c (73%, β only)
6c (84%, β only)
6c (93%, β only)
6d (85%, 1.5/1)
7d (81%, 1.2/1)
8d (82%, 1.0/1)
9d (80%, 3.0/1)
30 min
2 h
aperformed in the presence of molecular sieves 4 Å (or 3 Å in MeOTf-promoted reactions, entries 2, 8, and 13).
599

Beilstein J. Org. Chem. 2012, 8, 597–605.
NIS/TMSOTf is a powerful promoter for the activation of the remote allyl moiety (B, Pathway B). In addition, in the latter
both O-pentenyl and thioglycosides. It was also found to experiment we detected the presence of adduct 12, which was
be effective for the activation of AP glycosyl donor 1a, formed as the result of a competing attack of the glycosyl
upon which disaccharide 6a was obtained in 80% yield. acceptor oxygen, as opposed to endocyclization of B
Even faster reaction and higher yield was obtained by through the anomeric oxygen leading to oxacarbenium inter-
using the NIS/TfOH promoter system, wherein the resulting mediate C.
disaccharide 6a was obtained in 90% yield (Table 1, entry 4).
The latter reaction conditions were chosen for use in the investi- In accordance with Fraser-Reid’s armed–disarmed approach,
gation of the glycosylation of the secondary glycosyl acceptors electronically activated (armed) glycosyl donors are chemose-
3–5.
lectively activated over deactivated (disarmed) glycosyl accep-
tors bearing the same type of leaving group [30,35]. To explore
These couplings were also proven to be feasible, and the corres- this avenue, we obtained a disarmed (benzoylated) 6-OH AP
ponding disaccharides 7a–9a were obtained in 72–82% yield glycosyl acceptor 13 (Supporting Information File 1), which
(Table 1, entries 5–7). As anticipated, the reactivity of the was coupled with the armed AP glycosyl donor 1a in the pres-
perbenzoylated (disarmed) counterpart 1b was significantly ence of TMSOTf. As anticipated, this reaction was feasible and
lower than that of 1a, and TMSOTf-promoted glycosylation of the expected disaccharide 14 was obtained in 78% yield
1b was practically ineffective (Table 1, entry 9). This observa- (Table 2, entry 1). With the ultimate goal of developing distinct
tion along with the fact that the armed AP leaving group in 1a orthogonal differentiation of AP and thioglycosides, we next
can be readily activated with TMSOTf (Table 1, entry 1) obtained glycosyl acceptor 15 [36] equipped with an ethylthio
suggests that AP glycosides can be applied in accordance with leaving group. TMSOTf-promoted chemoselective glycosyl-
the classic armed–disarmed strategy [33]. NIS-promoted glyco- ation between building blocks 1a and 15 produced the expected
sylations of 1b have proven to be of preparative value and the disaccharide 16 in 71% yield (Table 2, entry 2).
desired disaccharides 6b and 9b were isolated in 71–78% yield
(Table 1, entries 10–12). In order to gain a more flexible acti- In a selective activation fashion, glycosyl acceptors 17 [37] and
vation profile for the synthesis of 1,2-trans glycosides, we also 19 [38], equipped with S-tolyl (STol) and S-phenyl leaving
investigated AP glycosyl donor 1c, bearing a superarming groups, respectively, were glycosylated with AP glycosyl donor
protecting-group pattern [31]. As expected, all of the previ- 1a to afford disaccharides 18 and 20 in 75 and 90% yield, res-
ously established activation conditions were very effective, and pectively (Table 2, entries 3 and 4). Also the disarmed SPh
glycosylation of 1c with acceptor 2 readily produced acceptor 21 [39] led to disaccharide 22 in 98% yield. The syn-
disaccharide 6c (Table 1, entries 14–16). Again, particularly thesis of a 1,2-trans-linked disaccharide was also possible with
efficient was the NIS/TfOH-promoted reaction wherein glycosyl donor 1c leading to the corresponding β-linked disac-
disaccharide 6c was isolated in 93% yield (Table 1, entry 16). charide 23 in 75% yield (Table 2, entry 6). This series of experi-
To broaden the scope of the AP approach, we tested its applic- ments clearly demonstrates that the AP leaving group can be
ability to the synthesis of D-galactosides, which are a highly reliably activated with TMSOTf in the presence of S-alkyl/aryl
important and abundant sugar series. All glycosylations of AP leaving groups. We next investigated glycosyl acceptor 25
donor 1d proceeded smoothly in the presence of NIS/TfOH and equipped with the AP leaving group. MeOTf-promoted
the corresponding disaccharides 6d–9d were obtained in glycosylation of SEt, STaz, STol, and SPh glycosyl donors 24
80–85% yield (Table 1, entries 17–20). To verify the two antici- [40], 27 [14], 28 [41], and 29 [42], respectively, with acceptor
pated activation pathways by which the AP group may depart, 25 afforded the respective disaccharide 26 in 78–97% yield
all components of the key experiments (Table 1, entries 1 and 3) (Table 2, entries 7–10). These series of results indicates a
wherein glycosyl donor 1a reacted with glycosyl acceptor 2 in completely orthogonal character of AP and the thioglycosides.
the presence of TMSOTf and NIS/TMSOTf, respectively, were To expand this observation, disaccharide 26 was coupled with
separated and analyzed. In the TMSOTf-promoted reaction, thioglycoside acceptor 21 in the presence of TMSOTf leading
(o-allylphenoxy)trimethylsilane (10) was isolated and identi- to trisaccharide 30 in 90% (Scheme 3). Since 30 is equipped
fied by comparison with analytical data obtained from a with the SPh anomeric leaving group, it is available for further
commercial sample. This result suggests that the activation of chain elongation directly. In a similar fashion, thioglycoside
the AP moiety with TMSOTf takes place through the anomeric disaccharide 16 was coupled with AP acceptors 25 and 13 in the
oxygen atom (A, Pathway A, Scheme 2). In the NIS/TMSOTf- presence of MeOTf to afford trisaccharides 31 and 32 in 50 and
promoted reaction, 2-iodomethyl-2,3-dihydrobenzofuran (11) 80% yield, respectively. Since these trisaccharides are equipped
[34] was isolated and its identity was proven by spectral with the AP leaving group, their direct application to further
methods indicating that activation with I+ takes place through chain elongation can be envisaged.
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Beilstein J. Org. Chem. 2012, 8, 597–605.
Scheme 2: Determination of the AP activation pathways.
Table 2: AP glycosides as glycosyl donors and acceptors in chemoselective and selective activations.
entry
donor;
promotera
time
product (yield, α/β ratio)
acceptor
1a (LG1 = OAP, R1 = R2 = Bn);
13 (LG2 = OAP, R3 = Bz)
1
2
3
4
5
6
A
A
A
A
A
A
10 min
15 min
1 h
14 (78%, 1.0/1)
16 (71%, 1.0/1)
18 (75%, 2.4/1)
20 (90%, 1.0/1)
22 (98%, 1.8/1)
23 (75%, β only)
1a;
15 (LG2 = SEt, R3 = Bn)
1a;
17(LG2 = STol, R3 = Bz)
1a;
1 h
19 (LG2 = SPh, R3 = Bn)
1a;
2 h
21 (LG2 = SPh, R3 = Bz)
1c (LG1 = OAP, R1 = Bz, R2 = Bn);
21
30 min
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Beilstein J. Org. Chem. 2012, 8, 597–605.
Table 2: AP glycosides as glycosyl donors and acceptors in chemoselective and selective activations. (continued)
24 (LG1 = SEt, R1 = R2 = Bn);
25 (LG2 = OAP, R3 = Bn)
7
B
B
B
B
2 h
1 h
4 h
6 h
26 (82%, 1.8/1)
26 (78%, 1.0/1)
26 (97%, 1.2/1)
26 (90%, 1.0/1)
27 (LG1 = STaz, R1 = R2 = Bn);
25
8
28 (LG1 = STol, R1 = R2 = Bn);
25
9
29 (LG1 = SPh, R1 = R2 = Bn);
25
10
aperformed in the presence of molecular sieves 4 Å (A: TMSOTf) or 3 Å (B: MeOTf) at rt or 0 °C (entry 6).
Scheme 3: AP building blocks in oligosaccharide synthesis.
Conclusion
of the AP moiety to biomolecules, monolayers, arrays, etc.,
In conclusion, we investigated the O-allylphenyl (AP) anomeric should be possible by executing thiol–ene chemistry [43],
moiety as a new leaving group that can be activated for chem- ozonolysis/reductive amination [44-46], or other ligation proto-
ical glycosylation under a variety of conditions including Lewis cols [47,48].
acid and iodonium ion mediated pathways. The two activation
Experimental
pathways were confirmed by a mechanistic study. We also
demonstrated that the application of the AP moiety allows General remarks
executing oligosaccharide assembly by an orthogonal concept. Column chromatography was performed on silica gel 60
The application of the AP glycosides may stretch well beyond (EM Science, 70–230 mesh), reactions were monitored by TLC
their initial intended purpose because the alkene moiety can be on Kieselgel 60 F254 (EM Science). The compounds were
utilized in a variety of other modes. Similar to that of detected by examination under UV light and by charring
O-pentenyl [30], it can be temporarily deactivated toward the I+ with 10% sulfuric acid in methanol. Solvents were removed
activation pathway by the addition of Br2, which can be under reduced pressure at <40 °C. CH2Cl2 and ClCH2CH2Cl
reverted as needed (active–latent strategy). Direct conjugation were distilled from CaH2, directly prior to application.
602

Beilstein J. Org. Chem. 2012, 8, 597–605.
Anhydrous DMF (EM Science) was used as received. sieves (4 Å, 150 mg) in 1,2-dichloroethane (1.6 mL) was stirred
Methanol was dried by heating under reflux with magnesium under argon for 1 h. NIS (0.22 mmol) and TfOH (0.022 mmol)
methoxide, distilled and stored under argon. Pyridine and were added and the reaction mixture was monitored by TLC.
acetonitrile were dried by heating under reflux with Upon completion, the mixture was diluted with CH2Cl2, the
CaH2 and then distilled and stored over molecular sieves (3 Å). solid was filtered off, and the residue was rinsed with CH2Cl2.
Molecular sieves (3 Å or 4 Å), used for reactions, were The combined filtrate (30 mL) was washed with 10% aq
crushed and activated in vacuo at 390 °C during 8 h in the first Na2S2O3 (10 mL) and water (3 × 10 mL). The organic layer
instance and then for 2–3 h at 390 °C directly prior to was separated, dried with MgSO4 and concentrated in vacuo.
application. DOWEX MONOSPHERE 650C (H) was washed The residue was purified by silica gel column chromatography
three times with MeOH and stored under MeOH. Optical (ethyl acetate/hexanes gradient elution) to afford the corres-
rotations were measured with a Jasco P-1020 polarimeter. ponding oligosaccharide.
1H NMR spectra were recorded in CDCl3 at 300 MHz;
13C NMR spectra were recorded in CDCl3 at 75 MHz (Bruker Typical NIS/TMSOTf-promoted glycosylation procedure
Avance) or 125 MHz (Varian). Anomeric ratios were deter- (Method D). A mixture of glycosyl donor (0.11 mmol),
mined by comparison of the integral intensities of the respec- glycosyl acceptor (0.10 mmol), and freshly activated molecular
tive groups of signals in the 1H NMR spectra. HRMS determi- sieves (4 Å, 150 mg) in 1,2-dichloroethane (1.6 mL) was stirred
nations were made with the use of a JEOL MStation (JMS-700) under argon for 1 h. NIS (0.22 mmol) and TMSOTf
mass spectrometer.
(0.022 mmol) were added and the reaction mixture was moni-
tored by TLC. Upon completion, the mixture was diluted with
CH2Cl2, the solid was filtered off, and the residue was rinsed
Synthesis of glycosides
Typical MeOTf-promoted glycosylation procedure with CH2Cl2. The combined filtrate (30 mL) was washed with
(Method A). A mixture of glycosyl donor (0.11 mmol), 10% aq Na2S2O3 (10 mL) and water (3 × 10 mL). The organic
glycosyl acceptor (0.10 mmol), and freshly activated molecular layer was separated, dried with MgSO4 and concentrated in
sieves (3 Å, 300 mg) in 1,2-dichloroethane (1.4 mL) was stirred vacuo. The residue was purified by silica gel column chroma-
under argon for 1 h. MeOTf (0.33 mmol) was added and the tography (ethyl acetate/hexanes gradient elution) to afford the
reaction mixture was monitored by TLC. Upon completion corresponding oligosaccharide.
(Table 1, Table 2), the solid was filtered off and the residue was
rinsed with CH2Cl2. The combined filtrate (30 mL) was washed
Supporting Information
with 20% aq NaHCO3 (10 mL) and water (3 × 10 mL). The
organic layer was separated, dried with MgSO4 and concen-
Supporting Information File 1
trated in vacuo. The residue was purified by silica gel column
chromatography (ethyl acetate/hexanes gradient elution) to
afford the corresponding oligosaccharide.
Experimental procedures, extended experimental data,
1H and 13C NMR spectra for all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-66-S1.pdf]
Typical TMSOTf-promoted glycosylation procedure
(Method B). A mixture of glycosyl donor (0.11 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
sieves (4 Å, 150 mg) in 1,2-dichloroethane (1.6 mL) was stirred
under argon for 1 h. TMSOTf (0.22 mmol) was added and the
reaction mixture was monitored by TLC. Upon completion
(Table 1, Table 2), the solid was filtered off and the residue was
rinsed with CH2Cl2. The combined filtrate (30 mL) was washed
with 20% aq NaHCO3 (10 mL) and water (3 × 10 mL). The
organic layer was separated, dried with MgSO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (ethyl acetate/hexanes gradient elution) to
afford the corresponding oligosaccharide.
Acknowledgements
This work was supported by an award from the NIGMS
(GM077170). H. D. P. is grateful to UMSL Graduate School for
proving her with the Dissertation Fellowship. Dr. Winter and
Mr. Kramer (UM – St. Louis) are thanked for HRMS determi-
nations.
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