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ABSTRACT: Isolated from Hypericum species H. chinese L. var. salicifolium, biyouyanagin A was assigned structure 1a or 1b on the basis of NMR spectroscopic analysis. This novel natural product exhibited significant anti-HIV properties and inhibition of lipopolysaccharide-induced cytokine production. Described herein are the total syntheses of biyouyanagin A and several analogues (3-11), structural revision of biyouyanagin A to 2b, and the biological properties of all synthesized compounds. The total synthesis proceeded through cascade sequences that efficiently produced enantiomerically pure key building blocks 15b (ent-zingiberene) and 18 (hyperolactone C) and featured a novel [2 + 2] photoinduced cycloaddition reaction which occurred with complete regio- and stereoselectivity. Biological investigations with the synthesized biyouyangagins A (2-11) and hyperolactones C (12-16) revealed that the activity of biyouyanagin A most likely resides in its hyperolactone C structural domain.
Journal of the American Chemical Society 08/2008; 130(33):11114-21. · 9.91 Impact Factor
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ABSTRACT: Molecular design and chemical synthesis of several palmerolide A analogues allowed the first structure activity relationships (SARs) of this newly discovered marine antitumor agent. From several analogues synthesized and tested (ent- 1, 5- 14, 21- 26, 50, 51), compounds 25 (with a phenyl substituent on the side chain) and 51 (lacking the C-7 hydroxyl group) were the most interesting, exhibiting approximately a 10-fold increase in potency and equipotency, respectively, to the natural product. These findings point the way to more focused structure activity relationship studies.
Journal of the American Chemical Society 08/2008; 130(30):10019-23. · 9.91 Impact Factor
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ABSTRACT: Molecular design and chemical synthesis of several palmerolide A analogues allowed the first structure activity relationships (SARs) of this newly discovered marine antitumor agent. From several analogues synthesized and tested (ent-1, 5−14, 21−26, 50, 51), compounds 25 (with a phenyl substituent on the side chain) and 51 (lacking the C-7 hydroxyl group) were the most interesting, exhibiting approximately a 10-fold increase in potency and equipotency, respectively, to the natural product. These findings point the way to more focused structure activity relationship studies.
07/2008;
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ABSTRACT: As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).
Journal of the American Chemical Society 07/2008; 130(23):7466-76. · 9.91 Impact Factor
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Chemical Communications 07/2008; · 6.17 Impact Factor
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ABSTRACT: A concise and efficient cascade-based total synthesis of artochamins F, H, I, and J is described. The potential biogenetic connection between artochamin F, or a derivative thereof, and artochamins H, I, and J, through an unusual formal [2+2] cycloaddition process, was shown to be feasible. An alternative mechanism for this transformation is also proposed.
Tetrahedron 06/2008; 64(21):4736-4757. · 3.03 Impact Factor
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ABSTRACT: Palmerolide A is a recently disclosed marine natural product possessing striking biological properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised [ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-2, 3, ent-3, 4, and ent-4, and their assembly and elaboration to the target compounds. For the union of the building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination and the Yamaguchi lactonization were also investigated and found successful as a means to construct the palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a copper-catalyzed coupling process.
Journal of the American Chemical Society 04/2008; 130(11):3633-44. · 9.91 Impact Factor
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ABSTRACT: The total syntheses of the thiopeptide antibiotics GE2270A (7), GE2270T (8), and GE2270C1 (9) are described. The original synthetic strategies employed utilized the hetero-Diels-Alder reaction to construct the pyridine core of the target molecules and relied on a macrolactamization process to construct the macrocycle. The hetero-Diels-Alder-based strategy finally evolved allows the introduction of all four thiazole units attached to the pyridine ring and a one-pot sequence for macrocyclization and side-chain extension, culminating in highly convergent and expedient syntheses of these molecules as exemplified by a 24-step synthesis of GE2270C1 (9).
Chemistry - An Asian Journal 03/2008; 3(2):413-29. · 4.50 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(22):4217-20. · 13.45 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(9):1780-3. · 13.45 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(1):185-9. · 13.45 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(5):944-6. · 13.45 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(8):1432-5. · 13.45 Impact Factor
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ABSTRACT: The unprecedented structure of the marine natural product brevetoxin B was elucidated by the research group of Nakanishi and Clardy in 1981. The ladderlike molecular architecture of this fused polyether molecule, its potent toxicity, and fascinating voltage-sensitive sodium channel based mechanism of action immediately captured the imagination of synthetic chemists. Synthetic endeavors resulted in numerous new methods and strategies for the construction of cyclic ethers, and culminated in several impressive total syntheses of this molecule and some of its equally challenging siblings. Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, but is also the largest nonpolymeric natural product known to date. This Review begins with a brief history of the isolation of these biotoxins and highlights their biological properties and mechanism of action. Chemical syntheses are then described, with particular emphasis on new methods developed and applied to the total syntheses. The Review ends with a discussion of the, as yet unfinished, story of maitotoxin, and projects into the future of this area of research.
Angewandte Chemie International Edition 02/2008; 47(38):7182-225. · 13.45 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(38):7310-3. · 13.45 Impact Factor
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ABSTRACT: The chemical synthesis and biological evaluation of carbaplatensimycin, the carbon analogue of the recently reported antibiotic platensimycin has been accomplished. Carbaplatensimycin exhibited similar potency to the natural product as an antibacterial agent against a variety of strains, including methicilin- and vancomycin-resistant bacteria.
Journal of the American Chemical Society 01/2008; 129(48):14850-1. · 9.91 Impact Factor
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Angewandte Chemie International Edition 01/2008; 47(35):6579-82. · 13.45 Impact Factor
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11/2007: pages 397 - 409; , ISBN: 9780470277874
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Journal of the American Chemical Society 09/2007; 129(34):10356-7. · 9.91 Impact Factor
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ABSTRACT: A new synthetic method providing expedient access to a wide range of polyfunctionalized N-hydroxyindoles (IV) is reported. These unique constructs are assembled by nucleophilic additions to in situ generated α,β-unsaturated nitrones (III) through carbon-carbon and carbon-heteroatom bond formation. The new synthetic technology was applied to the synthesis of nocathiacin I (1) model systems (2 and 3a-c) containing the N-hydroxyindole structural motif.
Tetrahedron 07/2007; 63(27):6088-6114. · 3.03 Impact Factor
