Lewis Acid‐Mediated Addition of Amino Acid‐Substituted α‐Allylsilanes to Aromatic Acetals

Abstract Unnatural amino acids extend the pharmacological formulator's toolkit. Strategies to prepare unnatural amino acid derivatives using Lewis acid‐activated allylsilane reactions are few. In this regard, we examined the utility of allylsilanes bearing an amino acid substituent in the reaction. Diastereoselective addition of methyl 2‐( N ‐PG‐amino)‐3‐(trimethylsilyl)pent‐4‐enoate and methyl ( E )‐2‐( N ‐PG‐amino)‐3‐(trimethylsilyl)hex‐4‐enoate (PG=protecting group), 2 and 13 , respectively, to aromatic acetals in the presence of Lewis acids is described. Of those examined, TiCl 4 was found to be the most effective Lewis acid for promoting the addition. At least 1 equiv. of TiCl 4 was required to achieve high yields, whereas 2 equiv. of BF 3 ⋅OEt 2 were required for comparable outcomes. Excellent selectivity (>99% syn / anti ) and high yield (up to 89%) were obtained with halo‐substituted aromatic acetals, while more electron‐rich electrophiles led to both lower yields and diastereoselectivities.