The conformation of [D-MeSe?-D-Ser-(O-Gly)*]CS, a water soluble cyclosporin derivative, has been determined in (D,)DMSO and in water using NMR. In these polar solvents the conformation is identical and very similar to the structure found in the cyclophilin-cyclosporin complex. However, it differs significantly from its conformation in deuterated chloroform. This demonstrates unambiguously that the large structure change is induced primarily by the polar solvent rather than by complex formation with cyclophilin.

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The diastereoisomeric 2-substituted 2-azabicyclo[2.2.l]hept-5-enes 2 4 were prepared by aza-Diels-Alder reaction of cyclopentadiene with the corresponding methaniminium ions. Their relative configurations were deduced using 'H,'H-ROESY experiments, and their absolute configurations were assigned from the crystal structure of the aziridinium derivative (-)-5. The absolute configuration of (+)-1, i.e. (lR), was assigned by CD spectroscopy.Introduction. -Following Grieco and Larsen's pioneering report of the aza-DielsAlder reaction between cyclopentadiene and N-benzylmethaniminium ion, formed in situ in aqueous medium [I], many groups exploited and extended this reaction [2]. Analogous diastereoselective reactions were described using amino acids [3] [4] as chiral sources.The absolute configurations of the aza-Diets-Alder adducts with chiral l-phenylethylamine were, however, unknown. In the course of our syntheses of muscarinic agonists [5] and terpene alkaloids [6], we needed the aza-Diels-Alder adducts in enantiomerically pure form and knowledge of their absolute configuration. Thus, we assigned the relative configurations of the adducts using 2D-ROESY experiments and confirmed the validity of the NMR method by independent assignment of the absolute configuration of aziridinium bromide (-)-5 by X-ray crystallography. With this knowledge in hand, the absolute configurations of the enantiomers of 1 could be deduced by CD spectroscopy.

The procedure of structure elucidation of natural products at Novartis is discussed. Structure elucidation in an industrial environment has to be time efficient, which is achieved by an optimized workflow and a close integration of all analytical methods used in this process. After a preliminary dereplication step based on LC/MS, compounds are delivered to the structure analysis unit. A second dereplication step is based on IR spectroscopic data. Subsequent MS analysis leads to the molecular weight or molecular composition. NMR spectroscopy is finally used for complete structure elucidation, respectively for confirmation of structural suggestions made on the basis of IR and MS data. Challenges like a large number of structure elucidation requests, low amounts of material, variation of sample purity or complexity of structures are faced with modern analytical equipment and high expertise in all disciplines.

structure structure (organic substances) K 9000 34 -037 Absolute Configuration of 2-Substituted 2-Azabicyclo(2.2.1)hept-5enes. -A series of diastereomeric title bicycles (cf. (IV)/(V); 8 examples), potential precursors of muscarinic agonists and terpene alkaloids, is synthesized by aza-Diels-Alder reaction of cyclopentadiene with benzylamines and formaldehyde. Their absolute configurations are established by 2D-COSY/ROESY experiments in conjunction with CD spectroscopy. An X-ray analysis confirms the validity of the above method for the assignment of absolute configurations. -(POMBO-VILLAR, E.; BOELSTERLI, J.; CID, M. M.; FRANCE, J.; FUCHS, B.; WALKINSHAW, M.; WEBER, H.-P.; Helv. Chim. Acta 76 (1993) 3, 1203-1215; Preclin. Res.,