Asymmetric Synthesis of 3-Substituted Morpholinones and Piperazinones by L-Malate-mediated Dynamic Kinetic Resolution of α-Bromo Esters

Abstract

Chiral auxiliary-mediated dynamic resolution of α-halo esters has been known as an effective method for asymmetric synthesis of α-heteroatom substituted carboxylic acid derivatives.1 While the synthetic method can achieve a useful level of stereoselectivity, it is still of interest to find novel ways to utilize the dynamic resolution for practical synthesis. We have previously reported L-malate-mediated dynamic kinetic resolution of α-bromo esters with various aryl amines for asymmetric synthesis of N-aryl substituted amino acid derivatives.2 Herein we report our results on the extension of the methodology to various alkyl amines for practical asymmetric syntheses of morpholin-2-ones and piperazin-2-ones.Initial studies on L-malate-mediated dynamic kinetic resolution were performed with α-bromo esters 1a-b and dibenzylamine (Bn 2 NH) as shown in Scheme 1. When the diastereomeric mixture (1:1) of dimethyl ester (αRS)-1a was treated with tetrabutylammonium iodide (TBAI, 1.0 equiv), diisopropylethylamine (DIEA, 1.0 equiv) and dibenzylamine (1.5 equiv) in CH 2 Cl 2 at room temperature for 24 h, the amino acid derivative (αR)-2a was produced in 76% yield with 85:15 diastereomeric ratio (dr). Also, we examined the substitution of diisopropyl ester (αRS)-1b under the same reaction condition. The reaction of 1b gave amino acid derivative (αR)-2b with a slightly higher dr of 88:12 in 73% yield. Subsequent reductive cleavage of (αR)-2b using LiAlH 4 furnished the enantioenriched N,N-dibenzyl 2-aminoalcohol (R)-3 in 77% yield with 88:12 enantiomeric ratio (er). The results imply that α-bromo carbon center is configurationally labile and α-bromo esters 1a-b are dynamically resolved under the reaction condition.A series of reactions were examined with diisopropyl ester 1b and dibenzylamine to assess the effect of solvent and temperature on yield and selectivity as shown in Table 1.

Asymmetric Synthesis of Both Diastereomers of α,α′‐disubstituted Iminodiacetic Acid Derivatives Using Stereoselective Nucleophilic Substitution of α‐Bromo Esters

“…Three different chiral alcohols known to give (α R )‐product, such as L ‐mandelate, L ‐malate and L ‐lactate have been tested for their stereocontrolling ability in dynamic kinetic resolution of α‐bromo esters . Initial studies were carried out with methyl L ‐mandelate.…”

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

“…These piperazin‐2‐ones mimic inverse γ‐turns in peptides, which play crucial roles in the secondary structures of proteins 16. Chiral piperazin‐2‐ones17 can be prepared from amino acids or other members of the chiral pool18 or by chiral‐auxiliary‐mediated alkylations19 or dynamic resolutions 20. However, most of the available methods are not capable of generating chiral α‐tertiary piperazin‐2‐ones ( 6 ; Figure 2) and there are no previous examples for preparation of this motif by catalytic enantioselective methods.…”

Racemization-Free Synthesis of Morpholinone Derivatives from α-Amino Acids

“…14 Morpholinone derivatives have also been synthesized from α-bromo esters by L-malate-mediated dynamic kinetic resolution. 15 Very recently, the synthesis of trans-selective oxomorpholinecarboxylic acid derivatives from dioxanedi-one and aromatic imines has been reported. 16 We surmised that enantiopure morpholin-2-one derivatives might be readily synthesized from N-protected chiral α-amino acids by a base-mediated cyclization reaction with a 1,2-dihaloethane (Scheme 1).…”