The combination of synthesis and ultra-high-resolution NMR spectroscopy reveals the correct structure of caylobolide A

Malcolm R.P. George; Max Deering; Daniele Fiorito; Keren Solomon; Kevin Tidgewell; Adam Noble; Craig P. Butts; Varinder K. Aggarwal

doi:10.1038/s44160-025-00762-2

The combination of synthesis and ultra-high-resolution NMR spectroscopy reveals the correct structure of caylobolide A

Malcolm R.P. George, Max Deering, Daniele Fiorito, Keren Solomon, Kevin Tidgewell, Adam Noble, Craig P. Butts, Varinder K. Aggarwal

Research output: Contribution to journal › Article › peer-review

Abstract

Polyketide-derived natural products bearing repeat 1,5-polyols are commonly encountered but their structures are notoriously difficult to determine using spectroscopic techniques. The presence of distal 1,5-diol moieties frequently leads to spectral overlap and chemical shift degeneracy, giving rise to ambiguity in their assignment. Caylobolide A is a representative member of this class of natural products, bearing a 36-membered lactone, with six 1,5-diol units and two 1,3-diol units. Its partial structure had been proposed, but only 4 of the 12 stereogenic centres had been assigned. Here we report a blueprint for the structure determination of this class of natural products, comprising the use of ultra-high-resolution NMR spectroscopy, Mosher’s ester analysis and an efficient mixed isomer synthesis to unveil the correct structure of caylobolide A. With this approach, the partial stereochemistry proposed and the position of the triol unit within the carbon chain has been reassigned, culminating in the total synthesis of caylobolide A in 17 steps. (Figure presented.)

Original language	English
Pages (from-to)	859-868
Number of pages	10
Journal	Nature Synthesis
Volume	4
Issue number	7
DOIs	https://doi.org/10.1038/s44160-025-00762-2
State	Published - Jul 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

M.R.P.G. and M.D. thank the Bristol Chemical Synthesis Centre for doctoral training, funded by the EPSRC (EP/S024107/1). We thank AstraZeneca for support of this work. D.F. thanks the Swiss National Science Foundation for an Early Postdoc Mobility Fellowship (P2GEP2_194799). V.K.A. and C.B. thank the EPSRC (EP/T033584/1) and K.T. thanks the NIH (2R15AT008060-02) for support.

Funders	Funder number
Bristol Chemical Synthesis Centre
UK Medical Research Council, Engineering and Physical Sciences Research Council	EP/S024107/1
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	P2GEP2_194799, EP/T033584/1
National Institutes of Health (NIH)	2R15AT008060-02

ASJC Scopus subject areas

Chemistry (miscellaneous)
Inorganic Chemistry
Organic Chemistry
Materials Chemistry

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title = "The combination of synthesis and ultra-high-resolution NMR spectroscopy reveals the correct structure of caylobolide A",

abstract = "Polyketide-derived natural products bearing repeat 1,5-polyols are commonly encountered but their structures are notoriously difficult to determine using spectroscopic techniques. The presence of distal 1,5-diol moieties frequently leads to spectral overlap and chemical shift degeneracy, giving rise to ambiguity in their assignment. Caylobolide A is a representative member of this class of natural products, bearing a 36-membered lactone, with six 1,5-diol units and two 1,3-diol units. Its partial structure had been proposed, but only 4 of the 12 stereogenic centres had been assigned. Here we report a blueprint for the structure determination of this class of natural products, comprising the use of ultra-high-resolution NMR spectroscopy, Mosher{\textquoteright}s ester analysis and an efficient mixed isomer synthesis to unveil the correct structure of caylobolide A. With this approach, the partial stereochemistry proposed and the position of the triol unit within the carbon chain has been reassigned, culminating in the total synthesis of caylobolide A in 17 steps. (Figure presented.)",

author = "George, \{Malcolm R.P.\} and Max Deering and Daniele Fiorito and Keren Solomon and Kevin Tidgewell and Adam Noble and Butts, \{Craig P.\} and Aggarwal, \{Varinder K.\}",

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AU - Fiorito, Daniele

AU - Solomon, Keren

AU - Tidgewell, Kevin

AU - Noble, Adam

AU - Butts, Craig P.

AU - Aggarwal, Varinder K.

PY - 2025/7

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N2 - Polyketide-derived natural products bearing repeat 1,5-polyols are commonly encountered but their structures are notoriously difficult to determine using spectroscopic techniques. The presence of distal 1,5-diol moieties frequently leads to spectral overlap and chemical shift degeneracy, giving rise to ambiguity in their assignment. Caylobolide A is a representative member of this class of natural products, bearing a 36-membered lactone, with six 1,5-diol units and two 1,3-diol units. Its partial structure had been proposed, but only 4 of the 12 stereogenic centres had been assigned. Here we report a blueprint for the structure determination of this class of natural products, comprising the use of ultra-high-resolution NMR spectroscopy, Mosher’s ester analysis and an efficient mixed isomer synthesis to unveil the correct structure of caylobolide A. With this approach, the partial stereochemistry proposed and the position of the triol unit within the carbon chain has been reassigned, culminating in the total synthesis of caylobolide A in 17 steps. (Figure presented.)

AB - Polyketide-derived natural products bearing repeat 1,5-polyols are commonly encountered but their structures are notoriously difficult to determine using spectroscopic techniques. The presence of distal 1,5-diol moieties frequently leads to spectral overlap and chemical shift degeneracy, giving rise to ambiguity in their assignment. Caylobolide A is a representative member of this class of natural products, bearing a 36-membered lactone, with six 1,5-diol units and two 1,3-diol units. Its partial structure had been proposed, but only 4 of the 12 stereogenic centres had been assigned. Here we report a blueprint for the structure determination of this class of natural products, comprising the use of ultra-high-resolution NMR spectroscopy, Mosher’s ester analysis and an efficient mixed isomer synthesis to unveil the correct structure of caylobolide A. With this approach, the partial stereochemistry proposed and the position of the triol unit within the carbon chain has been reassigned, culminating in the total synthesis of caylobolide A in 17 steps. (Figure presented.)

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The combination of synthesis and ultra-high-resolution NMR spectroscopy reveals the correct structure of caylobolide A

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