Total Synthesis of Plusbacin A₃ and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié–Ugi Three-Component Reaction

Abstract

Full details of our synthetic studies toward plusbacin A (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.

Cyclic Imines in Ugi and Ugi-Type Reactions

“…42 From now, JU-3CR enables the construction of Pro(3-OH) as the main skeleton of some peptide-based natural products in a single step instead of 14 or 15 steps. 43 In addition to the synthesis of prolines, JU-3CR can also be a powerful diversityoriented synthetic method for the preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds baring peptide backbone. In this context, various scaffolds such as benzodiazepines, lactams, indazoles, and piperazine drugs associated with these skeletons that are retrieved from Drug Bank 44 are summarized in Table 1.…”

“…The key intermediates were synthesized efficiently by this method (Scheme 30). 43,118 Cyclic Imines via Fischer Indole Synthesis. Compounds containing indole moiety exist in many natural products and bioactive compounds.…”

“…In this regard, the use of cyclic imines in the Ugi reaction (JU-3CR) permits to introduce proline-like skeletons in the structure of the resultant products with high diastereoselectivities . From now, JU-3CR enables the construction of Pro­(3-OH) as the main skeleton of some peptide-based natural products in a single step instead of 14 or 15 steps . In addition to the synthesis of prolines, JU-3CR can also be a powerful diversity-oriented synthetic method for the preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds baring peptide backbone.…”

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

“…Shiina conditions gave a complex product mixture, if the TIPS group was present, whereas the desilylated acid provided a product that apparently had undergone dehydration, as judged by TLC–MS coupling. In course of their recent synthesis of plusbacin A 3 , Ichikawa et al experienced similar difficulties when attempting esterification of a bulky β-OTIPS-substituted amino acid with a secondary alcohol under a variety of conditions [49].…”

Interfacial properties of morpholine-2,5-dione-based oligodepsipeptides and multiblock copolymers

“…[8][9][10] From natural sources like marine invertebrates and cyanobacteria mainly cyclic ODPs are isolated which exhibit antimicrobial or protease inhibition activities, or cytotoxicity against cancer cells. [11][12][13][14] While initially, poly(depsipeptide)s were synthesized via polycondensation of activated depsipeptides, [15] the state of the art synthetic route is ring opening polymerization of 2,5morpholine derivatives. [16] By variation of the side-chains, different functionalities are introduced, enabling to tailor the properties of the macromolecules, which can be used as telechelics in building blocks for biomedical applications.…”