Chiral oxazolidinones from N-Boc derivatives of β-amino alcohols. Effect of a N-methyl substituent on reactivity and stereoselectivity

Experimental and DFT study of the conversion of ephedrine derivatives into oxazolidinones. Double SN2 mechanism against SN1 mechanism

“…In this context, a S N 1 mechanism has been suggested. 8,10,12 The substitution at the N atom (NeH or NeMe), as reported by other researchers, 8,9 is not decisive for the retention or inversion of configuration at C5 (see entries 2 and 4). The alkyl substituent at the N atom (NeMe) only gives a lower proportion of retention product (entry 2).…”

“…Once the benzylic alcohol is converted into the corresponding sulfonate, this reacts quickly to give the final products. Although the sulfonate intermediate has sometimes been isolated, 8,22,23 it has always been in cases where the sulfonates were not benzylic, which are less reactive towards nucleophilic attack through S N 1 or S N 2 processes. As can be seen in Table 1, the tosylation of the compounds 1a and 3a (entries 1 and 3) afforded the corresponding 1,3-oxazolidin-2-ones 7 and 9 with inversion of configuration at C5.…”

“…Despite the great importance of this type of compounds there is not reasonable explanation of the causes of this phenomenon, only a S N 1 mechanism has been suggested by some researchers. 8,10,12 Another reaction that can be used to convert the hydroxy group into a good LG is the Mitsunobu reaction 13 (Ph 3 P, dialkyl azodicarboxylate). Intramolecular attack of the carbonyl group of the carbamate to the phosphonium intermediate would lead to the oxazolidinone with a predictable inversion of configuration at C5 (Scheme 1, Path 2, R 2 ¼Ph 3 P þ ).…”

“…Using this method, the compounds 1ae4a have been converted into 1,3-oxazolidin-2-ones with different stereochemical results depending on the reaction conditions. 8 It is possible to prepare the corresponding 1,3-oxazolidin-2-ones with retention of configuration at C5 on using a proper base, trough an intramolecular transesterification of the initially formed alkoxide (Scheme 1, Path 1). 9e11 On the other hand, the conversion of the hydroxy group into a suitable leaving group (LG) allows the intramolecular attack of the Boc group leading, through a S N 2 process, to an inversion of configuration at C5 (Scheme 1, Path 2).…”

Ring Expansions of Nonactivated Aziridines and Azetidines

“…Interestingly, this reaction was completely annihilated in the case of NHBoc derivatives (240, R¼H), reacting in this case through a more classical ring opening by the halide anion to yield 243 (Scheme 63). This spectacular effect of substitution at the nitrogen atom has precedents and can be ascribed to a Thorpe-Ingold effect at the nitrogen atom [121]. …”