Cyclic Allene Approach to the Manzamine Alkaloid Keramaphidin B

Abstract

We report an approach to the core of the manzamine alkaloid keramaphidin B that relies on the strain-promoted cycloaddition of an azacyclic allene with a pyrone trapping partner. The cycloaddition is tolerant of nitrile and primary amide functional groups and can be complemented with a subsequent retro-Diels–Alder step. These efforts demonstrate that strained cyclic allenes can be used to build significant structural complexity and should encourage further studies of these fleeting intermediates.

Access to Complex Scaffolds Through [2 + 2] Cycloadditions of Strained Cyclic Allenes

“…For example, arynes (e.g., 7a and 7b ) − and nonaromatic cyclic alkynes (e.g., 7c and 7d ) − are highly reactive, in situ-generated intermediates that can readily engage in [2 + 2] cycloadditions due to their significant strain energies, typically ranging from 40 to 50 kcal/mol (Figure B) . A comparatively less well-studied class of compounds is strained cyclic allenes 8 . − Like cyclic alkynes, strained cyclic allenes 8 contain a functional group that typically prefers a linear geometry but is bent due to ring constraint, leading to significant strain energy (∼30 kcal/mol). , Although historically understudied, cyclic allenes 8 are emerging building blocks in the synthetic community. − Recent advances include cycloaddition chemistry by West, ,− the synthesis of DNA-encoded libraries by Schreiber, and several studies from our laboratory, ,− including the recent use of strained cyclic allenes in total synthesis . With regard to [2 + 2] cycloadditions of strained cyclic allenes, seminal studies by Christl and others validated reactivity. − More recently, elegant studies by West have demonstrated [2 + 2] cycloadditions of acetoxy-substituted carbocyclic allenes, as well as intramolecular trappings, using silyl bromide precursors to cyclic allenes.…”

Evaluation of Retro-Aldol vs Retro-Carbonyl-Ene Mechanistic Pathways in a Complexity-Generating C–C Bond Fragmentation

“…Such compounds, such as benzyne ( 1 ), indolyne 2 , and strained cyclic allene 3 (Figure A), have seen use in a variety of applications. This includes, but is not limited to, use of strained intermediates toward the synthesis of important molecules such as bioactive compounds, − natural products, − DNA-encoded libraries, ligands, , and stimulus-responsive materials . A related class of strained intermediates comprises 1,2,3-cyclohexatrienes ( 4 , Figure B).…”

Isolable Spirocyclic Silylone: π-Delocalized Spiro[3.3]heptasila-2,6-diylidone

“…Despite once being only scientific curiosities, such strained cyclic derivatives are currently used in various applications has been utilized in a variety of synthetic organic applications, especially total synthesis (Chart a). − A stable cyclic allene II (Chart b), confining the bent >CCC< skeleton in a five-membered nitrogen-containing ring, arouses two lone pairs of electrons on the central carbon atom, which is regarded as a carbo­(dicarbene) derivative − They are defined as tetrylones and possess two lone pairs of electrons on the central E 0 centers.…”