Total synthesis of tetronolide, the aglycon of tetrocarcins

Takeda, Kazuya; Kawanishi, Eiji; Nakamura, Hitoshi; Yoshii, Eiichi

doi:10.1016/s0040-4039(00)93498-1

Cited by 54 publications

(45 citation statements)

References 32 publications

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“…Yoshii and coworkers reported the chemical synthesis of (+)-tetronolide, the aglycone of tetrocarcin (5), in 1991. 25 Enantioselective synthesis of (−)-chlorothricolide, the aglycone of chlorothricin (4), was accomplished by Roush and Sciotti in 1994. 26 Both syntheses employed intramolecular DielsAlder cyclizations to construct the spirotetronate and octahydronaphthalene portions of the aglycones.…”

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confidence: 99%

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

et al. 2007

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The antibiotic kijanimicin produced by the actinomycete Actinomadura kijaniata has a broad spectrum of bioactivities as well as a number of interesting biosynthetic features. To understand the molecular basis for its formation and to develop a combinatorial biosynthetic system for this class of compounds, a 107.6 kb segment of the Actinomadura kijaniata chromosome containing the kijanimicin biosynthetic locus was identified, cloned, and sequenced. The complete pathway for the formation of TDP-L-digitoxose, one of the two sugar donors used in construction of kijanimicin, was elucidated through biochemical analysis of four enzymes encoded in the gene cluster. Sequence analysis indicates that the aglycone kijanolide is formed by the combined action of a modular Type-I polyketide synthase (PKS) and a conserved operon involved attachment and intramolecular cyclization of a glycerate-derived three-carbon unit, which forms the core of the spirotetronate moiety. The genes involved in the biosynthesis of the unusual deoxysugar D-kijanose [2,3,4,6-tetradeoxy-4-(methylcarbamyl)-3-C-methyl-3-nitro-D-xylo-hexopyranose], including one encoding a flavoenzyme predicted to catalyze the formation of the nitro group, have also been identified. This work has implications for the biosynthesis of other spirotetronate antibiotics and nitro sugar-bearing natural products, as well as for future mechanistic and biosynthetic engineering efforts.Kijanimicin (1) is a spirotetronate antibiotic isolated from Actinomadura kijaniata, a soil actinomycete. It has a broad spectrum of antimicrobial activity against Gram-positive bacteria, anaerobes, and the malaria parasite Plasmodium falciparum, 1 and also shows antitumor activity. 2 The structure of kijanimicin (1) consists of a pentacyclic core, which is equipped with four L-digitoxose (2) units and a rare nitro sugar, 2,3,4,6-tetradeoxy-4-(methylcarbamyl)-3-C-methyl-3-nitro-D-xylo-hexopyranose, commonly known as D-kijanose (3). More than sixty kijanimicin-related spirotetronate-type compounds have been reported. Most are made by strains of high-GC Gram positive bacteria (Actinomycetes), including Streptomyces, 3-8 Micromonospora, 9-12 Actinomadura, 1,13,14 Saccharothrix, 15 and Verrucosispora. 16 A species of Bacillus has also been identified as a producer of a member of this class of compounds. 17 Nearly all members of this class exhibit both antibacterial and antitumor activities, and many possess other biological activities. Well-known examples include chlorothricins (4), the anticholesterolemic agents; 18,19 tetronothiodin, a cholecystokinin B (CCK-B) inhibitor; 4 MM46115, an antiviral drug effective against parainfluenzae virus 1 and 2; 13 and tetrocarcins (5) and arisostatins, both of which have been shown to have therapeutic potential as inducers of apoptosis. 20-23 In a recent study, a collection of tetrocarcin analogues was prepared synthetically and some of them showed improved apoptosis-inducing activity. 24 Hence, compounds of this class have broad therapeutic potential wort...

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Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

et al. 2007

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“…Since the mid 1980s, extensive attempts to synthesize aglycones have been made, resulting in the total synthesis of (ϩ)-tetronolide of TCA and (Ϫ)-chlorothricolide of chlorothricin (CHL) (the first member to be discovered and structurally elucidated in this family [Fig. 1]) (4,30,31,36). However, the synthesis of the entire molecule of either TCA or CHL has not yet been achieved.…”

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confidence: 99%

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

et al. 2008

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Tetrocarcin A (TCA), produced by Micromonospora chalcea NRRL 11289, is a spirotetronate antibiotic with potent antitumor activity and versatile modes of action. In this study, the biosynthetic gene cluster of TCA was cloned and localized to a 108-kb contiguous DNA region. In silico sequence analysis revealed 36 putative genes that constitute this cluster (including 11 for unusual sugar biosynthesis, 13 for aglycone formation, and 4 for glycosylations) and allowed us to propose the biosynthetic pathway of TCA. The formation of D-tetronitrose, L-amicetose, and L-digitoxose may begin with D-glucose-1-phosphate, share early enzymatic steps, and branch into different pathways by competitive actions of specific enzymes. Tetronolide biosynthesis involves the incorporation of a 3-C unit with a polyketide intermediate to form the characteristic spirotetronate moiety and trans-decalin system. Further substitution of tetronolide with five deoxysugars (one being a deoxynitrosugar) was likely due to the activities of four glycosyltransferases. In vitro characterization of the first enzymatic step by utilization of 1,3-biphosphoglycerate as the substrate and in vivo cross-complementation of the bifunctional fused gene tcaD3 (with the functions of chlD3 and chlD4) to ⌬chlD3 and ⌬chlD4 in chlorothricin biosynthesis supported the highly conserved tetronate biosynthetic strategy in the spirotetronate family. Deletion of a large DNA fragment encoding polyketide synthases resulted in a non-TCA-producing strain, providing a clear background for the identification of novel analogs. These findings provide insights into spirotetronate biosynthesis and demonstrate that combinatorial-biosynthesis methods can be applied to the TCA biosynthetic machinery to generate structural diversity.

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“…The reagent TPAP/NMO/PMS/CH 2 Cl 2 was also used in a step in the synthesis of the colony-stimulating factor leustroducsin B (TPAP) [96]; for the antiparasitic spiroketal macrolide (+)-milbemycin a 1 [97]; the antiparasitic insecticide (+)-milbemycin-b 1 (secondary alcohol to a ketone step also) [98]; the sesquiterpenes nortrilobolide, thapsivillosin F and trilobolide (a second step involving the reagent was a lactol-to-lactone transformation) [64]; the marine alkaloid norzoanthamine (secondary alcohol to ketone step also) [99]; the eunicellin ophirin B [84]; the biologically active diterpene phomactin A [100]; the macrolide prelactone B (primary alcohol to lactone) [101]; the spiroketal ionophore antibiotic routiennocin [102,103]; the macrolides salicylihalamides A and B [104]; the anti-tumour microtubulin stablising agents sarcodictyins A and B [105]; the polypropionate siphonarienolone [106]; the antibiotic (+)-tetronomycin [107], and the aglycon of the antitumour antibiotic tetronolide [108]. During synthesis of the protein phosphatase inhibitor okadaic acid three oxidations with TPAP/NMO/PMS/CH 2 Cl 2 were used, two of a primary alcohol to aldehydes and one of a diol to a lactone [109]; the reagent was used in the synthesis of a fragment of the antibiotic sorangicin A [110].…”

Section: Natural Product/pharmaceutical Syntheses Involving Primary Amentioning

confidence: 99%

Oxidation of Alcohols, Carbohydrates and Diols

Griffith

2009

Catalysis by Metal Complexes

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This is one of the most important classes of oxidation effected by Ru complexes, particularly by RuO 4 , [RuO 4 ] − , [RuO 4 ] 2− and RuCl 2 (PPh 3 ) 3 , though in fact most Ru oxidants effect these transformations. The chapter covers oxidation of primary alcohols to aldehydes (section 2.1), and to carboxylic acids (2.2), and of secondary alcohols to ketones (2.3). Oxidation of primary and secondary alcohol functionalities in carbohydrates (sugars) is dealt with in section 2.4, then oxidation of diols and polyols to lactones and acids (2.5). Finally there is a short section on miscellaneous alcohol oxidations in section 2.6.In this chapter the first of the two most important categories of oxidations catalysed by Ru complexes (the other being alkene and alkyne oxidations in Chapter 3) are considered. The approach in this and subsequent chapters differs from that of Chapter 1, concentrating here on the substrate rather than on the oxidant. The text is divided into the categories of alcohols and their oxidations. There are summaries in section 2.3.6 of systems of limited applicability which are mentioned only in Chapter 1, and in section 2.3.7 of large-scale (>1 g) oxidations.The first oxidations of alcohols by stoicheiometric RuO 4 /H 2 O were reported in 1958, of primary alcohols to aldehydes or carboxylic acids and secondary alcohols to ketones [1]. The first Ru-catalysed oxidation of an alcohol was reported in 1965 when Parikh and Jones used RuO 2 /aq. Na(IO 4 )/CCl 4 1 ( Table 2.3) [2] to oxidise secondary alcohol groups in carbohydrates.Oxidation of alcohols is the most frequently reviewed topic for Ru-catalysed oxidations [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Mechanisms of alcohol oxidation by Ru complexes have been reviewed [21].

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Total synthesis of tetronolide, the aglycon of tetrocarcins

Cited by 54 publications

References 32 publications

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

Oxidation of Alcohols, Carbohydrates and Diols

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