Mechanochemical enzymatic resolution of N-benzylated-ß3-amino esters.

The use of mechanochemistry to carry out enantioselective reactions has been explored in the last ten years with excellent results. Several chiral organocatalysts and even enzymes have proved to be resistant to milling conditions, which allows for rather efficient enantioselective transformations under ball-milling conditions. The present article reports the first example of a liquid-assisted grinding (LAG) mechanochemical enzymatic resolution of racemic ß3-amino esters employing Candida antarctica lipase B (CALB) to afford highly valuable enantioenriched N-benzylated-ß3-amino acids in good yields. Furthermore the present protocol is readily scalable.

Correction: Mechanochemical enzymatic resolution of N-benzylated-ß3-amino esters.

[This corrects the article DOI: 10.3762/bjoc.13.167.].

Asymmetric allylation of α-ketoester-derived N-benzoylhydrazones promoted by chiral sulfoxides/N-oxides Lewis bases: highly enantioselective synthesis of quaternary α-substituted α-allyl-α-amino acids.

Chiral sulfoxides/N-oxides (R)-1 and (R,R)-2 are effective chiral promoters in the enantioselective allylation of α-keto ester N-benzoylhydrazone derivatives 3a-g to generate the corresponding N-benzoylhydrazine derivatives 4a-g, with enantiomeric excesses as high as 98%. Representative hydrazine derivatives 4a-b were subsequently treated with SmI2, and the resulting amino esters 5a-b with LiOH to obtain quaternary α-substituted α-allyl α-amino acids 6a-b, whose absolute configuration was assigned as (S), with fundament on chemical correlation and electronic circular dichroism (ECD) data.

Biostable beta-amino acid PK/PBAN analogs: agonist and antagonist properties.

The pyrokinin/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a significant role in a multifunctional array of important physiological processes in insects. PK/PBAN analogs incorporating beta-amino acids were synthesized and evaluated in a pheromonotropic assay in Heliothis peltigera, a melanotropic assay in Spodoptera littoralis, a pupariation assay in Neobellieria bullata, and a hindgut contractile assay in Leucophaea maderae. Two analogs (PK-betaA-1 and PK-betaA-4) demonstrate greatly enhanced resistance to the peptidases neprilysin and angiotensin converting enzyme that are shown to degrade the natural peptides. Despite the changes to the PK core, analog PK-betaA-4 represents a biostable, non-selective agonist in all four bioassays, essentially matching the potency of a natural PK in pupariation assay. Analog PK-betaA-2 is a potent agonist in the melanotropic assay, demonstrating full efficacy at 1pmol. In some cases, the structural changes imparted to the analogs modify the physiological responses. Analog PK-betaA-3 is a non-selective agonist in all four bioassays. The analog PK-betaA-1 shows greater selectivity than parent PK peptides; it is virtually inactive in the pupariation assay and represents a biostable antagonist in the pheromonotropic and melanotropic assays, without the significant agonism of the parent hexapeptide. These analogs provide new, and in some cases, biostable tools to endocrinologists studying similarities and differences in the mechanisms of the variety of PK/PBAN mediated physiological processes. They also may provide leads in the development of PK/PBAN-based, insect-specific pest management agents.

Identification of selective and non-selective, biostable beta-amino acid agonists of recombinant insect kinin receptors from the southern cattle tick Boophilus microplus and mosquito Aedes aegypti.

The multifunctional arthropod 'insect kinins' share the evolutionarily conserved C-terminal pentapeptide motif Phe-X1-X2-Trp-Gly-NH2, where X1=His, Asn, Ser, or Tyr and X2=Ser, Pro, or Ala. Eight different analogs of the insect kinin C-terminal pentapeptide active core in which the critical residues Phe 1, Pro3 and Trp 4 are replaced with beta 3-amino acid and/or their beta2-amino acid counterparts were evaluated on recombinant insect kinin receptors from the southern cattle tick, Boophilus microplus (Canestrini) and the dengue vector, the mosquito Aedes aegypti (L.). A number of these analogs previously demonstrated enhanced resistance to degradation by peptidases. Single-replacement analog beta 2 Trp 4 and double-replacement analog [beta 3 Phe 2, beta 3 Pro 3] of the insect kinins proved to be selective agonists for the tick receptor, whereas single-replacement analog beta 3 Pro 3 and double-replacement analog [beta 3 Phe, beta 3 Pro 3] were strong agonists on both mosquito and tick receptors. These biostable analogs represent new tools for arthropod endocrinologists and potential leads in the development of selective, environmentally friendly arthropod pest control agents capable of disrupting insect kinin-regulated processes.

Preparation of chiral derivatives of beta-Ala containing the alpha-phenylethyl group: useful starting materials for the asymmetric synthesis of beta-amino acids.

The use of microwave (MW) irradiation for the condensation reaction between acetophenone and alpha-phenylethylamine to prepare (R,R)-bis[alpha-phenylethyl]amine results in significantly reduced reaction times relative to the use of conventional heating. In this protocol, a secondary amine, (R,R)-bis(alpha-phenylethyl)amine is treated with acryloyl chloride to afford conjugated amide N,N-bis[(R)-alpha-phenylethyl]prop-2-enamide, (R,R)-3. 1,4-Addition of alpha-phenylethylamine to unsaturated (R,R)-3 affords propanamide N,N-Bis[(R)-alpha-phenylethyl]-3-N-[(S)-alpha-phenylethyl]amino-propanamide, (R,R,S)-4, which can be alkylated with high diastereoselectivity to give derivative N,N-Bis[(R)-alpha-phenylethyl]-3-N'-[(S)-alpha-phenylethyl]amino-propanamide, (R,R,S,S)-5. Hydrogenolysis of (R,R,S,S)-5 catalyzed by palladium hydroxide and final hydrolysis (4 N HCl) resulting in the formation of (S)-alpha-benzyl-beta-alanine, (S)-7, is facilitated by MW irradiation. The use of MW irradiation in this step prevents racemization of the desired amino acid. The present protocol constitutes one of the simplest strategies for the asymmetric synthesis of biologically relevant alpha-substituted-beta-amino acids since it takes advantage of inexpensive, commercially available beta-Ala and either (R)- or (S)-alpha-phenylethylamine as chiral auxiliary. The required time for this protocol is approximately 90 h, which can be carried out in 5 d.

Beta-amino acid analogs of an insect neuropeptide feature potent bioactivity and resistance to peptidase hydrolysis.

Insect neuropeptides of the insect kinin class share a common C-terminal pentapeptide sequence F(1)X(1)(2)X(2)(3)W(4)G(5)-NH(2) (X(2)(3) = P, S, A) and regulate such critical physiological processes as water balance and digestive enzyme release. Analogs of the insect kinin class, in which the critical residues of F(1), P(3), and W(4) were replaced with beta(3)-amino acid or their beta(2)-homo-amino acid variants, have been synthesized by the solid phase peptide strategy. The resulting single- and double-replacement analogs were evaluated in an insect diuretic assay and enzyme digestion trials. Analogs modified in the core P(3) position produce a potent and efficacious diuretic response that is not significantly different from that obtained with the endogenous achetakinin peptides. The analogs also demonstrate enhanced resistance to hydrolysis by ACE and NEP, endopeptidases that inactivate the natural insect neuropeptides. This paper describes the first instance of beta-amino acids analogs of an arthropod peptide that demonstrate significant bioactivity and resistance to peptidase degradation.