2. Essential Components: Earlier Developments 5449 2.1. Activated alkenes/alkynes 5450 2.1.1. Acyclic activated alkenes/ alkynes 5450 2.1.2. Cyclic activated alkenes 5451 2.2. Electrophiles 5451 2.3. Catalysts 5452 3. Essential Components: Recent Developments 5452 3.1. Activated Alkenes/Alkynes 5452 3.2. Electrophiles 5460 3.3. Catalysts 5477 4. Asymmetric Baylis-Hillman Reaction: Earlier Developments 5495

Recent contributions from the Baylis-Hillman reaction to organic chemistry.

Ionic liquids are solvents that consist entirely of ions. These nonvolatile and nonflammable solvents offer interesting opportunities for lanthanide and actinide chemistry. They can replace the organic phase in solvent extraction systems and can be used as nonaqueous electrolytes for electrodeposition of metals. Ionic liquids could find applications in the nuclear fuel cycle. Lanthanide coordination compounds or lanthanide-containing nanoparticles can be obtained via ionothermal or microwave-assisted synthesis in ionic liquids. Lanthanide-doped ionogels are a new type of luminescent hybrid materials. Ionic liquids can serve as solvents for lanthanide-mediated organic reactions, and there are several examples of high reactivity and selectivity.

Lanthanides and Actinides in Ionic Liquids

Interactions of Cyclophilin with the Mitochondrial Inner Membrane and Regulation of the Permeability Transition Pore, a Cyclosporin A-sensitive Channel

Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/psc.491

The cyclization of peptides and depsipeptides

Use of Lawesson's reagent in organic syntheses.

Strong bases (lithium diisopropylamide (LDA) or BuLi) convert cyclosporin A (CS) to hexalithio derivative containing a Li alkoxide, four Li azaenolate, and one Li enolate units. The Li6 compound is solubilized in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reactions with electrophiles (alkyl halides, aldehydes, ClCO2R, CO2, (RS)2, D2O) at low temperatures give products containing new side chains in amino-acid residue 3 of the cyclic undecapeptide (see 1–13, Schemes 1, and 2, and Figs. 1 and 2) in moderate to high yields and, with Re- or Si-selectivities, depending upon the conditions of lithiation of up to 7:1, Pure CS derivatives (Scheme 2, Table 1 in the Exper. Part) can be isolated by column chromatography. N-Alkylations or cleavage of the peptide backbone by carbonyl addition occur only at higher temperatures and/or with prolonged reaction times (see 14 and 15 in Scheme 4). Very little or no epimerization of stereogenic centers occurs under the conditions employed. Possible reasons for the feasibility of these surprizing conversions of CS are discussed (Schemes 4 and 5 and Fig. 3). For comparision, [MeAla3]CS (2b) and [D-MeAla3]CS (2a) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7). Their 1H- and 13C-NMR spectra are compared with those of CS (Table 2 in the Exper. Part).

Modification of Cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles

The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl O-atoms and/or the hydroxy O-atom of the MeBmt residue are replaced by an S-atom. The position of the S-atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X-ray crystallography. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for CsA in CDCL3, two conformers A and B, in a ratio 58:42 are found for [1ψ2, CS–NH]CsA. Extensive NMR studies including new 2D and 3D heteronuclear techniques and restrained MD calculations using ROE effects demonstrate that the major conformer A is identical to CsA, while the minor conformer B contains an additional cis peptide bond between the Sar3 and MeLeu4 residues. [4ψ5, CSNH; 7ψ8, CS–NH]CsA exhibits a conformation very similar to crystalline CsA. However, the D-Ala8NH, MeLeu6Co γ-turn H-bond is not present in this dithio analogue. Also different is the MeBmt1side-chain conformation, the dithio conformation showing a strong MeBmt1OH, Sar3CO H-bond. Immunosuppressive activities of thiocyclosporins are measured in IL-2 and IL-8 reporter gene assays. Their activities are discussed in relation to their conformations.

Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity

A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified t...

2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (SDZ NKT 343), a Potent Human NK1 Tachykinin Receptor Antagonist with Good Oral Analgesic Activity in Chronic Pain Models

Soo Y. Ko

Papers

Modification of Cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles

Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity

2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (SDZ NKT 343), a Potent Human NK1 Tachykinin Receptor Antagonist with Good Oral Analgesic Activity in Chronic Pain Models

Thioamide synthesis : thioacyl-n-phthalimides as thioacylating agents

Synthetic applications of the cyclic iminocarbonate rearrangement: enantioselective syntheses of chloramphenicol and 4-epi-cytoxazone