Asymmetric Giese additions employing chiral unsaturated acylammonium salts & Synthetic studies toward curromycin A




Kasper, Kristiana

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Lactams have high bioactivity because of their structural similarity to nitrogenous bases1,2 and peptide bonds.3 The asymmetric synthesis of lactams continues to be an important endeavor, since active pharmaceutical ingredients (APIs) require absolute stereocontrol to bind to their cellular targets. Isothiourea catalysts, such as benzotetramisole (BTM), react with α-β unsaturated acid chlorides and other activated esters to form unsaturated acylammonium salts, enabling a variety of subsequent anionic reactions. Anionic nucleophiles such as activated imines,4 enamides,5 aminothiols,6 azodicarboxylates,7 and aminomalonates5 can utilize chiral acylammonium intermediates towards optically active lactam synthesis.8 In these cases, the electron-withdrawing groups that facilitate anion formation determine the substitution at the C-C bond formation site. In contrast, this study employs a diastereoselective Giese addition of amine-tethered carbon radicals to generalize the scope of accessible products. It builds on recent work by Smith9 and Melchiorre,10 using facially selective α-radical trapping to generate a second stereocenter. Efforts toward optimization and applications of this methodology are described.

Curromycin A shows antibacterial,11 antitumor (IC50 = 84 μM against P388,12 IC50 = 6.0 nM GRP78 inhibition via luciferase assay13, IC50 = 22 pM against MKN45 via MTT assay), and antiviral (IC50 = 9.1 nM14 against human immunodeficiency virus) activity. Its spiro-β-lactone-γ-lactam core is homologous to that of known covalent modifiers whose mechanism of action involves acylation of nucleophilic amino acids.15,16 This core is joined to an oxazole triene via a β-hydroxy pivalamide. Interestingly, each of these three moieties shows evidence for independent bioactivity,17 reinforcing the importance of structure-activity relationship (SAR) studies. ‘Pharmacophore-directed retrosynthesis’ (PDR), while maintaining the chemical elegance and efficiency typical of traditional retrosynthesis, plans targets that not only function as synthetic intermediates, but also serve as candidates for biological testing to expand the SAR profile of the target natural product. For example, a modular route allows transposable coupling with both the E,E,E- and Z,Z,E-trienes to interrogate the effects of the triene geometry on bioactivity. Previous work toward the Z,Z,E-triene was hindered by the generation of an undesired allene product upon deprotection of an alkyne intermediate, forming a fully conjugated system with the oxazole. The current strategy towards this triene, heavily inspired by previous synthetic efforts toward analogous natural product inthomycin A,18 deprotects and reduces the alkyne before the oxazole coupling. A regioselective Grignard addition to propyn-3-ol is subsequently captured by an electrophilic iodine source, a cis-diimide reduction generates the second Z-alkene, and a Stille cross-coupling reaction forges the triene. The culmination of the proposed synthesis is a clickable β-lactone derivative of inthomycin A, as well as its application to the overall synthetic studies of curromycin A.