Oxazolidinone formation

Chiral active pharmaceutical ingredients, 18 725-726. See also Enantio- entries Chiral additives, 6 75—79 Chiral alcohols, synthesis of, 13 667-668 P-Chiral alcohols, synthesis of, 13 669 Chiral alkanes, synthesis of, 13 668-669 Chiral alkenes, synthesis of, 13 668—669 Chiral alkoxides, 26 929 Chiral alkynes, synthesis of, 13 668-669 Chiral ammonium ions, enantiomer recognition properties for, 16 790 Chiral ansa-metallocenes, 16 90 Chiral auxiliaries, in oxazolidinone formation, 17 738—739... 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

Oxazolidinone formation with carbonyldiimidazole leads to 37, the reduction of which generates aldehyde 38 [61]. A nucleophilic alaninol synthon 41 was derived from 35 by protection of the alcohol and amine moieties as a carbamate on treatment with phosgene. Reduction of the ester gave the corresponding alaninol 39, which was tosylated. The tosylate was then successively displaced with iodide and triphenylphosphine yielding 41 [62] (Scheme 13.24)... 

Phosgene or triphosgene in the presence of a hase such as TEA or pyridine in CH2CI2 is a common method for oxazolidinone formation. Triphosgene has the advantage that it is an easily handled solid. ... 

While the majority of Rh-catalyzed C-H amination processes employ hyperva-lent iodine oxidants and sulfonamide derivatives, Lebel and coworkers have demonstrated that /V-tosyloxycarbamates will engage with catalytic Rh2(02CCPh3)4 and K2CC>3 to afford products of intramolecular C-H insertion (Fig. 22) [104, 5, 105]. Similar to Du Bois earlier work involving oxidative cyclization with 1 ° carbamates [94], the /V-tosyloxy derivatives display a strong bias for oxazolidinone formation. Selectivity trends and other mechanistic data support a reaction pathway involving a Rh-nitrene oxidant. Intermolecular amination of simple benzylic substrates... 

It had been hoped that the acidic conditions of this deprotection would induce in situ oxazolidinone formation and give compound 81 directly. However, the tandem cyclization process did not occur. To bring about ring closure, 82 had to be exposed to 1.5 eq. of sodium hydride in THF at room temperature for 30 minutes, whereupon the desired oxazolidinone 81 was formed in essentially quantitative yield. 

Whatever the actual source of our problems, in our third-strike strategy to (-)-agelastatin A, we resolved to delay oxazolidinone formation until after the cyclopentene ring had been formed and, accordingly, we... 

Oxazolidinone formation. Catalyzed epoxide opening and the subsequent formal [3+2]cycloaddition to isocyanates constitute a useful synthetic transformation. 

Tosyl isocyanate (226) was allylated smoothly with the alkenyloxirane 225 using isopropyl phosphite as a ligand to give the oxazolidinone 227 in 75 % yield, which was converted to the syn amino alcohol 228 in high yield. Oxazolidinone formation proceeds with overall retention of configuration, and is used for the synthesis of regioisomers of sphingosine [82],... 

Another issue is the formation of oxazolidinones, which has been the subject of study by several research groups and is considered to be part of a parasitic equilibrium for proline-catalysed aldol reactions. More recent studies have indicated that this parasitic equilibrium may not be true, and that reversible oxazolidinone formation may help keep proline in solu-tion. Figure 5.3 illustrates a generalised mechanism for proline catalysis involving enamine intermediates. As aforementioned, the formation of oxazolidinones may or may not be part of a parasitic equilibrium. 

SCHEME 2.6. Proline deactivation by oxazolidinone formation from electron-deficient aldehydes. 

SCHEME 2.7. Thiourea-assisted oxazolidinone formation and aldol reaction in nonpolar solvents. 

Unfortunately, the isolation of 30 was not possible, because it underwent rapid cyclization to the oxazolidinone. Additional qualitative evidence for an intermediate in the cyclization comes from ReactIR experiments. When benzaldehyde is added to a CH2CI2 solution of the acid chloride in the presence of catalytic SnCU, a new carbonyl resonance at 1800 cm" is observed, which is attributed to the oxazolidinone product. The benzaldehyde signal at 1702 cm disappears at ca. 3 times faster rate than the appearance of the oxazolidinone signal, suggesting the formation of an intermediate which is transformed into the oxazolidinone product at a slightly slower rate. Scheme 11 shows the proposed mechanism for oxazolidinone formation. 

Pro line tetrazole catalysts (category C in Figure 1.1) are readily accessible from L-proline (1) [158]. They are remarkably useful in asymmetric synthesis [159]. As shown in Figure 1.2, the pfCj of tetrazole is very similar to that of carboxyUc acid. Moreover, the advantage of tetrazole catalysts is their robust and lipophihc nature compared to L-proline (1) itself, which allows them to escape parasitic bicyclo-oxazolidinone formation [160]. 

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