- Total Synthesis of Plusbacin A3 and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié-Ugi Three-Component Reaction
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Full details of our synthetic studies toward plusbacin A3 (1), which is a depsipeptide with antibacterial activity, and its dideoxy derivative are described. To establish an efficient synthetic route of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was used to construct trans-Pro(3-OH) in a small number of steps. Two strategies were investigated toward the total synthesis. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a macrolactonization at the final stage of the synthesis. The JU-3CR using alkyl isocyanides in 1,1,1,3,3,3-hexafluoroisopropanol provided the trans products, and the coupling of the fragments to prepare the macrocyclization precursor proceeded smoothly. However, attempts toward the macrolactonization did not provide the desired product. Then, the second strategy that included esterification in an initial stage was investigated. Methods for constructing trans-Pro(3-OH) were examined using a convertible isocyanide, which could be converted to a carboxylic acid required for the following amidation. Ester bond formation was achieved through an intermolecular coupling using a hydroxyl-Asp derivative and the corresponding alcohol, and the amidation afforded a linear depsipeptide. The macrolactamization of the linear peptide gave the cyclic depsipeptide, and then the global deprotection accomplished the total synthesis of 1 and its dideoxy derivative.
- Katsuyama, Akira,Yakushiji, Fumika,Ichikawa, Satoshi
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p. 7085 - 7101
(2018/07/15)
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- Total synthesis of the ramoplanin A2 and ramoplanose aglycon
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Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon are disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1,2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected L-threo-β-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 °C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist β-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, two macrocyclization sites, Phe9-D-Orn10 and Gly14-Leu15, were examined. Macrocyclization at the highly successful Phe9-D-Orn10 site (89%) may benefit from both β-sheet preorganization as well as closure at a D-amine terminus within the confines of a β-turn at the end of the H-bonded antiparallel β-strands. A more modest, but acceptable macrocyclization reaction at the Gly14-Leu15 site (40-50%) found at the other end of the H-bonded antiparallel β-strands within a small flexible loop may also benefit from preorganization of the cyclization substrate, is conducted on a substrate incapable of competitive racemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn1 side-chain introduction provides future access to analogues of the aglycons which themselves are equally potent or more potent than the natural products in antimicrobial assays.
- Jiang, Wanlong,Wanner, Jutta,Lee, Richard J.,Bounaud, Pierre-Yves,Boger, Dale L.
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p. 1877 - 1887
(2007/10/03)
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- Total synthesis of the ramoplanin A2 and ramoplanose aglycon
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A convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon is disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26, and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected l-threo-β-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 °C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist β-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. As such, macrocyclization at the chosen Phe9-d-Orn10 site may benefit from both β-sheet preorganization as well as closure at a d-amine terminus. Deliberate late stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn1 side chain introduction provides future access to analogues of the aglycons which themselves are reported to be equally potent or more potent than the natural products in antimicrobial assays. Copyright
- Jiang, Wanlong,Wanner, Jutta,Lee, Richard J.,Bounaud, Pierre-Yves,Boger, Dale L.
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p. 5288 - 5290
(2007/10/03)
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