Synthesis Of β-Amino Acid Derivatives Research Articles

Advances in Transition-Metal Catalysis and Organocatalysis Approaches towards Asymmetric Synthesis of β-Amino Acid Derivatives

AbstractThe stereoselective synthesis of β-amino acids has attracted major attention among the synthetic community in recent years. This review provides an overview of the important advances in chiral β-amino acid synthesis over the past decade. It covers the development of enantioselective methods using transition-metal complexes or organocatalysts, mainly including catalytic asymmetric hydrogenation, the Mannich reaction, multicomponent reactions of diazo compounds, and conjugate addition. Additionally, the asymmetric synthesis of optically active β-amino acids by other approaches are also summarized.1 Introduction2 Strategies towards the Asymmetric Synthesis of β-Amino Acids2.1 Hydrogenation2.2 Mannich Reaction2.3 Conjugate Addition2.4 Multicomponent Reactions2.5 Miscellaneous2.5.1 Synthesis of β-Amino Acids from Chiral Amines2.5.2 Synthesis of β-Amino Acids from Isoxazolidinones2.5.3 Synthesis of β-Amino Acids by Other Methodologies3 Summary and Outlook

Synthesis of β-Amino Acid Derivatives via Enantioselective Lewis Base Catalyzed N-Allylation of Halogenated Amides with Morita-Baylis-Hillman Carbonates.

Trifluoro- and trichloroacetamides serving as pronucleophiles undergo enantioselective Lewis base catalyzed N-allylation with Morita-Baylis-Hillman carbonates to produce enantioenriched β-amino acid derivatives. The reactions proceed as a kinetic resolution to give the allylation products and the remaining carbonates in good yields and high enantioselectivity. The obtained products are amenable to diastereoselective derivatization to produce a library of spiro-isoxazoline lactams.

Synthesis of β-amino acid derivatives via photoredox-catalyzed radical cross–coupling of anilines with diazo compounds

A photoredox-catalyzed radical cross–coupling protocol for the synthesis of β-amino acid derivatives has been developed. This atom-economic protocol enables the synthesis of a range of β-amino acid esters in moderate to excellent yields.

Photochemical single-step synthesis of β-amino acid derivatives from alkenes and (hetero)arenes

β-Amino acids are frequently found as important components in numerous biologically active molecules, drugs and natural products. In particular, they are broadly utilized in the construction of bioactive peptides and peptidomimetics, thanks to their increased metabolic stability. Despite the number of methodologies established for the preparation of β-amino acid derivatives, the majority of these methods require metal-mediated multistep manipulations of prefunctionalized substrates. Here we disclose a metal-free, energy-transfer enabled highly regioselective intermolecular aminocarboxylation reaction for the single-step installation of both amine and ester functionalities into alkenes or (hetero)arenes. A bifunctional oxime oxalate ester was developed to simultaneously generate C-centred ester and N-centred iminyl radicals. This mild method features a remarkably broad substrate scope (up to 140 examples) and excellent tolerance of sensitive functional groups, and substrates that range from the simplest ethylene to complex (hetero)arenes can participate in the reaction, thus offering a general and practical access to β-amino acid derivatives.

Evaluation of N-aryl-β-alanine derivatives as anticancer agents in triple-negative breast cancer and glioblastoma in vitro models

Synthesis of β-amino acid derivatives containing hydrazone and azole moieties is described. For this purpose, the appropriate hydrazide was treated with aromatic aldehydes, ketones and phenyl iso(thio)cyanates to obtain the desired outcome. The synthesized target compounds were evaluated for their anticancer properties. The assay displayed 3,3′-((2,6-diethylphenyl)azanediyl)bis(N′-(benzylidene)propanehydrazide) to possess the convincing anticancer effect against triple-negative breast cancer cells in vitro. To further study the anticancer properties of compounds containing a hydrazone moiety in breast cancer, series of previously and newly prepared dihydrazones were investigated. It was determined that derivatives with the bis(N′-(4-bromobenzylidene) fragment in the structure are exclusively cytotoxic to cancer cells. The most active compounds against both cell lines were those containing electron withdrawing 4-BrPh or 4-ClPh moieties, together with either chlorine, bromine or iodine groups in para position of phenyl ring. Selected two representative compounds showed migrastatic activity in MDA-MB-231 cell line, where both of them reduced the growth of breast cancer and glioblastoma cell 3D cultures and inhibited cell colony formation. 2009 Elsevier Ltd. All rights reserved.

Nickel-Catalyzed Synthesis of β-Amino Acid Derivatives

Nickel-Catalyzed Synthesis of β-Amino Acid Derivatives

Cu-Catalyzed Ligand-Controlled Synthesis of β-Amino Acid Derivatives

Cu-Catalyzed Ligand-Controlled Synthesis of β-Amino Acid Derivatives

Enantioselective Synthesis of β-Amino Acid Derivatives Enabled by Ligand-Controlled Reversal of Hydrocupration Regiochemistry.

A Cu-catalyzed enantioselective hydroamination of α,β-unsaturated carbonyl compounds for the synthesis of β-amino acid derivatives was achieved through ligand-controlled reversal of the hydrocupration regioselectivity. While the hydrocupration of α,β-unsaturated carbonyl compounds to form α-cuprated species has been extensively investigated, we report herein that, in the presence of an appropriate ancillary chiral ligand, the opposite regiochemistry can be observed for cinnamic acid derivatives, leading to the delivery of the copper to the β-position. This copper can react with an electrophilic aminating reagent, 1,2-benzisoxazole, to provide enantioenriched β-amino acid derivatives, which are important building blocks for the synthesis of natural products and bioactive small molecules.

Synthesis of β-amino acid derivatives and their inhibitory profiles against some metabolic enzymes.

Sulfamate and its derivatives have a range of biological activities. One-pot cyclocondensation of alkenes (1a-i) with chlorosulfonyl isocyanate generates β-lactams. β-Amino acid derivatives (2a-i) from β-lactams were synthesized. Then, these highly reactive compounds were opened with MeOH to produce the corresponding sulfamate derivatives in good yields. The inhibitory effects of the novel sulfamate derivatives were tested on human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). Novel sulfamate derivatives showed Ki values in the range of 23.81-42.97 nM against hCA I, 8.95-52.23 nM against hCA II, 8.10-45.51 nM against AChE, 23.16-81.84 nM against BChE, and 14.02-48.68 nM against α-Gly. As a result, the novel sulfamate derivatives had potent inhibitory effects against both isoenzymes. Overall, due to the inhibitory effects of the novel sulfamate derivatives on the tested metabolic enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, epilepsy, leukemia, Alzheimer's disease, and type 2 diabetes mellitus, which are associated with high enzymatic activity of the indicated metabolic enzymes.

Stereoselective Synthesis of β-Amino Acid Derivatives by Asymmetric Mannich Reaction in Flow

Abstract A continuous flow synthesis of β-amino acid derivatives has been demonstrated using an asymmetric Mannich reaction. An enolate of tert-butyl acetate was successfully prepared in 10 s at room temperature in a flow reactor, and the desired β-amino acid derivatives were stereoselectively obtained within a short residence time (40 s) in moderate-to-good yields. Sequential N-alkylation of the Mannich product in the flow reactor was also achieved in the presence of DMPU that provided N-alkylated β-amino acid derivatives in good yields.

Enantioselective synthesis of β-amino acid derivatives via nickel-promoted regioselective carboxylation of ynamides and rhodium-catalyzed asymmetric hydrogenation.

We succeeded in the development of a new method for enantioselective synthesis of α-substituted-β-amino acid derivatives. Thus, nickel(0)-promoted carboxylation of ynamide gave the α-substituted-β-aminoacrylate derivative in a highly regioselective manner. Then, rhodium-catalyzed asymmetric hydrogenation of the α-substituted β-aminoacrylate produced the corresponding α-substituted β-amino acid derivative as an optically active form.

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. 6Li and 15N NMR spectroscopic studies of doubly labelled 6lithium (S)-15N-benzyl-15N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C2-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.

ChemInform Abstract: Monoterpene‐Based Chiral β‐Amino Acid Derivatives Prepared from Natural Sources: Syntheses and Applications

AbstractReview: 46 refs.

Monoterpene-based chiral β-amino acid derivatives prepared from natural sources: syntheses and applications

Natural monoterpenes have proved to be good starting materials for the synthesis of β-amino acid derivatives. In the past decade, a number of well-known synthetic procedures have been applied for the preparation of monoterpene-based β-amino acid derivatives, e.g. from β-lactams via the 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to commercial or readily available monoterpenes [e.g. (+)- and (-)-α- or δ-pinene, (+)-3- and 2-carene, (+)- and (-)-apopinene], the conjugate addition of amides to monoterpene-based α,β-unsaturated esters or the transformations of (-)-cis-pinonoic acid prepared by the oxidative cleavage of (+)- and (-)-verbenone. β-Amino acid derivatives are excellent building blocks for versatile transformations, e.g. multicomponent reactions resulting in β-lactams, syntheses of 1,3-heterocycles and diaminopyrimidine derivatives or the formation of peptides containing an H12 helix. 1,3-Amino alcohol derivatives prepared from β-amino esters have been applied as chiral catalysts in enantioselective transformations. Several of these compounds are of noteworthy pharmacological importance, such as tyrosine kinase Axl inhibitor diaminopyrimidine-coupled β-aminocarboxamides, MDR inhibitor thiourea derivatives of β-amino esters or 2-imino-1,3-oxazines, which exhibit marked growth inhibitory activity on multiple cancer cell lines. The present review summarizes recent developments relating to the syntheses, applications and pharmaceutical importance of monoterpene-based β-amino acids and their derivatives.

Synthesis of β-Amino Acid Derivatives via Copper-Catalyzed Asymmetric 1,4-Reduction of β-(Acylamino)acrylates

A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or (Z)-substrates.

ChemInform Abstract: Highly Efficient Asymmetric Synthesis of β-Amino Acid Derivatives via Rhodium-Catalyzed Hydrogenation of β-(Acylamino)acrylates.

ChemInform Abstract: Highly Efficient Asymmetric Synthesis of β-Amino Acid Derivatives via Rhodium-Catalyzed Hydrogenation of β-(Acylamino)acrylates.

ChemInform Abstract: A New Method for the Synthesis of β-Amino Acid Derivatives and β-Lactams. Reaction of N-Alkoxycarbonyl-1-methoxyamines with Esters.

The reaction of N-alkoxycarbonyl-1-methoxyamines with esters is an alternative to the reaction of imines with esters for the synthesis of β-amino acid derivatives. In this reaction, N-alkoxycarbonyl-1-methoxyamines corresponding to unstable imines can also be employed. Although anti adducts were obtained preferentially in the absence of Ti complexes, the diastereoselectivity of this reaction was reversed by the addition of Ti(OPr-i)4. The obtained adducts were transformed to the corresponding β-lactams.

Reactions of Morita-Baylis-Hillman Acetates with Huisgen Zwitterions: A Novel Strategy for the Synthesis of β-Amino Acid Derivatives

The reaction of Huisgen Zwitterion with Morita―Baylis― Hillman acetates afforded β-amino acid derivatives.

Diastereoselective synthesis of β-amino acid derivatives from dihydropyridones

A new method for the diastereoselective preparation of stereoisomeric 2,3-disubstituted β-amino acids is presented. It is based on trans- and cis-2,3-disubstituted dihydropyridones, which were derived from 2-monosubstituted N-acyl dihydropyridone derivatives. Alkylation of the enolates of 2-substituted dihydropyridones gave trans-2,3-disubstituted dihydropyridones with high diastereoselectivities. Inversion of the stereocenter at C-3 of the dihydropyridone nucleus by a deprotonation/reprotonation sequence yielded the stereoisomeric cis-2,3-disubstituted dihydropyridones in high yields and diastereoselectivities. Following removal of the N-acyl protective group, oxidative degradation of the resulting cis- or trans-2,3-disusbtituted dihydropyridones, respectively, by sodium periodate led to the corresponding diastereomeric β-amino acids.

Chemoselective synthesis of β-amino acid derivatives by hydroamination of activated olefins using AlSBA-15 catalyst prepared by post-synthetic treatment

β-Amino acid derivatives have a wide variety of applications viz. in the synthesis of peptide analogues, precursor for amino alcohols, optically active amino acids, lactums and diamines. Chemoselective anti-Markovnikov hydroamination reaction of activated olefins was effectively used to synthesize β-amino acid derivatives using AlSBA-15 and AlMCM-41 catalysts. These catalysts with different Si/Al ratios were synthesized by isomorphous substitution of aluminium into the framework of SBA-15, which induces the Brönsted and Lewis acid sites. The structural integrity of the catalysts was established by characterizing with XRD, N 2-sorption, TEM, NH 3-TPD, 27Al MAS NMR and 29Si MAS NMR techniques. Hydroamination of ethyl acrylate with aniline was used as a test reaction, which gave N-[2-(ethoxycarbonyl)ethyl]aniline with high selectivity. The performance of AlSBA-15 catalyst was also determined with different acrylates and amines to know the general applicability of the catalyst in hydroamination reactions.