Application of Chiral Auxiliaries in Industry

Despite the relatively recent advent of chiral auxiliaries, they have some limited use at multikilogram industrial scale. 

It was found that the acylation step could be run efficiently at 0°C. However, even a slight excess of -BuLi ( 5%) resulted in a 15% yield loss at the acylation step, accounted for by the epimerization of the carbon adjacent to the phenyl ring on the oxazolidinone. It was noticed that a red color resulted when excess w-BuLi was present, due to the formation of a dianionic species. Thus, stopping the addition when only the characteristic yellow color was present maintained the normally high yields (95%) for this acylation. 

Overall recovery of the auxiliary was 64%. Upon cost estimates for scale-up work, it was found that the aforementioned chiral auxiliary route exceeded the desired cost by a factor of six, primarily because of the cost of the chiral oxazolidinone and a yield of 33% over 10 steps. The route was ultimately replaced with a classical resolution protocol using mandelic acid. 

There are numerous examples in which the potential for the application of chiral auxiliaries, once again primarily oxazolidinones, exists for an industrial setting. 

Alternatively, diltiazem (21) has been prepared using the Evans auxiliary 22 derived from L-valine (Seheme 5) [50], After dehydration of the adduct from the condensation of 22 with anisaldehyde through the mesylate, the enol ether was formed with a Z E ratio of 4 1. This imide was then treated with 2-aminothi-ophenol in the presence of 0.1 equivalents of 2-aminothiophenoxide with no change in the isomer ratio. The auxiliary was removed with trimethylaluminum, with concomitant fonnation of the lactam. After separation by crystallization, the correct diastereoisomer was converted to diltiazem in 99% ee. 

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