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Totally Synthetic by Paul H. Docherty, 17 May 2009

Total Synthesis of Eudesmantetraol, 11-Epieudesmantetraol & Pygmol


K. Chen, P. S. Baran, Nature 2009, 459, 824-828.

DOI: 10.1038/nature08043

Baran published a reexamination of chemical methodology of the past using modern techniques and reagents to solve problems in an orthogonal fashion and to avoid common retrosynthetic failings, such as recursive oxidation / reduction and excessive use of protecting groups. Today’s target are terpenes, for which remote oxidations are often used.

Baran made the skeleton to work with rather quickly: The synthesis starts with an organocatalytic step, using a standard proline based catalyst for an enantioselective Michael addition. Addition of base give the cyclohexenone in great e.e. and decent yield. Notable is the low catalyst loading, and the use of a catechol to activate the enone for addition.

A few steps further on, and they constructed a second ring featuring a cross-conjugated diene and a single stereocenter in place. However, three simple reaction allowed the group to greatly enhance the stereocomplexity: addition of a cuperate followed by a pair of reductions constructed four additional stereocenters. Nice synthesis!

A carbamate featuring a trifluroethyl chain was then append as a controlling group for the remote oxidation - . This choice was directed by their methodology for 1,3-oxidation published last year in JACS, and is related to the Hofmann-Loffler-Freytag reaction (1,3-bromination via atom transfer). Their development of this chemistry lead to the use of a trifluroethyl group to encourage N-centered radical formation, increasing selectivity. However, there’s a complication as three possible tertiary centers are avaliable. Rationalisation using 13-C NMR to probe the electronegativity of the various carbons, confirmed that they had a good chance of selectivity. In this case, it works really quite well, using methyl(trifluoromethyl)dioxirane - a variant of DMDO in which is more active, and selective for equitorial C-H bonds.

The next most reactive position for this chemistry was dealt with accordingly, but this time doing a bromination to provide a common intermediate, 18. In the simplest case, treatment with silver carbonate resulted in the diol, which after clevage gave pygmol in cracking yield over four steps. It’d be interesting (but a lot of work) to see if this could’ve been stereoselecive, had the center been prochiral.

Using the same intermediate, Baran was able to complete two more targets, 11-epieudesmantetraol and eudesmantetraol, by firstly eliminating the bromide with tetramethylpiperidine, and then brominating with NBS to form a cyclic carbonate. This time we’re stereoselecitive, and it remained so when thye opened the carbonate, which closed onto the primary bromide to give a terminal epoxide. Only one step was required to access each natural product, choosing either acidic or basic condition to open the epoxide.

This is a fantastic total synthesis and well executed. However, it’s worth remembering that this approach isn’t entirely new, as remote oxidation was a very popular technique for steroid chemists. Use of transition-metal oxidants, such as iron coordination complexes was common, such as in this example by Paul Grieco. However, Baran had taken this idea and modernised it considerably, with the NMR/X-ray analysis of reactivity as critical steps.