Structure Revision of Hexacyclinol / Total Synthesis pt. I
Total Synthesis: La Clair. ACIE, 2006, 45, 2769. DOI: 10.1002/anie.200504033
Stuctural Reassignment: Rychnovsky. Org. Lett., 2006, ASAP. DOI: 10.1021/ol0611346
After reading some very interesting discussion at Dylan’s Tenderblog, and receiving this request, I’ve decided to post on this intriguing issue. Some months back, La Clair at the Xenobe Research Institute (San Diego) published the first total synthesis of hexacyclinol. This synthesis was an impressive piece of work, including an interesting [2+2+2] step to put in the peroxide.
Based on the isolation by GrÃ¤fe, using structure 1 as the target, this work now seems to be in dispute. Scott Rychnovsky has just published in a thorough Org. Lett. on the reassignment on hexacyclinol based upon calculated 13C chemical shift data using HF/3-21G geometries and mPW1PW91/6-31G(d,p) GIAO NMR predictions. His conclusions have resulted in the structure 2, shown above.
Comparing the assignments, both structures do contain similar features, and share some functional groups. However, it is clear that there are massive discrepancies, especially in the construction of the main ring-systems and the controversial peroxide.
Rychnovsky’s work gains extra credence, as his structure is moderately similar to three other natural products, namely elisapterosin B, maoecrystal V, and elisabethin A. Using the same calculation techniques, his predictions match the structures of these compounds remarkably well. Also, his biosynthesis pathway is reasonable, and contains species with similar spectra to the natural product.
Thus, one must examine the data used by LaClair, which begins to look questionable in the publication notes (quoting directly): “The 1H NMR spectra for this Communication were determined by contract services. The spectra provided in the Supporting Information were collected by N. Voss (Berlin, Germany). The operator added the peak for CDCl3 to the spectrum of synthetic hexacyclinol (1), however, this was done incorrectly at [~]7.5 ppm and against the request of the author. Additionally, one spectrum was duplicated and a copy of the spectra for natural 5-epi-hexacyclinol was not provided.”
Intriguing stuff. So how closely to the data sets for the synthetic product and that obtained from nature match? “Samples of synthetic hexacyclinol … were identical in Rf, HPLC retention, physical properties, and spectral data to authentic samples … isolated in our laboratories. The optical rotation of synthetic 1 … was comparable to that obtained in samples of isolated 1 … as well as that reported by GrÃ¤fe and co-workers … thereby confirming the absolute stereochemistry of hexacyclinol (1).” Interestingly, that reference, , points to unpublished work.
So, irrefutable proof of missasignment, and a possible retraction looming? No. Not until more evidence is gathered (e.g. a synthesis of 2 or an x-ray structure). But I’ll keep you posted.