The "azido gauche effect" was examined both experimentally and theoretically and was found to determine the conformation of, for example, (4R)- and (4S)-azidoproline (Azp) derivatives. For (4R)Azp derivatives, the azido gauche effect induces a preferred C(4)-exo conformation of the pyrrolidine ring, which leads to stabilization of the s-trans amide conformer of, e.g., Ac-(4R)Azp-OCH(3) (5R) via an n-->pi interaction between the nonbonding electrons of the oxygen of the acetyl group and the carbonyl group of the ester. For (4S)Azp derivatives, the azido gauche effect results in a C(4)-endo conformation of the pyrrolidine ring that does not allow for this stabilizing n-->pi interaction of the s-trans conformer. Consequently, a significantly higher s-trans:s-cis amide conformer ratio is observed for (4R)Azp compared to (4S)Azp derivatives (e.g., 6.1:1 versus 2.6:1 in D(2)O for Ac-(4R)Azp-OCH(3) (5R) compared to Ac-(4S)Azp-OCH(3) (5S)). These conformational preferences are reflected in the higher tendency of (4S)Azp-containing peptides to form cyclic peptides with all-cis amide bonds compared to (4R)Azp derivatives. Ab initio calculations demonstrate that the strength of the azido gauche effect is comparable to that of the well-known "fluorine gauche effect". For azidoethane derivatives N(3)-CH(2)CH(2)-X (X = N(3), NHCOH, NHAc, or N(CH(3))Ac), the ab initio calculations revealed energy differences of 5-13 kJ mol(-)(1) between the anti and gauche conformations in favor of the gauche conformer. Calculations were also performed for the (4R)Azp and (4S)Azp derivatives 5R and 5S, supporting the experimentally observed data.

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Dengue fever is a viral disease that affects 50-100 million people annually and is one of the most important emerging infectious diseases in many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report on the discovery of new inhibitors of the viral NS5 RNA methyltransferase, a promising flavivirus drug target. We have used a multistage molecular docking approach to screen a library of more than 5 million commercially available compounds against the two binding sites of this enzyme. In 263 compounds chosen for experimental verification, we found 10 inhibitors with IC(50) values of <100 microM, of which four exhibited IC(50) values of <10 microM in in vitro assays. The initial hit list also contained 25 nonspecific aggregators. We discuss why this likely occurred for this particular target. We also describe our attempts to use aggregation prediction to further guide the study, following this finding.

During the synthesis of the new antimalarial drug candidate NITD609, a high degree of diastereoselectivity was observed in the Pictet-Spengler reaction. By isolating both the 4E and 4Z imine intermediates, a systematic mechanistic study of the reaction under both kinetic and thermodynamic conditions was conducted. This study provides insight into the source of the diastereoselectivity for this important class of compounds.

Vom Einzelnen zum Ganzen: Die Totalsynthese des natürlichen Makrolids Oasomycin A wurde abgeschlossen. Zu den zentralen Fragmentverknüpfungen gehören eine anti‐Felkin‐selektive Aldoladdition (grün), Kociensky‐Julia‐Olefinierungen (rot) und eine konkurrierende Weinreb‐Amid‐Acylierung (blau). Die Nützlichkeit von 4,5‐Diphenyloxazol als Carboxy‐Ersatz und die zu einem späten Zeitpunkt durchgeführte Makrolactonisierung, die den 42‐gliedrigen Makrocyclus von Oasomycin A liefert, werden ebenfalls beschrieben.

Dedicated to Professor Y. Kishi on the occasion of his 70th birthday.Herein we address the total synthesis of the natural product oasomycin A by assembly of the C1-C12, C13-C28, and C29-C46 subunits, whose syntheses have been described in the preceding Communications.[1]The synthesis plan (Scheme 1) incorporates a speculative late-stage macrolactonization of the linear seco acid precursor to form a 42-membered lactone that upon global deprotection would provide the natural product. Since oasomycin A is known to rearrange to the oasomycins D and E under basic conditions, [2] an acid-mediated global deprotection was obligatory. It was our intention to assemble the requisite seco acid by using an aldol addition of the C1-C28 ketone I to the C29-C46 aldehyde II with a concomitant installation of the C29 stereocenter, followed by a stereoselective reduction of the C27 ketone.The assembly of ketone I through a Kocienski-Julia olefination [3] of the C13-C28 aldehyde III with C1-C12 fragment IV was undertaken first (Scheme 2). Sulfone 1 was selectively deprotonated with KHMDS and treated with aldehyde 2[3] to afford the coupling product 3 a as a 7:1 mixture of E/Z isomers (57 % yield). In addition, a significant amount of a by-product was consistently formed in 15-25 % yield in this and related olefinations. This by-product with the general structure 3 b (Scheme 2) may be rationalized by a Brook rearrangement of the Julia intermediate followed by alkoxide attack on the sulfur center. All efforts to suppress this side reaction were unsuccessful. [4] With both the C1-C28 and C29-C46 subunits in hand, we addressed the aldol coupling which would provide the oasomycin A skeleton. The logic behind the selection of an aldol addition to form the C28 À C29 bond was based on the fact that the diastereoselectivity of this reaction should be reinforced by resident chirality in both reaction partners: the C25 stereocenter on the enolate [Eq. (1)], [5] and the C31 stereocenter on the aldehyde fragment [Eq. (2)].[6] Although Scheme 1. Assembly of oasomycin A subunits.

Enantioselective Synthesis of Oasomycin A (I). Part 1. Synthesis of the C1-C12 and C13-C28 Subunits. -(EVANS*, D. A.; NAGORNY, P.; MCRAE, K. J.; REYNOLDS, D. J.; SONNTAG, L.-S.; VOUNATSOS, F.; XU, R.; Angew. Chem., Int. Ed. 46 (2007) 4, 537-540; Dep. Chem. Biochem., Harvard Univ., Cambridge, MA 02138, USA; Eng.) -Lindner 21-192

The synthesis and conformational analysis of C 3 -symmetric cyclotri[(4S)-aminoproline] as a bowl-shaped scaffold for three-armed receptors is described.Synthetic receptors are typically based on a template that is functionalized with recognition elements. 1 While the recognition elements can be regarded as the selectivity determining modules, the template is responsible for directing the recognition elements into a conformation that allows for intermolecular interactions. Thus, the choice of the template is crucial for the binding properties of synthetic receptors. Generally, templates with a defined curvature and attachment sites for the recognition elements that point into the same direction have proven superior to flexible, conformationally undefined templates. 2,3 Over the last decade, receptors based on templates that allow for the attachment of two peptides as recognition elements have shown good to excellent binding selectivities towards peptidic guest molecules. [2][3][4][5] Receptors with an additional third recognition element can be expected to exhibit even higher binding specificities and particularly affinities due to a three-point rather than a two-point binding motif. However, examples of peptide receptors with a parallel alignment of three recognition elements are still rare. 6Here we describe the synthesis of the cyclotriproline derivative 1 that allows for the attachment of three recognition elements after reduction of the azide functionalities. The acetylated cyclotriproline derivative 2 served as a minimal fragment of three-armed receptors for the conformational analysis of the tripodal scaffold.For the synthesis of 1 we envisioned the linear triprolines 3 and 4 as cyclization precursors ( Figure 1). Their synthesis starts from N-Boc-(4S)-N 3 -Pro-OCH 3 5 that was on one hand N-Boc deprotected to the HCl-salt 6 and on the other hand hydrolyzed to acid 7, which then was transformed to pentafluorophenyl (Pfp) ester 8. Mixing of 6 with 8 in the presence of Hünig's base provided dipeptide 9. The tripeptide 10 was obtained after methylester hydrolysis of 9 followed by coupling of the resulting acid and 6 with HATU. 7 Hydrolysis of the methylester 10 provided the acid 11 that was partially converted into the Pfpester 12. N-Boc deprotection of 11 and 12 with HCl in dioxane yielded the cyclization precursors 3 and 4 (Scheme 1).The formation of 1 was on one hand examined by the cyclization of the Pfp-ester 4 in pyridine and on the other hand by cyclizing the acid 3 in the presence of different coupling reagents. For the cyclization of the Pfp-ester, a solution of 4 in DMF containing 1% acetic acid was slowly added to a heated solution of pyridine to a final peptide Figure 1 Cyclotriproline derivatives 1 and 2 Scheme 1 Synthesis of the linear triprolines 3 and 4. Reagents and conditions: (a) 4 M HCl in dioxane, quant; (b) NaOH, quant.; (c) C 6 F 5 OH, EDC, 93%; (d) i-PrNEt 2 , 90%; (e) i. NaOH, ii. 5a, HATU, i-PrNEt 2 , 73%; (f) same as (b), 97%; (g) same as (c), 93%; (h) same as (a), quant.concentrati...