[31] Synthesis of carnitine precursors and related compounds

This chapter discusses the synthesis of carnitine precursors and related compounds. L-Carnitine contains a quaternary nitrogen atom which is formed biosynthetically early in the pathway. Thus several intermediates in the pathway are quaternary amines which can readily be synthesized from the commercially available parent primary amines. These intermediates include ɛ-N-trimethyl-L-lysine (from α-N-acetyl-L-lysine), γ-N-trimethylaminobutyraldehyde (from 4-aminobutyraldehyde diethyl acetal), and γ-butyrobetaine (from γ- aminobutyric acid). Other compounds of interest which are synthesized by this general method include δ-N-trimethylaminovaleric acid (from δ-aminovaleric acid) and ɛ-N-trimethylaminocaproic acid (from ɛ-aminocaproic acid). Another carnitine precursor, β-hydroxy-ɛ-N-trimethyl-L-lysine, is prepared by condensation of γ-N-trimethylaminobutyraldehyde with glycine in the presence of potassium carbonate and copper sulfate, yielding a diastereomeric mixture. Carnitine is synthesized, as a racemic mixture, by several related methods. For example, DL-carnitine is prepared by reaction of epichlorhydrin with NaCN followed by condensation with trimethylamine, and subsequent hydrolysis. Neurospora crassa (but apparently not in mammals) ɛ-N-methyl-L-lysine and ɛ-N-dimethyl-L-lysine are direct precursors of L-carnitine. The latter compound is prepared by reductive methylation of α-N-acetyl- L-lysine with formaldehyde and H2/Pd catalyst. α-Keto-ɛ-N-trimethylaminocaproic acid, a catabolic product of ɛ-N-trimethyl- L-lysine, is synthesized enzymatically by reaction of ɛ-N-trimethyl- L-lysine with commercial L-amino acid oxidase. The chapter describes the representative synthetic procedures for ɛ-N- Trimethyl-L-lysine, ɛ-N-[methyl-14C]DimethyI-L-lysine, β-Hydroxy-ɛ-N-[methyl-3H]trimethyl-L-lysine, γ-[1-14C]Butyrobetaine, and L-[methyl-3H] Carnitine.