The Asymmetric Synthesis of Erythromycin B

The effectiveness of two activation techniques, collision activated dissociation (CAD) and infrared multiphoton dissociation (IRMPD), is compared for structural characterization of protonated and lithium-cationized macrolides and a series of synthetic precursors in a quadrupole ion trap (QIT). Generally, cleavage of the glycosidic linkages attaching the sugars to the macrolide ring and water losses constitute the major fragmentation pathways for most of the protonated compounds. In the IRMPD spectra, a diagnostic fragment ion assigned as the desosamine ion is a dominant ion that is not observed in the CAD spectra because of the higher m/z limit of the storage range required during collisional activation. Activation of the lithium-cationized species results in new diagnostic fragmentation pathways that are particularly useful for confirming the identities of the protecting groups in the synthetic precursors. Multi-step IRMPD allows mapping of the fragmentation genealogies in greater detail and supports the proposed structures of the fragment ions. (J Am Soc Mass Spectrom 2002, 13, 630 -649)

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“…SP1 and SP2 were degraded from natural erythromycin B [31]. SP3 [32] and SP4 [33] were prepared by synthetic methods.…”

Section: Methodsmentioning

confidence: 99%

Characterization of erythromycin analogs by collisional activated dissociation and infrared multiphoton dissociation in a quadrupole ion trap

Crowe

Brodbelt

Goolsby

et al. 2002

J. Am. Soc. Mass Spectrom.

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“…104 Using chemistry developed previously, 2-ethylfuran ( 49 ) was converted to polyketide precursor 50 , which undergoes relatively straightforward aldol chemistry to yield seco -acid 51 . Lactonization using Yamaguchi’s method was particularly efficient with an impressive 93% yield.…”

Section: Macrolides and Ketolides–from Fermentation To Synthesismentioning

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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“…Eight simple building blocks (1)(2)(3)(4)(5)(6)(7)(8), two of which are commercially available and six of which are synthesized in sequences of 3-6 steps in 30-150-g amounts, are assembled in a highly convergent manner (Fig. 2).…”

Section: Synthesis Of 14-membered Azaketolidesmentioning

confidence: 99%

“…Macrolide antibiotics (macrocyclic lactones with one or more pendant glycosidic residues), which have proven to be safe and effective for use in treating human infectious diseases such as community-acquired bacterial pneumonia, gonorrhoea and others, provide a compelling case in point. Since the discovery of erythromycin from a Philippine soil sample in 1949 4 , in spite of extraordinary efforts leading to fully synthetic [5][6][7][8] and modified biosynthetic routes [9][10][11][12] to macrolide antibiotics, all members of this class approved or in clinical development for use in humans have been manufactured by chemically modifying erythromycin (erythromycin itself is unstable in the stomach, and rearranges to form a product with gastrointestinal side-effects) 13 . Thus, azithromycin is prepared from erythromycin in four steps 14 , clarithromycin requires six steps 15 , and the advanced clinical candidate solithromycin is currently produced from erythromycin by a 16-step linear sequence ( Fig.…”

mentioning

confidence: 99%

A platform for the discovery of new macrolide antibiotics

Seiple

Zhang

Jakubec

et al. 2016

Nature

297

214

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The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

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The Asymmetric Synthesis of Erythromycin B

Cited by 61 publications

References 16 publications

Characterization of erythromycin analogs by collisional activated dissociation and infrared multiphoton dissociation in a quadrupole ion trap

Characterization of erythromycin analogs by collisional activated dissociation and infrared multiphoton dissociation in a quadrupole ion trap

Natural Products as Platforms To Overcome Antibiotic Resistance

A platform for the discovery of new macrolide antibiotics

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