Chemoenzymatic Approach to (S)‐1,2,3,4‐Tetrahydroisoquinoline Carboxylic Acids Employing D‐Amino Acid Oxidase

Abstract

Optically pure 1,2,3,4‐tetrahydroisoquinoline carboxylic acids constitute an important class of building blocks for the synthesis of natural products and synthetic pharmaceuticals. However, redox deracemization of racemic 1,2,3,4‐tetrahydroisoquinoline carboxylic acids as an attractive method is still challenging for the lack of suitable oxidoreductases. Herein, a D‐amino acid oxidase from Fusarium solani M‐0718 (FsDAAO) with broad substrate scope and excellent enantioselectivity was exploited through genome mining, and applied for the kinetic resolution of a number of racemic 1‐ and 3‐carboxyl substituted tetrahydroisoquinolines to yield the corresponding (S)‐enantiomers with excellent enantiomeric excess (ee) values (up to >99%). By using FsDAAO in combination with ammonia‐borane in one pot, deracemization of these racemic carboxyl‐substituted tetrahydroisoquinolines was achieved with conversions up to >98% and >99% ee. Preparative‐scale deracemization of racemic 1,2,3,4‐tetrahydroisoquinoline‐1‐carboxylic acid and 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid was also demonstrated with good isolated yields (82% and 73%, respectively) and ee>99%. Our study provides an effective method for the synthesis of enantiomeric pure 1,2,3,4‐tetrahydroisoquinoline carboxylic acids. This method is expected to provide access to chiral carboxyl‐substituted 1,2,3,4‐tetrahydroquinolines and 1,2,3,4‐tetrahydro‐ß‐carbolines.

Recent trends in biocatalysis

“…and yield (Scheme 2G). 273 This is similar to a previously developed MAO-artificial transferhydrogenase system for deracemization of simple THIQs. 274 Another very famous natural THIQ alkaloid, Colchicine, is a potent microtubule inhibitor used for the treatment of inflammatory disorders as well as a research tool for many years.…”

“…and yield ( Scheme 2G ). 273 This is similar to a previously developed MAO-artificial transferhydrogenase system for deracemization of simple THIQs. 274 …”

“…For the 1- and 3-carboxyl-THIQs, a d -amino acid oxidase (DAAO) was successfully employed for deracemization. 272 Furthermore, by combining DAAO-catalysed oxidation and a reductase (DpkA)-mediated reduction, the Wu group developed a fully biocatalytic deracemization process to produce ( S )-1-carboxyl-THIQs in excellent enantiomeric excess (e.e.) and yield ( Scheme 2G ).…”

Using enzyme cascades in biocatalysis: Highlight on transaminases and carboxylic acid reductases

“…An excellent recent example of this is the deracemization of tetrahydroisoquinolines [34]. This one-pot enzymatic cascade improved on a previously described chemoenzymatic reaction [35]. Triangular cascades involve the conversion of an initial substrate to an intermediate that then combines with the ini tial substrate in a later step (with an example in [36]).…”

Diastereoselective Synthesis of (–)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid via Morpholinone Derivatives

“…THIQs containing natural and synthetic molecules have been qualified as ‘privileged scaffolds’ to identify, design, and synthesize novel biologically active derivatives of interest in drug development, from anti-inflammatory, anti-viral, anti-fungal, or anti-cancer compounds to Parkinson’s disease treatment [ 4 , 5 , 6 , 7 ]. 1,2,3,4-Tetrahydroisoquinoline carboxylic acids in their optically pure form are important building blocks for the synthesis of natural products and synthetic pharmaceuticals, and are currently subject to growing interest [ 8 , 9 , 10 , 11 , 12 ]. Recently, a series of optically active substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives ( A ) ( Figure 1 ) such as esters and amides have been synthesized and evaluated as potent influenza virus polymeraze acidic (PA) endonuclease domain inhibitors [ 10 ].…”