Total Synthesis of Lycogarubin C and Lycogalic Acid

Abstract

Two complementary concise total syntheses of lycogarubin C (1) and lycogalic acid (2, aka chromopyrrolic acid) are detailed utilizing a 1,2,4,5-tetrazine → 1,2-diazine → pyrrole Diels-Alder strategy and enlisting acetylenic dienophiles.Lycogarubin C (1) and lycogalic acid (2) were first identified as natural products in 1994, having been isolated independently by Steglich 1 and Akazawa 2 from Lycogala epidendrum, a slime mold (Figure 1). More recently, lycogalic acid, also referred to as chromopyrrolic acid (CPA), 3 has been identified as a common intermediate in the biosynthesis of the indolo[2,3-a]carbazole alkaloids including rebeccamycin (6) and staurosporine (7) that exhibit broad spectrum activity as inhibitors of protein kinases as well as Topoisomerase I. 4 As the efforts to elucidate the details of this biosynthetic pathway have progressed, the oxidation of chromopyrrolic acid (2) to 4 via 3 has attracted considerable interest since it involves an unusual oxidative aryl-aryl coupling reaction. 3,5 Moreover, in exploration of the individual enzymecatalyzed steps in the pathway, 5 was isolated as an aerobic product following the oxidative coupling of 2 effected by RebP/StaP. 6 As an off pathway intermediate that does not lead to formation of 4, it is likely that 5 and related compounds may well constitute the newest members of this class of natural products. As a result, we initiated efforts on the synthesis of 1 and 2 that in turn may serve as synthetic as well biosynthetic precursors to these potential newest members of this class of natural products.Complementary to reports of the synthesis of 1 or 2, 1,7-9 we anticipated that 1 and 2 would be readily accessible through use of a 1,2,4,5-tetrazine → 1,2-diazine → pyrrole Diels-Alder strategy that appears ideally suited for their preparation. 10 Thus, the inverse electron demand Diels-Alder reaction of a 1,2-bis(indol-3-yl)acetylene (8) with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (9) 11 followed by a reductive ring contraction reaction of the resulting 1,2-diazine 12 to a dimethyl pyrrole-2,5-dicarboxylate could directly provide 1 or a protected penultimate precursor (Figure 2). Moreover, the potential use of the mono methyl esters derived from such dimethyl pyrrole-2,5-dicarboxylates to directly access products like 5 via a unique oxidative decarboxylation reaction 13 provided the additional incentive for us to pursue the synthesis of 1 and 2. The recent disclosure of Fu and Gribble 9 reporting that this direct strategy was not successful and their development of a clever alternative, using an olefinic versus boger@scripps.edu. Supporting Information Available. Full experiment details and compound characterizations are provided. This material is available free of charge via the internet at

A molecular electron density theory study of the participation of tetrazines in aza-Diels–Alder reactions

“…1,2,4,5-Tetrazine 1 has proven to be a useful reagent that participates in aza-Diels-Alder (ADA) reactions with a wide range of ethylene and acetylene derivatives, providing rapid access to a range of highly substituted pyridazines. [1][2][3][4][5][6][7][8] The expected bicyclic compounds such as 3 have never been observed, with pyridazine 4 being the product obtained by loss of molecular nitrogen (see Scheme 1).…”

Fast Halogenation of Some N‐Heterocycles by Means of N,N′‐Dihalo‐5,5‐dimethylhydantoin

“…1 H NMR (400 MHz, CD 3 Cl): δ =7.92 (1 H, s), 7.06 (1 H, d, J =7.6 Hz), 6.92 (1 H, d, J =8.0 Hz), 6.81 (3 H, m, J =7.0 Hz); 13 C NMR (150.9 MHz, CD 3 Cl): δ=135.7, 129.8, 128.6, 123.3, 121.0, 120.8, 111.4, 57.5; MS (EI): m/z (%)=242.9 (M + , 100), 116.0 (75), 89 (47). The recorded spectral data were in accordance with the literature 29…”

Synthesis of Nucleoside Derivatives of <i>N</i>-Acetyl-7-nitroindoline, Their Incorporation into the DNA Oligomer, and Evaluation of Their Photoreactivity in the DNA/RNA Duplex

“…In a preliminary study using N-acetyl-7-nitroindoline and 3′-O-,5′-O-bis tert-butyldimethylsilyl (TBS)-protected 2′-deoxycytidine in CH 3 CN, N-acetyl cytidine and 7-nitroindoline were formed by UV irradiation at 365 nm. To investigate the photo-reactivity of the N-acetyl-7-nitroindoline derivative in nucleic acids, new nucleoside analogs (7)(8)(9) were designed ( Fig. 1).…”