Angelw: Construction of cyclobutyl borate by increasing ring tension driven by visible light

Cyclobutane with crowded structure has been widely used in the field of pharmaceutical chemistry, such as paesslerin a, a toxic natural product, and ivabradine, a drug for the treatment of stable angina pectoris The synthesis of cyclobutane is very challenging because of its high spatial structure and high ring tension The classical synthesis methods of cyclobutane include [2 + 2] cycloaddition reaction, 1,4-cyclization reaction, cyclopropane ring expansion reaction, etc However, there are few reports on the construction of cyclobutane skeleton by ring reduction strategy under conventional conditions In order to produce cyclobutane from cyclopentane with very small ring tension, it is necessary to overcome the obvious ring tension and release high-energy by-products to drive the reaction, Recently, Professor varinder K Aggarwal of the University of Bristol, UK, based on the addition reaction of alkyl radicals to unsaturated borates, which was developed by the research group in the early stage, namely, single electron oxidation / 1, The strategy of 2-Metal salt rearrangement developed a visible light driven ring shrinking reaction of boroheterocyclopentane under very mild conditions, which was used to construct highly crowded Cyclobutanes and high tension benzocyclobutanes (scheme 1C ）This reaction has excellent stereoselectivity The source of stereoselectivity was studied by theoretical calculation The content was published in angel Chem Int ed (DOI: 10.1002/anie.201915409) (picture source: angelw Chem Int ed.) using the lithium boration reaction previously developed by the research group, the author starts from different alkenyl iodine 7, and generates boron heterocyclopentane under the action of tert butyl lithium; then adds DMI (1) of electron absorption substituted alkyl iodide 8 to the reaction system at room temperature, 3-dimethyl-2-imidazolinone) solution, which was excited by blue light, was able to generate multi substituted cyclobutane derivative 6 (scheme 2) in medium to excellent yield The reaction can be compatible with a variety of functional groups, including indole, cyano, amide, sulfone and other substituents are not affected in the reaction process By changing reaction solvent and reducing temperature, 1,1,2-trisubstituted cyclobutane and 1,1,2,2-tetrasubstituted cyclobutane were synthesized In the process of alkyl migration, the original stereocenters in the substrate are not affected, and the new quaternary carbon centers in the process of migration also have very good stereoselectivity The reaction can produce optically active cyclobutyl borates in excellent yield, which provides a new method for the synthesis of these compounds (picture source: angelw Chem Int ed.) in the above experiments, the author found that this method can overcome the significantly increased ring tension in the cyclopentane ring shrinking process Therefore, the author thought that if this method could be used to further synthesize benzocyclobutane compounds with higher ring tension (scheme 3) Starting from phenylborate ester 10, benzoboracic heterocyclopentane was synthesized by lithium boration reaction The solvent was replaced by acetonitrile and alkyl iodine was added into it After blue light excitation, benzocyclobutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutyl borate 9 with high ring tension could be produced in medium yield (image source: angelw Chem Int ed.) cyclobutylbronate can further undergo multiple transformations (scheme 4) Through oxidation lactonization, the tricyclic compound 11a was obtained in quantitative yield; through Zweifel olefinization and Matteson homologation, the carbon boron bond was converted into carbon carbon bond, and then the alkenylation product and alkylation product 11b and 11C were obtained respectively; through the debonding reaction initiated by TBAF, the reduction product 11d was obtained These reactions all proved that the cyclobutane has certain stability (photo source: angelw Chem Int ed.) the author proposed the mechanism of the reaction (scheme 5a) based on the previous work At first, under the excitation of high-energy blue light, the carbon iodine bond of the alkyl iodide substituted by the electron absorbing group splits, and the electrophilic alkyl radical 12 is formed, which is added with boron heterocyclopentane 5 to form the anion radical 13 In the process of free radical chain growth, 13 is oxidized to zwitterionic intermediate 14 by single electron under the action of alkyl iodide, and at the same time to alkyl radical 8; 14 is rearranged by 1,2-metal salt to form cyclobutyl borate 6 In order to explain the stereoselectivity observed in the synthesis of polysubstituted cyclobutyl borates, the author calculated the reaction intermediates The results show that the stereoselectivity of the reaction is locked in the process of anion radical intermediate 13 and metal salt migration The gauche conformation between the intermediate alcohols of 13a ′ and 13L ′ and the alkyl substituents has a certain steric repulsion effect, which leads to the increase of the conformational energy This effect is very significant in the formation of benzocyclobutyl borate (Δ e = + 2.7 kcal / mol), but has little effect on the formation of alkyl cyclobutyl borate (Δ e = + 0.3kcal / mol) Therefore, the author speculates that other effects (such as the interaction between lithium solvent clusters and electron absorbing groups) may have some influence on the formation of alkyl cyclobutyl borates The result shows that the stereoselectivity of the product is significantly reduced (2.4:1 for tetrahydrofuran vs > 20:1 for propiononitrile) when the substrate reacts in strong coordination solvent tetrahydrofuran, compared with that in weak coordination solvent propiononitrile (image source: angelw Chem Int ed.) Professor varinder K Aggarwal, Department of chemistry, University of Bristol, UK, has developed a visible light-induced addition reaction of alkyl radicals to unsaturated borates: single electron oxidation / 1, 2-Metal salt rearrangement strategy is used to construct highly crowded Cyclobutanes and benzocyclobutanes with high tension The reaction overcomes the high tension of cyclobutane from cyclopentane to cyclobutane under very mild conditions The reaction has a wide functional compatibility and excellent stereoselectivity It provides a new and simple method for the synthesis of cyclobutane derivatives with a wide range of biological activities.