Preparation of the β3‐Homoselenocysteine Derivatives Fmoc‐β3hSec(PMB)‐OH and Boc‐β3hSec(PMB)‐OH for Solution and Solid‐Phase‐Peptide Synthesis and Selenoligation

The title compounds, 4 and 7 , have been prepared from the corresponding α‐amino acid derivative selenocystine ( 1 ) by the following sequence of steps: cleavage of the Se? Se bond with NaBH₄, p‐methoxybenzyl (PMB) protection of the SeH group, Fmoc or Boc protection at the N‐atom and Arndt–Eistert homologation (Schemes 1 and 2). A β³‐heptapeptide 8 with an N‐terminal β³‐hSec(PMB) residue was synthesized on Rink amide AM resin and deprotected (‘in air’) to give the corresponding diselenide 9 , which, in turn, was coupled with a β³‐tetrapeptide thiol ester 10 by a seleno‐ligation. The product β³‐undecapeptide was identified as its diselenide and its mixed selenosulfide with thiophenol (Scheme 3). The differences between α‐ and β‐Sec derivatives are discussed.     

Automated Solid‐Phase Synthesis and Structural Investigation of β‐Peptidosulfonamides and β‐Peptidosulfonamide/β‐Peptide Hybrids: β‐Peptidosulfonamide and β‐Peptide Foldamers are Two of a Different Kind

Fmoc‐protected β‐aminoethane sulfonylchlorides can be employed for efficient automated solid phase synthesis of β‐peptidosulfonamides and β‐peptidosulfonamide/β‐peptide hybrids containing one or more β‐peptidosulfonamide residues. Thus, Fmoc‐protected β‐aminoethane sulfonylchlorides 5a – c led to the hexa‐β‐peptidosulfonamide 9 and the nona‐β‐peptidosulfonamide 10 . In addition, the β‐peptidosulfonamide/β‐peptide hybrids 13 and 16 , consisting of six and nine β‐residues, respectively, and containing a single β‐peptidosulfonamide unit in the middle, as well as the peptidosulfonamide/β‐peptide hybrid 15 with nine β‐residues, including an N‐terminal β‐peptidosulfonamide residue, were synthesized by automated solid‐phase synthesis. Both CD and NMR spectroscopic measurements did not indicate any helical secondary structure for 9 and 10 . As was shown by CD‐measurements, the β‐peptidosulfonamide residue in the hybrids 13, 15 , and 16 acts as a ‘helix breaker', especially when located in the middle of the hybrid chain ( 13 and 16 ), but, although to a lesser extent, also at the N‐terminus.     

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.     

Preparation of the β2‐Homoselenocysteine Derivatives Fmoc‐(S)‐β2hSec(PMB)‐OH and Boc‐(S)‐β2hSec(PMB)‐OH for Solution and Solid‐Phase Peptide Synthesis

Fmoc‐β²hSer(^tBu)‐OH was converted to Fmoc‐β²hSec(PMB)‐OH in five steps. To avoid elimination of HSeR, the selenyl group was introduced in the second last step (Fmoc‐β²hSer(Ts)‐OAll→Fmoc‐β²hSec(PMB)‐OAll). In a similar way, the N‐Boc‐protected compound was prepared. With the β²hSe‐derivatives, 21 β²‐amino‐acid building blocks with proteinogenic side chains are now available for peptide synthesis.     

The Efficient Synthesis of the Optically Active β‐Hydroxyl‐γ‐Butyrolactone Derivatives

The optically active β‐hydroxyl‐γ‐butyrolactones were synthesized from nonchiral starting material by employing reductive cleavage reaction, sharpless asymmetric epoxidation and dihydroxylation, and Lewis acid‐catalysed cyclization as key steps. This strategy can be used to prepare many chiral β‐hydroxyl‐γ‐butyrolactone analogues.     

Interaction of Fluorescently Labeled Triethyleneglycol and Peptide Derivatives with β‐Cyclodextrin

A triethyleneglycol (TEG) chain, a linear peptide, and a cyclic peptide labeled with 7‐methoxycoumarin‐3‐carboxylic acid (MC) and 7‐diethylaminocoumarin‐3‐carboxylic acid (DAC) were used to thoroughly study Förster resonance energy transfer (FRET) in inclusion complexes. ¹H NMR evidence was given for the formation of a 1:1 inclusion complex between β‐cyclodextrin (β‐CD) and the fluorophore moieties of model compounds. The binding constant was 20 times higher for DAC than for MC derivatives. Molecular modeling provided additional information. The UV/Vis absorption and fluorescence properties were studied and the energy transfer process was quantified. Fluorescence quenching was particularly strong for the peptide derivatives. The presence of β‐CDs reduced the FRET efficiency slightly. Dye‐labeled peptide derivatives can thus be used to form inclusion complexes with β‐CDs and retain most of their FRET properties. This paves the way for their subsequent use in analytical devices that are designed to measure the activity of matrix metalloproteinases.     

Stereoselective Organocatalyzed Synthesis of α‐Fluorinated β‐Amino Thioesters and Their Application in Peptide Synthesis

α‐Fluorinated β‐amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of α‐fluorinated monothiomalonates (F‐MTMs) to N‐Cbz‐ and N‐Boc‐protected imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling‐reagent‐free peptide synthesis in solution and on solid phase. The α‐fluoro‐β‐(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.     

Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Enantioselective Palladium‐Catalyzed Oxidative β,β‐Fluoroarylation of α,β‐Unsaturated Carbonyl Derivatives

The site‐selective palladium‐catalyzed three‐component coupling of deactivated alkenes, arylboronic acids, and N‐fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step‐economical approach to the stereoselective β‐fluorination of α,β‐unsaturated systems.     

Rapid Synthesis of α,β-Didehydroaspartic-Acid Derivatives Carrying a β-Substituent

A convenient preparation of N-(alkoxycarbonyl)-2,3-didehydroaspartic acid anhydrides 4 with substitution at the 3-position is reported. The key step is a cobalt-mediated acylation of an acetylene moiety, producing the highly functionalized didehydroamine acid derivative in good yield. Unnatural didehydroaspartates are readily accessible.     

Inverse Peptide Synthesis via Activated α‐Aminoesters

A mild, practical, and simple procedure for peptide‐bond formation is reported. Instead of activation of the carboxylic acid functionality, the reaction involves an unprecedented use of activated α‐aminoesters. The method provides a straightforward entry to dipeptides and was effective when a sensitive cysteine residue was used, as no epimerization was detected in this case. The applicability of this method to iterative peptide synthesis was illustrated by the synthesis of a model tetrapeptide in the challenging reverse N→C direction.     

Catalytic Asymmetric 1,2‐Addition of α‐Isothiocyanato Phosphonates: Synthesis of Chiral β‐Hydroxy‐ or β‐Amino‐Substituted α‐Amino Phosphonic Acid Derivatives

α‐Amino phosphonic acid derivatives are considered to be the most important structural analogues of α‐amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2‐addition reactions of α‐isothiocyanato phosphonate were developed. Through these processes, derivatives of β‐hydroxy‐α‐amino phosphonic acid and α,β‐diamino phosphonic acid, as well as highly functionalized phosphonate‐substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α‐phosphonic acid derivatives.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.