Synthesis of α-Amino Acids Based on Chiral Tricycloiminolactone Derived from Natural (+)-Camphor

Abstract

Amino acids are one of the most important classes of the building blocks of life: they are the structural subunits of proteins, peptides, and many secondary metabolites. In addition to the 20 α-amino acids that constitute the backbone of proteins, hundreds of other natural α-amino acids have been discovered either in free form or as components in natural products. The difference between these molecules is the substituents at the chiral carbon situated between the amino and carboxyl moieties; this carbon (and any atom along a chain attached to it) is thus an important synthetic target. Because tailor-made α-amino acids are increasingly popular in biochemistry and organic synthesis, further refinement in synthetic methods to generate both natural (L-configuration) and unnatural (D-configuration) amino acids is a very active area of current research. In this Account, we examine the tricycloiminolactones, which are versatile glycine equivalents derived from natural camphor. We have developed the tricycloiminolactones in our laboratory and used them in the synthesis of several kinds of enantiopure α-amino acids. As nucleophiles, enolated tricycloiminolactones were shown to successfully participate in alkylations, Aldol reactions, Michael additions, and Mannich reactions. These reactions all gave excellent stereoselectivities and high yields. Simple conversion of the products offered α-alkyl-α-amino acids, α,α-dialkyl-α-amino acids, β-hydroxy-α-amino acids, α,γ-diamino acids, and α,β-diamino acids. One particular advantage is that the same electrophile can react with two chiral templates in the same way, thus affording access to both enantiomeric amino acids. In other words, some natural (L-configuration) α-amino acids and their unnatural (D-configuration) counterparts can be prepared very conveniently. The relation between substrate structures and product stereoconformations derived from our investigations serves as a convenient guide in the synthesis of useful chiral amino acids. In addition, highly stereoselective 1,3-diploar cycloadditions between alkenes and chiral nitrones derived from tricycloiminolactones provide a potential method for the synthesis of γ-hydroxy-α-amino acids. We also discuss applications of our methods in the synthesis of complex natural products, including conagenin, polyoxamic acid, lactacystin, and sphingofungin F. The preparation of some clinically important drug molecules, such as thiaphenicol, florfenicol, and chloramphenicol, was greatly simplified with our methods. The tricycloiminolactones offer a number of advantages in the synthesis of both natural and unnatural α-amino acids and provide many useful building blocks in the synthetic pursuit of complex molecules.