Triflate, trimethylsilyl synthesis

After the readily available Friedel-Crafts catalyst, tin(IV) chloride, had been established as a catalyst for nucleoside synthesis, several other new catalysts, such as trimethylsilyl triflate (trimethylsilyl trifluoromethanesulfonate TMSOTf), etc., which are less acidic as Lewis acids... 

Two other trialkylsilyl trifluoromethanesulphonates, the TBDMS and tri-isopropylsilyl (TIPS) compounds, have been prepared and used in silylation reactions catalysed by 2,6-lutidine " TBDMS triflate allows formation of TBDMS ethers from tertiary and unreactive secondary alcohols, and TIPS triflate reacts effectively with primary and secondary alcohols. Use of the perfluorinated resin sulphonic acid trimethylsilyl ester Nafion-TMS , an immobilized TMS triflate, as a silylating agent for alcohols cf. 5,167) is discussed in a publication on applications of TMS triflate in synthesis. ... 

Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate) is the most synthetically useful representative of the family of trialkylsilyl perfluoroalkane-sulfonates (for a review, see reference 101) This reagent is commercially available or can be prepared easily by the reaction of chlorotrimethylsilane and triflic acid [101] It has wide application in organic synthesis as an excellent silylating reagent... 

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. 

The addition of alkyl nitronate anions to imines in the presence of a Lewis acid proceeds in high yield with up to 10 1 diastereoselection favoring the anti isomer. This reaction is used for the stereoselective synthesis of 1,2-diamines (Eq. 4.121).167 Scandium triflate catalyzes the addition of 1-trimethylsilyl nitropropanoate to imines with a similar selectivity.35... 

The most versatile approach to disulfonium dications - reaction of triflic anhydride with monosulfoxides of bis-sulfides - has certain limitations in the case of selenium. Most importantly, selenoxides that contain (3-hydrogen atoms are labile.120 122 Trimethylsilyl triflate was used instead of triflic anhydride for synthesis of dication 112 from a selenoxide 111 (Scheme 43).123... 

Nucleophilic addition of furan to nitrone occurs upon treatment with trimethyl-silyl triflate (TMSOTf) (586, 587). Catalyzed TMSOTf stereoselective addition of 2-[(trimethylsilyl)oxy]furan to chiral nitrones was carried out in a short synthesis of [IS (la, 2[), 7f>, 8a, 8aa)]-l,2-di(t-butyldiphenylsilyloxy)-indolizidine-7,8-diol (588). Addition to N -gulosyl-C-alkoxymethyl nitrones led to the synthesis of the core intermediate of polyoxin C (218). 

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... 

Scheme 9.8 The synthesis of methyl pentamannoside 2. The numerals indicate reagents used in the synthetic sequence (1) trimethylsilyl triflate, methylene chloride, 4 A molecular sieves (2) DBU, methanol. The final deprotection conditions shown in Scheme 9.7 were employed.

In large measure, the problem associated with the execution of a stereoselective aldol condensation has been reduced to the generation of a specific enolate geometry. The recent results of Kuwajima (66a), which demonstrate that enolsilanes may be transformed into boryl enolates without apparent loss of stereochemistry (eq. [53]), should enhance the utility of vinyloxyboranes in stereoselective synthesis. The only current drawback to this procedure is associated with the presence of trimethylsilyl triflate (69), which must be removed from the reaction medium before the aldol condensation. It has recently been established that 69 is an effective catalyst for the aldol process (4). 

Six years later, the same authors reported an improved version of their earlier synthesis of ellipticine (228) (527) (Scheme 5.197) by using the l-(p-methoxybenzyl)-5,6-dihydropyridone (1197) as 3,4-pyridyne surrogate (702,703). Thus, the dimethyl-furoindole 544 was treated with the unsaturated lactam 1197 (prepared from 5-valerolactam in three steps) in the presence of trimethylsilyl triflate (TMSOTf) to afford the carbazole 1199 as a single product in 40% yield. The low yield is presumably a consequence of decomposition of the intermediate adduct 1198 during... 

A further example of the diazaphosphole synthesis by [3 + 2] cycloaddition is given by the reaction of a phosphoranediyl diazomethane (26) (R = NPr j) with P-chloro-bis(trimethylsilyl)-phosphaethene. The adduct loses trimethylchlorosilane and yields a 3-phosphoranediyl-l,2,4-diazaphosphole (or 3-phosphonio-l,2,4-diazaphospholide) (27). The analogous addition to the trimethylsilyl substituted P-chloro-bis(methylene)phosphorane (28) yields a 4-methylene derivative (29) of this diazaphosphole (molecular structure in Table 1). It provides the only fully characterized example of this type up to 1995. Methyl triflate methylates the compound at N-1 and gives a phosphonio methylene diazaphosphole cation (30). 

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. 

We have found that the secret to a successful synthesis of the alkenyl glycosides 64 lies in obtaining the pure -acetate 65 [47]. Condensation of the acetate 65 with the appropriate alkenol,in the presence of a small amount (5-20 mol% depending on the scale) of trimethylsilyl triflate, gave the alkenyl glycosides 64 in excellent yield. Oxidation of the alkene 64 with dimethyldioxirane, followed by deacetylation, then gave the putative enzyme inhibitors 60. 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Synthesis of O-Linked 2-Deoxyglycosyl Amino Adds Using Trimethylsilyl Triflate... 

Scheme 11 Synthesis of a-2-Deoxyglycosyl Amino Acids Using Trimethylsilyl Triflate 263 ...

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of haIides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsilyl cyanide in EtjN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

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]. 

In their prominent synthesis of brevetoxin B, Nicolaou et al. have investigated, among some other methods for construction of oxepine ring system, the reductive cyclization of keto alcohol 37 with triethylsilane and trimethylsilyl triflate giving oxepane 38 (Equation 12) <1995JA1173>. 

Spirocycles.1 In the presence of trimethylsilyl triflate, the silyl enol ether of an aldehyde reacts selectively with the acetal function of 1 to form an intermediate with a carbonyl group that can then react with the initially inert allylsilane group of 1 to form a spirocyclic system. This methodology permits synthesis of spirocyclic sys-... 

A new, direct route to 0,S-acetals is based in part on the ability of trimethylsilyl triflate to mediate synthesis of 0,0-acetals from carbonyl compounds and silyl ethers (10, 439). Thus reaction of 1 1 mixtures of a silyl ether and phenylthiotrimethylsilane with an aldehyde in the presence of catalytic to stoichiometric amounts of trimethylsilyl triflate can give 0,S-acetals in 37-93% yield. Acetone is amenable to this 0,S-ketalization, but reactions with cyclohexanone result mainly in 0,0-ketals. 

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