Amino Acids (2007) 32: 401–404 DOI 10.1007/s00726-006-0384-0 Printed in The Netherlands Enantiopure b 3 -amino acids-2,2-d 2 via homologation of proteinogenic a-amino acids R. Caputo and L. Longobardo Dipartimento di Chimica Organica e Biochimica, Universit a di Napoli Federico II, Napoli, Italy Received May 23, 2006 Accepted June 28, 2006 Published online September 15, 2006; # Springer-Verlag 2006 Summary. A procedure for the synthesis of enantiopure b 3 -amino acids from proteinogenic a-amino acids, developed by our group a few years ago, has been modified to enable the production of C-2 fully deuterated, C-protected b 3 -amino acids and, even more important, the synthesis of valuable deuterium labelled N(Boc)-protected chiral synthons, such as 2-aminoalcohols, 2-aminoiodides, and b 3 -amino nitriles. Keywords: b 3 -amino acids – a-amino acid homologation – C-2-dideu- terated amino acids – 2-aminoalcohols-d 2 – 2-aminoiodides-d 2 – b 3 -amino nitriles-d 2 Introduction Isotopically labelled molecules are important synthetic targets. Labelled a-amino acids bearing deuterium atoms (Lygo and Humphreys, 2002) at either a- or side-chain carbons have been used for the elucidation of several bio- synthetic pathways (Church and Young, 1998; Brandl et al., 2005) as well as for the study of reaction mechanisms based on MS and=or NMR spectrometries. Most recently, deuter- ium labelled amino acids and their derivatives have been incorporated in reagents and auxiliaries of analytical inter- est: two important classes include ICAT (Isotope Coded Affinity Tag) reagents (Gygi et al., 1999; Schrimpf et al., 2005), used for accurate quantifications of individual pro- teins within complex mixtures, and SIDA (Stable Isotope Dilution Assay) auxiliaries, for the determination of trace compounds in foodstuffs (Rufia ´n-Henares and Morales, 2006; Stark et al., 2006). Incorporation of labelled a-amino acids into peptides and proteins often helps in the assignment of spectroscopic data and in the investigation of secondary and tertiary struc- tures (Gardner and Kay, 1997; Sack et al., 2000). Considering the interesting biological properties of b- amino acids and their role in natural product biosynthesis (Seebach et al., 2004), as well as the emerging properties of b-peptide oligomers in the field of foldamer chemistry (Cheng et al., 2001; Seebach et al., 2004), deuterium labelled b-amino acids are logical synthetic targets. The simplest member in b-amino acid series is 3-amino- propanoic acid, better known as b-alanine, and several dif- ferent approaches have been so far used for its stereocon- trolled labelling, from biocatalysis to asymmetric synthesis (Basak, 1997). Other isotopically labelled b-amino acids have been used for revealing the role of the amino acidic moiety in natural product biosynthesis: they have mostly been prepared by either enzyme-mediated transformations or miscellaneous chemical methods (Sewald et al., 1995; Basak, 1997). Following our interest in the synthesis of enantiopure b 3 - amino acids 1) from proteinogenic a-amino acids, by way of an efficient and scalable multi-step procedure developed by our group a few years ago (Caputo et al., 1995a, b), we are currently involved in the exploitation of the inter- mediates of such procedure as chiral synthons (Bolognese et al., 2006). Under these circumstances, we report now a simple modification of our procedure that enables the synthesis of unprecedented C-protected C-2-dideuterated b 3 -amino acids and, possibly more significant, the produc- tion of valuable deuterium labelled N(Boc)-protected chiral synthons, like 2-aminoalcohols, 2-aminoiodides, and b 3 - amino nitriles. 1) In b-amino acids, two carbon atoms separate carboxyl function and amino group. The number(s) on b indicates which of such carbons carries the amino acid side chain.