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Synthesis of (-)-longithorone A: using organic synthesis to probe a proposed biosynthesis.

ABSTRACT: We present a full report of our enantioselective synthesis of (-)-longithorone A (1). The synthesis was designed to test the feasibility of the biosynthetic proposal for 1 put forward by Schmitz involving intermolecular and transannular Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if the biosynthesis does involve these two Diels-Alder reactions, the intermolecular Diels-Alder reaction likely occurs before the transannular cycloaddition. The intermolecular Diels-Alder precursors, [12]-paracyclophanes 38, 49, 59, and 60, were prepared atropselectively, providing examples of ene-yne metathesis macrocyclization. The 1,3-disubstituted dienes produced from the macrocyclizations represent a previously unreported substitution pattern for intramolecular ene-yne metathesis. Protected benzylic hydroxyl stereocenters were used as removable atropisomer control elements and were installed by using a highly enantioselective vinylzinc addition to electron-rich benzaldehydes 26 and 27.

SUBMITTER: Morales CA

PROVIDER: S-EPMC514430 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Synthesis of (-)-longithorone A: using organic synthesis to probe a proposed biosynthesis.

Morales Carl A CA Layton Mark E ME Shair Matthew D MD

Proceedings of the National Academy of Sciences of the United States of America 20040609 33

We present a full report of our enantioselective synthesis of (-)-longithorone A (1). The synthesis was designed to test the feasibility of the biosynthetic proposal for 1 put forward by Schmitz involving intermolecular and transannular Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if the biosynthesis does involve these two Diels-Alder reactions, the intermolecular Diels-Alder reaction likely occurs before the transannular cycloaddition. The intermolecular Diels-A ...[more]

PMID: 15190180

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Project description:Owing to extensive metagenomic studies, we now have access to numerous sequences of novel bacteriocin-like antimicrobial peptides encoded by various cultivable and noncultivable bacteria. However, relatively rarely, we even have access to these cultivable strains to examine the potency and the targets of the predicted bacteriocins. In this study, we evaluated a heterologous biosynthetic system to produce biologically active nonnative novel lantibiotics, which are modified bacteriocins. We chose Streptococcus mutans, a dental pathogen, as the host organism because it is genetically easy to manipulate and is inherently a prolific producer of various bacteriocins. We chose the S. mutans T8 strain as the host, which produces the lantibiotic mutacin II, to express 10 selected homologs of mutacin II identified from GenBank. These lantibiotic peptides either are novel or have been studied very minimally. The core regions of the selected lantibiotic peptides were fused to the leader sequence of the mutacin II peptide and integrated into the chromosome such that the core region of the native mutacin II was replaced with the new core sequences. By this approach, using the mutacin II biosynthesis machinery, we obtained one bioactive novel lantibiotic peptide with 52% different residues compared to the mutacin II core region. This unknown lantibiotic is encoded by Streptococcus agalactiae and Streptococcus ovuberis strains. Since this peptide displays some homology with nukacin ISK-1, we named it nukacin Spp. 2. This study demonstrated that the mutacin II biosynthesis machinery can be successfully used as an efficient system for the production of biologically active novel lantibiotics. IMPORTANCE In this study, we report for the first time that Streptococcus mutans can be used as a host to produce various nonnative lantibiotics. We showed that in the T8 strain, we could produce bioactive lacticin 481 and nukacin ISK-1, both of which are homologs of mutacin II, using T8's modification and secretion apparatus. Similarly, we also synthesized a novel bioactive lantibiotic, which we named nukacin Spp. 2.

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Synthesis of (-)-longithorone A: using organic synthesis to probe a proposed biosynthesis.

Publications

Synthesis of (-)-longithorone A: using organic synthesis to probe a proposed biosynthesis.

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