Restricted Conformation Analogues of an Anthelmintic Cyclodepsipeptide

Dutton, Fred E.; Lee, Byung H.; Johnson, Sandra S.; Coscarelli, Eileen M.; Lee, Pil

doi:10.1021/jm020482k

Cited by 38 publications

(19 citation statements)

References 17 publications

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“…Backbone rigidization, e.g. synthesis of conformationally restricted analogues of 1 by fusing fivemembered (Scherkenbeck et al 1999(Scherkenbeck et al , 2002 to sevenmembered lactam rings (Dutton and Lee 1998;Lee et al 2002;Dutton et al 2003) or b-turn mimics (Dyker et al 2004) within the 24-membered macrocycle.…”

Section: Introductionmentioning

confidence: 99%

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

et al. 2005

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The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.

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Section: Introductionmentioning

confidence: 99%

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

et al. 2005

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“…At this stage of the project, rapid access to both enantiomers of stannane 5 and its acetonide derivative 13 were required (Scheme 4). To this end, the aldehyde 14, prepared in three steps from (R)-malic acid, [12] was converted into the corresponding vinyl dibromide 15 (81 %). [6] Pleasingly, a palladium-catalyzed one-pot debromination/stannylation protocol, which exploits the differing reactivity of the trans-and cis-bromides through selective reductive (E)-debromination [13] ([Pd(PPh 3 ) 4 ], Bu 3 SnH, 40 8C) followed by buffered bromine-tin exchange (Me 6 Sn 2 , 808C), [14] provided solely the (Z)-alkenyl stannane 13 (74 %); the antipodal stannane ent-13 was obtained in an analogous fashion from (S)-malic acid.…”

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confidence: 99%

Total Synthesis of Spirastrellolide A Methyl Ester—Part 2: Subunit Union and Completion of the Synthesis

et al. 2008

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The marine macrolide spirastrellolide A (1, Scheme 1) is a potent and selective protein phosphatase inhibitor, causing premature cell entry into mitosis.[1] Synthetic interest [2] in the spirastrellolides derives not only from their unique molecular architecture, but also from their potential as lead structures for the development of novel anticancer agents. [3] In the preceding communication, [2] we described our optimized and scalable approach to the construction of the key C17-C40 bisspiroacetal intermediate 3, which forms the foundation of our strategy towards these challenging natural products. Herein, we report the completion of the first total synthesis of spirastrellolide A methyl ester (2, Scheme 1), as well as the single-crystal X-ray diffraction analysis of an advanced intermediate that reveals the conformation of the spirastrellolide macrocycle and plays a vital role in our end-game strategy.A summary of our synthetic plan, which was designed to provide maximum flexibility in terms of fragment coupling and diastereomer selection, is outlined in Scheme 1. This optimized retrosynthesis leads to three key subunits-the C17-C40 aldehyde 3, the C1-C16 alkyne 4, and the C43-C47 stannane 5. The planned completion of the total synthesis of spirastrellolide A methyl ester (2) would thus proceed through the union of aldehyde 3 with alkyne 4, with subsequent elaboration to introduce the BC spiroacetal domain, and macrolactonization to generate the 38-membered macrolide core. A series of manipulations at C40 (in the truncated side chain) would precede the end game of the synthesis, which would involve a cross-coupling reaction with stannane 5 to install concurrently the 40E and 43Z double bonds as well as the terminal a-hydroxy ester in structure 2.The first requirement for this synthetic plan was the preparation of the C1-C16 alkyne 4. We have previously reported the synthesis of a close relative of this alkyne [4] by using Jacobsens hydrolytic kinetic resolution of epoxides. [5] Building on this earlier work, installation of a PMB ether was now required at C1 such that our envisaged BC-spiroacetalization step would result in simultaneous deprotection at this position. The most convenient point to undertake this modification was deemed to be the vinyl dibromide 6 (Scheme 2). Thus, selective desilylation at C1 was followed by formation of the PMB ether under mild conditions by using PMB trichloroacetimidate. Subsequent conversion of the vinyl dibromide into the alkyne 4 proceeded uneventfully on treatment with base (66 % yield, over 3 steps). [6] The union of the C1-C16 and C17-C40 subunits through addition of the lithium anion of alkyne 4 to the DEF aldehyde Scheme 1. Spirastrellolide A (1), its methyl ester (2), and retrosynthetic analysis leading to key building blocks 3-5. PMB = para-methoxybenzyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl.

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“…In one series 111a-c, a carbon-based molecular bridge joins the N-methyl of a leucine residue with the methyl of its closest lactic acid residue to form five-, six-and sevenmembered Freidinger lactam analogs in which the exocyclic nitrogen is replaced by oxygen (Scheme 22). Decreasing the size of the small ring in the lactam series increasingly distorts the macrocycle and consistently decreases activity relative to PF1022A [91].…”

Section: Anthelmintic Therapeutic Agentsmentioning

confidence: 99%

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Perdih¹,

Kikelj

2006

CMC

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Peptides exist in solution as an equilibrium mixture of conformers. The backbone conformational constraints are of interest as a means of limiting degrees of freedom and thereby constraining a synthetic peptide into the bioactive conformation. This concept plays an important role in the design of peptidomimetics in the drug development process. In the early eighties, Freidinger proposed the concept of protected lactam-bridged dipeptides, which was a milestone in the design of conformationally constrained peptides. These types of compounds, now widely known as Freidinger lactams, have been of interest to many medicinal and peptide chemists. This review seeks to present the various applications that Freidinger lactams and their hetero-, fused- and unsaturated analogs have found in the design of conformationally constrained peptidomimetics in different therapeutic areas.

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Restricted Conformation Analogues of an Anthelmintic Cyclodepsipeptide

Cited by 38 publications

References 17 publications

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

Total Synthesis of Spirastrellolide A Methyl Ester—Part 2: Subunit Union and Completion of the Synthesis

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

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