Activation with trimethylsilyl triflate

The Glaxo synthesis of zanamivir (2) started with the esterification of commercially available A-acetyl-neuraminic acid (88) with methanolic HCl to give the methyl ester as shown in Scheme 7.14 (Chandler and Weir, 1993 Chandler et ah, 1995 Patel, 1994 Weir et al., 1994). Global acetylation of all the hydroxyl groups with acetic anhydride in pyridine with catalysis by 4-(dimethylamino)pyridine (DMAP) led to the penta-acetoxy compound 89. Treatment of 89 with trimethylsilyl triflate in ethyl acetate at 52°C introduced the oxazoline as well as the 2,3-double bond to provide 86. Addition of trimethysilyl azide to the activated allylic oxazoline group led to the stereoselective introduction of azide at the C-4 position to afford 83 as in Scheme 7.13. 

Imines may be activated by complexation with Lewis acids, but this also increases the acidity of a-hydrogen atoms. A combination of copper(i) halide and boron trifluoride etherate is a possible solution to the problem [6, 7]. Activation by trimethylsilyl triflate is also effective with aldimines (though not with ketimines) [7, 8]. 

The quatemization of imines to form mote reactive iminium salts has had limited synthetic utility since the activating substituents are often not easily removed. For this reason Lewis acids have been utilized to activate imines. MacLean and cowotkers have also addressed this problem and found that si-lylation of 3,4-dihydroisoquinolines and 3,4-dihydro-P-carbolines with trimethylsilyl triflate (TMS-OTf) provides a reactive, yet labile, silyl iminium salt which undergoes nucleophilic addition (Scheme 9). With this procedure, 3,4-dihydro-6,7-dialkoxyisoquinoline (54) was converted to amidine (56) in 98% yield. In the absence of TMS-OTf no addition occurred. 

Bis-trimethylsilylated a-hydroxy acids can be reacted with pivaldehyde with trimethylsilyl triflate catalysis to give l,3-dioxolane-4-ones47 (equation 39). In a similar vein the bis-trimethylsilylated enantiomerically enriched (88% ee) /Miydroxy acid 19 can be condensed with aldehydes in the presence of trimethylsilyl triflate to produce the 1,3-dioxane-4-ones48 (equation 40). These were in turn reacted with organocuprates to provide optically active secondary alcohols. 

A systematic investigation of the use of glycosyl acetates with trimethylsilyl triflate as activator in disaccharide synthesis has been conducted. ... 

It appeared that iodoacetate 46 is an excellent glycosyl donor when activated by trimethylsilyl triflate at low temperatures high a-stereoselectivity and excellent yields were obtained with warious acceptors including glycals such as 47 which gave a disaccharide glycal 48 incorporated into the total synthesis of olivomycin A... 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

Trimethylsilyl triflate is also a powerful catalyst for acylation by anhydrides. Reactions of alcohols with a modest excess (1.5 equival) of anhydride proceed in inert solvents at 0°C. Even tertiary alcohols react rapidly.114 The active acylation reagent is presumably generated by O-silylation of the anhydride. 

Mukaiyama aldol reactions of aldehydes with silyl enol ethers are amongst the most widely used Lewis-acid-mediated or -catalyzed reactions. However, trimethylsilyl triflate is not active enough to promote these reactions,66 and more active silicon-based Lewis acids have been developed. One example is the species generated by mixing trimethylsilyl triflate (or chloride) and B(OTf)3,319,320 for which the formulation R3Si + [B(OTf)4] is suggested by NMR experiments. Only a catalytic amount of this was needed to complete Mukaiyama aldol reactions of... 

While triflic anhydride activation of sulfoxides is the norm, other activation procedures have been employed. In the synthesis of the ciclamycin 0 trisaccharide, catalytic triflic acid (TfOH) was employed.19 Trimethylsilyl triflate (TMSOTf), in conjunction with triethyl phosphite (a scavenger for phenylsulfenic acid), has also been used.20... 

To a stirred mixture of a-73 [Eq. (12)] (1.00 g, 1.5 mmol), activated 4-A powdered molecular sieves (1.0 g), dry CH2C12 (12 mL), and triethylsilane (2.4 mL, 15.0 mmol) was added dropwise trimethylsilyl triflate (775 p.L, 4.2 mmol). The mixture was stined at room temperature for 30 min and then neutralized with Et3N, diluted with CH2C12, filtered through Celite, and concentrated. The residue was eluted from a column of silica gel with 5 2 petroleum ether-ethyl acetate to give 85 (0.87 g, 96%) as a syrup [a]D 0°, [a]436 —3.9° (c 1, CHClj). 

Recently, substantial progress in stereochemistry of the cycloaddition reaction has been reported [34], Cycloaddition between optically active oxadiene 13 and l-acetoxy-2-ethoxy-ethylene, promoted by dimethylaluminum chloride, leads to dihydropyran 14, with a very high endo-exo stereoselectivity (54 1) and in an almost quantitative yield (see Scheme 6). When trimethylsilyl triflate was used as the promoter in this reaction, the reverse endo-exo selectivity (1 5) has been noted. The dihydropyrans obtained served as substrates for the synthesis of (3-d- and 3-L-mannopyranosides [34]. 

The activated a-trimethylsilyl group on the pyrimidine moiety reacts with the triflate ion 26 to regenerate the triflate catalyst. Under reversible and thus thermodynamically controlled conditions, the nucleophilic silylated base 23 attacks the carbohydrate cation 25 only from the top (/(-side) to afford exclusively the /(-nucleoside. 

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