Oxidative dehydrogenative couplings of alkenyl phenols.

Alkenyl phenols are utilized by nature in the construction of one of the most important biopolymers, lignin. Using similar building blocks, an array of distinct structures can be formed by selective dimerization of the starting phenols to form lignans, neolignans, oxyneolignans, and norlignans. Given the multitude of possible outcomes, many methods have been reported to affect the desired bond formations and access these biologically relevant scaffolds. The most biomimetic of these methods, discussed here, involve the unprotected phenols undergoing oxidative bond formation that proceeds via dehydrogenative coupling. This review aims to place the known literature in context, highlight the progress made toward the synthesis of these important molecules, and recognize the gaps and limitations that still exist.

Total Synthesis of Pyrolaside B: Phenol Trimerization through Sequenced Oxidative C-C and C-O Coupling.

A facile method to oxidatively trimerize phenols using a catalytic aerobic copper system is described. The mechanism of this transformation was probed, yielding insight that enabled cross-coupling trimerizations. With this method, the natural product pyrolaside B was synthesized for the first time. The key strategy used for this novel synthesis is the facile one-step construction of a spiroketal trimer intermediate, which can be selectively reduced to give the natural product framework without recourse to stepwise Ullmann- and Suzuki-type couplings. As a result, pyrolaside B can be obtained expeditiously in five steps and 16 % overall yield. Three other analogues were synthesized, thus highlighting the utility of the method, which provides new accessibility to this area of chemical space. A novel xanthene was also synthesized through controlled Lewis acid promoted rearrangement of a spiroketal trimer.

Diastereoselective Synthesis of Benzoxanthenones.

An oxidative catalytic vanadium(V) system was developed to access the naturally nonabundant diastereomers of carpanone from the corresponding alkenyl phenol monomer in one pot by tandem oxidation, oxidative coupling, and 4+2 cyclization. This system was applied to the synthesis of two other analogues of carpanone. Mild oxidizing silver salts were used as the terminal oxidant to minimize background oxidation which produces the natural diastereomer of carpanone. Further, the first examples of enantioselective oxidative benzoxanthenone formation are reported. Solvent polarity has a strong effect on enantioselectivity, consistent with a mechanism involving binding of vanadium Schiff base catalysts to the alcoholic moiety of the alkenyl phenols during the cyclization step.

Vanadium-Catalyzed Selective Oxidative Homocoupling of Alkenyl Phenols to Synthesize Lignan Analogs.

The oxidative homocoupling of para-alkenyl phenols and subsequent trapping of the resulting quinone methide with a variety of oxygen and nitrogen nucleophiles was achieved. Both ß-ß and ß-O coupling isomers can be synthesized via either C-C coupling and two nucleophilic additions of one water molecule (ß-ß isomer) or C-O coupling followed by one nucleophilic addition of a water molecule (ß-O isomer), respectively. Selectivity between these outcomes was achieved by leveraging understanding of the mechanism. Specifically, a qualitative predictive model for the selectivity of the coupling was formulated based on catalyst electronics, solvent polarity, and concentration.