Relative Stereochemical Determination and Synthesis of the C17–C25 δ-Lactone Fragment of Hemicalide

Abstract

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined the relative stereochemistry of the C8-C13 hexad by synthesizing the C1-C13 fragment. Presently, we report the assignment of the C17-C25 δ-lactone fragment. NMR analysis of authentic hemicalide along with a computational conformation study allowed us to reduce the number of putative relative isomers from 16 to 4. Concise syntheses of the four candidate diastereomers were achieved using a common strategy based on a Dias aldehyde allylation reaction, an intramolecular Horner-Wadsworth-Emmons olefination, and a dihydroxylation reaction. Finally, thorough NMR comparisons enabled us to deduce the relative stereochemistry of the C1-C17 fragment with high certainty.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide

“…Comparison of the NMR spectra of structurally related model compounds with those of hemicalide allowed for the relative stereochemical assignment of the C8–C13 hexad and the C36–C42 subunit, which was confirmed by gauge‐invariant atomic orbital (GIAO) NMR chemical shifts calculations coupled with a probability program (DP4) . The relative configuration of C24 and C18 was first tentatively attributed by analysis of the NMR spectra of some simplified model compounds possessing a silyloxy substituent at C17; the assignment of C18 was subsequently revised by the GIAO–DP4 method and through the synthesis of more realistic model compounds possessing a trisubstituted alkene at C16‐C17 (Figure ) …”

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

“…Interestingly, the most likely candidate showed a syn relationship between the adjacent methyl and acyloxy groups at C-18 and C-19 (38A), in contrast to the one originally suggested by Ardisson and co-workers 32 (fragment 38B). In addition, the calculations suggested a 1,5-syn relationship between C-18 and C-24, opposed to the anti configuration proposed by Ardisson and co-workers.…”

“…However, in 2016, Paterson and co-workers 35 challenged the assignment made by Ardisson and co-workers 32 on the relative configuration of the C-16/C-25 fragment ( Figure 7). In particular, they considered that the 1 H NMR splitting pattern and 3 J coupling constants that lead to the proposed H-18/H-19 anti relationship, did not represent an incontrovertible proof for that assignment.…”

“…Once the configuration of the C-8/C-13 stereohexad was settled, the same Ardisson and co-workers 32 next moved on to the C-17/C-25 δ-lactone fragment of hemicalide. Having access to authentic NMR data of the natural product, the presence of NOESY correlations between H-22 and H-20 along with a 3 J = 11.3 Hz coupling between H-19/H-20 was consistent with a δ-lactone in its chair conformation with the two hydroxyl groups at C-21 and C-22 in a cis relative orientation and the side chain at C-19 directed to the other face of the molecule.…”

Strength by Joining Methods: Combining Synthesis with NMR, IR, and Vibrational Circular Dichroism Spectroscopy for the Determination of the Relative Configuration in Hemicalide

“…Whereas the C45 and the C36 stereocenters in δ‐lactone 2 both originated from the chiral pool, the absolute configurations of C37, C39, and C40 were controlled by diastereoselective reactions and unambiguously confirmed by NMR (NOESY) spectroscopy. To create the sixth stereocenter at C42, hydrogenation of the trisubstituted alkene at C42C43 in δ‐lactone 2 was carried out in the presence of Crabtree’s catalyst 4. Although the diastereoselectivity was not high, this transformation conveniently afforded a 63:37 mixture of the epimers at C42, 3 and 3 ′, which was useful for comparison.…”