A Versatile Enantioselective Synthesis of Azabicyclic Ring Systems: A Concise Total Synthesis of (+)‐Grandisine D and Unnatural Analogues

Abstract

Closing in on azacines: We have developed a new six step approach for the rapid and enantioselective synthesis of indolizidine, pyrrolo[1,2‐a]azepine, and pyrrolo[1,2‐a]azocine azabicyclic systems and their respective lactam congeners, which are found in a host of natural products as well as pharmaceutical preparations. This protocol enables a concise enantioselective total synthesis of (+)‐grandisine D in 16.4 % overall yield from commercial materials (see scheme).

Enantioselective Total Synthesis of (+)-Amabiline

“…1–5 The majority of these approaches rely on the chiral pool, employing l -proline, malic acid or carbohydrates as chiral starting materials. 1 Based on the synthetic challenge, the diverse biological activity and our recently reported methodology to construct multiple bicyclic azacine systems, 8 we decided to apply our methodology towards the enantioselective synthesis of (+)-amabiline ( 3 ), an unsaturated pyrrolizidine alkaloid, isolated in 1967 from Cynoglossum amabile , that has yet to be the subject of a total synthesis. 7,9–12 …”

“…6 has been synthesized previously, but the most expedient route required 18 steps. 13 By employing a novel extension of our newly developed azacine methodology, 8 6 would be accessed from 8 , which would be derived form commercial diol 10 and ( S )- tert -butyl sulfinimine 11 . (−)-Viridifloric acid ( 7 ) would be prepared as prescribed by Schulz, 14 via 9 , from commercial 12 and 13 .…”

“…Condensation of 17 with ( S )- tert -butyl sulfinimine 11 gave 18 in 79% yield. 8,15–17 Addition of Grignard reagent 19 provides 20 in >9:1 dr , 8,15–21 which is subsequently allylated to deliver 21 in 77% yield for the two steps. A ring closing metathasis reaction employing Grubbs II 22 smoothly led to pyrrolidine 22 , and a TBAF deprotection generated the key intermediate 8 .…”

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

“…This synthesis is shown in Scheme 6 and starts from commercially available 2-methylene-1,3-propanediol ( 11 ). Mono-protection of this diol as a TBS ether and activation of the remaining alcohol as a mesylate according to previously reported procedures [57–58], gave allylic mesylate 12 , which was next reacted with potassium phthalimide in DMF at 90 °C, affording the corresponding N -allylphthalimide. Deprotection of the phthalimide by hydrazinolysis followed by protection of the resulting primary amine as a tert -butyl-carbamate gave the Boc-protected amine 13 required for the synthesis of the substrate of the anionic cyclization.…”

Synthesis and biological evaluation of cremastrine and an unnatural analogue

“…1,2 As such, 1 would have the potential to treat irritable bowel syndrome, chronic obstructive pulmonary disease and asthma. 2 Based on our lab’s interest in muscarinic drug discovery 3 and our recently developed methodology to rapidly construct enantiopure idolizines, pyrrolo[1,2- a ]azepines and pyrrolo[1,2- a ]azocines, 4 application of this methodology to the synthesis of the related pyrrolizidine core seemed warranted. In this letter, we report the first total synthesis of cremastarine ( 1 ) employing a new synthetic strategy, distinct from previous pyrrolizidine syntheses, 5–8 (Scheme 1), that afforded 1 in 7 total synthetic steps and an overall yield of 25.2% that enabled biological evaluation.…”