Anomeric Group Transformations Under Phase-Transfer Catalysis

Chapter 13

Anomeric Group Transformations Under Phase-Transfer Catalysis 1

R. Roy, F. D. Tropper , S. Cao, and J. M. Kim

Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: February 1, 1997 | doi: 10.1021/bk-1997-0659.ch013

Department of Chemistry, University of Ottawa, Ottawa, Ontario KIN 6N5 Canada

Liquid-liquid phase transfer catalysis (PTC) has been used for the synthesis of a wide range of anomeric glycosyl derivatives including C-, Ν-, Ο-, S-, and Se-glycosides. Moreover, glycosyl azides, enol ethers, esters, halides, hydroxysuccinimides, imides, phosphates, thiocyanates, and xanthates have also been stereospecifically obtained from glycosyl halides. PTC reactions have been successfully applied to mono- and disaccharides, sialic acid, 2-deoxy-2-acetamido sugars, and to D-xylose. All the reactions were efficiently accomplished at room temperature under mildly basic conditions. Ethyl acetate or in some cases dichloromethane appear to be the organic solvents of choice for fast and high yielding reactions. Examination of a number of PTC catalysts has indicated that one molar equivalent of tetrabutylammonium hydrogen sulfate provided optimum results. The reactions proceeded with good to excellent yields and were essentially complete within 3 hours. Preliminary mechanistic studies together with the scope and applications will be discussed.

Over the years, phase transfer catalysis (PTC) has emerged as a very useful and far reaching methodology for many common synthetic transformations. First devised to bring reagents and relatively simple organic substrates having incompatible solubilities together so that a chemical reaction could take place, PTC has evolved in a method where more complex substrates and chemical transformations can be adapted with great success. Included in this is the use of PTC methods in natural product synthesis. As a contribution to the use of PTC in natural product chemistry, we present here some of our synthetic work on important phase transfer catalyzed syntheses of carbohydrate derivatives. This chapter will deal with practical methods and the mechanistic aspects surrounding glycosylation reactions when performed under PTC conditions. 1

Current address: Glycodesign, Inc., 480 University Avenue, Suite 900, Toronto, Ontario, Canada

© 1997 American Chemical Society

In Phase-Transfer Catalysis; Halpern, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.


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Of the many types of natural products, carbohydrates are particularly challenging to the synthetic chemist. Carbohydrates are often delicate molecules that possess a variety of functional groups, ring sizes, branch points and stereocenters. As such they require special attention during synthesis. Traditional synthetic pathways are often long and tedious as a result of the need for elaborate chemo- and regioselective protection and deprotection sequences. These often require very reactive promoters and reagents that can be very noxious, costly and difficult to handle. There is often also the need for very polar and high boiling solvents that can prove tedious and time consuming to dry, purify and remove once the reaction is complete. Alternatively, PTC methodology is well suited to carbohydrate synthesis as reaction conditions can be quite mild and large scale preparations can be easily accommodated. Furthermore, the ability to use non-anhydrous conditions with relatively low boiling, non-anhydrous technical or reagent grade solvents can alleviate much of the technical work. In addition and of notable importance to the carbohydrate chemists is the fact that glycosides are prone to hydrolysis under acidic conditions. Thus PTC conditions are well suited to carbohydrates as reactions are carried out in near neutral or alkaline conditions that do not affect the glycosidic linkages. Carbohydrate chemists have used PTC to perform important synthetic transformations but the practice is not common. A recent review describing PTC work surrounding carbohydrates has been published (1). Known examples of carbohydrate transformations by PTC methods include complete or regioselective protection of hydroxyl groups by acetalation (2), acylation (3), benzylation (4) or silylation (5). Chain elongation by Wittig reaction (6) as well as oxidation (7) and reduction (8) reactions have also been performed on carbohydrate substrates under PTC conditions. Although such traditional chemical transformations are equally important to the carbohydrate chemists, no other reaction is more closely identified with the carbohydrate chemists than glycosylation reactions. The anomeric center and the ability to control the stereochemistry of synthetic transformations at this position can be quite challenging and is perhaps the most important to the carbohydrate chemists. So far, PTC has been used by other groups to provide only a limited number of glycosides (9-20). We present here our results demonstrating PTC as a simple and effective general methodology to perform a variety of stereoselective glycosylation reactions. We have shown that by using relatively labile glycosyl halides in an aqueous/organic two phase system, a variety of 0-, -ON-, S-, N-, Se- and Cglycosides can be prepared in a mild, simple and efficient manner when soft nucleophiles in combination with catalysts such as tetraalkylammonium salts are used. Using a PTC approach, we have stereoselectively synthesized a wide range of important glycosides in the form of prodrugs, glycoprobes such as lectin and enzyme substrates, precursors to neoglycoconjugates (protein and polymer), glycosyl donors for new and existing block oligosaccharide synthesis strategies, drug metabolites, glycopeptide and glycopeptoid precursors, as well as unusual glycosides that can be found in complex natural products. This chapter will describe our work in the area of PTC glycosylations and provide an insight to the mechanistic aspects surrounding this important synthetic transformation. Further, it will give an overview of some of the important glycosides that have been efficiently prepared using a PTC methodology and how they relate to the study fundamental biological phenomena.


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Mechanistic Considerations Ideally, anomeric nucleophilic substitutions under PTC conditions should occur stereospecifically. That is, α-glycosyl halides should provide exclusively the newly formed glycosyl derivatives with β-anomeric configurations. Alternatively, β-glycosyl halides should only furnish α-anomers (Scheme 1). For optimum predictability, this situation should be valid for all sugars irrespective of the halides, the nature of the protecting groups, and the conditions used.


(Nucleophile)

Nu

PTC

RO β-Anomer

X (Nucleophile) RO

Nu

PTC

β-Anomer

oc-Anomer

Scheme 1. Idealized anomeric nucleophilic substitutions under PTC conditions. However, in principle, anomeric group transformations of glycosyl halides can trigger a cascade of events which may lead to complex reaction mixtures. For anomeric nucleophilic substitutions of glycosyl halides, the outcome of the reactions will ultimately depend on the structure of the carbohydrate itself, the leaving group, the nucleophile, the solvent, and the presence or absence of neighboring protecting groups. In general, when ethers are used as neighboring protecting groups, there is no possibility of anchimeric group participation. This feature, can provide easier mechanistic interpretations. Alternatively, when esters are used, their electron withdrawing properties tend to destabilize oxocarbenium ion intermediates or transition states depending on whether the reactions will undergo mono- or bi-molecular substitutions. If the process follows a pure SN2 pathway, anomeric nucleophilic substitutions will inevitably provide glycosyl derivatives with inverted anomeric configurations (Scheme 2). Under these conditions, the nature of the protecting groups, if present, should not affect the stereochemical outcome of the reactions and the reactions will be stereospecific. However, if S 1 conditions prevail, oxocarbenium ions will result and scrambling of the anomeric configuration will ensue. The reactions will then give rise to an anomeric mixture of the desired glycosyl derivatives. Moreover, under liquid-liquid PTC conditions, the released halide anions may compete with the nucleophiles for the phase transfer catalysts and may return in the organic phase, thus giving rise to glycosyl halides with inverted anomeric configurations. For this reason, phase transfer catalyst containing halide anions should be strictly avoided. N


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PHASE-TRANSFER CATALYSIS

H 0^ 2

RO

RO

\^Nu

e

(SN2)

Nu®


SN1

RO

Nu

Br

Scheme 2. Possible side-reactions for anomeric nucleophilic substitutions under liquid-liquid two phases PTC conditions. Since it is generally easier to synthesize anomerically pure glycosyl halides having ester functionality as protecting groups, peracetylated glycosyl halides have been the most common starting materials for PTC studies. However, the hydrolysis of the ester function may occur with highly basic aqueous phase. Therefore, highly concentrated solutions of NaOH should similarly be avoided as a secondary liquid phase. Moreover, as most nucleophiles of interest are somewhat polar, the organic phase of choice should also contain solvents of relatively high polarity. Prior to our work, most PTC transformations were effected in refluxing benzene with 40% aqueous NaOH (1). We found that either EtOAc or CH C1 and 1M NaHC0 or 1M Na C0 at room temperature gave most satisfactory results (21-23). In all the PTC reactions, elimination through E l or E2 mechanisms together with hydrolysis accounted for some of the by-products obtained. As mentioned above, the nature of the neighboring protecting groups may interfere with the anomeric substitutions. This is particularly true for esters such as acetates and benzoates. For instance, with 1,2-cw peracetylated glycosyl bromides, the lost of bromide anions followed by anchimeric group stabilization of the oxocarbenium cation by the neighboring 2-0-acetoxy group will provoke formation of an acyloxonium ion which will then block the α-side (bottom) of the molecule (Scheme 3). The approaching nucleophiles will then attack from the top (β-face) of the molecule with the resulting formation of a β-glycosyl derivative starting from an ocglycosyl halide. The neat result however, still appears as an S 2-like reaction occurring by inversion of configuration. With harder nucleophiles, the reaction may 2

2

3

2

N


3

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even take the course of acyloxonium ion trapping with the resulting formation of an "orthoester" like products. For instance, 1,2-cis glycosyl halides 1,2, and 5 provided exclusively thioglycosides 3 (11), 4 (18), and 6 (24) with inverted configuration (Scheme 4). The same anomeric inversions were obtained from 1 and 2 irrespective of the nature of the protecting groups on 0-2. SN2


}

SN2

Scheme 3. Hypothesized effects of 2-acetoxy groups on the nucleophilic substitutions 1,2-cis and 1,2-trans peracetylated glycopyranosyl bromides under PTC conditions. The most striking evidence accumulated against the "hypothesis" of anchimeric group participation in anomeric nucleophilic substitutions of glycosyl halides under PTC conditions came from experiments with 1,2-trans peracetylated glycosyl halides 7 and 9 (Scheme 3). In these cases, if 2-acetoxy group participation would have prevailed, glycosyl derivatives resulting from retention of configuration would have resulted. This has not been the situation in any example studied so far in our laboratory. For instance, peracetylated oc-D-mannopyranosyl bromide (7) and ct-Lrhamnopyranosyl bromide (9) with 1,2-trans diaxial configuration provided exclusively


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the phenyl l-thio^-glycosyl derivatives 8 or 10 with soft a nucleophile such as thiophenol (Scheme 4). One report however has described the exclusive formation of orthothioester when peracetylated β-D-glucopyranosyl chloride having 1,2-trans diequatorial configuration was treated with thiophenol in benzene and NaOH (18).

Scheme 4. Stereochemical outcome for the PTC transformation of 1,2cis and 1,2-trans glycosyl bromides into phenyl 1-thio-glycopyranosides. Conditions, A: PhSH, CH C1 , NaOH, TEBAC, r.t.; B: PhH, NaOH, TBAB, r.t.; C: EtOAc, 1M Na C0 , TBAHS, r.t. 2

2

2

3

Furthermore, treatment of peracetylated 2-acetamido-2-deoxy-oc-D-glucopyranosyl chloride 11 under similar conditions afforded the corresponding phenyl 1thio-glucopyranoside 12 with inverted configuration in essentially quantitative yield (25). This results and numerous others indicated that an acetamide protecting group in the C-2 position is compatible with the PTC conditions. Interestingly, the a priori anticipated product resulting from anchimeric group participation, that is, the oxazoline {2-methyl-(3,4,6-tri-0-acetyl-1,2-dideoxy-oc-D-glucopyrano)-[2, l-d]-oxazoline} (see 16 below) did not constitute a major side reaction pathway for this particular reaction. Additionally, treatment of 3-deoxy ketoside 13 (sialic acid), having no protecting group suitably positioned for anchimeric group participation, provided thioglycoside 14 with inversion of configuration at the anomeric center, even though it contains a tertiary halide (Scheme 5). The fascinating result obtained for this particular carbohydrate derivative has been fully exploited for the syntheses of a wide number of other sialic acid analogs (26-32).


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As anticipated, products resulting from hydrolysis, elimination, and anchimeric group participation have all been observed, although products resulting from these side-reactions were only observed in minor quantities. "Ortho-ester-like" products have only been occasionally encountered with peracetylated 1,2-trans glycosyl halides and "harder" nucleophiles such as azide anions (24, 25). In none of the literature surveyed, anomeric mixtures have been observed, suggesting that oxonium ion intermediates were not formed. Therefore, phase transfer catalyzed anomeric nucleophilic substitutions can be best generalized as occurring with inversion of configuration by a clean bimolecular S 2 mechanism.


N

Scheme 5. Stereochemical outcome for the PTC transformation of 2acetamido-2-deoxy (11) and 3-deoxy-2-ketoside (13) into phenyl 1-thioglycopyranosides. To further assess the stereochemical outcome of phase transfer catalyzed anomeric nucleophilic substitutions, anomeric pairs of 2,3,4-tri-0-acetyl-a^-Dxylopyranosyl chlorides (15, 16) were independently prepared (Scheme 6). Each anomer was then treated with either thiophenol or sodium azide under optimized PTC conditions (EtOAc, 1M NaHC0 , r.t.,

Anomeric Group Transformations Under Phase-Transfer Catalysis

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