Reductive Fragmentation of Tetrazoles: Mechanistic Insights and Applications toward the Stereocontrolled Synthesis of 2,6-Polysubstituted Morpholines.

A new methodology to synthesize 2,6-di-, and 2,2',6-trisubstituted morpholines via the reduction of oxabicyclic tetrazoles under mild conditions is described. The reaction proved successful for a wide range of tetrazoles, including sterically encumbered ones harboring -substituents on tertiary carbon centers. The mechanism for the decades-old reduction of tetrazoles to secondary amines is elucidated.

Total synthesis of pactamycin and pactamycate: a detailed account.

This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions.

Total synthesis of (+)-ent-cyclizidine: absolute configurational confirmation of antibiotic M146791.

The first total synthesis of the enantiomer of the indolizidine alkaloid, cyclizidine, was accomplished from readily available d-serine as the starting chiron. The relevant key reactions involve the stereocontrolled construction of the indolizidine ring system with the required functionality and further elaboration to install the cyclopropyl dienyl side chain. With this total synthesis, the absolute configuration of the natural product based on a redetermination of its X-ray structure has been confirmed.

Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity.

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2.

Total synthesis of oidiodendrolides and related norditerpene dilactones from a common precursor: metabolites CJ-14,445, LL-Z1271gamma, oidiolactones A, B, C, and D, and nagilactone F.

An efficient, high-yielding strategy has been developed for the asymmetric total synthesis of seven norditerpenoid dilactones known for their diverse biological properties. The three key steps employed to obtain a tricyclic lactone intermediate involved a Morita-Baylis-Hillman reaction, the stereocontrolled construction of a gamma-lactone through bromolactonization, and an efficient catalytic Reformatsky-type reaction. Access to CJ-14,445, LL-Z1271gamma, oidiolactones A, B, C, and D, and nagilactone F was possible from a common intermediate.

Proximity-assisted cycloaddition reactions--facile Lewis acid-mediated synthesis of diversely functionalized bicyclic tetrazoles.

Aliphatic azidonitriles separated by three or four carbon atoms undergo facile Lewis acid-induced cycloadditions to give bicyclic tetrazoles, even at 0 degrees C. Extension to 3-azido-2-aryl-1,3-dioxolanes and the corresponding 1,3-dioxanes in the presence of TMSCN and BF3.OEt2 leads to a series of diversely functionalized novel oxabicyclic tetrazoles.