Following an ISES Lead:  The First Examples of Asymmetric Ni(0)-Mediated Allylic Amination

Abstract

An ISES (in situ enzymatic screening) lead pointed to conditions (PMP N-protecting group, Ni(cod)(2) catalyst precursor) under which chiral, bidentate phosphines could promote Ni(0)-mediated allylic amination. Therefore, bidentate phosphines bearing central, axial, and planar chirality were examined with two model substrates of interest for PLP-enzyme inhibitor synthesis. In the best case, with (R)-MeO-BIPHEP, vinylglycinol derivative 2 was obtained in 75% ee (97% ee, one recrystallization) from 1. Further manipulation provided a Ni(0)-mediated entry into l-vinylglycine. [reaction: see text]

The In Situ Enzymatic Screening (ISES) Approach to Reaction Discovery and Catalyst Identification

“…The first iteration of ISES was developed to explore catalytic combinations for a transition metal-mediated intramolecular amination (Berkowitz et al, 2002; Berkowitz and Maiti, 2004; Berkowitz et al, 2004) reaction upon an allylic ethyl carbonate substrate (Figure 1, Basic Protocol 1). Turnover of such substrates is expected to proceed via formation of a π-allyl or σ-allyl-metal intermediate with release of the ethyl carbonate leaving group in each catalytic cycle.…”

“…Indeed, ISES was used to identify the combination of p-methoxyphenyl (PMP) protection on the nucleophilic nitrogen, Ni(cod) 2 and bidentate phosphine ligands were found to be optimal based solely on iterative ISES screening (Berkowitz et al, 2002). This ultimately led to the first examples of asymmetric Ni(0)-mediated allylic amination chemistry and to the first asymmetric base metal-mediated synthesis of L-vinylglycine (Berkowitz and Maiti, 2004; Berkowitz et al, 2004). …”

Electrochemistry and complexation of Josiphos ligands

“…1). Josiphos ligands provide chiral catalysts that display two types of chirality, planar and central [5,6]. The two types of chirality have been found to be advantageous in a number of catalytic applications such as asymmetric allylic aminations and the asymmetric reduction of b-bdisubstituted enoates [5].…”

Combinatorial Catalysis Employing a Visible Enzymatic Beacon in Real Time: Synthetically Versatile (Pseudo)Halometalation/Carbocyclizations

“…A chromophore may be installed into the substrate [13] or product [14] of the reaction under study. Alternatively, one can exploit chromophores inherent in proteins [15] or enzyme-associated reactions, [16] and use these sensors to report back on product formation and composition.Our group has developed an in situ enzymatic screening (ISES) approach whereby an organometallic reaction under study is coupled to an enzymatic reporting reaction in real time.[17] This screening method led to the discovery of the first asymmetric allylic amination with nickel(0) [18] and to the identification of novel salen [salen = N,N'-bis(salicylidene)-ethylenediamine)] ligands with promise for asymmetric synthesis. …”