The biosynthesis of ephedrine

Abstract

It is shown by 13C nuclear magnetic resonance spectroscopy that the labelled C2 fragment of [2,3-13C2]pyruvic acid is transferred intact into the C-methyl group and the adjacent carbon atom of the Ephedra alkaloids, norephedrine, ephedrine, norpseudoephedrine, and pseudoephedrine, in growing plants of Ephedragerardiana. This finding serves to identify pyruvate as the elusive precursor of the aliphatic C2 terminus of the skeleton of the alkaloids. In earlier experiments with C-labelled substrates, label from [3-14C]pyruvic acid was incorporated mainly, but not exclusively, into the C-methyl group of ephedrine, and label from [2-14C]pyruvate was incorporated similarly into the carbon atom adjacent to the C-methyl group. A C6–C1 unit related to benzaldehyde or benzoic acid has long been known to generate the benzylic fragment of the carbon skeleton of the Ephedra alkaloids. It is likely that the carbon skeleton of ephedrine is generated from pyruvate and either benzaldehyde or benzoic acid, by a reaction analogous to the formation of acetoin or diacetyl from pyruvate and acetaldehyde or acetic acid, respectively. Keywords: biosynthesis of ephedrine, Ephedra alkaloids, 13C NMR spectra, ephedrine, biosynthesis of pyruvic acid, incorporation into ephedrine13C NMR spectra.

Expressed sequence tag analysis of khat (Catha edulis) provides a putative molecular biochemical basis for the biosynthesis of phenylpropylamino alkaloids

“…Together, these phenylalkylamino alkaloids comprise a unique class of compounds derived from L-phenylalanine (Phe) ( Figure 1 ). Early pulse-labeling studies using Catha edulis ( Leete, 1958 ) and Ephedra distachya ( Yamasaki et al , 1969 , 1973 ) established that only the C 6 -C 1 component of ephedrine alkaloids is derived from Phe, whereas later studies suggested that the C 2 -C 3 unit derives from pyruvic acid ( Grue-Sørensen and Spenser, 1988 , 1989 ). A related study suggested that Phe-derived benzoic acid is an intermediate in the formation of phenylpropylamino alkaloids ( Grue-Sørensen and Spenser, 1994 ) although the involvement of benzoyl-CoA ( Krizevski et al , 2010 ) or benzaldehyde cannot be ruled out.…”

Ephedrine and Pseudoephedrine (C6–C1 Part Derived from l-Phenylalanine and Nitrogen Derived by Transamination)

“…However, Shibata et al [16] showed by biosynthetic experiments with Ephedra distachya (no incorporation of 2-14 C(AE)-phenylalanine into (À)-ephedrine) that the skeletal alkaloidal N is not supplied by L-phenylalanine, as suggested by Leete Fig. 20.9 Industrial preparation of (À)-ephedrine [13,14] 20.8 Biosynthesis of Ephedra Alkaloidscomes from transamination after the basic carbon connectivity is over [17,18]. Thus, the formation of the skeletal structure of the Ephedra alkaloids is outlined below.…”

“…The origin of the remaining C 2 unit of the Ephedra alkaloid skeleton remained obscure for >30 years till Spenser et al identified the CH 3 CO moiety of pyruvic acid as its source in the four alkaloids in E. geradiana sikkimensis [17]. Biosynthetic experiments done by them by feeding the growing plants with suitable 13 C labeled precursors [17,18] led to the following conclusion. Benzoic acid, rather than benzaldehyde, was found to be incorporated.…”

Employing Two‐stage Derivatisation and GC–MS to Assay for Cathine and Related Stimulant Alkaloids across the Celastraceae

“…Grue‐Sørensen and Spenser, ; Caveney et al ., ) have found alkaloids in species closely related to the original taxon from which an alkaloid was initially described. For example, ephedrine‐type alkaloids were initially described from Ephedra distachya (Grue‐Sørensen and Spenser, ) and subsequently described from more Ephedra species as assays expanded to broader sampling within the genus (Grue‐Sørensen and Spenser, ; Caveney et al ., ). The phylogenetic reconstruction of Simmons et al .…”