Total synthesis of honokiol by selective samarium-mediated allylic benzoate reduction

Abstract

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

Chelation and Stereodirecting Group Effects on Regio- and Diastereoselective Samarium(II)-Water Allylic Benzoate Reductions

“…This method then featured in our synthesis of the biologically active natural product honokiol to simultaneously install both allyl substituents found in the target compound from the bisallylic benzoate precursor 3. 13 Scheme 1 (A) Regioselective SmI 2 allyl benzoate reductions and (B) its application to a synthesis of honokiol Applied to trisubstituted alkene-containing substrates, we recognized that the reaction would generate a new stereocenter (*), and became interested in finding ways to develop this reaction as a new strategy for stereoselective synthesis (Scheme 2). 14 We hypothesized that incorporation of a Lewis basic chelating element (e.g., OP) and stereo- For the chelating element we chose to focus on oxygen given the well-established oxophilicity of samarium.…”

Regio- and Diastereoselective Samarium-Mediated Allylic Benzoate Reductions

“…5 This method then featured as part of our synthesis of the biologically-relevant natural product honokiol, used to simultaneously install both allyl substituents found in the target compound. 6 As an extension of that work, we began investigating the reaction applied to trisubstituted alkene substrates. For instance, treatment of allyl benzoate 3 7 with SmI 2 /MeOH led to its rapid and clean conversion to 3-phenyl-1-butene with complete regioselectivity by 1 H NMR analysis (Scheme 2).…”

Samarium(ii) iodide-mediated reactions applied to natural product total synthesis

“…In 2016, O'Neil and colleagues 46 reported the total synthesis of the honokiol 59 in 4 steps and 42% overall yield. The key steps were a Suzuki coupling to construct the biphenyl core and a samarium-mediated bis-benzoyl ester reduction to install both allyl groups at the same time at the last stage to avoid problems related to allylic deprotonation or isomerization.…”