Synthesis of Atisine, Ajaconine, Denudatine, and Hetidine Diterpenoid Alkaloids by a Bioinspired Approach

Abstract

A unified approach to four different (atisine, ajaconine, denudatine, and hetidine) diterpenoid alkaloid skeletons was developed and applied to the total synthesis of the natural products dihydroajaconine (2, atisine type) and gymnandine (4, denudatine type). The synthesis features a biogenetically inspired strategy that relies on C-H oxidation, aza-pinacol coupling, and aza-Prins cyclization as key steps.

Magnesiate Addition/Ring-Expansion Strategy To Access the 6–7–6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids

“…The synthesis of the related hetidine-type core, which lacks the N-C6 bond (Figure 1), has seen more recent success, with routes from our group 7 as well as the laboratories of Baran 8 and Qin. 9 While early work by Okamoto suggested a final N-C6 bond could be formed at a late stage through HLF-type chemistry, 10 this transformation has not been successfully realized by other investigators, suggesting the need for novel strategies that incorporate the formation of this N-C6 bond into the synthetic plan.…”

Studies towards Bioinspired Synthesis of Hetidine‐Type C20‐Diterpenoid Alkaloids

“…The atisine-type intermediate 29 bearing a C(7) functionality could in turn be prepared via an oxidative dearomatization/intramolecular Diels-Alder cycloaddition (IMDA) cascade [12] and Corey-Seebach reaction [13] from the building blocks 30 and 31. [5] Based on the aforementioned strategy, we first concentrated on the preparation of the pentacyclic atisine core structure through a concise synthetic route. As shown in Scheme 4, treatment of the in situ generated 2-lithio-1,3-dithiane species from 31 with iodide 30, [5] followed by removal of the methoxymethyl (MOM) group using concentrated HCl in MeOH, provided olefinic phenol 32 with 80% overall yield.…”

“…[5] Based on the aforementioned strategy, we first concentrated on the preparation of the pentacyclic atisine core structure through a concise synthetic route. As shown in Scheme 4, treatment of the in situ generated 2-lithio-1,3-dithiane species from 31 with iodide 30, [5] followed by removal of the methoxymethyl (MOM) group using concentrated HCl in MeOH, provided olefinic phenol 32 with 80% overall yield. The planed oxidative dearomatization/IMDA cascade reaction proceeded smoothly by subjection of 32 to PhI(OAc) 2 in MeOH, yielding the pentacycle 33 as a single Scheme 2 Attempted biomimetic synthesis of the hetidine skeletons by Baran and our group Scheme 3 Retrosynthetic analysis of hetidine-type alkaloid based on the proposed biosynthetic hypothesis Scheme 4 Preparation of the atisine-type core structure bearing a C(7) functional group diastereomer, the structure of which was verified by X-ray crystallography analysis.…”

“…[5] 1 mmol) in toluene (60 mL) was added. The reaction was then heated to 80 ℃, kept stirring for 5 h, and cooled down to room temperature before it was quenched by saturated NH 4 Cl solution (120 mL).…”

“…[5] This paper describes the details of our synthetic efforts towards the hetidine-type C 20 -diterpenoid alkaloid skeleton that rely on the biogenetically related atisine and ajaconine intermediates.…”