Crystallization of Arthrobacter sp. strain 1C N-(1-D-carboxyethyl)-L-norvaline dehydrogenase and its complex with NAD+

The novel NAD+-linked opine dehydrogenase from a soil isolate Arthrobacter sp. strain 1C belongs to an enzyme superfamily whose members exhibit quite diverse substrate specificites. Crystals of this opine dehydrogenase, obtained in the presence or absence of co-factor and substrates, have been shown to diffract to beyond 1.8 ? resolution. X-ray precession photographs have established that the crystals belong to space group P21212, with cell parameters a = 104.9, b = 80.0, c = 45.5 ? and a single subunit in the asymmetric unit. The elucidation of the three-dimensional structure of this enzyme will provide a structural framework for this novel class of dehydrogenases to enable a comparison to be made with other enzyme families and also as the basis for mutagenesis experiments directed towards the production of natural and synthetic opine-type compounds containing two chiral centres.     

Biomimetic total synthesis of malbrancheamide and malbrancheamide B

The biomimetic total syntheses of both malbrancheamide and malbrancheamide B are reported. The synthesis of the two monochloro species enabled the structure of malbrancheamide B to be unambiguously assigned. The syntheses each feature an intramolecular Diels-Alder reaction of a 5-hydroxypyrazin-2(1H)-one to construct the bicyclo[2.2.2]diazaoctane core, which has also been proposed as the biosynthetic route to these compounds.     

Concise, Biomimetic Total Synthesis of d,l-Marcfortine C

A biomimetic total synthesis of the fungal metabolite marcfortine C utilizing an intramolecular Diels-Alder reaction is described. In addition, a key stereoselective oxaziridine-mediated oxidation/pinacol rearrangement of indole 24 was used to complete the total synthesis.     

6-(2-Haloethyl)-2,2-dimethyl-4H-1,3-dioxins: versatile haloethyl vinyl ketone equivalents for carbocycle construction

6-(2-Iodoethyl)-2,2-dimethyl-4H-1,3-dioxin has been prepared in five steps from ethyl acetoacetate. A variety of enolates were then alkylated with this iodide. The resulting 6-alkyl-4H-1,3-dioxins were either subjected to further transformations and/or heated (or subjected to a Lewis acid) to effect facile retrocycloaddition reactions. The resulting enones were found to smoothly participate in conjugate addition or olefin metathesis reactions to provide various carbocyclic ring systems. Collectively, these examples document the synthetic equivalency of dioxin 2 with iodoethyl vinyl ketone and, moreover, delineate a strategy for accomplishing the sequential reactions with nucleophiles at the β′, followed by the β electrophilic sites.     

Synthetic Studies on Palau'amine. Construction of the Cyclopentane Core via an Asymmetric 1,3-Dipolar Cycloaddition

The cyclopentane core of palau’amine has been constructed in optically pure form through the use of an asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction.     

6-Bromomethyl-4H-1,3-dioxin: a versatile bromomethyl vinyl ketone equivalent for heterocycle and carbocycle construction

6-Bromomethyl-4H-1,3-dioxin has been prepared in three steps from allyl iodide. A variety of enolates were then alkylated with this bromide. The resulting 6-alkyl-4H-1,3-dioxins were either subjected to further multistep transformations and/or heated to effect facile retrocycloaddition reactions. The resulting enones smoothly participated in novel endo-conjugate addition reactions with both carbon and nitrogen nucleophiles. For example, several bicyclo[4.3.1]decan-3,10-diones, the carbon framework of the CP compounds, were constructed using this novel annulation strategy. In another natural product study, a benzazocine related to the heterocyclic framework of the ring-opened tautomeric form of FR-900482 was also prepared using this methodology. Finally, a piperidin-4-one obtained from a 6-endo conjugate addition was converted to the naturally occurring (2S,4R)-4-hydroxypipecolic acid. Collectively, these examples document the synthetic equivalency of dioxin 1 with bromomethyl vinyl ketone and, moreover, delineate a strategy for accomplishing the sequential reactions with nucleophiles at the alpha' followed by the beta electrophilic sites.     

Synthesis of Complex Druglike Molecules by the Use of Highly Functionalized Bench‐Stable Organozinc Reagents

The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross‐coupling reactions was evaluated by high‐throughput experimentation protocols. The high‐fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug‐discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable‐space coverage.