Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene

Abstract

Small rings that contain allenes are unconventional transient compounds that have been known since the 1960s. Despite being discovered around the same time as benzyne and offering a number of synthetically advantageous features, strained cyclic allenes have seen relatively little use in chemical synthesis. We report a concise total synthesis of the manzamine alkaloid lissodendoric acid A, which hinges on the development of a regioselective, diastereoselective, and stereospecific trapping of a fleeting cyclic allene intermediate. This key step swiftly assembles the azadecalin framework of the natural product, allows for a succinct synthetic endgame, and enables a 12-step total synthesis (longest linear sequence; 0.8% overall yield). These studies demonstrate that strained cyclic allenes are versatile building blocks in chemical synthesis.

Catalyst-Controlled Annulations of Strained Cyclic Allenes with π-Allylpalladium Complexes

“…Arynes − and cyclic alkynes , (e.g., 1 – 3 , Figure A) have been most well-studied with applications spanning the synthesis of heterocycles, , ligands (such as XPhos), natural products, − agrochemicals, and organic materials. , A related class of strained intermediates discovered around the same time as arynes and cyclic alkynes is strained cyclic allenes, such as 1,2-cyclohexadiene ( 4 ). , The cumulated diene confined to a small ring leads to ∼30 kcal/mol of strain energy, making cyclic allenes well-suited for strain-promoted reactions. − However, these intermediates have received significantly less attention compared to arynes and cyclic alkynes despite possessing many attractive attributes that substantiate their value as building blocks for the synthesis of complex sp 3 -rich scaffolds. Recent studies of strained cyclic allenes have led to advances in cyclic allene generation protocols, − cycloaddition reactions, − metal-catalyzed processes, ,, trapping in a single-electron process, DNA-encoded library synthesis, and total synthesis …”

“…Recent studies of strained cyclic allenes have led to advances in cyclic allene generation protocols, 24−26 cycloaddition reactions, 27−36 metal-catalyzed processes, 24,37,38 trapping in a single-electron process, 39 DNAencoded library synthesis, 40 and total synthesis. 41 An attractive yet underdeveloped approach to leveraging strained cyclic allenes in synthesis utilizes transition metal catalysis. 42,43 Only three reports of such transformations have been demonstrated in the literature.…”

Cyclic Allene Approach to the Manzamine Alkaloid Keramaphidin B

“…50 This was achieved by subjecting cycloadduct 14 to allylic oxidation conditions, followed by a diastereoselective 1,4-reduction using modified Stryker's reagent. 13 Product 15 was obtained in 48% yield over two steps with >20:1 dr. Next, heating 15 to 80 °C in acetonitrile facilitated a retro-Diels−Alder reaction. Treatment of the product with TFA led to the removal of the Boc protecting groups, thus affording the desired substrate 16.…”

“…Specifically, we questioned whether azacyclic allenes ( 2 ) could be used to assemble the azadecalin core and generate the C8a quaternary stereocenter of keramaphidin B ( 1 , Figure ). The use of strained cyclic allenes in the context of total synthesis has remained underexplored, especially in comparison to related aryne chemistry, which has been used in >100 total syntheses to date. − Encouraged by our group’s recent success in using an azacyclic allene ( 2 ) in the total synthesis of (−)-lissodendoric acid A, we sought to further expand cyclic allene chemistry by utilizing these fleeting intermediates to build the highly complex bridged azadecalin core of keramaphidin B ( 1 ).…”

“…To evaluate the key step, 11 was subjected to pyrone 12 in the presence of CsF at 23 °C. Notably, pyrone 12 was chosen as the trapping partner for this cycloaddition, as it has been demonstrated to be a competent diene for the strain-promoted Diels–Alder cycloaddition with azacyclic allenes . We were delighted to obtain cycloadduct 14 in 56% yield.…”