Oxazolidinones silylation

Unsaturated acyl derivatives of oxazolidinones can be used as acceptors, and these reactions are enantioselective in the presence of chiral to-oxazoline catalysts.321 Silyl ketene acetals of thiol esters are good reactants and the stereochemistry depends on the ketene acetal configuration. The Z-isomer gives higher diastereoselectivity than the Zf-isomer. 

Conditions for arylation of enolate equivalents have also been developed. In the presence of ZnF2, silyl enol ethers, silyl ketene acetals, and similar compounds react. For example, the TMS derivatives of /V-acyl oxazolidinones can be arylated. 

Verma and Ghosh [72] desymmetrized a a-symmetric 3-dimethyl(phe-nyl)silyl substituted glutaric anhydride (127) with Evans oxazolidinone 128 (Scheme 32) as one of the key steps in their synthesis of (+)-preussin. 

In a related contribution O Brien described the AA on styrenes and converted the amino alcohols into enantiopure diamines by using a reaction strategy similar to Janda s [83], Further synthetic applications of the AA include a new access to Evans chiral oxazolidinones [84], the enantioselective synthesis of a-amino ketones from silyl enol ethers [85], the stereoselective synthesis of cyclohexyl norstatine [86], and a route towards amino cyclitols by aminohydroxy-lation of dienylsilanes [87]. 

Silylation of carboxylic acids.1 The reagent converts carboxylic acids into silyl carboxylates within 15-20 minutes in CC14 at 65-77° in the absence of a catalyst. The by-product is 2-oxazolidinone (insoluble in CC14). It is particularly useful for silylation of gem- or 1,2-dicarboxylic acids, which are easily decarboxylated when heated or in the presence of bases. 

Titanium enolates. These enolates have generally been prepared by transmet-talation of alkali-metal enolates or silyl enolate ethers. Surprisingly, Evans et al. find that a titanium enolate can be prepared directly from the oxazolidinone 1 by reaction with TiCl4 (1 equiv.) in CH2C12 and shortly thereafter with ethyldiisopropyl-amine (or triethylamine) at 0°. The enolate may actually be an ate complex (2a)... 

Schering-Plough uses (S)-4-phenyl-2-oxazolidinone in the large-scale production of their cholesterol absorption inhibitor Zetia (ezetimibe) (11) (Scheme 23.l).40 2 Condensation of the alcohol 12 with imine 13 in the presence of a Lewis acid such as TiCl4 and tertiary amine base yields compound 14. Silylation followed by intramolecular cyclization with tetrabutylammonium fluoride (TBAF) yields the protected ezetimibe 15. Removal of the protecting groups is carried out with weak acid to afford Ezetimibe (11). 

A six-membered chairlike transition state was proposed in which the ( )-ketene silyl acetal is placed in the opposite direction to the oxazolidinone carbonyl to avoid dipole moment repulsion, with the allylic moiety oriented away from the hindered indane backbone. This transition state would account for the direction of the asymmetric induction and also explain the better results observed with smaller silylating groups (Figure 24.7).108... 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Asymmetric Diels-Alder reaction of acryloyl oxazolidinone and 1,3-cyclohexa-diene using the chiral silyl cationic catalyst (5)-29 (Sch. 24, TPFPB = tetrakis(penta-fluorophenyl)borate) was recently reported by Jprgensen and Helmchen [41], This work was based on two concepts ... 

Ketones could be silylated with trimethylsilyl triflate, generated in situ from iV-trimethylsilyl-2-oxazolidinone and triflic acid in the presence of DBU, to give the enol silyl ether in excellent yields (84CJC336). 

The phenylalanine-derived oxazolidinone 108 undergoes a diastereoselective aldol reaction with crotonaldehyde to give the syn product 109. Formation of the Weinreb amide, followed by silylation of the crude secondary alcohol, provides 110. The chiral auxiliary is recovered at this stage. Product 110 is a potential precursor of all kinds of monosaccharides and analogs, including 1-deoxynojirimycin (Scheme 13.43) [85]. 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

Unsaturated acyl oxazolidinones 1 undergo enantiospecific [2 + 2] cycloadditions with 1,1-di-methylthioethylene and a catalyst consisting of a 1 1 mixture of diisopropoxytitanium dichloride and the chiral diol 243,44. The cyclobutane 3 is obtained in excellent yield with high enantiomeric excess. This is the first example of the enantiospecific [2 + 2] cycloaddition yielding a cyclobutane using an external chiral auxiliary as a chiral catalyst. Unfortunately, the scope of this reaction is quite limited since it fails with vinyl ethers, silyl enol ethers and ketene silyl acetals. 

Michael reaction of an oc,p-unsaturated ketone with a silyl enol ether (Scheme 26) and a Diels-Alder reaction of an oxazolidinone derivative with cy-clopentadiene (Scheme 27) also worked well using MC Sc(OTf)3. Moreover, a Friedel-Crafts acylation proceeded smoothly to produce an aromatic ketone in a good yield (Scheme 28). Friedel-Crafts alkylation and acylation reactions are fundamental and important processes in organic synthesis as well as in indus-... 

In our synthesis [36] of spiruchostatin A, we followed Simon s procedure for the preparation of 3. We too were unable to achieve the Carreira aldol in good yield. Moreover, the reaction requires the preparation of three noncommercial materials the binaphthyl chiral aminophenol, the t-butyl salicaldehyde, and the silyl ketene acetal. Instead, we opted for a diastereoselective aldol with the Nagao auxiliary. For reasons that are not completely clear, the Nagao thiazolidinethione auxiliary exhibits high diastereoselectivity in acetate aldols unlike the more popular Evans oxazolidinone auxiliary. In this case, aldol adduct 7 was obtained in good yield (Scheme 12-3). Unlike the other syntheses, this was coupled directly to the peptide rather than hydrolyzed to the acid 5. 

---