Synthetic Studies toward the C32–C46 Segment of Hemicalide. Assignment of the Relative Configuration of the C36–C42 Subunit

Abstract

The synthesis of five diastereomeric model compounds incorporating the C32-C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,β-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia-Kocienski olefination. Comparison of the (1)H and (13)C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36-C42 subunit.

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

“…Initially, the NMR shifts of all possible 16 isomers of the virtual fragment 45 were calculated, and the fragment 45A was identified as the preferred candidate in 84% probability ( Figure 11). Since this assignment challenged the findings of Cossy and co-workers 34 (compound 37, Figure 9), the computational predictions were revised. In particular, the NOE correlation experimentally observed between H-37 and H-40 clearly confirmed that both protons should be on the same side of the molecule, which was not the case in 45A.…”

“…In good agreement with their previous work, a nice match between the 1 H and 13 C NMR shifts corresponding to the C-8/C-24 region of the synthesized compound with those of hemicalide was observed (Dd up to 0.12 and 1.2 ppm, respectively). 33 In the meantime, Cossy and co-workers 34 decided to study the C-36/C-46 unit. In view of the six stereocenters in that region, up to 32 possible diastereoisomers might be postulated.…”

“…After the final reports of Cossy and co-workers, 34 it seemed that the relative configurations of the three stereoclusters of hemicalide had been determined, remaining pending the final connection between them to achieve the first total synthesis and final structural elucidation.…”

“…On that basis, and considering that the problem might be due to a structural simplicity of the chosen fragment model, the authors next undertook a similar NMR protocol using a more realistic fragment 46, including the extended sidechain with an hydroxyl group at C-45. To reduce the computational cost, only six fragment isomers were taken into consideration: four with the relative stereochemistry considered by Cossy and co-workers 34 following NOE constraints, and the two most likely from DP4f calculations on fragment 45. Interestingly, now isomer 46A was the most likely candidate in 99% probability, a prediction that was in good agreement with the Ardisson, Cossy and coworkers 34 finding of a 1,4-anti relationship between C-42 and C-45.…”

“…To reduce the computational cost, only six fragment isomers were taken into consideration: four with the relative stereochemistry considered by Cossy and co-workers 34 following NOE constraints, and the two most likely from DP4f calculations on fragment 45. Interestingly, now isomer 46A was the most likely candidate in 99% probability, a prediction that was in good agreement with the Ardisson, Cossy and coworkers 34 finding of a 1,4-anti relationship between C-42 and C-45. The authors hypothesized that this change in the DP4f predictions might be due because the hydroxyl group at C-45 might affect the conformational equilibria by introducing additional elements of hydrogen bonding.…”