A Formal Total Synthesis of Securinine via an Intramolecular [4+2] Cycloaddition Reaction

Abstract

An intramolecular Diels-Alder reaction of the enol ester derived from 2-acetylpyridine and sorbic anhydride gave the cycloaddition product, stereoselectively, which was further converted into the key intermediate for the synthesis of securinine.Securinine, 1 a member of the Securinega family of alkaloids having a tetracyclic indolizidine skeleton with an α,β-unsaturated γ-lactone, was originally isolated from Securinega suffruticasa, 2 and its structure was determined by chemical and spectroscopic studies, 3,4 and also by X-Ray crystallographic analysis 5 as shown in Figure 1. N O O H Figure 1. The structure of securinine.Since this alkaloid has been shown to exhibit a stereospecific GABAA receptor antagonist activity, a number of syntheses and synthetic approaches were developed with the hope of understanding the shape of the GABAA receptor site. 6 To date, only two total syntheses of securinine have been reported. 7 The first total synthesis of securinine was published by Horii and co-workers in 1967, 7a where cyclohexane-1,2-dione was employed as the A-ring precursor and 2-lithiopyridine was introduced as the C-ring moiety. Although a number of synthetic approaches to this alkaloid were developed after Horii's synthesis, most of them could not reach to its total synthesis. Very recently, a concise total synthesis of securinine was achieved by using a ring closing metathesis leading to the construction of the A-ring, as a key reaction by Liras and co-workers. 7b Due to the attractive biological activity and also its unique structural feature, we are also interested in developing a novel strategy for the synthesis of securinine, in N Boc O N Boc O O N Boc O O Scheme 2. 1) LDA, THF 2) sorbic anhydride 10 11 12Although the stereochemistry of the products could not be determined at this stage, the major product was Treatment of the diol (26) with thiocarbonyldiimidazole afforded the thionocarbonate (27) in 85% yield.Reductive deoxygenation of 27 with bis(1,5-cyclooctadiene)nickel(0) [Ni(COD) 2 ], 12 provided the olefin (28), mp 138°C, in 90% yield. Finally, the diene system was introduced by phenylselenylation of 28 in the presence of lithium diisopropylamide, followed by oxidative elimination of the selenide (Scheme 6).Since the compound (29) was already converted into securinine by Horii and co-workers, 7a this synthesis constitutes its formal synthesis.

Securinega Alkaloids from the Twigs of Securinega suffruticosa and Their Biological Activities

“…The molecular formula of securingine G ( 7 , colorless gum) was confirmed as C 13 H 11 NO 3 from the protonated HRESIMS ion peak at m / z 230.0816 (calcd for [M + H] + , 230.0817) and the 13 C NMR data. Inspection of the 1D NMR data of 7 (Table ) showed similarities to the data of 7a-(pyridin-2-yl)-7,7a-dihydrobenzofuran-2­(6 H )-one ( 8 ), but the signal for an oxygenated methine proton [δ C 66.9; δ H 4.61 (1H, brs)] in 7 was replaced by an aliphatic methylene [δ C 25.2; δ H 2.49 (1H, dt, J = 19.6, 5.3 Hz) and 2.24 (1H, m)] in 8 (Table ). With the guidance of HMBC cross-peaks of H-14/C-7 and H-8/C-7, the configuration of the hydroxy group was determined to be at C-7 (Figure ).…”

“…Compound 8 was elucidated as 7a-(pyridin-2-yl)-7,7adihydrobenzofuran-2(6H)-one by analysis of its 2D NMR data and was reported previously as an intermediate product in a synthetic pathway without determination of the absolute configuration. 11 In the present study, the full NMR assignments and the absolute configuration of 8 are reported (Table 2). The configuration of 8 was defined as 9S through the correlation of the experimental and calculated ECD spectra (Figure 3).…”

Selective C-H Fluorination of Pyridines and Diazines Inspired by a Classic Amination Reaction

“…Thus, the mild conditions, fast reaction times, broad scope, high tolerance for auxiliary functionality, and commercial availability of the reagent for the fluorination that we report create the ability to generate fluorinated pyridines and diazines. Considering the high interest in generating fluorinated drug and agrochemical candidates and the high utility of fluorinated heteroarenes as synthetic intermediates, we anticipate that synthetic chemists will rapidly adopt this class of halogenation reaction (45,46). The gravitational interaction of dust in the zodiacal cloud with individual planets is expected to give rise to ringlike features: Such a circumsolar ring has been observed associated with Earth, but such resonance rings have not been confirmed to exist for other planets.…”

An Efficient Approach to the Securinega Alkaloids Empowered by Cooperative N‐Heterocyclic Carbene/Lewis Acid Catalysis

“…Given these attributes, it is unsurprising that the synthetic community has devoted significant attention to this collection of compounds,5 particularly to the challenges posed by the key shared domains within 1 – 5 . Indeed, since the inaugural total synthesis of securinine ( 1 ) by Horii in 1966,5a several other successful and highly creative approaches for forging their fused bicyclic butenolide domains have been disclosed, efforts that include selenoxide eliminations,5b,e,f,h,i,r intramolecular Wittig olefinations,5e,f,o,p,t–v ring‐closing metatheses,5j–p,s,x and alkylation of allylic bromides or mesylates 5a,h,i–m,q,t–v,x. However, most of these strategies require multiple steps to execute, typically constituting the longest (and least efficient) portion of the overall route.…”