Mechanistic Insights on the Selectivity of the Tandem Heck–Ring-Opening of Cyclopropyldiol Derivatives

Abstract

The preparation of a new class of alkenyl cyclopropyl diols, easily available through a copper-catalyzed carbometalation reaction of cyclopropenes, has enabled the study of key mechanistic aspects of the tandem Heck–cyclopropane ring-opening reaction. Utilizing these substrates containing two distinct hydroxyl groups allowed us to examine parameters affecting the reaction outcome and selectivity. The combination of these experimental results with detailed DFT studies shed light on the mechanism governing the regio- and stereoselectivity of the cyclopropane ring-opening. A thorough investigation displayed the dual roles fulfilled by the hydroxyl group during the reaction, which is key to this remarkable transformation. In addition to its mechanistic implication, the reaction granted access to various lactones possessing up to four stereocenters as a single diastereomer, conveniently prepared in only two catalytic steps from easily accessible achiral cyclopropenes.

Preparation of Distant Quaternary Carbon Stereocenters by Double Selective Ring‐Opening of 1,1‐Biscyclopropyl Methanol Derivatives

“…[14] Although this strategy provides the two regioisomers 4 a and 4 b in moderate yields, the efficiency of this single‐pot operation coupled with the excellent diastereoselectivity of the process and the easy purification of the required final isomer 4 a revealed to be very attractive for our study. The particular design of the proposed substituted alkenyl‐[1,1]‐bicyclopropyl methanol 4 a was based on our recent experimental and theoretical finding on the required close proximity between the alcohol and the double bond, necessary for the subsequent reaction to proceed [15] . For the isomer 4 b , this proximity is not existing anymore and should therefore not be reactive under our experimental conditions.…”

“…Here again, the nature of the substituents present on the aryl moiety could be varied and, in all cases, very high diastereoslectivities were observed. Based on our previous studies on the diastereoselective Heck-addition, [6,15] we proposed that the aryl palladium complex [20] first interact with the alcohol and the alkene (formation of A, Scheme 6). From the two possible diastereotopic faces of the propenyl chain that could complex the palladium, only the one resulting from the s-trans conformer [15] should have a favorable interaction as it generates less steric hindrance with the remaining molecular backbone.…”

“…Based on our previous studies on the diastereoselective Heck-addition, [6,15] we proposed that the aryl palladium complex [20] first interact with the alcohol and the alkene (formation of A, Scheme 6). From the two possible diastereotopic faces of the propenyl chain that could complex the palladium, only the one resulting from the s-trans conformer [15] should have a favorable interaction as it generates less steric hindrance with the remaining molecular backbone. After a diastereoselective aryl-addition, the first stereogenic center in B is created and the configurationally stable palladium species undergoes its first selective carboncarbon bond cleavage to provide C. A subsequent second selective ring-opening occurs to provide D and, after a sequence of β-elimination and re-insertion of palladium hydride, the skipped diene 6 is finally obtained with three, including two distant quaternary, stereogenic centers within an acyclic system.…”

Regio- and Diastereoselective Carbometalation Reaction of Cyclopropenes

“…We were pleased to observe that addition of various aldehydes provided a single diastereomer at the carbinol center ( Scheme 9 b). 28 However, for unclear reasons, when the addition of alkyl magnesium halides followed by aldehydes were added to similar cyclopropenyl rings, the diastereoselectivity was drastically lower. 29 This drawback could be circumvented by addition of acylsilane to cyclopropenyl ester using slightly different experimental conditions ( Scheme 9 c).…”

“…While we were investigating the diastereoselective copper-catalyzed addition of alkenyl organomagnesium species to cyclopropenes, we were also interested to understand if the addition of a prochiral electrophile could allow the formation of an additional stereocenter with a complete control of the diastereoselectivity (Scheme a). We were pleased to observe that addition of various aldehydes provided a single diastereomer at the carbinol center (Scheme b) . However, for unclear reasons, when the addition of alkyl magnesium halides followed by aldehydes were added to similar cyclopropenyl rings, the diastereoselectivity was drastically lower .…”