The 1-Naphthylpropargyl Ether Group: A Readily Cleaved and Sterically Minimal Protecting System for Stereoselective Glycosylation

Abstract

The (1-naphthyl)propargyl group is introduced as a sterically unintrusive alcohol protecting group that is cleaved in a single step by exposure to dichlorodicyanoquinone in wet dichloromethane. In conjunction with a 4,6-O-benzylidene protecting group and the use of the sulfoxide glycosylation method, 3-O-naphthylpropargyl protected mannosyl donors are extremely β-selective.

The apposite use of protecting groups continues to be an essential element in preparative carbohydrate and oligosaccharide synthesis, with considerable effort devoted to their development in recent years.¹ This is due to the central role of protecting groups in modulating reactivity of both glycosyl donors and acceptors, and critically, in the control of regioselectivity, ² and stereoselectivity. ³ In response to a problem arising from the influence of protecting groups size on the stereoselectivity of a glycosylation reaction, ⁴ we recently described the successful application of propargyl ethers as sterically unintrusive donor protecting groups for β-mannosylation.⁵ However, while the propargyl ethers were readily introduced, and had the anticipated effect on stereoselectivity, they required a two step deprotection protocol: an initial treatment with base followed by catalytic osmoylation of the resulting allenyl ether (Scheme 1).

Scheme 1.

Deprotection of Propargyl Ethers

We considered that the advantages of the propargyl ether protecting system would be significantly enhanced if it could be modified in such a way as to be cleavable in a single step, orthogonal to the ubiquitous benzyl ethers. We report here on the successful accomplishment of this goal through the use of the naphthylpropargyl system.

The p-methoxybenzyl⁶ and naphthylmethyl⁷ ethers are widely employed as benzyl ether surrogates, cleavable under oxidative conditions. We reasoned that the insertion of an acetylenic group into the aryl-methylene bond of either the PMB or naphthylmethyl system would afford a system combining the steric advantages of the propargyl ether with the facile oxidative cleavage of the PMB and naphthylmethyl ethers. This line of thought led us to the ethers 1 and 2, which we assumed could be assembled from the known bromides 3 and 4.^8,9

Alkylation of 1,2;5,6-diacetone-D-glucofuranose with sodium hydride and bromide 4 gave the model ether 5 (Scheme 2). Treatment of this compound with DDQ in wet dichloromethane, typical conditions for the removal of PMB and naphthylmethyl ethers, returned the alcohol in 83% yield, thereby establishing proof of principle. Directly analogous transformations with the p-methoxyphenylproparyl protected system were also successful. However, it subsequently became clear that the more electron rich p-methoxyphenylpropargyl group 1 was incompatible with various glycosylation conditions leading to our subsequent preference for system 2.

Scheme 2.

Deprotection of a Naphthylpropargyl Ether

To examine the effect of the new protecting group 2 on stereoselectivity of glycoslation reactions, when located at both O2 and O3, we prepared donors 9 and 10 from known diol 6¹⁰ by standard means as set out in Scheme 3.

Scheme 3.

Preparation of Donors 9 and 10

Attempted activation of donors 9 and 10 by our standard treatment with 1-benzenesulfinyl piperidine (BSP) and trifluoromethanesulfonic anhydride¹¹ in the presence of the hindered base tri-tert-butylpyrimidine (TTBP) ¹² was unproductive affording little produts or no reaction. We turned, therefore, to the more potent combination of diphenyl sulfoxide (DPSO) and triflic anhydride¹³ when consumption of the donors was observed, but complex reaction mixtures were obtained. Study of the several products indicated that electrophilic attack on the arylpropargyl system was the root of the problem.

Precedent suggested, however, the activation of glycosyl sulfoxides with Tf₂O to be compatible with electron rich aromatic systems, especially when used in conjunction with an electrophile scavenger. ¹⁶ Accordingly donor 9 was oxidized to the sulfoxide 11 (Scheme 3), which was formed as a single diastereomer whose configuration rests on analogy.¹⁷

Treatment of 11 with triflic anhydride in the presence of TTBP at −78 °C in a 3:1 mixture of CH₂Cl₂ and 1-octene, to give an intermediate glycosyl triflate, ¹⁸ followed by addition of 1-adamantanol finally resulted in the formation of the β-mannoside 12a with impeccable selectivity (Table 1, entry 1). That 1-octene fulfilled its role of trapping of extraneous thiophilic species was established by isolation of 13.

Table 1.

Coupling Reactions of Donor 11

entry	acceptor	coupled product 12	yielda	ratiob β:α
1		12a	77%	β only
2		12b	46%	β only
3		12c	87%	13:1
4		12d	43%	β only
5		12e	74%	β only
6		12f	85%	β only

^aIsolated yields after column chromatography.

^bRatio was determined by ¹H-NMR of crude reaction mixtures.

A number of couplings were then conducted with more standard glycosyl acceptors, leading to the yields and selectivities collected in Table 1. The influence of the 3-O-naphthylpropargyl group on selectivty is best illustrated in entry 4 (Table 1): previously coupling of the. identical acceptor to the 3-O-tert-butyldimethylsilyl analog of 11 resulted in the formation of a 1.8:1 mixture of glycosides favoring the α-anomer.⁴

Oxidation of thioglycoside 10 afforded the sulfoxide 14, as a single diastereomer, in 94% yield. Activation of 14 under the conditions employed for 11 afforded β-mannosides with excellent selectivity (Table 2). Unfortunately, the reaction mixtures were relatively complex and included a significant byproduct, ketone 15, resulting from cyclization of the protecting group onto the activated glycosyl donor. In the face of this problem couplings to donor 14 were not pursued further.

Table 2.

Coupling Reactions of Donor 14

entry	acceptor	coupled product 16 yielda, β:αb
1		16a 67%, β only
2		16b 38%, β only
3		16c 13%, β only

^aIsolated yields after column chromatography.

^bRatio was determined based on ¹H-NMR of crude reaction mixtures.

The excellent stereoselectivity obtained with the 3-O-naphthylpropargyl protected donor 11 contrasts with the poor selectivity delivered by the corresponding 3-O-propargyl donor.^5b On the other hand, 4,6-O-benzylidene mannosyl donors carrying a 2-O-propargyl group were previously found to be highly efficient, in contrast to the 2-O-naphthylpropargyl system 14, and highly β-selective.⁵ Thus, in addition to their different requirements for deprotection, the propargyl and naphthylpropargyl systems are highly complementary.

In accordance with the model experiments (Scheme 2), selective deprotection of the glycosides 12 was accomplished with DDQ in CH₂Cl₂/H2O (20:1) over a period of 2–3 h at room temperature in excellent yield as reported in Table 3. The employment of other solvent systems recommended for the cleavage of 2-naphthylmethyl ethers, such as CH₂Cl₂/CH₃OH, ¹⁹ and CHCl₃/H₂O, and CH₂Cl₂ alone²⁰ was less satisfactory.

Table 3.

Cleavage of Naphthylpropargyl Ethers

entry	deprotected product 17	yielda
1	17a	86%
2	17b	80%
3	17c	89%
4	17d	90%
5	17e	84%
6	17f	86%

^aIsolated yields after column chromatography.

To conclude, we report the development of the naphthylpropargyl ether system. In conjunction with the sulfoxide glycosylation method, when introduced on the 3-position of 4,6-O-benzylidene protected mannosyl donors this system affords extremely β-selective coupling reactions, and the possibility of orthogonal cleavage in a single step with DDQ. We anticipate that this group will find application in oligosaccharide synthesis and, because of its minimal steric character and ease of deprotection, beyond the confines of carbohydrate chemistry.

Supplementary Material

si20060804_115. Supporting Information Available.

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Scheme 3.

Preparation of Sulfoxide 11