The Correct Structure of Aquatolide—Experimental Validation of a Theoretically-Predicted Structural Revision

Abstract

Aquatolide has been reisolated from its natural source, and its structure has been revised on the basis of quantum-chemical NMR calculations, extensive experimental NMR analysis, and crystallography.

Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

“…In 2012, Tantillo and co-workers 77 computed NMR chemical shifts for structure 152 at the CPCM/mPW1PW91/6-311+G(2d,p)//B3LYP/6-31+G(d,p) level of theory, and although the proposed structure was consistent with all the reported experimental data, including NOE, the calculated chemical shifts for the proposed structure deviated from the experimental data available for the natural product. The authors undertook a combination of both rational and arbitrary changes to the proposed structure, followed by recalculation of the 1 H and 13 C chemical shifts and coupling constants at the more affordable CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level, and concluded that structure 153 was the most probable one for aquatolide (Figure 30).…”

“…X-ray studies carried out with such metabolite confirmed its structure as 153. More recently, Gary Williamson and coworkers 77 alternatively revealed the structure of aquatolide as 153 using anisotropic NMR measurements, including residual dipolar coupling (RDCs) and residual chemical shift anisotropy (RCSAs).…”

“…The structure 153 proposed by Tantillo and co-workers 77 was eventually prepared by Hiemstra and co-workers 77 featuring an intramolecular [2 + 2]-photocycloaddition between an allene and an α,β-unsaturated δ-lactone as the key step to construct its tricyclic core (Scheme 20). 79 The synthesis started with a Ti(O i Pr) 4 promoted cross aldol involving isobutyraldehyde (154) and propargylic aldehyde which required conversion of the product into the corresponding dimetylacetal 155.…”

Total Synthesis of Aquatolide

“…Recently, Tantillo and co-workers reinvestigated the compound because of serious doubts about structure 1 on the basis of quantum-chemical NMR calculations. 2 After reisolation of the natural product and an X-ray crystallographic study, the structure was revised to 2, an isomer of 1. 2 There is an interesting relationship between structures 1 and 2 as they are in principle the straight and crossed [2 + 2]-photocycloaddition products from the asteriscunolides (3), of which all four geometric isomers also occur in the same plant.…”

“…2 After reisolation of the natural product and an X-ray crystallographic study, the structure was revised to 2, an isomer of 1. 2 There is an interesting relationship between structures 1 and 2 as they are in principle the straight and crossed [2 + 2]-photocycloaddition products from the asteriscunolides (3), of which all four geometric isomers also occur in the same plant. 3 These interesting butenolides bridged with a large ring have been found to have anticancer activity, 4 and two of the isomers, asteriscunolide C and D, have been prepared by total synthesis.…”