Total synthesis of lycogarubin C utilizing the Kornfeld–Boger ring contraction

Fu, Liangfeng; Gribble, Gordon W.

doi:10.1016/j.tetlet.2009.11.085

Cited by 30 publications

(17 citation statements)

References 25 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

2020

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The reactions of eight tetrazines of increased electrophilic character with nucleophilic tetramethyl ethylene (TME) and with electrophilic tetracyanoethylene (TCE) have been studied using Molecular Electron Density Theory. These reactions are domino processes comprising an aza-Diels-Alder (ADA) reaction followed by an extrusion of molecular nitrogen, yielding a dihydropyridazine. Analysis of the conceptual DFT (CDFT) indices showed an increase of the electrophilicity and a decrease of the nucleophilicity of tetrazines with an increase of the electron-withdrawing character of the substituent. A very good correlation between the global electron density transfer at the transition structures and the activation enthalpies for the ADA reactions involving TME was found. However, tetrazines have no tendency to react with electrophilic ethylenes such as TCE. Bonding Evolution Theory (BET) analysis of the ADA reaction of dinitro tetrazine with TME showed that the activation energy is mainly associated with the continuous depopulation of the C-C and C-N double bonds. † Electronic supplementary information (ESI) available: Figure with the geometries of MCa and MCh. Figures with the attractor positions of the ELF valence basins of the relevant IRC structures of the ADA reaction between dinitro tetrazine 14a and TME 15, and those of TS1a-h.Table with MPWB1K/6-311G(d,p) global CDFT reactivity indices for the studied reagents. Tables with the MPWB1K/6-311G(d,p) electronic energies, enthalpies, entropies and Gibbs free energies for the stationary points involved in the domino reactions of the series tetrazine derivatives 14a-h with TME 15, and those of the domino reactions of the series tetrazine derivatives 14f-h with TCE 18. Table with the MPWB1K/6-311G(d,p) unique imaginary frequency of TS1a-k and TS2a-k. See

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Section: Introductionmentioning

confidence: 99%

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

2020

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“…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-diazine12 to a dimethyl pyrrole-2,5-dicarboxylate could directly provide 1 or a protected penultimate precursor (Figure 2).…”

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confidence: 99%

Total Synthesis of Lycogarubin C and Lycogalic Acid

Oakdale

Boger

2010

Org. Lett.

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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

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“…It is interesting to note that Sherman 11 (2005) and Walsh 12 (2007) have suggested that lycogallic acid is a biosynthetic precursor to the important naturally occurring, antitumor agents rebeccamycin and staurosporin. Previous syntheses of members of the lycogarubin/lycogallic acid family of natural products have been accomplished by Steglich 9 (1994), Furstner 2 (2002), Onaka 13 (2006), Boger 14 (2010), Gribble 15 (2010) and more recently by Xie 16 (2014). The Boger and Gribble syntheses both rely on the Kornfeld-Boger ring contraction methodology to generate the pyrrole core.…”

Section: Resultsmentioning

confidence: 99%

The application of formyl group activation of bromopyrrole esters to formal syntheses of lycogarubin C, permethyl storniamide A and lamellarin G trimethyl ether

et al. 2014

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Lycogarubin C, permethyl storniamide A and lamellarin G trimethyl ether are pyrrole containing, natural products, which exhibit interesting biological properties. Such properties include anti-tumor activity on a variety of cancer cell lines including those that confer drug resistance, inhibition of HIV integrase and vascular disrupting activity. We now describe the use of methyl and ethyl 3-bromo-2-formylpyrrole-5-carboxylate as building blocks for the formal synthesis of these three highly functionalized, bioactive pyrroles. These new building blocks will now provide ready access to the natural products and many novel analogs due to the ability to easily modify positions 2,3,4 and 5 of the pyrrole core.

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Total synthesis of lycogarubin C utilizing the Kornfeld–Boger ring contraction

Cited by 30 publications

References 25 publications

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

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

Total Synthesis of Lycogarubin C and Lycogalic Acid

The application of formyl group activation of bromopyrrole esters to formal syntheses of lycogarubin C, permethyl storniamide A and lamellarin G trimethyl ether

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