Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

Studies on the Mass Spectra of N‐Aryl α,β‐Unsaturated γ‐Lactams

The mass spectra of a series of N‐aryl α,β‐unsaturated γ‐lactams were studied. Besides the molecular ion, the three characteristic fragments such as [M⁺‐29], [M⁺‐55], and [M⁺‐82] were commonly found in a series of N‐Aryl α,β‐unsaturated γ‐lactams in EI/MS. Further more the mechanism for the interpretation of these fragments is also de scribed.     

Tandem IBX‐Promoted Primary Alcohol Oxidation/Opening of Intermediate β,γ‐Diolcarbonate Aldehydes to (E)‐γ‐Hydroxy‐α,β‐enals

A tandem IBX‐promoted oxidation of primary alcohol to aldehyde and opening of intermediate β,γ‐diolcarbonate aldehyde to (E)‐γ‐hydroxy‐α,β‐enal has been developed. Remarkably, the carbonate opening delivered exclusively (E)‐olefin and no over‐oxidation of γ‐hydroxy was observed. The method developed has been extended to complete the stereoselective total synthesis of both (S)‐ and (R)‐coriolides and d ‐xylo‐ and d ‐arabino‐C‐20 guggultetrols.     

Tetramethyl‐m‐benziporphodimethene and Isomeric α,β‐Unsaturated γ‐Lactam Embedded N‐Confused Tetramethyl‐m‐benziporphodimethenes

The condensation reaction of α,α′‐dihydroxy‐1,3‐diisopropylbenzene, pyrrole, and an aldehyde leads to the formation of tetramethyl‐m‐benziporphodimethene and outer α‐pyrrolic carbon oxygenated N‐confused tetramethyl‐m‐benziporphodimethenes containing a γ‐lactam ring in the macrocycle. Two isomers with the carbonyl group of the lactam ring either close to (O‐Up) or away from (O‐Down) the neighboring sp³ meso carbon were synthesized and characterized. The single crystal X‐ray diffraction analysis on the regular and γ‐lactam containing tetramethyl‐m‐benziporphodimethenes showed highly distorted macrocycles for all compounds. For O‐Up and O‐Down isomers, dimeric structures, assembling by intermolecular hydrogen‐bonding interactions through lactam rings, were observed in the solid state. Fitting the concentration dependent chemical shifts of the outer NH proton using the non‐linear regression method give a maximum association constant of 108.9 M ^?1 for the meso 4‐methylcarboxyphenyl substituted O‐Down isomer. The DFT calculations concluded that the O‐Up isomer is energetically more stable, and the keto form is more stable than the enol form.     

Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

Base‐Catalyzed Highly Stereoselective Conversion of γ‐Hydroxy‐α,β‐acetylenic Esters to γ‐Acetoxy Dienoates

A convenient route with high stereo control to γ‐acetoxy dienoates is provided by the reaction of methyl propiolate with aldehydes in the presence of ZnEt₂ and N‐methylimidazole at room temperature, followed by the catalytic conversion of the resulting γ‐hydroxy‐α,β‐acetylenic esters with p‐N,N‐dimethylaminopyridine (DMAP) in acetic anhydride (see scheme).

     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

A Flexible Approach to the γ－Amino－β－hydroxy Acid Moiety of Hapalosin

A flexible approach to ethyl (3R,4S)-N-Boc-4-amino-3-hydroxy-5-phenylpentanoate (N-Boc-AHPPA-OEt), the γ-amino-β-hydroxy acid moiety of hapalosin is described. The synthetic method features a ring-opening ethanolysis of an activated N-Boc-lactam, which is obtained via a diastereoselective reductive-alkylation of (R)-malimide derivative. The flexibility of the method resides in the introduction of the alkyl side chain by Grignard reagent addition.     

PPh3⋅HBr‐DMSO Mediated Expedient Synthesis of γ‐Substituted β,γ‐Unsaturated α‐Ketomethylthioesters and α‐Bromo Enals: Application to the Synthesis of 2‐Methylsulfanyl‐3(2 H)‐furanones

An efficient chemoselective general procedure for the synthesis of γ‐substituted β,γ‐unsaturated α‐ketomethylthioesters from α,β‐unsaturated ketones has been achieved through an unprecedented PPh₃?HBr‐DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of α‐bromoenals from enals. Furthermore, AuCl₃‐catalyzed efficient access to 3(2H)‐furanones from the above intermediates under extremely mild conditions are described.     

Spectroscopic and thermal characterization of the host–guest interactions between α‐, β‐ and γ‐cyclodextrins and vanadocene dichloride

Host–guest interactions between α‐, β‐ and γ‐cyclodextrins and vanadocene dichloride (Cp₂VCl₂) have been investigated by a combination of thermogravimetric analysis, differential scanning calorimetry, powder X‐ray diffraction and solid‐state and solution electron paramagnetic resonance (EPR) spectroscopy. The solid‐state results demonstrated that only β‐ and γ‐cyclodextrins form 1:1 inclusion complexes, while α‐cyclodextrin does not form an inclusion complex with Cp₂VCl₂. The β‐ and γ‐CD–Cp₂VCl₂ inclusion complexes exhibited anisotropic electron‐⁵¹V (I = 7/2) hyperfine coupling constants whereas the α‐CD–Cp₂VCl₂ system showed only an asymmetric peak with no anisotropic hyperfine constant. On the other hand, solution EPR spectroscopy showed that α‐cyclodextrin (α‐CD) may be involved in weak host–guest interactions in equilibrium with free vanadocene species. Copyright © 2008 John Wiley & Sons, Ltd.     

Towards Truly Sustainable Polymers: A Metal‐Free Recyclable Polyester from Biorenewable Non‐Strained γ‐Butyrolactone

The first effective organopolymerization of the biorenewable “non‐polymerizable” γ‐butyrolactone (γ‐BL) to a high‐molecular‐weight metal‐free recyclable polyester is reported. The superbase tert‐Bu‐P₄ is found to directly initiate this polymerization through deprotonation of γ‐BL to generate reactive enolate species. When combined with a suitable alcohol, the tert‐Bu‐P₄‐based system rapidly converts γ‐BL into polyesters with high monomer conversions (up to 90 %), high molecular weights (M_n up to 26.7 kg mol^?1), and complete recyclability (quantitative γ‐BL recovery).     

Metal‐Catalyzed Cyclization of β‐ and γ‐Allenols Derived from D‐Glyceraldehyde—Synthesis of Enantiopure Dihydropyrans and Tetrahydrooxepines: An Experimental and Theoretical Study

Regiocontrolled metal‐catalyzed preparations of enantiopure dihydropyrans and tetrahydrooxepines have been synthesized starting from β‐ and γ‐allenols derived from D ‐glyceraldehyde. The Pd^II‐catalyzed cyclizative coupling reactions of β‐allenols 1 a and 1 b with allyl bromide effectively afforded enantiopure tetrafunctionalized dihydropyrans through a 6‐endo oxycyclization protocol, whereas the gold‐, platinum‐, and palladium‐mediated heterocyclization of γ‐allenol 2 furnished tetrahydrooxepines 13 – 16 through regioselective 7‐endo‐trig oxycyclization reactions. Moreover, density functional calculations were performed to predict the regioselectivity of the γ‐allenol cycloetherification to tetrahydrooxepines on the basis of both the tether nature and characteristics of the metals, and to gain an insight into the mechanism of the oxycyclization reactions.     

Catalytic Enantioselective γ‐Selective Additions of 2‐Allylazaarenes to Activated Ketones

Reported herein is the first example of 2‐allylazaarenes in asymmetric catalysis. Highly γ‐selective allylation was demonstrated for activated ketones, including isatins and trifluoromethyl ketones. In the presence of either an amino‐acid‐based tertiary amine or quaternary ammonium salt catalyst, two series of tertiary hydroxy‐containing moieties were installed at the remote δ‐position of azaarenes in good chemical yields, excellent enantioselectivities, and E /Z ratios. The success of current γ‐selective reactions should provide inspiration for expansion to other allylazaarene derivatives and would open up new paradigms for the synthesis of chiral γ‐ and/or δ‐functionalized azaarenes.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

A New Route to N‐Aryl 2‐Alkenamides,N‐Allyl N‐Aryl 2‐Alkenamides,and N‐Aryl α,β‐Unsaturated γ‐Lactams from N‐Aryl 3‐(Phenylsulfonyl)propanamides

A series of N‐aryl 2‐alkenamides were produced efficiently by treating N‐aryl 3‐(phenylsulfonyl)‐propanamides with potassium tert‐butoxide in THF at 0°C. With out isolation, it was further treated with an additional equivalent of potassium tert‐butoxide and allyl bromide to give N‐allyl N‐aryl 2‐alkenamides in one pot in good yields. Followed by a ring‐closing metathesis reaction, these N‐allyl N‐aryl 2‐alkenamides were respectively converted into corresponding N‐aryl α,β‐unsaturated γ‐lactams in moderate yields.     

A Copper(I)‐Catalyzed Enantioselective γ‐Boryl Substitution of Trifluoromethyl‐Substituted Alkenes: Synthesis of Enantioenriched γ,γ‐gem‐Difluoroallylboronates

The first catalytic enantioselective γ‐boryl substitution of CF₃‐substituted alkenes is reported. A series of CF₃‐substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active γ,γ‐gem‐difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene‐containing homoallylic alcohols using highly stereospecific allylation reactions.     

The influence of the substituent position in monocarboxymethyl‐γ‐cyclodextrins on enantioselectivity in capillary electrophoresis

Three newly synthesized chiral selectors, namely, 2^I‐O‐, 3^I‐O‐, and 6^I‐O‐carboxymethyl‐γ‐cyclodextrin, native γ‐cyclodextrin, and commercially available carboxymethylated γ‐cyclodextrin with degree of substitution of 3–6 were used as additives in a background electrolyte composed of phosphate buffer at 20 mmol/L concentration and pH 2.5. This system was used for the analysis of several biologically significant low‐molecular‐mass chiral compounds by capillary electrophoresis. The results confirmed that the position of carboxymethyl group influences the enantioseparation efficiency of all the studied analytes. The 2^I‐O‐ and 3^I‐O‐ regioisomers provide a significantly better resolution than native γ‐cyclodextrin, while the 6^I‐O‐regioisomer gives only a slightly better enantioseparation than native γ‐cyclodextrin. The application of γ‐cyclodextrin possessing higher number of carboxymethyl groups led to the best resolution for the majority of the compounds analyzed.     

Copper‐Catalyzed γ‐Selective and Stereospecific Allylic Cross‐Coupling with Secondary Alkylboranes

The scope of the copper‐catalyzed coupling reactions between organoboron compounds and allylic phosphates is expanded significantly by employing triphenylphosphine as a ligand for copper, allowing the use of secondary alkylboron compounds. The reaction proceeds with complete γ‐E‐selectivity and preferential 1,3‐syn stereoselectivity. The reaction of γ‐silicon‐substituted allylic phosphates affords enantioenriched α‐stereogenic allylsilanes.     

Efficient Access to Enantiopure γ4‐Amino Acids with Proteinogenic Side‐Chains and Structural Investigation of γ4‐Asn and γ4‐Ser in Hybrid Peptide Helices

Hybrid peptides composed of α‐ and β‐amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ‐ and hybrid γ‐peptides composed of γ⁴‐amino acids are less studied than their β‐counterparts. However, recent investigations reveal that γ⁴‐amino acids have a higher propensity to fold into ordered helical structures. As amino acid side‐chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ⁴‐residues with functional proteinogenic side‐chains and their structural analysis in hybrid‐peptide sequences. Here, the efficient and enantiopure synthesis of various N‐ and C‐terminal free‐γ⁴‐residues, starting from the benzyl esters (COOBzl) of N‐Cbz‐protected (E)‐α,β‐unsaturated γ‐amino acids through multiple hydrogenolysis and double‐bond reduction in a single‐pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ⁴‐amino acids (γ⁴‐Val, γ⁴‐Leu, γ⁴‐Ile, γ⁴‐Thr(OtBu), γ⁴‐Tyr, γ⁴‐Asp(OtBu), γ⁴‐Glu(OtBu), and γ‐Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C^γ? C^β bond. To study the behavior of γ⁴‐residues with functional side chains in peptide sequences, two short hybrid γ‐peptides P1 (Ac‐Aib‐γ⁴‐Asn‐Aib‐γ⁴‐Leu‐Aib‐γ⁴‐Leu‐CONH₂) and P2 (Ac‐Aib‐γ⁴‐Ser‐Aib‐γ⁴‐Val‐Aib‐γ⁴‐Val‐CONH₂) were designed, synthesized on solid phase, and their 12‐helical conformation in single crystals were studied. Remarkably, the γ⁴‐Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side‐chain amide groups. Furthermore, the hydroxyl side‐chain of γ⁴‐Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ⁴‐residues in peptide single‐crystals reveal that the γ⁴‐residues in 12‐helices are more ordered as compared with the 10/12‐ and 12/14‐helices.     

Influence of substituent position and cavity size of the regioisomers of monocarboxymethyl‐α‐, β‐, and γ‐cyclodextrins on the apparent stability constants of their complexes with both enantiomers of Tröger's base

Enantiomers of Tröger's base were separated by capillary electrophoresis using 2^I‐O‐, 3^I‐O‐, and 6^I‐O‐carboxymethyl‐α‐, β‐, and γ‐cyclodextrin and native α‐, β‐, and γ‐cyclodextrin as chiral additives at 0–12 mmol/L for β‐cyclodextrin and its derivatives and 0–50 mmol/L for α‐ and γ‐cyclodextrins and their derivatives in a background electrolyte composed of sodium phosphate buffer at 20 mmol/L concentration and pH 2.5. Apparent stability constants of all cyclodextrin–Tröger's base complexes were calculated based on capillary electrophoresis data. The obtained results showed that the position of the carboxymethyl group as well as the cavity size of the individual cyclodextrin significantly influences the apparent stability constants of cyclodextrin–Tröger's base complexes.