Total Synthesis of the β-Catenin Inhibitor, (−)-Agelastatin A: A Second-Generation Approach Based on Radical Aminobromination

Abstract

The second-generation approach to (-)-agelastatin A has been established. The present strategy features the FeBr(2)-mediated radical cyclization of 2-cyclopentenyloxycarbonyl azide that allows for the stereoselective installation of a cis-vicinal aminobromo functionality suitable for producing the BCD-ring system of agelastatin A. The aminobromination method streamlines access to oxazolidinone, a key intermediate in the previously reported synthesis, thereby culminating in the new total synthesis of (-)-agelastatin A.

Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids

“…85 The same approach was also utilized in their second generation synthesis completed the following year. 86 Also in 2009, the strategy employed by Chida featured an elegant sequential Overman/Mislow-Evans rearrangement of bis-trichloroimidate 141 followed by ring-closing metathesis that established cyclopentene 140 . 87 In 2009, DuBois disclosed an 11-step synthesis of (−)-agelastatin A, 88 hinging on a novel catalytic intramolecular aziridination method applied to sulfonamide 144 derived from heterobicyclic 145 , followed by sequential regioselective ring openings to afford the completely functionalized C ring 143 .…”

Formal synthesis of (−)-agelastatin A: an iron(II)-mediated cyclization strategy

“…N -Tosyloxycarbamate 8 was prepared from alcohol 6 , which was obtained by a previously reported protocol (Scheme 2) [26–27]. Alcohol 6 was first treated with CDI ( N , N ’-carbonyldiimidazole) and then with hydroxylamine hydrochloric acid salt to afford N -hydroxycarbamate 7 in 67% yield [36].…”

“…The second-generation strategy involved the radical aminobromination of azidoformate 3 followed by lactamization of the resultant bromide 5a to furnish a tetracyclic compound (structure not shown), which was transformed into the natural product [27]. In the present study, we disclose a new approach to the key intermediate for AA synthesis in which N -tosyloxycarbamate 8 , a nonhazardous azidoformate surrogate, is transformed into aminohalogenated compounds 5a and 5b by FeBr 2 /Bu 4 NBr [28–29], FeCl 2 /Bu 4 NCl, or FeCl 2 /TMSCl [30–35] (Scheme 2).…”

Total Synthesis of All (–)‐Agelastatin Alkaloids

“…46 Importantly, (−)-O-methyl-di-epi-agelastatin A (29) served as a versatile precursor for the synthesis of (-)-Agelastatin C (3, Scheme 2). Heating a solution of (−)-O-methyl-di-epiagelastatin A (29) in pyridine afforded (−)-dehydroagelastatin A (30, Scheme 2) in 99% yield. 55 As anticipated, treatment of 30 with dimethyldioxirane (DMDO) gave (−)-di-epiagelastatin C (31, 98%) via oxidation on the convex face.…”