The Stereocontrolled Total Synthesis of Polyketide Natural Products: A Thirty-Year Journey (original) (raw)
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Hutchinson's legacy: keeping on polyketide biosynthesis
J Antibiot, 2011
Professor Charles Richard Hutchinson (Hutch) dedicated his research to the study of polyketide compounds, in particular, those produced by actinomycetes. Hutch principally centered his efforts to study the biosynthesis of bioactive compounds, antibiotic and antitumor drugs, and to develop new derivatives with improved therapeutic properties. After dedicating 40 years to the study of polyketides, Hutch leaves us, as legacy, the knowledge that he and his collaborators have accumulated and shared with the scientific community. The best tribute we can offer to him is keeping on the study of polyketides and other bioactive compounds, in an effort to generate more safer and useful drugs. In this review, the work on the polyketides, borrelidin, steffimycin and streptolydigin, performed at the laboratory of Professors Salas and Mé ndez at University of Oviedo (Spain) during the last 10 years, is summarized.
Total Synthesis of Oxacyclic Macrodiolide Natural Products
Chemical Reviews, 2005
where he received his Ph.D. degree on the biosynthetic studies on fungal tropolones and vitamin B12 under the supervision of Professor A. I. Scott. After postdoctoral research with Professor K. Nakanishi at Columbia University on R-ecdysone synthesis, he spent a year and half at Zoecon Corporation working on the biosynthesis of insect juvenile hormones.
Angewandte Chemie International Edition, 2002
Callipeltoside A (1) was isolated by Minale and co-workers in 1996 from the shallow water sponge callipelta sp., collected off the east coast of New Caledonia. [1] This new macrolide was found to inhibit the proliferation of NSCLC-L6 human bronchopulmonary nonsmall-cell-lung carcinoma (11.26 mg mL À1 ) and P388 (15.26 mg mL À1 ) cells in vitro. [1a] The small amount (3.5 mg) of 1 obtained led to the determination of its structure by extensive NMR spectroscopic studies. The relative stereochemical relationship of callipeltose to the macrolactone has been assigned based on two NOE interactions-an assignment supported by our recent total synthesis of deschlorocallipeltoside A. [1a, 2] Two main stereochemical issues remain unsolved: a) the absolute configuration, and b) the relative configuration of the trans chlorocyclopropane with regard to the macrolactone. Indeed, the isolation of the chlorocyclopropane from the rest of the molecule provides no detectable bias by NMR spectroscopy, as shown by the synthesis of two diastereoisomers of the aglycon of callipeltoside A by Paterson et al.. In spite of these structural ambiguities, many groups have embarked on the total synthesis of the compound, with different stereoisomers as targets. We report the unambiguous assignment of the absolute and relative configuration of callipeltoside A by means of the total synthesis of several stereoisomers.
Bisai et al 2018 Asian Journal of Organic Chemistry
Diels-Alder reactions and hetero Diels-Alder reactions play crucial role in building complexity in many naturally occurring isoprenoids. A number of structurally intriguing complex isoprenoids have been isolated form Nature, those are believed to follow a [4+2]-cycloaddition reaction in their biosynthetic proposal. In this focus review, we discuss on the recent efforts on biomimetic total syntheses of complex isoprenoids utilizing Diels-Alder and hetero Diels-Alder reactions. In particular, we have considered isoprenoids arising from a basic icetaxane, abietane, dinor-abietane, and abeo-abietane structural scaffolds.
Computer assisted design of potentially active anti-trypanosomal compounds
Journal of Molecular Structure-theochem, 2002
A computer assisted molecular modeling was used to design molecules having a shape complementary to the active site of glutathione reductase (GR) and trypanothione reductase (TR). The designed 5-nitro compound derivatives, were obtained from structural knowledge gleaned on glutathione (GSSG), trypanothione (T[S] 2 ) and GSP disul®de (glutathionylspermidine disul-®de). These molecules form complexes with the enzymes GR and TR. The theoretical lead compound was: N1-[1-(5-nitro-2furyl)methylidene]-N4-{4-[3-(2,2,2-tri¯uoroacetyl)hexahydro-1-1-pyrimidynil]butyl} semicarbazide (NPIPCO). A multidisciplinary team developed around the efforts to synthesize this lead. In this work we report on eight compounds that were synthesized in the pathway to NPIPCO: 4-(2-methoxyethyl)-1-, 4-butyl-1-, 4-hexyl-1-and 2-methoxphenyl-1-(5-nitrofurfurilidene) semicarbazides and the corresponding 5-nitrothiophenes. These substances are expected to act as pro-transition state analogues. Enzymologic studies proved that many of these compounds are inhibitors of TR. Furthermore, they showed inhibitory activity on Tripanosoma cruzi growth in vitro. q Journal of Molecular Structure (Theochem) 584 (2002) 95±105 0166-1280/02/$ -see front matter q (O. Tapia).
Total Synthesis of (−)-Reidispongiolide A, an Actin-Targeting Marine Macrolide
Angewandte Chemie International Edition, 2007
Reidispongiolide A (1), isolated by D Auria et al. from the sponge Reidispongia coerulea, which was collected off the coast of New Caledonia, [1] and sphinxolide B (2) [2] are representative members of a structurally unique family of cytotoxic marine macrolides. [3] Their interaction with actin in the cell cytoskeleton leads to microfilament destabilization, and they show potent antiproliferative activity (for example, IC 50 = 0.04 and 0.01 mg mL À1 against human colon carcinoma HT29) and the ability to circumvent multidrug resistance. This profile makes these macrolides valuable molecular probes in cell biology and promising lead compounds for the development of novel chemotherapeutic agents that target actin. [4, 5] Their structures comprise a highly oxygenated 26-membered macrolactone, containing a d-lactone ring, and appended with an elaborate side chain at C25 which terminates in an N-vinylformamide group. Through the combination of degradation fragment [2d, 6, 7] synthesis and detailed NMR analysis, we determined the stereochemistry of the entire reidispongiolide macrolide to be that shown in 1 (Scheme 1). [8] Subsequently, Rayment and co-workers [9] reported the X-ray crystal structure of actin-bound reidispongiolide A, assigning the complete configuration and revealing its intriguing mechanism of microfilament destabilization. The sparse natural supply of the reidispongiolides [1] and sphinxolides [2] makes total synthesis of paramount importance, not only to support further biological applications but also to enable structure-activity relationship (SAR) studies. Herein, we report the first total synthesis of reidispongiolide A based on a highly convergent modular assembly process that evolved from our stereochemical analysis groundwork. [7a, 8] As outlined in Scheme 1, our synthetic strategy for reidispongiolide A involves a late-stage introduction of the C30-C36 side-chain segment 3, which incorporates the sensitive N-vinylformamide functionality, through a suitable aldol coupling with the macrolactone aldehyde 4. We elected to disassemble the macrolide 4 into key subunits 5 (C14-C29) and 6 (C4-C13) based on an envisaged second aldol coupling to introduce the stereocenter at C13. The remaining subunit 7 Scheme 1. Synthetic strategy for reidispongiolide A (1) that involves the key building blocks 3, 5, and 6.
Inspirations from nature. New reactions, new therapeutic leads, and new drug delivery systems
Pure and Applied Chemistry, 2000
Studies in our laboratory focus on problems in chemistry (new reactions and synthesis), biology (novel modes of action), and medicine (new therapeutic leads and drug delivery systems). These interconnected and often synergistic activities are inspired by an interest in novel structures, frequently from nature, that possess unique modes of action and significant clinical potential. Described herein are some examples of recent work from our laboratory that have led to new transition metal-catalyzed reactions, a new and remarkably potent therapeutic lead, and new drug delivery systems that are in clinical trials.