Organocatalyst-controlled stereoselective head-to-tail macrocyclizations.
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| Title: | Organocatalyst-controlled stereoselective head-to-tail macrocyclizations. |
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| Authors: | Rackl, Jonas W. (AUTHOR), Boll, Linus B. (AUTHOR), Wennemers, Helma (AUTHOR) |
| Source: | Science. 2/26/2026, Vol. 391 Issue 6788, p931-936. 6p. |
| Subjects: | Organocatalysis, Macrocyclic compounds, Asymmetric synthesis, Organic synthesis |
| Abstract: | Chiral macrocycles are key to the discovery of new medicines. Their synthesis is, however, challenging and typically requires the often-cumbersome installation of stereochemical features in a linear precursor. In this study, we report a catalyst-controlled stereoselective head-to-tail macrocyclization. The method utilizes a bifunctional peptide catalyst to template the terminal functional groups of the linear precursor, thereby favoring intra- over intermolecular reaction and enabling exquisite control over the stereochemistry of the emerging stereogenic centers. Diverse 12- to 18‐membered macrocyclic lactones and lactams were obtained from achiral linear precursors. The organocatalyst even dictates the stereochemical outcome upon cyclizing a chiral linear precursor. This catalyst-controlled stereoselective head-to-tail macrocyclization provides a practical route to chiral macrocycles with predictable stereochemical outcomes. The utility was highlighted by synthesizing the core of the natural product robotnikinin. Editor's summary: A common strategy for producing large molecular rings is to first generate a linear precursor and then loop it back on itself with a favorable clasping reaction. Rackl et al. present an innovative catalyst for this type of loop closure in 12- to-18 membered rings: directing a conjugate addition between an aldehyde and a ketovinyl ester (see the Perspective by Dong and Zhao). The tripeptide catalyst selects for just one of two possible mirror image configurations at the linkage point, even overriding existing stereochemical bias in the precursor. —Jake S. Yeston [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Chiral macrocycles are key to the discovery of new medicines. Their synthesis is, however, challenging and typically requires the often-cumbersome installation of stereochemical features in a linear precursor. In this study, we report a catalyst-controlled stereoselective head-to-tail macrocyclization. The method utilizes a bifunctional peptide catalyst to template the terminal functional groups of the linear precursor, thereby favoring intra- over intermolecular reaction and enabling exquisite control over the stereochemistry of the emerging stereogenic centers. Diverse 12- to 18‐membered macrocyclic lactones and lactams were obtained from achiral linear precursors. The organocatalyst even dictates the stereochemical outcome upon cyclizing a chiral linear precursor. This catalyst-controlled stereoselective head-to-tail macrocyclization provides a practical route to chiral macrocycles with predictable stereochemical outcomes. The utility was highlighted by synthesizing the core of the natural product robotnikinin. Editor's summary: A common strategy for producing large molecular rings is to first generate a linear precursor and then loop it back on itself with a favorable clasping reaction. Rackl et al. present an innovative catalyst for this type of loop closure in 12- to-18 membered rings: directing a conjugate addition between an aldehyde and a ketovinyl ester (see the Perspective by Dong and Zhao). The tripeptide catalyst selects for just one of two possible mirror image configurations at the linkage point, even overriding existing stereochemical bias in the precursor. —Jake S. Yeston [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aec8992 |
