Enantiomerically pure a-amino-acid derivatives with the side chains of A h , Val, and Leu in the 2-or 3-position (8'-and P3-amino acids, resp.), as well as with substituents in both the 2-and 3-positions (Pz.3-amino acids, of like-configuration) have been prepared (compounds 8-17) and incorporated (by stepwise synthesis and fragment coupling, intermediates 24-34) into P-hexa-, P-hepta-, and j-dodecapeptides (1 -17). The new and some of the previously prepared P-peptides (35-39) showed NHiND exchange rates (in MeOH at room temperature) with T~,~ values of up to 60 days, unrivalled by short chain a-peptides. All P-peptides 1-7 were designed to be able to attain the previously described 3,-helical structure (Figs. I and 2). C D Measurements (Fig. 4), indicating a new secondary structure of certain P-peptides constructed of P'-and p3-arnino acids, were confirmed by detailed NMR solution-structure analyses: a P*-heptapeptide (2c) and a Pz.3-hexapeptide (7c) have the 3,-helical structure (Figs. 6 and 7), while to a P2/P3-hexapeptide (4) with alternating substitution pattern H-(P2-Xaa-P3-Xaa),-OH a novel, unusual helical structure (in (DJpyridine, Fig. 8; and in CD30H, Figs. 9 and f0) was assigned, with a central ten-membered and two terminal twelve-membered H-bonded rings, and with C=O and N-H bonds pointing alternatively up and down along the axis of the helix (Fig. 11). Thus, for the first time, two types of fi-peptide turns have been identified in solution. Hydrophobic interactions ofand hindrance to solvent accessibility by the aliphatic side chains are discussed as possible factors influencing the relative stability of the two types of helices.

The properties of peptides and proteins depend on their three-dimensional structure, which itself is determined by the sequence of the amino acids, that is, the primary structure. The mechanisms of formation and the parameters determining the stability of secondary structures of proteinsÐincluding not only the helix, the pleated sheet, and the turn, but also the random-coiled regionÐare not yet fully understood.[1] In contrast, b-peptides (oligomers of b-amino acids [2] ) adopt predictable [3] secondary structures that can also be identified by calculations.[4] This also holds for b-peptides whose backbones are not conformationally restricted by cyclic residues. Thus, b-peptides composed of more than five homochiral b 2 -, b 3 -, or like-b 2, 3

The Diels-Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large-scale applications (>1 kg) from a process research and development perspective.

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) through S1P(5). Agonists of the S1P(1) receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure-activity relationships of a novel class of S1P(1) receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P(1) receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of 8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.

Dedicated to Professor A. I. Meyers, University of Colorado, For! Collins, on the occasion of his 65th birthday N-Fmoc-Protected (Fmoc = (9H-fluoren-9-y1methoxy)carbonyl) /+amino acids are required for an efficient synthesis of fl-oligopeptides on solid support. Enantiomerically pure F~n o c -~~-a m i n o acids (f13: side chain and NH, at C(3)(= C(p))) were prepared from Fmoc-protected (S)-and (R)-a-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-P2-Amino acids (p' side chain a! C(2), NH, at C(3)( = C(fi))) configuration bearing the side chain o f Ala, Val, Leu, and Phe were synthesized viu the Evans' chiral auxiliary methodology. The target p3-heptapeptides 5-8, a f13-pentadecapeptide 9 and a f12-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of f13-peptides, two methods were used to anchor the first [j-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-/l-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzy1oxy)henzyl alcohol resin (Wung resin) with the ketene intermediates from the Worff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolffrearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12). The CD spectra of the p2-and P3-peptides 5, 9, and 10 show the typical pattern previously assigned to an (M) 3 , helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5, this corresponds to a 2.5 fold increase in the molar ellipticity per residue!