A Practical, Enantioselective Synthetic Route to a Key Precursor to the Tetracycline Antibiotics

Brubaker, Jason D.; Myers, Andrew G.

doi:10.1021/ol071377d

Cited by 75 publications

(64 citation statements)

References 22 publications

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“…at −70°C provided the 4S-alcohol 20 selectively (diastereomeric ratio 12∶1), by which we infer that the substrate had reacted via bidendate coordination to the organometallic reagent (33). The product was susceptible to lactonization and so was protected immediately as the 4-methoxybenzyl ether (21) using 4-methoxybenzyl trichloroacetimidate (2.0 eq) and ScðOTfÞ 3 as catalyst (0.03 eq, 57% yield over two steps, 12∶1 mixture of C4 diastereomers, 17.8-g scale).…”

Section: Resultsmentioning

confidence: 81%

A multiply convergent platform for the synthesis of trioxacarcins

Švenda

Hill

Myers

2011

Proc. Natl. Acad. Sci. U.S.A.

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Many first-line cancer drugs are natural products or are derived from them by chemical modification. The trioxacarcins are an emerging class of molecules of microbial origin with potent antiproliferative effects, which may derive from their ability to covalently modify duplex DNA. All trioxacarcins appear to be derivatives of a nonglycosylated natural product known as DC-45-A2. To explore the potential of the trioxacarcins for the development of smallmolecule drugs and probes, we have designed a synthetic strategy toward the trioxacarcin scaffold that enables access to both the natural trioxacarcins and nonnatural structural variants. Here, we report a synthetic route to DC-45-A2 from a differentially protected precursor, which in turn is assembled in just six steps from three components of similar structural complexity. The brevity of the sequence arises from strict adherence to a plan in which strategic bond-pair constructions are staged at or near the end of the synthetic route.chemical synthesis | DNA alkylation | anticancer T he trioxacarcins are highly concatenated, densely oxygenated molecules encoded within the genes of various streptomycetes and potently inhibit the growth of cultured human cancer cell lines (1-4). Approximately 20 individual trioxacarcins have been structurally characterized; all appear to be built upon or closely related to the natural product DC-45-A2 (1) (5). The diversity of the trioxacarcin class is well represented by the four compounds that are depicted in Fig. 1 alongside the anthracycline antibiotic daunomycin (daunorubicin, long used in chemotherapy for acute myelogenous leukemias) and nogalamycin, presented in a manner that emphasizes their structural similarities. The trioxacarcins, however, have unique glycosylation patterns, contain a distinct linear aromatic core, and bear as their most distinguishing feature a highly unusual condensed polycyclic trisketal containing a spiro-epoxide. The latter is implicated to be key to the observed antiproliferative effects of the trioxacarcins, for it has been shown to serve as the point of covalent attachment of trioxacarcin A (6-8), the most potent family member in clonogenic assays (4) (with subnanomolar IC 70 values), to G residues of duplex DNA. An X-ray crystallographic analysis of a 2∶1 complex of trioxacarcin A and an 8-mer duplex DNA oligonucleotide (8) reveals that the structure has features related to the (2∶1) nogalamycin-DNA complex (9), with the linear aromatic cores of both small molecules bound intercalatively through the base stack and sugar residues positioned in the major and minor grooves, but unlike nogalamycin, trioxacarcin A covalently modifies the DNA duplex, by reaction of the spiro-epoxide with N7 of a flanking G residue as nucleophile (8). Other structurally distinct natural product families appear to function by pathways that may be mechanistically related (10, 11).To realize their full potential as chemotherapeutic agents and to enable a broader study of the trioxacarcin class of DNA-binding molecules, we ...

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Section: Resultsmentioning

confidence: 81%

A multiply convergent platform for the synthesis of trioxacarcins

Švenda

Hill

Myers

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The recent report of Myers on the asymmetric addition of zinc reagents to an isoxazole aldehyde,2 prompts this description of our own studies on an analogous C-4 functionalized system 3. Since the landmark report of the selective glutamate receptor ligand AMPA (Chart 1),4 the Krogsgaard-Larsen group has continued to uncover groundbreaking sub-type selectivity, exemplified by the recent observation of GluR1 selectivity of the 2-Benzyl-tetrazole (2-Bn-Tet) analog of AMPA 5,6.…”

mentioning

confidence: 61%

The catalytic asymmetric addition of alkyl- and aryl-zinc reagents to an isoxazole aldehyde

Nelson¹,

Twamley²,

Villalobos³

et al. 2008

Tetrahedron Letters

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Nucleophilic addition of alkyl-and aryl zinc reagents to a C(4) functionalized isoxazolyl aldehyde proceeded effectively with high enantioselectivity (85-94% e.e.). The amino alcohol catalyst (S)-2-piperidinyl-1,1,2-triphenyl ethanol (10) afforded the (R)-product 2b, as established by x-ray crystallography.Functionalized isoxazoles represent an extremely important class of compounds in the synthesis of therapeutically relevant molecules. 1 The recent report of Myers on the asymmetric addition of zinc reagents to an isoxazole aldehyde, 2 prompts this description of our own studies on an analogous C-4 functionalized system. 3 Since the landmark report of the selective glutamate receptor ligand AMPA (Chart 1), 4 the Krogsgaard-Larsen group has continued to uncover groundbreaking sub-type selectivity, exemplified by the recent observation of GluR1 selectivity of the 2-Benzyl-tetrazole (2-Bn-Tet) analog of AMPA. 5,6 In order to expand upon our previously reported catalytic asymmetric synthesis of isoxazole containing glutamate analogs, 7-9 we came to examine the nature of asymmetric addition of carbon-based nucleophiles to isoxazolyl aldehyde 1 for the synthesis of novel ACPA analogues, 3.Numerous methods exist for the nucleophilic addition of alkyl and aryl groups to aldehydes. The use of zinc-based reagents was chosen based on (1) The abundance of chiral catalysts which afford the products in high yield and high enantiomeric excesses (ee's); (2) The availability of a wide variety of alkyl and aryl substituents on zinc (either commercially, or via a single synthetic step); and (3) The rate of the uncatalysed (racemic) reaction is most often near zero in the absence of a catalyst, theoretically leading to very high ee's.Results from alkyl zinc additions to isoxazolyl aldehyde 1 are summarized in Table 1. The proof of concept for this series of reactions was initially examined with Et 2 Zn as nucleophile and a BINOL/Ti(OiPr) 4 co-catalysts system developed by Walsh, 10 et al. This system was chosen due to the wide variety of functional groups tolerated as well as the consistently high yields and high ee's of products formed. Unfortunately, repeated attempts at nucleophilic addition to 1 using this method failed completely. The product from aqueous workup following © 2008 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: 406-243-4132; fax: 406-243-5228; e-mail: Nicholas.natale@umontana.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the reaction appears to have...

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“…[30] Zentrales Element dieser Synthese war ein konvergenter Zusammenbau des Kohlenstoffgerüsts über eine Diels-Alder-Cycloaddition im späten Stadium des Molekül-aufbaus. [28] Das AB-Ringsystem 34 (Schema 2) wurde ursprünglich aus Benzoesäure hergestellt, [30] doch eine verbesserte Synthese dieser Verbindung [31] begann mit der enantioselektiven Addition von Divinylzink an den Isoxazolcarbaldehyd 27, die durch das von Norephedrin abgeleitete chirale Auxiliar 28 katalysiert wurde [32] und mit einer Enantioselektivität von 93 % zum optisch aktiven Alkohol 29 führte. Dieser wurde zum tertiären Amin 30 umgesetzt, das lithiiert wurde, und das Anion wurde mit dem Furancarbaldehyd 31 abgefangen, wobei man das Intermediat 32 als Diastereomerengemisch erhielt.…”

Section: Tetracyclineunclassified

“…Schlüsselschritte der zweiten Art der Synthese des AB-Ringsystems über 34 . [31] Schema 3. Schlussschritte der Totalsynthese von Tetracyclin nach Myers .…”

Section: Thiopeptid-antibiotikaunclassified

Fortschritte in der Chemie und Biologie natürlicher Antibiotika

et al. 2009

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Seit der bahnbrechenden Entdeckung von Penicillin wurde die Vielfalt natürlich vorkommender Moleküle ausgiebig hinsichtlich ihrer Eignung als Medikamente sowie zum Auffinden neuer Leitstrukturen beim Wirkstoffdesign untersucht. Die Suche nach Wirkstoffen, mit denen Infektionskrankheiten bekämpft werden können, war dabei von besonderem Interesse und verlief sehr erfolgreich. Die Erforschung der Antibiotika weist eindrucksvolle Entdeckungen und Geschichten über die Entwicklung von Wirkstoffen auf, von denen die große Mehrheit ihren Ursprung in Naturstoffen hat. Die Chemie und besonders die chemische Synthese haben eine bedeutende Rolle dabei gespielt, natürlich vorkommende Antibiotika und deren Derivate für die medizinische Anwendung bereitzustellen, und zweifellos werden diese Disziplinen auch künftig Schlüsseltechnologien sein. In dieser Übersicht stellen wir einige der bedeutendsten neueren Entwicklungen und Fortschritte in der Chemie, Biologie und Medizin natürlich vorkommender Antibiotika vor, wobei die Totalsynthese, das Design von Analoga und die biologische Bewertung von Molekülen mit neuartigen Wirkmechanismen im Vordergrund stehen.

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A Practical, Enantioselective Synthetic Route to a Key Precursor to the Tetracycline Antibiotics

Cited by 75 publications

References 22 publications

A multiply convergent platform for the synthesis of trioxacarcins

A multiply convergent platform for the synthesis of trioxacarcins

The catalytic asymmetric addition of alkyl- and aryl-zinc reagents to an isoxazole aldehyde

Fortschritte in der Chemie und Biologie natürlicher Antibiotika

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