Rahman Studies in Natural Products Chemistry

1. Auflage 2014
ISBN: 978-0-444-63440-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band Volume 43, 514 Seiten

Reihe: Studies in Natural Products Chemistry

Natural products in the plant and animal kingdom offer a huge diversity of chemical structures that are the result of biosynthetic processes that have been modulated over the millennia through genetic effects. With the rapid developments in spectroscopic techniques and accompanying advances in high-throughput screening techniques, it has become possible to isolate and then determine the structures and biological activity of natural products rapidly, thus opening up exciting opportunities in the field of new drug development to the pharmaceutical industry. The series also covers the synthesis or testing and recording of the medicinal properties of natural products, providing cutting edge accounts of the fascinating developments in the isolation, structure elucidation, synthesis, biosynthesis and pharmacology of a diverse array of natural products. - Focuses on the chemistry of bioactive natural products - Contains contributions by leading authorities in the field - Presents exciting sources of new pharmacophores

Autoren/Hrsg.

Rahman, Atta-ur-

Leseproben

Chapter 1 Total Synthesis of Diterpenoid Pyrones, Nalanthalide, Sesquicillin, Candelalides A–C, and Subglutinols A, B
Tadashi Katoh    Laboratory of Medicinal and Synthetic Chemistry, Department of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai Japan Abstract
In this chapter, the total synthesis of biologically active diterpenoid pyrones—nalanthalide, sesquicillin, candelalides A–C, and subglutinols A, B—is reviewed with focus on their methodology and strategy. Danishefsky achieved the first total synthesis of (±)-sesquicillin, which features (i) stereoselective Eschenmoser–Claisen rearrangement to form the requisite decalin portion and (ii) aldol-type coupling to assemble the requisite carbon framework for a pyrone ring formation. The author completed the total synthesis of (-)-nalanthalide and (+)-sesquicillin in a highly convergent and unified manner, which features (i) [2,3]-Wittig rearrangement to construct the requisite decalin portion and (ii) coupling of the decalin portion with a pyrone moiety to assemble the desired carbon skeleton. The first total synthesis of candelalides A–C was accomplished by the author based on the strategy developed in our synthetic study of (-)-nalanthalide and (+)-sesquicillin. Hong achieved the first total synthesis of (-)-subglutinols A and B employing the Cu(I)-mediated intermolecular SN2' alkylation of a phosphate with a Grignard reagent to construct the requisite decalin portion fused with a characteristic tetrahydrofuran ring. The author achieved the second total synthesis of (-)-subglutinols A and B, which involved an internal SN2-type cyclization to construct the tetrahydrofuran ring as the crucial step. Keywords Nalanthalide Sesquicilin Candelalides Subglutinols Total Synthesis Abbreviations acac acetylacetonate AIBN 2,2'-azobisisobutyronitrile DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP 4-dimethyl- aminopyridine DMSO dimethyl sulfoxide EE ethoxyethyl IC50 half maximal (50%) inhibitory concentration LDA lithium diisopropylamide mCPBA 3-chloroperoxybenzoic acid Ms methanesulfonyl NMO 4-methylmorpholine N-oxide NMR nuclear magnetic resonance NOESY nuclear overhauser effect spectroscopy PCC pyridinium chlorochromate PPTS pyridinium 4-toluenesulfonate TBAF terea-n-butylammonium fluoride TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TES triethysilyl TIPS triisopropylsilyl Tf trifluoromethanesulfonate TMS trimethylsilyl TPAP tetra-n-propyl ammonium perruthenate Ts 4-toluenesulfonyl Introduction
In recent years, a number of diterpenoid pyrones and related compounds have been isolated from microorganisms, particularly from fungal strains [1–6]. Several of these natural products have been reported to exhibit a wide variety of biological properties such as insecticidal [1,3c], antihypertensive [3d], bronchospasmolytic [3d], anti-inflammatory [3d], laxative [3d], anticancer [3e], and immunosuppressive activities [3–6]. In most cases, however, further biological studies including structure–activity relationships (SARs) are severely restricted probably because of the limited structural diversity of microorganisms. Consequently, the development of efficient and flexible synthetic methods for this class of natural products and related compounds is quite desirable and worthwhile from the viewpoint of medicinal chemistry and pharmaceuticals. In 2001, the Merck research group reported the isolation and structure elucidation of nalanthalide (1, Fig. 1) from the culture broth of Nalanthamala sp. [2]. This natural product was found to be a novel blocker of the voltage-gated potassium channel Kv1.3 (IC50 = 3.9 µM) [7]. A closely related diterpenoid pyrone, sesquicillin (2), wherein the ?-pyrone ring of 1 is replaced by an a-pyrone ring, was isolated from the culture broth of Acremonium sp. by Erkel et al. [3a]. This natural product was first classified as an inhibitor of glucocorticoid-mediated signal transduction [3a]. Sesquicillin has been reported to strongly induce G1 phase arrest in human breast cancer cell lines [3b]. Recently, four additional and new sesquicillin analogues (named sesquicillins B–E) were isolated from the culture broth of Albophoma sp. in addition to 2 (renamed sesquicillin A) [3c]. These substances were reported to exhibit insecticidal and cytotoxic activities [3c]. The gross structure and stereochemistry of 1 and 2 have been determined by extensive NMR spectroscopic studies [2,3a], but their absolute configurations have not been assigned. These natural products consist of a trans-decalin skeleton connected with a fully substituted ?- or a-pyrone ring via a methylene linkage involving five asymmetric carbon centers [2,3a, c,]. Figure 1 Structures of nalanthalide (1), sesquicillin (2), candelalides A–C (3–5), and subglutinols A (6), B (7). Subsequent to the discovery of nalanthalide, the structurally similar diterpenoid pyrones—candelalides A (3), B (4), and C (5)—were successively isolated from a culture broth of Sesquicillium candelabrum by the Merck research group in 2001 [5]. These natural products were also found to be novel blockers of the voltage-gated potassium channel Kv1.3 (IC50 = 3.7 µM for 3, 1.2 µM for 4, 2.5 µM for 5) [5]. Kv1.3 channels plays pivotal roles in the control of membrane potential in human T cells, wherein it sets the resting potential. The blocking of Kv1.3 causes the membrane depolarization of human T cells, and this prevents Ca2 + entry required for T cell activation [7]. These processes lead to the diminution of lymphokine release and synthesis from the calcium-dependent pathway, thus suppressing the activation and proliferation of human T cells [7]. Consequently, nalanthalide and candelalides A–C are expected to be promising new agents for the treatment of T cell-mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and insulin-dependent diabetes [2,5,7]. The gross structure and stereochemistry of 3–5 have been determined by extensive spectroscopic studies including 2D NMR experiments, whereas their absolute configurations have not been confirmed [5]. Candelalides A–C possess a novel tricyclic decahydro- or dodecahydro-1H-benzo[f]chromene skeleton (ABC ring system) connected to a fully substituted ?-pyrone ring via a methylene linkage involving five to seven asymmetric carbons [5]. Interestingly, the candelalide with the most complex structure, 4, exhibits the most potent Kv1.3 blocking activity [5]. In 1995, Strobel and Clardy et al. reported the isolation and structural elucidation of two novel immunosuppressive diterpenoid pyrones, subglutinols A (6) and B (7) from the endophytic fungus Fusarium subglutinans [6]. The immunosuppressive activities of 6 and 7 are comparable; they were found to be equipotent in the mixed lymphocyte reaction (MLR) assay (IC50 = 0.1 µM) and the thymocyte proliferation (TP) assay (IC50 = 0.1 µM) [6]. However, their mechanism of action remains unclear. In comparison, cyclosporine A showed similar potency in the MLR assay and was 104× more potent in the TP assay [6]. Hence, subglutinols are also anticipated to be promising candidates or new leads for novel classes of immunosuppressive agents [6]. The relative stereochemistry of 6 and 7 was determined by extensive NMR spectroscopic and X-ray diffraction analysis, but their absolute configurations were not established [6]. These diastereomeric natural products (6 and 7) possess a novel tricyclic...