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Quaternary-centre-guided synthesis of complex polycyclic terpenes

Abstract

The presence of a quaternary centre—a carbon with four other carbons bonded to it—in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions—known as the Thorpe–Ingold effect—which has application in drug delivery for molecules with modest bioavailability1. Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability2. When present in chiral ligands3, catalysts4 and auxiliaries5, quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations6,7. For particularly challenging cases—for example, the vicinal all-carbon8, oxa- and aza-quaternary centres9 in molecules such as azadirachtin10,11, scopadulcic acid A12,13 and acutumine14—the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next—either through rate acceleration or blocking effects—then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.

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Fig. 1: Quaternary centres as a point of challenge and opportunity for organic synthesis.
Fig. 2: Quaternary-centre-guided synthetic analysis of the conidiogenones.
Fig. 3: Short, enantioselective synthesis of the conidiogenone family of natural products empowered by quaternary-centre-based synthetic planning.
Fig. 4: Quaternary-centre-guided synthetic analysis can apply to diverse targets.

Data availability

Data produced in this study is available in the Supplementary Information or on request from the corresponding author.

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Acknowledgements

We thank A. Filatov for obtaining an X-ray crystal structure of 36, and A. Jurkiewicz and C. J. Qin for assistance with NMR and mass spectrometry, respectively. Financial support came from the University of Chicago, the National Institutes of Health (R01-GM132570), a Bristol-Myers Squibb Graduate Fellowship (to P.H.), Metcalf Fellowships (to K.C.D. and I.T.H.) and a travel research fellowship from Nankai University and its Department of Chemistry (to X.G.).

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S.A.S. and P.H. conceived the project. S.A.S. directed the research, and S.A.S., P.H. and H.M.C. composed the manuscript and the Supporting Information section; all authors commented on the manuscript. P.H. and H.M.C. developed the synthesis of compound 10. P.H. completed the syntheses of compounds 9, 11, 38 and 41. H.M.C. synthesized the NHC and sulfonamide ligands and conducted the large-scale preparation of compounds 18, S12, S13 and S14. K.C.D. conducted large-scale racemic syntheses and reaction optimizations for compounds 18, 19, 20 and S3. X.G., J.H.K. and I.T.H. participated in material preparation and explored various alternative pathways towards the target molecules.

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Correspondence to Scott A. Snyder.

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This file contains Supplementary Text and Data, Supplementary Figures 1-5, Supplementary Tables 1-14 and Supplementary References – see Contents page for full details.

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Hu, P., Chi, H.M., DeBacker, K.C. et al. Quaternary-centre-guided synthesis of complex polycyclic terpenes. Nature 569, 703–707 (2019). https://doi.org/10.1038/s41586-019-1179-2

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