The total synthesis of the biologically relevant compound honokiol has been completed featuring a samarium-mediated bis-benzoyl ester reduction to simultaneously install both allyl substituents found in the natural product. This reaction was performed after a Suzuki coupling was used to generate the biphenyl core, thereby avoiding problems associated with the acidity of these allyl groups and their propensity to isomerize. In this way, the synthesis of honokiol could be completed in 4 steps and 42% overall yield. Honokiol (1) is a neolignan contained in the bark of Magnolia occifinalis that continues to elicit significant interest due to its range of promising biological activities including both antitumor 1 and anti-angiogenic 2 properties (Figure 1). Isolation of honokiol from the natural source is hampered by the presence of its isomeric compound magnolol (2). 3 The different bioactivities of magnolol 4 yet very similar physical properties to honokiol makes separation both necessary and challenging. 5 Thus several groups have pursued a total synthesis of honokiol, 6 the first by Takeya et al. 6a in 1986 and more recently Harada et al. in 2014. 6h Many of these syntheses have utilized an aromatic Claisen rearrangement (Figure 2). 6a,c-f This reaction is however limited in terms of regiochemistry, used primarily to generate ortho-allyl substituted phenols. 7 For instance Reddy et al. reported obtaining roughly 1:1 mixtures of honokiol (1) and isohonokiol (3) from the bis-Oallylbiphenyl 4. 6f

A representative substrate scope investigation for an enantioselective catalytic ketone-reduction has been performed as a single reaction on a mixture containing equimolar amounts of nine (9) prototypical compounds. The resulting analyte pool containing 18 potential products from nine different reactions could all be completely resolved in a single chromatographic injection using comprehensive two-dimensional gas chromatography (GC×GC) with time-of-flight mass spectrometry, allowing for simultaneous determination of percent conversion and enantiomeric excess for each substrate. The results obtained for an enantioselective iron-catalyzed asymmetric transfer hydrogenation using this one-pot/single-analysis approach were similar to those reported for the individualized reactions, demonstrating the utility of this strategy for streamlining substrate scope investigations. Moreover, for this particular catalyst, activity and selectivity were not greatly affected by the presence of other ketones or enantioenriched reduced products. This approach allows for faster and greener analyses that are central to new reaction development, as well as an opportunity to gain further insights into other established transformations.

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