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.

Fig. 1.. Strained intermediates and overview of current study.

(A) Seminal strained cyclic intermediates 1, 2, and 4 and bioorthogonal cyclooctyne reagents 3. (B) Geometry-optimized structure of strained azacyclic allene 5 [ωB97XD/6–31G(d)] and key features. CO₂Me is omitted from the three-dimensional representations for clarity. (C) Our synthetic target, lissodendoric acid A (6), and our synthetic approach by using a [4+2] cycloaddition to access 7 from cyclic allene 8 and pyrone 9 (R’, R”, R”’ = alkyl).

Fig. 2.. Regioselectivity and stereospecificity studies using variable cyclic allene precursors and [4+2] cycloaddition partners.

(A) Use of cyclic allene precursor 12 allows for efficient and stereospecific cycloadditions. (B) Stereospecificity is modest when using pseudo-isomeric silyltriflate 16. (C) Switching to silylbromide 18 as the cyclic allene precursor allows for regioselective and stereospecific cycloaddition reactions, while providing a plausible entryway to enantioenriched material. Highlights indicate the primary differences between cyclic allene precursors 12, 16, and 18. Reaction conditions are provided in the supplementary materials.

Fig. 3.. Assembly of the azadecalin core of lissodendoric acid A (6) by using a strained cyclic allene.

(A) Synthesis of pyrone 22. (B) Enantioselective route to silyltriflate 27. (C) Cycloaddition of the strained cyclic allene derived from 27 with pyrone 22 proceeds with regioselectivity, diastereoselectivity, and stereospecificity to deliver enantioenriched adduct 28 with the desired quaternary stereocenter at C8a.

Fig. 4.

Completion of the total synthesis of lissodendoric acid A (6).