U.S. patent application number 15/192680 was filed with the patent office on 2019-09-05 for catalytic glycosylation with designer thioglycoside and novel protecting groups for same and for synthesis of oligosaccharides.
This patent application is currently assigned to University of Pittsburgh -- Of The Commonwealth System of Higher Education. The applicant listed for this patent is Xinyu Liu. Invention is credited to Xinyu Liu.
Application Number | 20190270763 15/192680 |
Document ID | / |
Family ID | 49715823 |
Filed Date | 2019-09-05 |
United States Patent
Application |
20190270763 |
Kind Code |
A9 |
Liu; Xinyu |
September 5, 2019 |
CATALYTIC GLYCOSYLATION WITH DESIGNER THIOGLYCOSIDE AND NOVEL
PROTECTING GROUPS FOR SAME AND FOR SYNTHESIS OF
OLIGOSACCHARIDES
Abstract
A catalytic glycosylation method comprising: installing
thioether to an anomeric carbon of a carbohydrate; and
catalytically activating the thioether with a non-oxophilic Lewis
acid. The thioether may comprise an anomerically stable thioether
leaving group. The catalytic glycosylation method may further
comprise: utilizing an acid-sensitive ester protecting group as
permanent protecting group or using a reactivity-based one-pot
glycosylation that employs a single-component catalyst to
accelerate an oligosaccharide assembly process. A protecting group
to mask hydroxyl functionalities in the production of
oligosaccharides, natural products or any molecule having a
hydroxyl group comprising an acid-labile ester protecting
group.
Inventors: |
Liu; Xinyu; (Pittsburgh,
PA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Liu; Xinyu |
Pittsburgh |
PA |
US |
|
|
Assignee: |
University of Pittsburgh -- Of The
Commonwealth System of Higher Education
Pittsburgh
PA
|
Prior
Publication: |
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Document Identifier |
Publication Date |
|
US 20170022237 A1 |
January 26, 2017 |
|
|
Family ID: |
49715823 |
Appl. No.: |
15/192680 |
Filed: |
June 24, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13912048 |
Jun 6, 2013 |
9399655 |
|
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15192680 |
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61656366 |
Jun 6, 2012 |
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61677993 |
Jul 31, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07H 15/203 20130101;
C07C 69/94 20130101; C07C 65/24 20130101; Y02P 20/55 20151101; C07C
69/88 20130101; C07C 59/66 20130101; C07H 1/00 20130101 |
International
Class: |
C07H 1/00 20060101
C07H001/00; C07H 15/203 20060101 C07H015/203 |
Claims
1. A catalytic glycosylation method comprising: installing
thioether to an anomeric carbon of a carbohydrate; and
catalytically activating the thioether with a non-oxophilic Lewis
acid.
2. The catalytic glycosylation method of claim 1 wherein the
thioether comprises an anomerically stable thioether leaving
group.
3. The catalytic glycosylation method of claim 1 further
comprising: utilizing an acid-sensitive ester protecting group as
permanent protecting group.
4. The catalytic glycosylation method of claim 1 further
comprising: using a reactivity-based one-pot glycosylation that
employs a single-component catalyst to accelerate an
oligosaccharide assembly process.
5. The catalytic glycosylation method of claim 1 further
comprising: utilizing an application of a 100%-PEG-based polymer as
insoluble support for solid-phase oligosaccharide synthesis.
6. The catalytic glycosylation method of claim 1 further
comprising: utilizing a designer thioglycoside that retains basic
properties of a parental thioglycoside, including the ease of
preparation and toleration of backbone protecting group
manipulation.
7. The catalytic glycosylation method of claim 1 further
comprising: applying an activator permitting an application of
highly acid-sensitive protecting groups; applying a 100%-PEG-based
polymer as insoluble support for solid-phase oligosaccharide
synthesis to streamline an oligosaccharide assembly.
8. The catalytic glycosylation method of claim 7 wherein the
activator is carbophilic.
9. The catalytic glycosylation method of claim 7 wherein the
activator is a cationic gold(I) complex.
10. A method of synthesizing an oligosaccharide, comprising the
steps of: tethering an acetyl ester and a benzoyl ester to a
saccharide with an alcohol group; and protecting the alcohol group
with an acid-labile ester protecting group.
11. The method of claim 10, further comprising the step of
deprotecting the ester group by acid treatment.
12. A method of synthesizing an oligosaccharide comprising the step
of activating a thioglycoside with a non-oxophilic Lewis acid.
13. The method of claim 12, wherein the Lewis acid comprises a
cationic gold(I) complex.
14. A method of synthesizing an oligosaccharide, comprising the
steps of: tethering an acetyl ester and a benzoyl ester to a
thioglycoside with an alcohol group; to protecting the alcohol
group with an acid-labile ester protecting group; deprotecting the
ester group by acid treatment; and activating the thioglycoside
with a non-oxophilic Lewis acid.
15. The method of claim 14, wherein the Lewis acid comprises a
cationic gold(I) complex.
16. A protecting group to mask hydroxyl functionalities in the
production of oligosaccharides, natural products or any molecule
having a hydroxyl group comprising an acid-labile ester protecting
group.
17. The protecting group of claim 16 wherein the acid-labile ester
protecting group is selected from a group consisting of an acetyl
ester tethered with a para methoxybenzyl (PMB) ether, an acetyl
ester tethered with a napthyl methyl (NAP) ether, a benzoyl ester
tethered with a PMB ether and a benzoyl ester tethered with an NAP
ether.
18. The protecting group of claim 17 wherein the tethering of an
acetyl ester or a benzoyl ester with an alcohol group that is
protected with an acid-labile ester protecting group can be
de-protected by an acid.
Description
RELATED APPLICATIONS
[0001] The present application is a DIVISIONAL of copending U.S.
patent application Ser. No. 13/912,048 entitled "CATALYTIC
GLYCOSYLATION WITH DESIGNER THIOGLYCOSIDE AND NOVEL PROTECTING
GROUPS FOR SAME AND FOR SYNTHESIS OF OLIOGOSACCHARIDES" and filed
Jun. 6, 2013 (the "'048 Application"), the entirety of which is
incorporated herein by reference for all purposes. The '048
Application claims priority benefit under 35 U.S.C. .sctn.119(e) of
U.S. Provisional Application No. 61/656,366, filed Jun. 6, 2012,
and of U.S. Provisional Application No. 61/677,993, filed Jul. 31,
2012.
TECHNICAL FIELD
[0002] The present disclosure generally relates to catalytic
glycosylation methods and protecting groups for the same and for
synthesis of oligosaccharides, natural products or any molecule
having a hydroxyl group.
BACKGROUND
[0003] Oligosaccharide is the third most abundant biopolymer in a
living system, next to nucleic acid and proteins. The biological
significance of oligosaccharide is undisputable, yet the rapid
preparation of homogeneous oligosaccharide by automation, analogues
to the synthesis of DNA/RNA oligonucleotides and peptides, remains
far beyond reach.
[0004] Two of the most fundamental issues in modern chemical
synthesis of oligosaccharides that requires innovation are 1)
chemical glycosylation method that permits the robust construction
of desired glycosidic linkage, 2) protecting groups that can be
strategically applied to the blockage of designated hydroxyl,
amino, carboxyl groups, yet can be readily removed to release the
desired oligosaccharide. The present disclosure addresses both of
these fundamental issues with respect to modern chemical synthesis
of oligosaccharides.
[0005] FIG. 1 shows a comparison of known catalytic glycosylation
methods with a preferred catalytic glycosylation method of the
present disclosure. Currently available chemical glycosylating
agents largely fall into two categories. One type is based on
anomerically labile leaving groups, which can be activated by
catalytic amount of a Lewis acid. The classical example is
trichloroacetaimidate based glycosylating agent (Schmidt donor),
but also includes glycosyl phosphite and ester-based glycosylating
agent. These glycosylating agents do not tolerate acid/base
treatment so that the leaving group itself has to be installed in
the last step of the monosaccharide or oligosaccharide building
block preparation prior to the actual glycosylation event as shown
in FIG. 1. From a practical point-of-view, this is a critical
drawback, as the preparation of any imidate-type glycosylating
agent requires the pre-selection of a protecting group to mask the
anomeric center and remove it at the penultimate step to install
the leaving group.
[0006] The other type of widely used glycosylating agent is based
on anomerically stable leaving group. The classical examples are
thioether or n-pentenyl ether based glycosylating agents. While
these types of leaving groups are anomerically stable, they have to
be activated by more than stoichiometric amount of activator and
require the usage of extra component, such as bulky
non-nucleophilic amine base to effectively quench the in-situ
generated acid.
[0007] Therefore, one would envision that an ideal type of chemical
glycosylating agent should combine the catalytic activator-feature
of glycosyl imidate and the anomeric stable feature of
thioglycoside. Preferred glycosylation methods of the present
disclosure fulfill this criterion. Moreover, the most commonly used
activators in chemical glycosylation are highly oxophilic Lewis
acids or thiophilic electrophiles. In both cases, the reaction will
be carried out in an acidic environment, which not only calls for
the extra non-nucleaphilic base (not atom-economical) but also
preludes the application of acid-sensitive protecting groups as
permanent protecting groups in oligosaccharide assembly. The
preferred glycosylation methods of the present disclosure provide a
new class of thioglycoside which permits the application of
cationic gold(I) complex as an activator, which is carbophilic
rather than oxophilic, thus circumventing the limitation associated
with the usage of oxophilic Lewis acid with conventional
glycosylation agents.
[0008] Another fundamental issue in modern chemical synthesis of
oligosaccharides is that too many orthogonal protecting groups for
hydroxyl and amino functionalities are introduced at the early
stage of the process. While the adoption of this strategy is
clearly understandable, as the carbohydrate backbone contains a
myriad of hydroxyls and amines which have to be "chemically
protected" properly in order to achieve regioselective chain
elongation, the excess orthogonalities in terms of chemical
reactivity that are present in a protected oligosaccharide make the
late stage chemical synthesis tedious which often results in
unpredictable failure.
[0009] Benzyl ethers and ester-type of protecting groups are two
most commonly used hydroxyl protecting groups in carbohydrate
synthesis that requires different chemical treatment for removal.
While benzyl ethers are usually sensitive to hydrogenolysis and
acid, esters are sensitive to base-catalyzed hydrolysis. Within the
present disclosure, it is desirable to design a series of hydroxyl
protecting groups that retain the basic properties of benzyl ethers
and esters, but can be deprotected by a common type of chemical
reagent, acid. This aspect of the present disclosure will
dramatically speed up the chemical synthesis of oligosaccharide,
particularly allowing for the automation process, when coupled with
a glycosylating agent that does not require strong acid for
activation.
SUMMARY
[0010] One aspect of a preferred embodiment of the present
disclosure comprises a catalytic glycosylation method comprising:
installing thioether to an anomeric carbon of a carbohydrate; and
catalytically activating the thioether with a non-oxophilic Lewis
acid.
[0011] In another aspect of a preferred catalytic glycosylation
method of the present disclosure, the thioether comprises an
anomerically stable thioether leaving group.
[0012] In a further aspect, a preferred catalytic glycosylation
method further comprises utilizing an acid-sensitive ester
protecting group as permanent protecting group.
[0013] In yet another aspect, a preferred catalytic glycosylation
method further comprises using a reactivity-based one-pot
glycosylation that employs a single-component catalyst to
accelerate an oligosaccharide assembly process.
[0014] In a further aspect, a preferred catalytic glycosylation
method further comprises utilizing an application of a
100%-PEG-based polymer as insoluble support for solid-phase
oligosaccharide synthesis.
[0015] In yet an additional aspect, a preferred catalytic
glycosylation method further comprises utilizing a designer
thioglycoside that retains basic properties of a parental
thioglycoside, including the ease of preparation and toleration of
backbone protecting group manipulation.
[0016] In yet another aspect, a preferred catalytic glycosylation
method further comprises applying an activator permitting an
application of highly acid-sensitive protecting groups; applying a
100%-PEG-based polymer as insoluble support for solid-phase
oligosaccharide synthesis to streamline an oligosaccharide
assembly.
[0017] In another aspect of a preferred catalytic glycosylation
method of the present disclosure the activator is carbophilic
[0018] In another aspect of a preferred catalytic glycosylation
method of the present disclosure the activator is a cationic
gold(I) complex.
[0019] Another aspect of a preferred embodiment of the present
disclosure comprises a method of synthesizing an oligosaccharide,
comprising the steps of: tethering an acetyl ester and a benzoyl
ester to a saccharide with an alcohol group; and protecting the
alcohol group with an acid-labile ester protecting group.
[0020] In a further aspect, a preferred method of synthesizing an
oligosaccharide further comprises the step of deprotecting the
ester group by acid treatment.
[0021] An additional aspect of a preferred embodiment of the
present disclosure comprises a method of synthesizing an
oligosaccharide comprising the step of activating a thioglycoside
with a non-oxophilic Lewis acid.
[0022] In another aspect of a preferred method of synthesizing an
oligosaccharide of the present disclosure the Lewis acid comprises
a cationic gold(I) complex.
[0023] A further aspect of a preferred embodiment of the present
disclosure comprises a method of synthesizing an oligosaccharide,
comprising the steps of: tethering an acetyl ester and a benzoyl
ester to a thioglycoside with an alcohol group; protecting the
alcohol group with an acid-labile ester protecting group;
deprotecting the ester group by acid treatment; and activating the
thioglycoside with a non-oxophilic Lewis acid.
[0024] In another aspect of a preferred method of synthesizing an
oligosaccharide of the present disclosure the Lewis acid comprises
a cationic gold(I) complex.
[0025] Another aspect of a preferred embodiment of the present
disclosure comprises a protecting group to mask hydroxyl
functionalities in the production of oligosaccharides, natural
products or any molecule having a hydroxyl group comprising an
acid-labile ester protecting group.
[0026] In another aspect of a preferred protecting group of the
present disclosure, the acid-labile ester protecting group is
selected from a group consisting of an acetyl ester tethered with a
para methoxybenzyl (PMB) ether, an acetyl ester tethered with a
napthyl methyl (NAP) ether, a benzoyl ester tethered with a PMB
ether and a benzoyl ester tethered with an NAP ether.
[0027] In a further aspect of a preferred protecting group of the
present disclosure, the tethering of an acetyl ester or a benzoyl
ester with an alcohol group that is protected with an acid-labile
ester protecting group can be de-protected by an acid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] The present disclosure is illustrated by way of example and
not limitation in the figures of the accompanying drawings, in
which:
[0029] FIG. 1 shows a comparison of known catalytic glycosylation
methods (top) with a preferred catalytic glycosylation method of
the present disclosure (bottom).
[0030] FIG. 2 shows a summary of the novel features of the
glycosylating methods/systems according to preferred embodiments of
the present disclosure.
[0031] FIG. 3 illustrates a first preferred catalytic glycosylation
method of the present disclosure.
[0032] FIG. 4 shows another preferred catalytic glycosylation
method of the present disclosure.
[0033] FIG. 5 illustrates an additional preferred catalytic
glycosylation method of the present disclosure.
[0034] FIG. 6 shows yet another preferred catalytic glycosylation
method of the present disclosure.
[0035] FIG. 7 illustrates reactivity-based glycosylation according
to preferred embodiments of catalytic glycosylation methods of the
present disclosure.
[0036] FIG. 8 illustrates additional reactivity-based glycosylation
according to preferred embodiments of catalytic glycosylation
methods of the present disclosure.
[0037] FIG. 9 shows preferred processes for attaching the designed
thioethers to carbohydrates and transforming to the designed
glycosylating agents with respect to preferred catalytic
glycosylation methods of the present disclosure.
[0038] FIG. 10 illustrates the compatibility of preferred
glycosylation agents to known protecting group manipulations for
use in preferred catalytic glycosylation methods of the present
disclosure.
[0039] FIG. 11 illustrates differences between known protecting
groups (top) and preferred acid-labile ester protecting groups for
use in preferred methods of the present disclosure.
[0040] FIG. 12 illustrates preferred examples of acid-sensitive
groups according to preferred embodiments of using novel protecting
groups of the present disclosure.
[0041] FIG. 13 illustrates preferred acidic conditions for removing
acid-labile ester protecting groups according to preferred
embodiments of the present disclosure.
[0042] FIG. 14 shows that preferred acid-labile ester protecting
groups of the present disclosure are chemically compatible as
substitutes for other known protecting groups.
[0043] FIG. 15 illustrates shows that preferred acid-labile ester
protecting groups of the present disclosure may be employed as a
global protecting group protecting all hydroxyl groups on an
oligosaccharide backbone according to preferred embodiments of the
present disclosure.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0044] The following description, taken in conjunction with the
referenced drawings, is presented to enable one of ordinary skill
in the art to make and use the disclosure and to incorporate it in
the context of particular applications. Various modifications, as
well as a variety of uses in different applications, will be
readily apparent to those skilled in the art, and the general
principles, defined herein, may be applied to a wide range of
aspects. The present disclosure is not intended to be limited to
the aspects disclosed herein. Instead, it is to be afforded the
widest scope consistent with the disclosed aspects.
[0045] In essence, the present disclosure details the rational
design of preferred anomerically stable thioglycosides that can be
catalytically activated by cationic gold (I) complex. The
glycosylating methods/system according to preferred embodiments of
the present disclosure are novel, as they represent the first
disclosed glycosylation platform which features an anomerically
stable leaving group that can be activated by a catalytic amount of
a single component activator. The activator itself (cationic
gold(I) complex) is a non-oxophilic Lewis acid that permits the
application of highly acid-sensitive protecting groups, as
described herein, as global protecting groups to dramatically
streamline the complex oligosaccharide synthesis. The overall
system is both robust and modular in terms of the glycosylating
agent itself and the activator, the reactivity of which can be
readily tuned to streamline the oligosaccharide assembly
process.
[0046] FIG. 2 shows a summary of the novel features of the
glycosylating method/system according to preferred embodiments of
the present disclosure including:
[0047] A preferred and the first catalytic glycosylation system
that features an anomerically stable thioether leaving group.
[0048] The preferred catalytic glycosylation methods/systems permit
the application of highly acid-sensitive protecting groups as
permanent protecting group using a series of preferred
acid-sensitive ester type protecting groups described herein.
[0049] The preferred catalytic glycosylation methods/systems permit
the reactivity-based one-pot glycosylation that employs a
single-component catalyst that dramatically accelerates the
oligosaccharide assembly process.
[0050] The preferred catalytic glycosylation methods/systems permit
the application of 100%-PEG-based polymer as insoluble support for
solid-phase oligosaccharide synthesis which cannot be achieved with
traditional oxophilic Lewis acid activator, as they will bind the
PEG backbone and diminish their activities as activators.
[0051] The designer thioglycoside according to preferred
embodiments of the present disclosure retains the basic properties
of parental thioglycoside, including the ease of preparation and
toleration of backbone protecting group manipulation, an essential
feature for preparative purpose.
[0052] FIGS. 3-5 illustrate first preferred catalytic glycosylation
methods of the present disclosure representing the first catalytic
glycosylation methods featuring an anomerically stable thioether
leaving group. The preferred catalytic glycosylation methods are
modular both in terms of the glycosylating agent, where the
backbone of thioaryl ether can be readily modified to change its
reactivity and also the activator. The preferred catalytic
glycosylation methods only require a single component cationic
gold(I) complex as the activator, which is drastically different
from conventional chemistry involving thioglycoside activation. The
by-product generated in the preferred catalytic glycosylation
methods of the present disclosure (benzothiophene) does not
participate the glycosylation, which is different from known
glycosyltrichloroimidate chemistry where the by-product
trichloroacetamide can serve as competitive nucleophile to
complicate the glycosylation reaction.
[0053] As shown in FIG. 6, the preferred catalytic glycosylation
methods of the present disclosure permit the application of highly
acid-sensitive protecting groups, described herein, as permanent
protecting group. These types of -transformations cannot be
routinely carried out with glycosyl imidates or conventional
thiolgycoside.
[0054] FIGS. 7-8 illustrate additional preferred catalytic
glycosylation methods of the present disclosure which permit the
reactivity-based one-pot glycosylation that employs a
single-component catalyst that dramatically accelerates the
oligosaccharide assembly process. FIG. 7 shows reactivity based
catalytic glycosylation while FIG. 8 illustrates reactivity based
catalytic glycosylation to access blood antigen
oligosaccharide.
[0055] The preferred catalytic glycosylation methods of the present
disclosure which permit the application of 100%-PEG-based polymer
as insoluble support for solid-phase oligosaccharide synthesis.
This cannot be achieved with traditional oxophilic Lewis acid
activator, as they will bind the PEG backbone and diminish their
activities as activators. 100%-PEG-based polymer is marketed by
Novabiochem and has been widely applied in peptide synthesis. The
preferred designer thioglycosides of the present disclosure retain
the basic properties of parental thioglycoside, including the ease
of preparation and toleration of backbone protecting group
manipulation, an essential feature for preparative purpose.
Novel Protecting Groups for Synthesis of Oligosaccharides and
Natural Products
[0056] The present disclosure preferably employs a series of
ester-type of protecting groups that are used to mask hydroxyl
functionalities. While traditional ester protecting groups require
base treatment for removal, by tethering acetyl ester and benzoyl
ester with an alcohol group that is protected with an acid-labile
protecting group, the ester group can be readily deprotected by
acid treatment. The preparation of this ester-protecting group is
straightforward and it can be done on a multi-gram scale in a
routine academic lab. By tuning the ester backbone as well as the
tethered alcohol protecting group, a set of new acid-responsive
ester protecting groups is preferably obtained. This not only can
be used as temporary protecting group from complex carbohydrate and
natural product synthesis, but can also be used as permanent
protecting group for complex carbohydrate synthesis, as outlined in
FIG. 15 showing the synthesis of an oligomannoside according to a
preferred embodiment of the present disclosure.
[0057] FIG. 9 shows preferred processes for attaching the designed
thioethers to carbohydrates and transforming to the designed
glycosylating agents with respect to preferred catalytic
glycosylation methods of the present disclosure. FIG. 10
illustrates the compatibility of preferred glycosylation agents to
known protecting group manipulations for use in preferred catalytic
glycosylation methods of the present disclosure.
[0058] The following examples/schemes, as depicted in FIGS. 11-15,
illustrate preferred aspects of oligosaccharide synthesis using
novel protecting groups of the present disclosure. The preferred
embodiments of the present disclosure will streamline the synthesis
of biologically important oligosaccharide by automation. To the
best of the inventor's knowledge, no acid sensitive ester-type
protecting group has ever been described in the context of complex
molecule synthesis. The present disclosure allows for the dramatic
enhancement of production efficiency of biologically active
compounds in both industrial and academic labs which are oriented
towards biological research.
[0059] It should be emphasized the technical difficulties
associated with the preparation of oligosaccharides largely exceeds
those of DNA, RNA and peptides. RNA, a homologue of DNA, but with
an extra hydroxyl group at C-2 position of ribose, was once
considered difficult to synthesize by automation, because of the
lack of proper protecting group to mask that functionality.
[0060] It should be understood that while this disclosure has been
described herein in terms of specific, preferred embodiments set
forth in detail, such embodiments are presented by way of
illustration of the general principles of the disclosure, and the
disclosure is not necessarily limited thereto. Certain
modifications and variations in any given material, process step or
chemical formula will be readily apparent to those skilled in the
art without departing from the true spirit and scope of the present
disclosure, and all such modifications and variations should be
considered within the scope of the claims that follow.
* * * * *