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Total Synthesis of (+)-Scholarisine A - Europe PMC …

Total synthesis of (+)-scholarasine A - ResearchGate

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Scholarisine A synthesis « Naturalproductman’s Blog

An effective total synthesis and assignment of the absolute configuration of the architecturally challenging (+)-scholarisine A has been achieved via a 20-step sequence. Highlights include a reductive cyclization, involving a nitrile and an epoxide; a modified Fischer indole protocol; a late stage oxidative-lactonization; and an intramolecular cyclization leading to the indolenine ring system of (+)-scholarisine A.

PRIME PubMed | Total synthesis of (+)-scholarisine

The structural complexity of the akuammiline alkaloid scholarisine A poses considerable synthetic challenges. Snyder and Smith report an elegant and short route to this natural product that relies on a Diels–Alder reaction and radical cyclization to provide rapid access to the target’s core. The indolenine is introduced in an intriguing late-stage C–H-arylation step. The architecturally unique alkaloid could thus be prepared in merely 15 steps. It is noteworthy that only one other synthesis of this challenging target has been reported so far (G. L. Adams, P. J. Carroll, A. B. Smith, III. , , 4037).

Total Synthesis of Calophyline A - Li - 2016 - …

The lactone of the natural product was introduced early in the synthesis through the Diels–Alder cycloaddition of dienophile and pyrone , which afforded in 83% yield and 3:1 dr. Cleavage of the acetonide followed by displacement of the resulting primary alcohol furnished bromide . Radical cyclization and subsequent trapping gave key intermediate in 59% yield as a single diastereomer. An epimerization–lactamization sequence afforded which was treated with 2-iodoaniline to give imine . This underwent the challenging tertiary C–H arylation, affording . A few transformations later the synthesis was completed.

The structurally unique akuammiline alkaloid (+)-scholarisine A was synthesized in 14 steps from a known enone (15 steps from commercial materials) through a route empowered by a unique C–H arylation reaction to forge its polycyclic core. Additional key steps include a pyrone Diels–Alder reaction and a radical cyclization/Keck allylation to fashion the core cage polycycle and one of the molecule’s quaternary centers, as well as the use of a carefully positioned pendant hydroxyl group to facilitate the chemoselective reduction of an extremely unreactive lactam in the presence of a readily reduced lactone.

Total Synthesis of (+)-Scholarisine A

Scholarisine A (1), a monoterpenoid indole alkaloid first isolated in 2008 from the leaves of Alstonia scholaris, comprises an unprecedented scaffold containing a bridged lactone inscribed in a cage-like skeleton (). Although no information on the bioactivity of scholarisine A (1) is currently available, congeners of a putative biosynthetic precursor, picraline (3), have been reported to be potent, selective inhibitors of SGLT2, a renal cortex membrane protein that regulates glucose re-absorption, that was recently validated as a target for type II diabetes intervention.

Alkaloids that derive biosynthetically from geissoschizine (5), via a cyclization leading to a bond between C-7 and C-16 are classified as the akuammiline alkaloids (), named after akuammiline (7), first characterized in 1932. Loss of the acetoxymethyl moiety leads to strictamine (6). Hydrolysis and further functionalization is envisioned to provide alkaloids with a furoindoline core such as aspidodasycarpine (8) and aspidophylline A (9), the latter the target of a recent elegant racemic total synthesis by Garg. Alternatively akuammiline (7) could give rise to picrinine (4) upon loss of the acetoxymethyl moiety from C-16 and oxidation at C-5. Scholarisine A (1), the target of this study, is proposed to arise from picrinine (4) via initial opening of the oxygen bridge at C-2 via participation of the indoline nitrogen and cleavage of the N-4 to C-5 bond to furnish an aldehyde at C-5; migration of the double bond, nucleophilic attack by the resulting enamine carbon, and capture of the resulting hydroxyl group by the methyl ester would lead to the lactone ring of scholarisine A (1).

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Synthesis of the Carbon Framework of Scholarisine A …

An effective total synthesis and assignment of the absolute configuration of the architecturally challenging compound (+)-scholarisine A has been achieved via a 20-step sequence. Highlights include a reductive cyclization involving a nitrile and an epoxide, a modified Fischer indole protocol, a late-stage oxidative lactonization, and an intramolecular cyclization leading to the indolenine ring system of (+)-scholarisine A.

Total Synthesis of (±)‐Aspidophylline A, Angewandte …

Given the novel architectural features of scholarisine A (1), in conjunction with the inherent synthetic challenge and the possibility of discovering a substrate that would permit a novel enantioselective route to the currently unobtainable akuammiline alkaloids via a late stage “retro-biosynthetic” fragmentation, we initiated a synthetic program to construct scholarisine A (1) in 2008. We report here the first total synthesis of (+)-scholarisine A (1), comprising an enantiospecific strategy.

Organic Synthesis: State of the Art, 2013-2015: 2013 …

Alstoscholarisines H–J (13), new monoterpenoid indole alkaloids with an unprecedented skeleton created via the formation of a C-3/N-1 bond, were isolated from . Their structures were established by extensive spectroscopic analyses and the assessment of single-crystal X-ray diffraction data. The total synthesis of alstoscholarisine H was achieved via the regioselective nucleophilic addition of pyridinium through a bioinspired iminium ion intermediate followed by Pictet–Spengler-like cyclization.

The Snyder Synthesis of (+)-Scholarisine A

From the retrosynthetic perspective, we envisioned scholarisine A (1) to arise via cyclization and oxidation of indole lactone 10 (). Construction of the latter would entail an oxidative-lactonization of diol 11 with subsequent deprotection. Diol 11 in turn could derive from lactone 12, via homologation and reduction, the latter obtained from tricyclic amine 13, upon amine protection, oxidation and a Fischer indole annulation. Amine 13, the cornerstone construct of this synthetic venture was envisioned to be the product of a reductive-cyclization involving the nitrile and epoxide functionalities present in lactone 14, which could be prepared from known bicyclic lactone (−)-15.

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