Angelw: organic catalytic asymmetric diene insertion reaction of 2-enoldehyde and cyclo-2-enone to construct a bicyclic framework containing bridged cyclolactone

In series reaction, simple precursors are transformed into complex molecules in an efficient way, which greatly improves the synthesis efficiency and reduces the waste of raw materials Because of the diversity of reaction sites, I (scheme 1) is often used as the starting material for the synthesis of complex molecules Melchiorre and bencivenni reported the asymmetric γ - addition reaction of 2-cyclohexanone with various electrophilic reagents (scheme 1, path a) catalyzed by the primary amine catalyst derived from cinchona alkaloids Chen and Gao team have developed the activation mode of dialienylamine, which can react at α 'and γ' sites of cyclo2-ketene to form a ring product (scheme 1, path B) Then, ye group reported various primary amines catalyzed asymmetric γ 'addition of 2-cyclopentenone (scheme 1, path C) But up to now, there is no report about the reaction at the γ and γ 'sites of 2-ketene Then, Zanardi and Chen reported that malondionitrile derivative II reacted with α, β - unsaturated aldehydes to form a ring product (scheme 1, path D and E) The special feature of this report is that after derivative II I, the acidity of cyclo-2-ketene ε and γ 'protons can be increased to promote the formation of cyclo-2-ketene ε and γ' protons Inspired by the report, Professor Georgios vassilikogiannakis of the University of Crete, Greece, conceived a new strategy based on LUMO reduction effect, which directly functionalized the γ and γ 'sites of 2-ketene In order to realize this assumption, two conditions must be met, that is, conjugation addition reaction between the electron acceptor reduced by LUMO and the cycloketene which is easy to enol (picture source: angel Chem Int ed.) on the basis of the above research, the author reported the first case of [3 + 3] cycloaddition reaction of α - ester cyclo 2-alkene ketone and LUMO reduced 2-alkene aldehyde at γ and γ 'positions to construct bicyclic [4,3,0] nonane and [4,4,0] decane skeleton (scheme 2) Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201901902) (picture source: angelw Chem Int ed.) firstly, the reaction conditions of 1 → 4A were screened with keto ester 1 and cinnamaldehyde 3A as template substrate The optimal conditions are: 20 mol% cat III as catalyst, methanol as solvent, 1 and 3a react at room temperature for 14 hours, and then the product is obtained with 100% conversion and 97% asymmetric selectivity It is worth mentioning that the reaction rate will be reduced obviously in the non proton solvent Then, the author added 1.2 times of ET 3N to convert 4A into 5A Then, 5A was dehydrated under the action of ET 3N and anhydrides to form the target product 6A A series of anhydrides were screened and tfaa was determined to be the optimal anhydrides The target product was obtained in 80% yield (picture source: angelw Chem Int ed.) under the optimal conditions, the author carried out substrate expansion for various α, β - unsaturated aldehydes (scheme 4) Various aryl substituted α, β - unsaturated aldehydes (3a - F) can be well adapted to the reaction conditions, and the target product (6a - F) with good yield and high asymmetric selectivity can be obtained However, alkylated olefin aldehyde 3G can not adapt to the reaction conditions well, and the yield and asymmetric selectivity of the target product are very low If catalyst I is used instead of catalyst III, and the temperature is reduced to 0 ℃, the yield and asymmetric selectivity of the reaction are obviously improved (picture source: angel Chem Int ed.) in the process of 4A to 5A, the author found an interesting phenomenon (scheme 5): adding 0.5 equivalent et 3N into the DCM solution of 4A, four compounds 5A (DR = 1 / 1.3 / 1.4 / 3.5) of non enantiomers will be obtained When et 3N was increased to 1.2 equivalent, the ratio of the four enantiomers changed significantly (DR = 11 / 1) Compound 5 is unstable and easy to dehydrate, but it can be reduced to stable compound 7 with five chiral centers, with high yield and asymmetric selectivity Under the optimal conditions, the substrate of different substituted 2-olefin aldehydes was expanded The product 7 with high Dr value can be obtained, but the EE value of 7 can not be measured by the liquid phase Therefore, the author reduced 7 to compound 10, and finally measured the product with high asymmetric selectivity, high yield and Dr value (image source: angelw Chem Int ed.) then, the author carried out a series of derivative reactions (scheme 6) on compound 7 When K 2CO 3 was added into acetone solution of 7 and refluxed, Claisen condensation reaction of 7 was reversed, and finally lactone 11 was synthesized, with high yield, asymmetric selectivity and optical purity If etona is added to the ethanol solution of 7a and K 2CO 3 for reflux, the bridge ring product 12a can be obtained (picture source: angelw Chem Int ed.) in order to further prove the universality of the synthesis method, the author has also carried out a substrate expansion (scheme 7) for 2-cyclohexanone 2 Under the optimal conditions, substrate 2 and 3a could not produce the target product Interestingly, when 1 equivalent of ET 3N is added to 2, olefin aldehyde 3a, 20 mol% cat III methanol solution, Michael addition reaction of diene insertion can take place, and 4A 'product with good regioselectivity can be obtained Then, the addition of PTSA and et3n promoted the dehydration of 4A 'to the target product 8A with good yield and high asymmetric selectivity Under the above optimal conditions, the substrate of 2-olefin aldehydes with different substituents was expanded The target product 8 with high yield and excellent asymmetric selectivity can be obtained no matter whether it is electron absorption or electron substitution on phenyl However, the alkylated 2-alkenaldehyde could not fit the reaction conditions and could not get the target product (picture source: angel Chem Int ed.) Summary: the author first reported the two consecutive insertional addition reactions of amphiphilic reagents with organic catalysis for LUMO reduction and cyclic 2-enone which is prone to enolization The [3 + 3] cycloaddition products were obtained, and the bicyclic [4,3,0] nonane and [4,4,0] decane skeleton containing bridged cyclolactone were constructed The method is simple, direct and the target product has good yield, high asymmetric selectivity and regioselectivity.