Bulky Alkenes Converted: New Hydroboration Technology

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By Sander Kluwer

Enantioselective hydroboration of C=C double bonds is a pivotal reaction in organic synthesis, enabling the synthesis of chiral organoboron compounds with high precision. This process involves the addition of borane to alkenes, favoring the formation of one enantiomer over the other. Historically, significant advancements have been made with mono-, di-, and trisubstituted alkenes, though tetrasubstituted alkenes have posed substantial challenges. Recent reports have begun to address these difficulties, promising broader applications in the synthesis of complex, enantioenriched molecules.

Hydroboration is a reaction between a borane and electron-rich alkenes. Generally, hydroboration is a syn-addition process, with addition occurring at the least-hindered alkenic face, and the overall sequence is an anti-Markovnikov addition. The extreme steric hindrance imposed by the tetrasubstituted alkenes hinders effective coordination and interaction with the metal center. This often results in no or exceptionally low reactivity. Additionally, one of the problems encountered is that metal hydrides often induce rapid alkene isomerization, leading to E/Z isomers and positional isomerization. This process produces less substituted alkenes which are more prone to hydroboration. Moreover, achieving regioselectivity and enantioselectivity is particularly challenging, as the catalyst must discriminate between the two carbons of the C=C double bond and the enantiotopic faces of the tetrasubstituted alkene.

In this respect, the recent contribution of Hong, Li, and co-workers is of interest. In their article (DOI doi.org/10.1021/jacs.4c04108), they proposed a strategy where a low-valent cationic catalyst binds to one of the functional groups present in the substrate, such as the carbonyl group of a tetrasubstituted α,β-unsaturated amide or enamide. This interaction would enhance the binding affinity for an adjacent tetrasubstituted alkene, facilitating the catalytic process. Such an approach has been used in the asymmetric hydrogenation of tetrasubstituted enamides as reported by us and others .

The authors screened an extensive ligand library comprising 50 members with varied electronic and steric properties. Most ligands resulted in the reduction of the C=C bond without producing the desired hydroboration product. However, the Rh/Josiphos catalyst family stood out as an exception. By optimizing the steric parameters of the ligand, the Rh/Josiphos catalyst achieved nearly exclusive selectivity for hydroboration, delivering high yield, complete diastereoselectivity, and excellent enantioselectivity. Testing the catalyst against a broad and diverse substrate library of α,β-unsaturated amides and tetrasubstituted enamides yielded good diastereoselectivity and high enantioselectivity.

The reaction was investigated using DFT calculations and the reaction mechanism proceeds via a typical oxidative addition, migratory insertion, reductive elimination sequence. The reductive elimination step is crucial, serving as both the enantio-determining step and the turnover-limiting step for product formation, with an overall activation barrier of 24.3 kcal/mol for the major enantiomer. Transition state analysis of the reductive elimi9nation step shows that the carbonyl of the amide functional group binds to the rhodium and locks its configuration. Additionally, non-covalent C–H···O interactions between the ligand’s phenyl group and the Bpin moiety further stabilize the transition state, facilitating the formation of the major enantiomer. Finally, the authors showcased the enantioselective hydroboration using the new catalyst for the synthesis of (R,S)-Clobutinol and a key intermediate for Amphidinolides B1.
This newly reported catalyst enables highly regio-, diastereo-, and enantioselective hydrofunctionalization of tetrasubstituted alkenes, producing valuable enantioenriched compounds with vicinal stereocenters. This advancement unlocks direct functionalization of highly hindered alkenes and suggests potential expansion into other enantioselective functionalizations of fully substituted alkenes.
Rhodium-Catalyzed Highly Enantioselective Hydroboration of Acyclic Tetrasubstituted Alkenes Directed by an Amide
Hou-Xiang Lu, Cheng Wang, Tao-Tao Gao, En-Ze Lin, Shou-Lin Lu, Xin Hong and Bi-Jie Li
J. Am. Chem. Soc.
DOI doi.org/10.1021/jacs.4c04108