Development of Fmoc-Protected Bis-Amino Acids toward Automated Synthesis of Highly Functionalized Spiroligomers.

We report the fluorenylmethoxycarbonyl (Fmoc) protection of functionalized bis-amino acid building blocks using a temporary Cu2+ complexation strategy, together with an efficient multikilogram-scale synthesis of bis-amino acid precursors. This allows the synthesis of stereochemically and functionally diverse spiroligomers utilizing solid-phase Fmoc/tBu chemistry to facilitate the development of applications. Four tetramers were assembled on a semiautomated microwave peptide synthesizer. We determined their secondary structures with two-dimensional nuclear magnetic resonance spectroscopy.

Electrophile-Directed Diastereoselective Oxonitrile Alkylations.

Diastereoselective alkylation of prochiral oxonitrile dianions with secondary alkyl halides efficiently installs two contiguous stereogenic centers. The confluence of nucleophilic trajectory and the electrophile chirality causes distinct steric differences that allow efficient discrimination for one of the six possible conformers. Numerous oxonitrile-derived dianions efficiently displace secondary alkyl halides propagating the electrophile chirality to efficiently install two contiguous tertiary centers. The prevalence of chiral, secondary electrophiles makes the interdigitated alkylation of chiral electrophiles a particularly attractive route because the resulting oxonitriles are readily transformed into bioactive heterocycles.

Alkenyl Isocyanide Conjugate Additions: A Rapid Route to γ-Carbolines.

Isocyanides are exceptional building blocks, the wide deployment of which in multicomponent and metal-insertion reactions belies their limited availability. The first conjugate addition/alkylation to alkenyl isocyanides is described, which addresses this deficiency. An array of organolithiums, magnesiates, enolates, and metalated nitriles add conjugately to ß- and ß,ß-disubstituted arylsulfonyl alkenyl isocyanides to rapidly assemble diverse isocyanide scaffolds. The intermediate metalated isocyanides are efficiently trapped with electrophiles to generate substituted isocyanides incorporating contiguous tri- and tetra-substituted centers. The substituted isocyanides are ideally functionalized for elaboration into synthetic targets as illustrated by the three-step synthesis of γ-carboline N-methyl ingenine B.