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.

Claims

1. A catalytic glycosylation method comprising: installing thioether to an anomeric carbon of a carbohydrate; and catalytically activating the thioether with an activator comprising a non-oxophilic Lewis acid comprising a cationic gold(I) complex.

2. The catalytic glycosylation method of claim 1 further comprising: applying a 100%-PEG-based polymer as insoluble support for solid-phase oligosaccharide synthesis to streamline an oligosaccharide assembly.

3. The catalytic glycosylation method of claim 2 wherein the activator is carbophilic.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The present disclosure is illustrated by way of example and not limitation in the figures of the accompanying drawings, in which:

(2) FIG. 1 shows a comparison of known catalytic glycosylation methods (top) with a preferred catalytic glycosylation method of the present disclosure (bottom).

(3) FIG. 2 shows a summary of the novel features of the glycosylating methods/systems according to preferred embodiments of the present disclosure.

(4) FIG. 3 illustrates a first preferred catalytic glycosylation method of the present disclosure.

(5) FIG. 4 shows another preferred catalytic glycosylation method of the present disclosure.

(6) FIG. 5 illustrates an additional preferred catalytic glycosylation method of the present disclosure.

(7) FIG. 6 shows yet another preferred catalytic glycosylation method of the present disclosure.

(8) FIG. 7 illustrates reactivity-based glycosylation according to preferred embodiments of catalytic glycosylation methods of the present disclosure.

(9) FIG. 8 illustrates additional reactivity-based glycosylation according to preferred embodiments of catalytic glycosylation methods of the present disclosure.

(10) 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.

(11) 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.

(12) 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.

(13) FIG. 12 illustrates preferred examples of acid-sensitive groups according to preferred embodiments of using novel protecting groups of the present disclosure.

(14) FIG. 13 illustrates preferred acidic conditions for removing acid-labile ester protecting groups according to preferred embodiments of the present disclosure.

(15) FIG. 14 shows that preferred acid-labile ester protecting groups of the present disclosure are chemically compatible as substitutes for other known protecting groups.

(16) 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

(17) 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.

(18) 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.

(19) FIG. 2 shows a summary of the novel features of the glycosylating method/system according to preferred embodiments of the present disclosure including:

(20) A preferred and the first catalytic glycosylation system that features an anomerically stable thioether leaving group.

(21) 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.

(22) 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.

(23) 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.

(24) 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.

(25) 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.

(26) 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.

(27) 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.

(28) 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.

(29) Novel Protecting Groups for Synthesis of Oligosaccharides and Natural Products

(30) 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.

(31) 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.

(32) 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.

(33) 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.

(34) 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.