Total Synthesis and Structure Confirmation of Elatenyne: Success of Computational Methods for NMR Prediction with Highly Flexible Diastereomers

Abstract

Elatenyne is a small dibrominated natural product first isolated from Laurencia elata. The structure of elatenyne was originally assigned as a pyrano[3,2-b]pyran on the basis of NMR methods. Total synthesis of the originally proposed pyrano[3,2-b]pyran structure of elatenyne led to the gross structure of the natural product being reassigned as a 2,2'-bifuranyl. The full stereostructure of this highly flexible small molecule was subsequently predicted by Boltzmann-weighted DFT calculations of (13)C NMR chemical shifts for all 32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the total syntheses of (E)-elatenyne and a related 2,2'-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of (13)C NMR chemical shifts coupled with biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related molecules.

Chromatography with silver nitrate: part 2

“…67 The starting carbinol 106 acted as a versatile building block to access both alkenes 107 and 108 required for the Hoveyed-Grubbs second generation cross metathesis, which gave a 3:1 mixture of geometrical isomers (60% yield). SNIS procured the desired alkene 109 in 45% yield (Scheme 17).…”

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

“…Inspired by this computational result, Burton, Kim and co-workers 59 joined forces and undertook the necessary synthetic work to finally settle the real structure of elatenyne. First, they proposed a biosynthetic path that relied on previous work by Murai and co-workers 60 disclosing that many C-15 halogenated natural products may be derived from laurediol through a bromoperoxidasemediated bromonium ion-induced cyclization.…”

“…Given the challenge to pursue that goal, the teams divided the work to simplify the problem. Burton and co-workers 59 followed a modular approach using stereochemically unambiguous reactions to synthesize ent-99, whereas Kim and co-workers 59 devised a biomimetic route to prepare its enantiomer 99 and provide additional insight to the biosynthetic path discussed above.…”

“…The synthesis performed by Burton and co-workers 59 is depicted in Scheme 13 and started with Sharpless asymmetric epoxidation (with concomitant kinetic resolution) of 1,5-hexadien-3-ol (106). The resulting epoxy alcohol 107 was protected and the epoxide opened at the terminal position with methylmagnesium bromide.…”

“…Finally, ozonolysis of the pendant alkene and Yamamoto-Peterson reaction between the resulting aldehyde and the in situ prepared 114 gave elatenyne ent-99. 59 Meanwhile, Kim and co-workers 59 carried out the biomimetic synthesis of 99 as summarized in Scheme 14. The hydroxyamide 116 was prepared in few steps from the known allylic alcohol 115.…”