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Total synthesis of complestatin (Chloropeptin II) - CORE

Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in S

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synthetic route for the synthesis of complestatin.

The chloropeptins have attracted considerable attention due to their reported anti-HIV activity, mediated through two independent sites of action (inhibit gp120-CD4 binding and HIV integrase), and their structural complexity.- Although structurally similar to the glycopeptide antibiotics, one of the characteristic diaryl ether linkages is replaced with a biaryl linkage to C6 or C7 of the indole of a (R)-tryptophan within the macrocyclic core, adopting a single atropisomer stereochemistry incapable of interconversion. In complestatin A and B (2 and 3), the embedded tryptophan indole of chloropeptin II (1, complestatin) has been oxidized to a 2-oxindole (2, complestatin A) or 3-hydroxy-2-oxindole (3, complestatin B). Although clearly related to the chloropeptins (1 and 4, ), whose stereochemistry has been firmly established by extensive NMR spectroscopy paired with computational modeling studies and confirmed by subsequent total syntheses,, both the atropisomer orientation of the tryptophan-derived indole and the assignment of the new stereocenter in complestatin A and B were not addressed at the time of their disclosures.

Total Synthesis Highlights - Organic Chemistry Portal

With effective protocols developed on the macrocyclic DEF right-hand subunit, we turned our attention to complestatin (1) itself. Initial efforts began with room temperature exposure of 1 to concentrated HCl in DMSO, the conditions adopted for (R)-8, and the studies indicated that the reaction was slower, with only a small amount of complestatin A detected. Encouraged by this initial result and in the absence of competitive rearrangement to provide chloropeptin I, additional acid catalyst was added, and further product conversion was observed. Additional optimization demonstrated that both natural and synthetic chloropeptin II (1) could be converted cleanly to complestatin A (2, neuroprotectin A) in superb yield (93%) over 24–48 h in the presence of reagent amounts of concentrated HCl in DMSO, with additional HCl added after 24 h if needed (). The 1H NMR spectrum of synthetic 2 was in complete agreement with the published data, reported for complestatin A (), confirming the structure and establishing the stereochemistry of the remaining indole-derived stereocenters in the natural product.

The first total synthesis of racemic perophoramidine is described

This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4 receptor

Recently, we reported the first total synthesis of chloropeptin II (1, complestatin), the more strained and challenging of the two naturally occurring chloropeptins. Central to the design of the approach and by virtue of a single-step, acid-catalyzed ring expansion rearrangement of chloropeptin II to chloropeptin I, the route also provided a total synthesis of chloropeptin I. Herein, we report a complementary and divergent oxidation of chloropeptin II (1, complestatin) to either complestatin A (2, neuroprotectin A) or complestatin B (3, neuroprotectin B), providing the first synthesis of the natural products and establishing their remaining stereochemical assignments. Key to the approach to complestatin A (2, neuroprotectin A) was the development of two different single-step indole oxidations (HCl–DMSO and NBS, THF–H2O) that avoid the rearrangement of chloropeptin II (1) to chloropeptin I (4), providing the 2-oxindole 2 in superb yields (93% and 82%). With a mechanistic understanding of features that impact the latter oxidation and an appreciation of the intrinsic reactivity of the chloropeptin II indole, its modification (NCS, THF–H2O; Cs2CO3, DMF–H2O) provided a two-step, single-pot oxidation of chloropeptin II (1) to afford directly the 3-hydroxy-2-oxindole complestatin B (3, neuroprotectin B). Extensive studies conducted on the fully functionalized synthetic DEF ring system of chloropeptin II were key to the unambiguous assignment of the stereochemistry as well as the exploration and subsequent development of the mild oxidation conditions used in the synthesis of complestatin A and B.

Complestatin was first isolated from the mycelium of SANK 60477 as an anticomplement agent in 1980.) It was reisolated from the sp. as an inhibitor of the binding of HIV gp120 to the CD4 protein and HIV replication.) Complestatin is a bicyclic chlorinated hexapeptide) belonging to the glycopeptide class. Glycopeptide antibiotics, such as vancomycin and teicoplanin, have unique tricyclic or tetracyclic heptapeptide aglycones, which are usually glycosylated and sometimes additionally acylated. Glycopeptide antibiotics are divided into four structural subclasses (I–IV) according to the substituents and type of residue at positions 1 and 3 of the heptapeptide backbone. Nicolaou designated complestatin as a type V class of glycopeptide aglycone, which have a tryptophan in place of a phenyl group in the heptapeptide core.) Glycopeptide antibiotics showed antibacterial activity by inhibiting the transglycosylation and/or transpeptidation steps associated with cell wall biosynthesis by binding of the heptapeptide backbone to the C-terminal L-Lys-D-Ala-D-Ala subunit of the peptidoglycan Lipid II five hydrogen bonds.) Aglycones of vancomycin and teicoplanin are known to retain antibacterial activity.,) An antimicrobial activity of complestatin, however, has not yet been reported.

Key Reviews and Natural Product Total Syntheses

complestatin synthesis essay

Unlike other glycopeptide antibiotics such as vancomycin inhibiting the transglycosylation and/or transpeptidation steps involved in cell wall synthesis,) complestatin is found to exhibit antibacterial activity by inhibiting fatty acid synthesis without affecting cell wall synthesis in this study. Interestingly, the difference in the antibacterial mechanism of complestatin from vancomycin is supported by the difference in their biosynthesis gene clusters. The biosynthesis gene clusters of vancomycin-type antibiotics contain their resistance genes (VanX, VanA, and VanH) for self-protection.,) However, there is no resistance gene as such in the biosynthesis gene cluster of complestatin.)

Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of FabI together with neuroprotectin A and chloropeptin I from AN1542. Complestatin and related compounds inhibited FabI with IC50 of 0.3–0.6 µM. They also prevented the growth of as well as methicillin-resistance (MRSA) and quinolone-resistant (QRSA), with minimum inhibitory concentrations (MICs) of 2–4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in , whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity inhibiting fatty acid synthesis.

Complestatin synthesis essay
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Thieme E-Journals - Synthesis / Full Text

During the solid phase peptide synthesis of linear complestatin analogues the strongly basic reaction conditions, which were partly essential for acceptable conversions, resulted in epimerisation of sensitive amino acids during coupling sequences.

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Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of FabI together with neuroprotectin A and chloropeptin I from AN1542. Complestatin and related compounds inhibited FabI with IC50 of 0.3–0.6 µM. They also prevented the growth of as well as methicillin-resistance (MRSA) and quinolone-resistant (QRSA), with minimum inhibitory concentrations (MICs) of 2–4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in , whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity inhibiting fatty acid synthesis.

Total synthesis of natural product | LSPN

The biaryl linkage between the central amino acid and the oxidized indole of 2 and 3 was shown to have the same C6 versus C7 connectivity as chloropeptin II (1), resulting in a more strained 16-membered versus 17-membered macrocyclic core., Complementary to the synthetic efforts of Hoveyda, Snapper, and others,- we reported the first total synthesis of chloropeptin II (1), the more strained and challenging of the two chloropeptins. Central to the design of our approach and by virtue of a remarkable single-step, acid-catalyzed ring expansion rearrangement of chloropeptin II (1) to chloropeptin I (4, ), the route also provided a total synthesis of 4. Herein, we report a single-step oxidation of 1 to either 2 or 3 and the use of this divergent strategy and the strain inherent in chloropeptin II (1) to provide the first synthesis of both complestatin A (2) and complestatin B (3), establishing their remaining stereochemical assignments.

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