Acid chlorides oxazolidinones, reaction with

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. 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

In addition to the availability issues of the oxazolidinone unit, there has been some reluctance to scale up the reactions because formation of the V-acyl derivatives usually uses n-butyl lithium as a base. This problem can be circumvented by the use of an acid chloride or anhydride (symmetric or mixed) with triethylamine as the base in the presence of a catalytic amount of DMAP (4-dimethylamino pyridine). The reaction is general and provides good yields even with a,P-unsatur-ated acid derivatives (Scheme 2.4).12... 

To a 0.3 M soln of the appropriate oxazolidinone in anhyd THF at — 78 "C is added 1.0 equiv of BuLi. After 15 min, 1.1 equiv of freshly distilled acid chloride is added. The mixture is stirred at —78 °C for 30 min and at O C for 15 min. The reaction is quenched with an excess of sat. aq NH4Cl, and the resultant slurry is concentrated in vacuo. The residue is diluted with Er20 and washed with sat. aq NaHCO, and sat. brine. The organic phases are dried over MgS04, filtered and concentrated in vacuo. The product is purified by flash chromatography (silica gel) to afford the desired /V-acyloxazolidinones yield 55 -97%. 

A comparison of the reaction products obtained from RCH=NPh (R = MeO, Ph, PhCH=CH) and two heterocyclic imines with ketenes, generated by photolysis of oxazolidine- and oxazolidinone-chromium carbene complexes and from the oxazolidi-none carboxylic acid chlorides, indicated high yields and high diastereoselectivities in some of these reactions... 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

A variety of catalysts were explored for the reaction of 2-arylaziridines 20 with CO2 in the absence of other solvents (Scheme 12) [28]. The best results were obtained with zirconyl chloride, which afforded selective formation of 5-aryl-2-oxazolidinones 21. Naturally occurring a-amino acids were also foxmd to be effective catalysts for this reaction [29]. The highest yield and selectivity were observed for L-histidine. The yields and selectivity of the reaction were depended on the conditions and substrate structure. N-Phenyl-substituted aziridine did not react with CO2. 

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