3-Benzyloxyisoxazole system in construction of tetracyclines

Stork, Gilbert; Hagedorn, Alfred A.

doi:10.1021/ja00479a060

Cited by 64 publications

(36 citation statements)

References 2 publications

(4 reference statements)

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“…The Stork-Hagedorn isoxazole ( 3 ) 9,10 was readily prepared in large amounts by the sequence outlined in Scheme 5, beginning with the known substance methyl 3-hydroxyisoxazole-5-carboxylate ( 10 ) (see Supporting Information for details † ). 15,16 …”

Section: Resultsmentioning

confidence: 99%

“…We refer to the latter compound as the Stork–Hagedorn isoxazole, recognizing the first reported use of the 3-benzyloxy-isoxazole function as a protective group for the A-ring of tetra-cyclines, an innovation critical to our own work. 9 The Stork laboratory subsequently described a remarkably efficient synthesis of C12a-deoxytetracycline from this same starting material using stepwise Michael and Claisen cyclization reactions to form the A-ring, with a different sequencing than that reported here. 10 In the present application, neither the feasibility nor the likely stereochemical outcome of the proposed single-step condensation ( 2 + 3 ) were known at the outset of our work.…”

Section: Retrosynthetic Analysismentioning

confidence: 85%

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A practical, convergent route to the key precursor to the tetracycline antibiotics

Kummer

Dion

et al. 2011

Chem. Sci.

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Here we describe a 5-step sequence to prepare the AB enone 1, the key precursor to fully synthetic tetracyclines, that begins with a diastereoselective Michael–Claisen coupling of two simple starting materials, a cyclohexenone (compound 2 or, in a refinement, a substituted variant, vide infra) and the isoxazole ester 3. This advance defines an 8-step linear sequence to 6-deoxytetracycline antibiotics from three components of similar complexity (cyclohexenone 2, isoxazole ester 3, and structurally diverse D-ring precursors) in which sequential diastereoselective Michael–Claisen cyclization reactions form the A- and C-rings, respectively, of the linearly fused ABCD tetracycline skeleton. In addition to providing a readily scalable, practical route to fully synthetic tetracyclines of broad structural diversity, the sequence reported comprises a series of non-obvious stereoselective transformations, including a novel means for C12a hydroxylation.

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Section: Resultsmentioning

confidence: 99%

Section: Retrosynthetic Analysismentioning

confidence: 85%

A practical, convergent route to the key precursor to the tetracycline antibiotics

Kummer

Dion

et al. 2011

Chem. Sci.

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“…145 Most impressive is the vast improvement in yield over previous work, rendering this approach attractive to industrial scale-up. Furthermore, the use of a benzyloxyisoxazole as a masked vinylogous carbamic acid on the A-ring was a key innovation, discovered in a previous effort, 146 that will allow more efficient syntheses in the future. While limited by its racemic nature, the synthesis nonetheless demonstrated that total synthesis of tetracyclines could be industrially feasible, providing a realistic alternative to semisynthesis.…”

Section: From Benchtop To Bedside—innovations In the Tetracyclinesmentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrowspectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

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“…The tert -butoxycarbonyl and tert butyldimethylsilyl protective groups were removed upon treatment of 14 with hydrofluoric acid in acetonitrile at 23 °C (2 days). Hydrogenolysis of the crude reaction product ( 15 ) in the presence of a palladium catalyst under an atmosphere of hydrogen in methanol-dioxane at 23 °C and subsequent purification by rp-HPLC then afforded 6-deoxytetracycline ( 7 ) in 85% yield 17. As the examples below will demonstrate, this two-step deprotection protocol has been found to be widely applicable, though in some instances it is advantageous to invert the ordering of the two steps.…”

Section: Resultsmentioning

confidence: 99%

A Robust Platform for the Synthesis of New Tetracycline Antibiotics

et al. 2008

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Tetracyclines and tetracycline analogs are prepared by a convergent, single-step Michael-Claisen condensation of the AB precursors 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at −78 °C, while Claisen cyclization of the enolate produced is ratedetermining, typically occurring upon warming to 0 °C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semi-synthetic methods (presently the only means of tetracycline production), and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.

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3-Benzyloxyisoxazole system in construction of tetracyclines

Cited by 64 publications

References 2 publications

A practical, convergent route to the key precursor to the tetracycline antibiotics

A practical, convergent route to the key precursor to the tetracycline antibiotics

Natural Products as Platforms To Overcome Antibiotic Resistance

A Robust Platform for the Synthesis of New Tetracycline Antibiotics

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