Lewis Acid-Promoted [2+2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis

Conspectus Cycloaddition reactions arean effective method to quickly buildmolecular complexity. As predicted by the Woodward-Hoffmannrules, concerted cycloadditions with alkenes allow for the constructionsof all possible stereoisomers of product by use of either the Z or E geometry. While this feature ofcycloadditions is widely used in, for example, [4 + 2] cycloadditions,translation to [2 + 2] cycloadditions is challenging because of theoften stepwise and therefore stereoconvergent nature of these processes.Over the past decade, our lab has explored Lewis acid-promoted [2+ 2] cycloadditions of electron-deficient allenes or ketenes withalkenes. The concerted, asynchronous cycloadditions allow for thesynthesis of various cyclobutanes with control of stereochemistry. Our lab developed the first examples of Lewis acid-promoted ketene-alkene[2 + 2] cycloadditions. Compared with traditional thermal conditions,Lewis acid-promoted conditions have several advantages, such as increasedreactivity, increased yield, improved diastereoselectivity, and, forcertain cases, inverse diastereoselectivity. Detailed mechanisticstudies revealed that the diastereoselectivity was controlled by thesize of the substituent and the barrier of a deconjugation event.However, these reactions required the use of stoichiometric amountsof EtAlCl2 because of the product inhibition, which ledus to investigate catalytic enantioselective [2 + 2] cycloadditionsof allenoates with alkenes. Through the use of chiral oxazaborolidines,a broad range of cyclobutanes can be prepared with the control ofenantioselectivity. Mechanistic experiments, including D-2-labled alkenes and Hammett analysis, illuminate likely transitionstate models for the cycloadditions. Additional studies led to thedevelopment of Lewis acid-catalyzed intramolecular stereoselective[2 + 2] cycloadditions of chiral allenic ketones/esters with alkenes. The methods we developed have been instrumental in the synthesisof several families of natural products. Specifically, one key lactonemotif in (& PLUSMN;)-gracilioether F was constructed by a ketene-alkene[2 + 2] cycloaddition and subsequent regioselective Baeyer-Villigeroxidation sequence. Enantioselective allenoate-alkene [2 +2] cycloadditions allowed for the synthesis of (-)-hebelophylleneE. Another attempt of applying this method in the synthesis of (+)-[5]-ladderanoicacid failed to deliver the desired cyclobutane because of an unexpectedrearrangement. The key cyclobutane was later assembled by a stepwisecarboboration/Zweifel olefination process. Finally, the stereoselective[2 + 2] cycloadditions of allenic ketones and alkenes was appliedin the syntheses of (-)-[3]-ladderanol, (+)-hippolide J, and(-)-cajanusine.

Automated summary

In this study, Lewis acid-promoted [2+2] cycloaddition reactions were used to synthesize various cyclobutanes with stereochemical control. Additionally, catalytic enantioselective [2+2] cycloadditions were achieved using chiral catalysts. These methods have proven to be instrumental in the synthesis of natural products.