Acetals Lewis acid induced

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

The Lewis acid induced reaction of silyl enol ethers and silyl ketene (thio)acetals with 4-acetoxyazetidinones is often used for introduction of a carbon substituent in the 4-position of the jS-lactam ring. Numerous examples are known, both with and without substituents at nitrogen, some of which are shown. 

Maeda K, Shinokubo H, Oshima K (1997) Lewis acid-induced chemo- and stereoselective allylation of a-iodo mixed acetal with allylsilane. J Org Chem 62 6429-6431... 

Polla, M., Frejd, T. Lewis Acid-induced alkoxyalkylation of aiiyisiianes with acetals (the Sakurai reaction) regio- and stereochemical aspects. Acta Chem. Scand. 1993,47, 716-720. 

In 1997 Kibayashi reported the first approach to the tricyclic framework of FR901483 [11] based on the synthesis of l-alkyl-2-azabicyclo[3.3.1]-nonanes (e.g. IX), as depicted in Scheme 30, through a nucleophilic bridgehead alkylation on an anti-Bredt iminium ion (e.g. VIII), which is available by means of the Lewis acid-induced cleavage of tricyclic N,0-acetals (e.g. VII). 

Scheme 30. Lewis acid-induced nucleophilic alkylation of A O-acetals in the approach by Kibayashi of the tricyclic core...

To guide the next series of experiments we formulated a working hypothesis which is summarized in Scheme 7. It is clear that the acetal may react either via Lewis acid-induced ioniza-... 

The capnellane (109) has been synthesized, using two dififerent annulation procedures (Scheme 11). The a/b ring junction was formed through consecutive Michael and ene-type reactions by addition of a lithium cuprate to 3-methyl-cyclopent-2-enone and trapping of the enolate anion that is thus formed as the enol acetate (110). Lewis-acid-induced cyclization then formed the ketone (111). 

The Lewis acid induced rearrangement of alkenyl acetals, known as the Ferrier reaction, is a very powerful synthetic tool for C-C bond formation. Rovis and coworkers have recently introduced a highly stereoselective method in which contrary to standard methods, during the conversion of C-0 bond to a C-C bond. 

The pivaloylamidobenzyl group was stable to acetic acid-water-90°, MeOH-NaOMe, iridium-induced allyl isomerization, and to many of the Lewis acids used in glycosylation. ... 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Lewis acids such as TiCl4 and SnCl4 induce addition of both silyl enol ethers and ketene silyl acetals to aldehydes.49... 

For the Cu(OTf)2-promoted reaction between ethyl diazoacetate and cinnam-aldehyde dimethyl acetal, products 143-145 account for only 35% the total yield. C/C and C/H insertion products 151 and 152 are obtained additionally in 49 and 14% yield, respectively154). It was assumed that the copper compound acts through Lewis-acid catalysis here, just as it is believed to do when orthoesters are used as substrates 160). According to this, catalyst-induced formation of a methoxy-... 

It has been shown that Lewis acid catalyzed isomerization of thionolactones provides access to thiolactones. For example, exposure of the substrate 22 to catalytic amounts of BF3 OEt2 led to efficient conversion to the thiolactone 23. Such transformations were also found to give minor amounts of lactone or dithiolactone side products <06TL6067>. Substituted tetrahydrothiophene derivatives have also been obtained from 1,4-dithiane-2,5-diol and 2-nitroethyl acetate derivatives by a base induced sequence featuring a Michael addition and a Henry reaction <06TL8087>. 

While the perfluorinated acetates do prefer insertion, they are still capable of forming 1,3-dipoles and have demonstrated interesting effects on the regioselectivity of intramolecular cycloaddition reactions, presumably through Lewis acid-mediated effects on the dipolarophile [83]. Other chemoselectivity effects have been noted in the intramolecular cycloaddition reactions and may or may not be partially induced by conformation and sterics [84]. It was further demonstrated thaL when possible, O-H insertion is the predominant outcome over other types of insertion for rhodium]II)-car-benes, independently of the catalyst. However, cycloaddition reactions have been demonstrated to be hgand-dependent [85]. 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

The esters, 7-ethoxycyclopropyl acetate (7 a) and benzoate (7b) have been synthesized by the addition of the Simmons-Smith reagent 22> to 1-ethoxy vinyl acetate and benzoate, respectively.4) A potential difficulty in this reaction lies in the fact that zinc iodide, a Lewis acid, is generated in the process and may induce cyclopropane ring opening (Section 4.3.3). However, when glyme is used as a solvent, the acid-labile bonds remain intact since the zinc salt is insoluble in this medium.23)... 

The silver(I)-mediated electrocyclic ring opening of halocyclopropanes has been used to induce extensive skeletal rearrangements in gcm-dibromospiropentanes, providing rapid construction of naphthalenes and/or indenes (Scheme4.21 ).34 A variety of Lewis acids, Brpnsted acids, and solvent effects were carefully examined before optimal conditions were identified. It was found that subjection of spirocycle 60 to silver acetate in trifluoroacetic acid afforded rearrangement products 61 and 62 in moderate to good yields. The proposed mechanism of the reaction is illustrated in Scheme 4.21. 

The second subset of acid labile protecting groups consists of 0,0-acetals. Like the protecting groups in the first subset, heterolysis of an OtO-aceta] is induced by protic acids and Lewis acids resulting in formation of a resonance stabilised intermediate — an oxonium ion 6 1 [Scheme 1.6]. In the presence of nucleophiles (e.g, water), the highly electrophilic oxonium ion reacts further to pro-... 

---