Proof Of Constitution Research Articles

24 hours – High-Throughput Crystal Structure Production

In the pharmaceutical industry crystal structures of low molecular weight compounds are analyzed for a variety of reasons: absolute structure determination, proof of constitution, characterization of different polymorphic forms, obtaining three-dimensional models as starting points for the study of structure-activity relationships, etc. Not for all purposes highly redundant, high-resolution data sets are needed; this thought, together with the purchase of a new hybrid pixel detector which can be operated in a very fast shutterless mode, initiated the idea to test how many useable crystal structures we can produce within 24 hours. Our goal was to invest as little effort as possible and to set up an automated process with minimal human intervention but a maximum chance of success which we defined as getting to a correct final result providing useful information, e.g., is it the correct compound? Is the sample chiral or racemic? Which crystal would be the best one for a full data collection? Is it a new polymorph? We selected a data collection protocol which yields an interpretable data set up to 1 Å resolution in less than 10 minutes, the diffraction images are indexed and processed using an in-house script arching over the necessary individual XDS steps, followed by space group determination (XPREP) and structure solution/refinement (SHELX). First results and findings of our experiment series will be presented and the adjustable parameters will be discussed. Ideas to adapt and improve the process will be offered.

Distamycin‐NA: A DNA Analog with an Aromatic Heterocyclic Polyamide Backbone. Part 1. Synthesis and structural analysis of monomers and dimers containing the nucleobase uracil

AbstractThe synthesis of the monomeric building block 13 and its constitutional isomer 12 of a new type of DNA analog, distamycin‐NA, is presented (Schemes 1 and 2). This building block consists of a uracil base attached to a thiophene core unit via a biaryl‐like axis. Next to the biaryl‐like axis on the thiophene chromophore, a carboxy and an amino substituent are located allowing for oligomerization via peptide coupling. The proof of constitution and the conformational preferences about the biaryl‐like axis were established by means of X‐ray analyses of the corresponding nitro derivatives 10 and 11. Thus, the uracil bases are propeller‐twisted relative to the thiophene core, and bidentate H‐bonds occur between two uracil bases in the crystals. The two amino‐acid building blocks 12 and 13 were coupled to give the dimers 15 and 16 using dicyclohexylcarbodiimide (DCC) in THF/LiCl and DMF, respectively. While the dimer 15 showed no atropisomerism on the NMR time scale at room temperature, its isomer 16 occurred as distinct diastereoisomers due to the hindered rotation around its biaryl‐like axis. Variable‐temperature 1H‐NMR experiments allowed to determine a rotational barrier of 19 ± 1 kcal/mol in 16. The experimental data were complemented by AM1 calculations.

Axinastatin 1 or malaysiatin? proof of constitution and 3D structure in solution of a cyclic heptapeptide with cytostatic properties

AbstractRecently, a cyclic heptapeptide with cytostatic activity was isolated from marine sources by three different groups independently. The sequence of the isolated peptide was ambiguous, since two different isomers have been proposed: cyclo(‐Asn1‐Pro2‐Phe3‐Val4‐Val5‐Pro6‐Val7‐) (1) also called axinastatin 1 resp. pseudoaxinellin and cyclo(‐Asn1#‐Pro2#‐Pro3# ‐Phe4#‐Val5#‐Val6#‐Val7#‐) (2) called malaysiatin. We synthesized both peptides 1 and 2 and compared their optical rotation, FAB‐MS, 1H‐ and 13C‐NMR data with those of the native compounds. Our results prove that peptide 1 has been assigned correctly, whereas the data of 2 differ significantly from those of the natural peptide. Peptide 1 adopts two conformations (90:10 ratio) in DMSO, interconverting slowly on the NMR time scale. According to MD simulations, using NOEs and J couplings as experimental restraints, a βVIa‐turn with a cis peptide bond between Val5‐Pro6 and a βI‐turn in the Asn1‐Val4 region are the characteristic secondary structural elements of the major conformer. Its backbone conformation is very similar to the X‐ray structure of a related peptide cyclo(‐Asna‐Leub‐Serc‐Phed‐Leue‐Prof‐Valg‐) called evolidine.

Synthesis and proof of constitution of the methylcyclopentenes

Synthesis and proof of constitution of the methylcyclopentenes

Herstellung und Eigenschaften deuteriumhaltiger Naphtalinderivate

Abstract1. The synthesis of 1‐D‐2‐naphthol and 1‐D‐2‐naphthol‐6:8‐disulphonic acid by quantitative isotope exchange is described. Proof of constitution is given by isotope analysis and degradation experiments.