Intramolecular Chemoselective Acylation of a Suitably Substituted Isoindole: Synthesis of (±)-Chilenine and (±)-Deoxychilenine

Abstract

Starting from 3,4-dimethoxyhomophthalic anhydride and 6-bromohomopiperonylamine, concise and efficient syntheses of Chilean berberis products chilenine and deoxychilenine have been demonstrated via partially divergent routes by taking advantage of facile air-oxidation of homophthalimide along with intramolecular chemoselective acylation as the key steps.Chilenine (1), deoxychilenine (2), and lennoxamine (3) were isolated, respectively, from Berbelis empetrifolia, Berbelis actinacantha, and Berbelis darwinii 1 and they belong to the isoindolobenzazepine class of alkaloids ( Figure 1). 2 These natural products are biogenetically related to protoberberines, hence their ring systems are accessible by oxidation of berberine alkaloids. 3 On the basis of the important biological properties of the berberine class of compounds and the intriguing structural features of these three natural products 1-3, several elegant synthesis of chilenine and lennoxamine have been reported. 4,5 Recently, Honda and Sakamaki have also reported the first synthesis of deoxychilenine employing a novel palladium-catalyzed intramolecular arylation. 4c In continuance of our comprehensive studies on cyclic anhydrides and derivatives to bioactive natural and unnatural products, 6 recently we serendipitously witnessed the facile air oxidation of homophthalimides and utilized it for the synthesis of nuevamine and isoindolo-b-carboline. 7 In this context, we herein report the total synthesis of chilenine and deoxychilenine from 3,4-dimethoxyhomophthalic anhydride via partially divergent routes utilizing intramolecular acylation as the decisive step 8 (Scheme 1).The reaction of 3,4-dimethoxyhomophthalic anhydride (4) 9,10 and homopiperonylamine (5a) in refluxing odichlorobenzene furnished the required homophthalimide 6a in 78% yield. As expected, the homophthalimide 6a underwent facile air oxidation at an activated benzylic position and provided the prospective precursor trione 7a in 94% yield. In principle the selective Friedel-Crafts-type intramolecular acylation of trione 7a would provide direct access to chilenine (1) via a ring-expansion and recyclization mechanism. However, all attempts to transform the trione 7a into 1 utilizing acid-catalyzed (TFA, H 2 SO 4 / AcOH, PTSA/xylene), Lewis acid catalyzed (BF 3 ·OEt 2 , AlCl 3 , AuCl 3 , TMSOTf), and thermal cyclization (DMSO reflux, neat heating 200 °C) conditions were unsuccessful and always ended up with either the unreacted starting material or excessive decomposition. The trione 7a on base-catalyzed regioselective methanolysis provided the ring-contraction product lactamol 8a in 96% yield with the desired free ester moiety. Figure 1 Chilean berberis productsAs depicted in Scheme 1, the product 8a was also directly obtained in one step from the corresponding homophthalimide 6a in 94% yield by utilizing the combination of a similar set of reaction conditions. Conversely, the multifunctional compound 8a under acidic conditions (TFA, H 2 SO 4 /AcOH, PTSA/CH 2 Cl 2 ) was very prone to sixmembered ...

[2 + 2 + 2] Cyclotrimerization with Propargyl Halides as Copartners: Formal Total Synthesis of the Antitumor Hsp90 Inhibitor AT13387

“…Synthesis of Diyne 12. 14 To the suspension of 4methylbenzenesulfonamide (10) (2.00 g, 11.7 mmol) in acetone, cesium carbonate (11.4 g, 35 mmol) was added and stirred for 15−20 min at room temperature. To this, propargyl bromide (11a) (4.16 g, 35 mmol) was added, and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo.…”

“…4a In 2010, Tatsuta group has reported the first total synthesis of lactonamycin, where they used a sequential intramolecular conjugate addition of alcohols to the acetylenic ester and stereoselective glycosylation of the tertiary alcohol and Michael−Dieckmann-type cyclization as key steps. 4b Stachflin (4), 5 stachybotrylactam (5), 6 memnobotrin A (6), 7 erinacerin A (7), 8 and hericinone B (8) 9 are meroterpenoids, and chilenine (9) 10 is an alkaloid containing an isoindolinone unit.…”