Dynamic Asymmetric Multicomponent Resolution: Lipase-Mediated Amidation of a Double Dynamic Covalent System

Abstract

The Strecker reaction is one of the most important multicomponent reactions developed, leading to alpha-aminonitriles that are versatile substrates for many synthetic applications. In the present study, this reaction type has been applied to a double dynamic covalent resolution protocol, leading to efficient C-C- and C-N-bond generation as well as chiral discrimination. The combination of transimination with imine-cyanation enabled the dynamic exchange in more than one direction around a single stereogenic center of restricted structure. This multiple exchange process could generate a vast range of compounds from a low number of starting materials in very short time. The resulting double dynamic covalent systems, created under thermodynamic control, were subsequently coupled in a one-pot process with kinetically controlled lipase-mediated transacylation. This resulted in complete resolution of the dynamic systems, yielding the optimal N-acyl-alpha-aminonitriles for the enzyme, where the individual chemoenzymatic reactions could produce enantiomerically pure acylated N-substituted alpha-aminonitriles in good yields.

Double parallel dynamic resolution through lipase-catalyzed asymmetric transformation

“…Within this context, however, dynamic systems have generally been based on single reversible reaction formats. The principle is certainly fully amenable to interconnected reversible reactions, generating systems of considerably higher complexity, 8,[15][16][17][18] but presents a challenge with respect to their generation and control. Yet, this represents an important development since higher order systems would lead to an increased understanding of molecular complexity in general (Fig.…”

Dynamic combinatorial chemistry at the phospholipid bilayer interface

“…For example, addition of a template (a guest molecule or a biomolecule) to a DCL will result in a stabilization of those library members that bind to the template, inducing a shift in the product distribution, ideally in favour of the best binders and at the expense of the other unwanted library members. This responsiveness makes dynamic combinatorial chemistry an important tool for the discovery of new synthetic receptors [12][13][14][15][16][17][18][19][20][21] and ligands for biomolecules [22][23][24][25]. Moreover, the technique has potential for the development of catalysts by using a transition-state analogue as a template [26,27].…”

Racemase Activity of B. cepacia Lipase Leads to Dual‐Function Asymmetric Dynamic Kinetic Resolution of α‐Aminonitriles

“…[6][7][8][9][10] Surprisingly, however, only rare examples concerning secondary amines have been reported. [11][12][13][14][15][16][17] We recently addressed this deficiency and demonstrated a method for the generation and screening of dynamic N-substituted a-aminonitrile systems through kinetically controlled lipase-mediated amidation. [17] The core aaminonitrile (Strecker) structures are synthetically very versatile.…”

“…[11][12][13][14][15][16][17] We recently addressed this deficiency and demonstrated a method for the generation and screening of dynamic N-substituted a-aminonitrile systems through kinetically controlled lipase-mediated amidation. [17] The core aaminonitrile (Strecker) structures are synthetically very versatile. For example, the hydrolysis, reduction, or alkylation of the nitrile functionality leads to a multitude of building blocks.…”

“…[18] Nevertheless, the enzymatic resolution of this class of compounds has not been much explored. [17,19,20] Accordingly, the information that we gained on substrate selectivity and stereoselectivity from the screening process in our study on lipase-mediated amidation prompted us to develop a practical method for the preparation of optically active Nmethyl a-aminonitrile derivatives.…”