Angelw: Construction of decalin derivatives by enantioselective (4 + 2) cycloaddition

Decalin ring is widely found in diterpenoids, steroids and other natural products (Figure 1) These compounds usually have anti-inflammatory, antibacterial and anti-tumor activities Therefore, the synthesis of decalin derivatives has become a hot spot of drug discovery and related research The ring system of decalin can be constructed by cycloaddition, cross coupling, polyene cyclization and Robinson cyclization Recently, fujietanaka research group, University of science and technology, Okinawa, Japan, used the quinidine derivative (dhqd) 2 aqn as catalyst to prepare the decalin derivative (scheme 1) through the enantioselective reaction of aldol - aldol cyclization The results were published in angew Chem Int ed (DOI: 10.1002 / anie 201808219) (source: angelw Chem Int ed.) (source: angelw Chem Int ed.) in this study, the researchers used diketone ester 1 and 1,3-cyclohexanedione 2 derived from pyruvic acid as the starting materials for the aldol-hydroxyaldehyde cyclization cascade reaction to construct the decalin derivative 3 or 4 (scheme 1) Due to the introduction of 2, this reaction is expected to form 5 to 6 stereocenters First, the reaction conditions were screened with 1a and 2A as substrates (Table 1) The optimum reaction conditions were as follows: 1.15 equivalent (dhqd) 2 aqn as catalyst, 1.0:0.12 toluene and N-methylpyrrolidone (NMP) as solvent, 0.5 equivalent tetraethyl ammonium bromide (teab) as additive, 1a and 2A reacted at room temperature for 60 H The yield of the target compound 3A was 72%, and the EE value was 87% (entry 4) (source: angelw Chem Int ed.) then, the researchers examined the applicability of substrate 1 (Table 2) The ethyl pyruvate derivatives containing various aryl substituents can react with 2A successfully to form the trihydronaphthalene derivatives 3A - 3G The reaction rate of tert butyl pyruvate derivatives is faster than that of ethyl ester and benzyl ester derivatives For this reason, the researchers explained two possible reasons One is that the stereovolume of tert butyl group can enhance the cyclization of 3 Second, because of the steric effect of tert butyl, the initiator 1 with tert butyl group is acyclic, which is propitious to react with 2 to form 3 In addition, all the reactions the researchers tried had excellent enantioselectivity (source: angelw Chem Int ed.) researchers have studied the process of aldol hydroxyaldehyde cyclization of diketide 1 and 1,3-cyclohexanedione 2 They detected the formation of 3 at the initial stage of the reaction, but did not observe the intermediate of hydroxyaldehyde However, when using silica gel column to purify the product, researchers found that the intermediate of hydroxyaldehyde existed in the reaction mixture This may be explained as follows: the reaction process of 1 and 2 forming intermediates is reversible In addition, the kinetic study shows that the rate limiting step is the second one As a result, the possible reaction mechanism (scheme 2) was proposed The first reaction is reversible In the second aldol reaction, an enantiomer was selectively used to form cyclized products In the transition state (TS), the substituents of ester group (coor 1), 1 and 2 (R 2 and R 3) are located at the equator This also explains why the reaction produces a single diastereomer In addition, the tertiary amine group of catalyst can act as acid and base according to the protonation state to accelerate the formation of C-C bond (source: angelw Chem Int ed.) in a word, under mild reaction conditions, using (dhqd) 2 aqn as catalyst, the enantioselective synthesis of decalin derivatives was realized by the reaction of pyruvate diketone ester derivatives with 1,3-cyclohexanedione's hydroxyaldehyde.