Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids

Abstract

Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, (S)-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes.

Nigritanine as a New Potential Antimicrobial Alkaloid for the Treatment of Staphylococcus aureus-Induced Infections

“…Since 1940, large-scale efforts have been made to evaluate the antibacterial effects of naturally occurring alkaloids. Several potent monomer and dimer alkaloids were identified, and synthetic modifications were investigated to improve their biological activity [8,9,10,11]. However, a tremendously wide discrepancy between their historical significance and their occurrence in modern drug development exists, and no alkaloids are available in the market as antibacterial drugs [12].…”

A unique high-diversity natural product collection as a reservoir of new therapeutic leads

“…With the aim of overcoming these issues, numerous attempts at synthesis have been made in order to easily access enantiomerically pure alkaloids. 108 In nature, the biosynthesis route to benzylisoquinoline alkaloids (BIAs), namely morphine, codeine, berberine, and papaverine, is a Pictet Spengler (P-S) cyclization, the precursor of which is a chiral tetrahydroisoquinoline (THIQ), namely S-norcoclaurine (NC). 109 Indeed, the enzymatic pathways of BIAs share a common route, in which the first committed step consists of a formal P-S condensation of 4-hydroxyphenylacetaldehyde (4-HPAA) with dopamine, stereospecifically catalyzed by the enzyme norcoclaurine synthase (NCS).…”

“…Therefore the analysis of mass fragmentation of 73 indicated the presence of truxinic acid, and along with NMR characterization assigned the structure of a dimer of 72 to 73. 108 The analytical structural elucidation of 73 was supported by two different treatments. A first alkaline hydrolysis (NaOH 2 N) yielded prenylagmatine (74), 3-methyl-but-2-enyl urea (78), and a crystalline product (73a) (Scheme 4).…”

Biocatalyzed C−C Bond Formation for the Production of Alkaloids

“…Additionally, a handful of new enzymes carrying the Pictet‐Spengler reaction such as salsolinol synthase, McbB from Marinactinospora thermotolerans , deacetylisoipecoside synthase, and deacetylipecoside synthase, two novel NCSs from Argemone mexicana (AmNCS1, AmNCS2) and one new NCS from Corydalis saxicola have recently been identified. The development in the understanding of these enzymes will further enrich the biocatalytic synthesis of a myriad of alkaloids with diverse pharmaceutical functions ,…”