Silyl triflates, hydrolysis

Mukaiyama aldol reactions using a catalytic amount of a Lewis acidic metal salt afford silylated aldols (silyl ethers) as major products, but not free aldols (alcohols). Three mechanistic pathways which account for the formation of the silylated aldols are illustrated in Scheme 10.14. In a metal-catalyzed process the Lewis acidic metal catalyst is regenerated on silylation of the metal aldolate by intramolecular or intermolecular silicon transfer (paths a and b, respectively). If aldolate silylation is slow, a silicon-catalyzed process (path c) might effectively compete with the metal-catalyzed process. Carreira and Bosnich have concluded that some metal triflates serve as precursors of silyl triflates, which promote the aldol reaction as the actual catalysts, as shown in path c [46, 47]. Three similar pathways are possible in the triarylcarbenium ion-catalyzed reaction. According to Denmark et al. triarylcarbenium ions are the actual catalysts (path b) [48], whereas Bosnich has insisted that hydrolysis of the salts by a trace amount of water generates the silicon-based Lewis acids working as the actual catalysts (path c) [47]. Otera et al. have reported that 10-methylacridinium perchlorate is an efficient catalyst of the aldol reaction of ketene triethylsilyl acetals [49]. In this reaction, the perchlorate reacts smoothly with the acetals to produce the actual catalyst, triethylsilyl perchlorate. 

In the late 1970s, Enders pioneered an elegant method for ketone and aldehyde alkylation involving the use of metalated chiral hydrazones [92, 93). Extensive studies with the (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 150, Scheme 3.24) auxiliary and its enantiomer RAMP established these as superb chiral auxiliaries with numerous applications. In a typical alkylation sequence, a RAMP/SAMP hydrazine is condensed with an aldehyde or a ketone to form the corresponding hydrazone, such as 152. This can subsequently be deprotonated and the resulting enolate trapped with a variety of electrophilic reagents including alkyl halides, aldehydes, Michael acceptors, silyl triflates, and disulfides. The RAMP/SAMP hydrazine auxiliary may be removed by acidic hydrolysis or ozonolysis to reveal the alkylated... 

Taking into account the competitive hydrolysis of the silyl enol ether, this reaction is remarkable. The method was shown to be general and was extended to a variety of aldehydes and several a,j9-unsaturated carbonyl compounds giving uniformly 1,4-addition with aldehydes and a mixture of 1,4- and 1,2-adducts in the case of ketones [187]. Later, this aqueous version of the Mukaiya-ma reaction was shown to give near quantitative yields in the presence of a water-tolerant Lewis acid such as ytterbium triflate [188]. Keeping with the same concept,copper(II) triflate [189],indium(III) trichloride [190],tris(pentafluoro-phenyl)boron [191] and scandium(III) triflate in the presence of a surfactant [192] have proved to be active catalysts. 

The demand for environmentally friendly chemistry and its widespread applicability have made water an increasingly popnlar solvent for organic transformations. Mixtures of water and other solvents snch as tetrahydrofnran are now commonly anployed for a number of organic transformations. For instance, the Lewis acid catalysed aldol reaction of silyl enol ethers, commonly known as the Mnkaiyama aldol reaction, which was firstly reported in the early seventies, can be carried ont in snch media. With titanium tetrachloride as the catalyst this reaction proceeds regioselectively in high yields, but the reaction has to be carried ont strictly nnder non-aqneons conditions in order to prevent decomposition of the catalyst and hydrolysis of the sUyl enol ethCTS. In the absence of the catalyst it was observed that water had a beneficial influence on this process (Table 4, entry D) . Nevertheless, the yields in the nncatalysed version WCTe still unsatisfactory. Improved results were obtained with water-tolerant Lewis acids. The first reported example for Lewis acid catalysis in aqueous media is the hydroxymethylation of silyl enol ethers with commercial formaldehyde solution using lanthanide trillates. In the meantime, the influence of several lanthanide triflates in cross-aldol reactions of various aldehydes was examined " " ". The reactions were most effectively carried out in 1 9 mixtures of water and tetrahydrofnran with 5-10% Yb(OTf)3, which can be reused after completion of the reaction (Table 19, entry A). Although the realization of this reaction is quite simple, the choice of the solvent is crucial (Table 20). 

Cyclohexylpropionic acid was deprotonated with 2.2 equivalent of lithium diisopropylamide and the resulting dianion was condensed with trifluoroacetaldehyde which was generated in situ from its ethyl hemiacetal. The P-hydroxy acid 1 was isolated as a racemic mixture of two diastereomers. Silylation with tert-butyldimethylsilyl triflate was followed by ester hydrolysis to give the acid 2. A Curtius rearrangement with diphenylphosphoryl azide in the presence of benzyl alcohol afforded the protected P-amino alcohol 3 which was used in the preparation of the trifluoromethyl alcohol I. Oxidation using the Dess-Martin periodinane reagent (9) yielded the trifluoromethyl ketone II as a mixture of diastereomers. The signal for the carbonyl carbon in the 13C-NMR spectrum of this ketone appeared at 94.5 ppm and this is consistent with the hydrated form of the trifluoromethyl ketone. 

With this bicyclic intermediate available in sizeable amounts, ready advance to 111 could be conveniently accomplished prior to annulation of the second five-membered ring (Scheme XIV). 1,3-Carbonyl transposition was realized by complete eradication of the original carbonyl by Ireland s method [60] followed by allylic oxidation. Application of the Piers cyclopentannulation protocol [61] to 111 made 113 conveniently available. Introduction of a methyl group into ring B was brought about by treatment of the kinetically derived enol triflate [62] with lithium dimethylcuprate [63], Hydrolysis of 114 gave the dienone, which was directly transformed into 115 by oxidation of its silyl enol ether with palladium acetate in acetonitrile [64],... 

Lanthanide triflates were found to be excellent Lewis acid catalysts not only in aqueous media but also in organic solvents. The reaction of ketene silyl acetal 3 with benzaldehyde proceeded smoothly in the presence of 10mol% Yb(OTf)3 in dichloromethane at -78°C, to afford the corresponding aldol-type adduct in 94% yield. The same reaction at room temperature also went quite cleanly without side reactions and the desired adduct was obtained in 95% yield. No adduct was obtained in THF-water or toluene-ethanol-water, because hydrolysis of the ketene silyl acetal preceded the desired aldol reaction in such solvents. In other organic solvents such as toluene, THF, acetonitrile, and DMF, Yb(OTf)3 worked well, and it was found that other Ln(OTf)3 also catalyzed the above aldol reaction effectively (85-95% yields). 

Trimethylsilylation has been accomplished with a large number of reagents most of which are commercially available. The cheapest (chlorotrimethylsilane) and the most reactive (trimethylsilyl triflate) rapidly silylate hydroxyl groups in the presence of a suitable base such as pyridine, triethylamine, i-Pr2NEt, imidazole, or DBU but an aqueous workup is required to ensure complete removal of the resultant amine hydrochloride or triflate whence hydrolysis of the nascent TMS ether may occur. In some cases the insoluble salt may be removed by filtration without aqueous workup. A wide range of solvents can be used for the reaction such as dichloromethane, acetonitrile, THF, or DMF. Care must be taken with trimethylsilyl triflate (TMSOTf) since it will convert aldehydes and ketones to the corresponding enol silanes and it will open epoxides in a reaction that has preparative significance [Scheme 4.6]. Similar transformations can be accomplished with tert-butyldimelhylsilyl triflate (TBSOTf) or triethylsilyl triflate (TESOTf). ... 

---