Chem. SCI.: operation and time economy in total synthesis of Corey lactone

For the ideal synthesis, it needs to have atomic economy, step economy and redox economy Recently, Yujiro Hayashi research group of Northeastern University of Japan put forward the concept of "operating economy" Nowadays, "one pot" synthesis can not only stereoselectively construct the key structural segments of molecules, but also carry out more and more chemical transformations In addition, the "one pot" synthesis avoids many purification steps through in-situ quenching, so as to minimize the generation of chemical waste and save time Therefore, the "one pot" operation is not only highly efficient, but also environmentally friendly Corey lactone has important value in synthesis, but its synthesis method usually involves many steps and is very time-consuming Stork group needs 7 steps to synthesize CIS cyclopentene-1,4-diol; Woodward group needs 11 steps to synthesize CIS cyclohexane-1,3,5-triol Corey group completed the synthesis of Corey lactone (scheme 1) with asymmetric Diels alder reaction catalyzed by chiral Lewis acid as the key step Doyle group reported that C-H insertion of diazoacetate mediated by chiral rhodium catalyst was used for the synthesis of key intermediate of Corey lactone; recently, Chen Fener group reported the kinetic resolution of asymmetric Baeyer Villiger oxidation Although the method reported by Corey is practical, it needs 10 steps and takes a long time (48 hours, excluding purification time) Therefore, starting from the raw materials on the market, it is still a challenge to carry out more effective asymmetric catalytic synthesis in a short time in a single container Recently, Yujiro Hayashi group developed a practical and high yield Corey lactone synthesis method with asymmetric [3 + 2] cycloaddition reaction mediated by new optimized organic catalyst as a key step The result was published in Chem SCI (DOI: 10.1039 / c9sc05824a) (photo source: chem SCI.) previously, the author has reported the asymmetric Michael addition reaction (Eq 1) between cyclohexanone and α, β - dialdehyde catalyzed by two amine catalysts (i.e (s) - diphenylproline methylsilyl ether and 4-hydroxyproline) Based on the fact that ketone can be used as Michael donor, a series Michael / Michael addition reaction of 3 - (dimethylphenylsilyl) acrolein (1) and 4-oxo-2-pentenoic acid ethyl ester (2) was designed After the first Michael addition, there are two possible ways (scheme 2): after the first Michael addition, 4 may be obtained by the reaction of 5-exo mode with α, β - unsaturated ester, or 5 may be obtained by the reaction of 6-endo mode with α, β - unsaturated ketone After several studies, the author only observed cyclopentanone derivative 4, and no cyclohexanone 5 (eq.2) was found (picture source: chem SCI.) the author also found that in the presence of (R) - Diphenylprolinol silyl ether (R) - 3 and p-nitrophenol, the Michael / Michael addition can be carried out in series, and cyclopentanone 4 can be obtained with good yield and excellent enantioselectivity, and three consecutive chiral centers have been successfully established After obtaining the cyclopentanone parent nucleus of Corey lactone, the author further studied the "one pot" synthesis of Corey lactone Since several unrelated reactions are involved, such as reduction and oxidation reactions under different conditions, and residual reagents may interfere with subsequent reactions, it is challenging to carry out multiple transformations in the same reactor (such as reduction of aldehydes, stereoselective reduction of ketones, lactonization and Tamao Fleming oxidation for conversion of c-Si bond to C-O bond) After strict condition screening, the author finally completed the rapid "one pot" continuous synthesis (scheme 3) The total synthesis of Corey lactone (9) was completed in a single container with a total yield of 50% in 152 minutes (picture source: chem SCI.) this "one pot" synthesis involves a series reaction consisting of two reaction steps: 1) asymmetric Michael addition of ketone and α, β - olefin aldehyde, 2) continuous intramolecular Michael addition, and the following five reaction steps, including: 3) reduction of aldehyde, 4) stereoselective reduction of ketone, 5) formation of lactone, 6) Si pH bond is converted to Si-F bond and 7) c-sime2f to c-oh bond In addition, HbF 4 plays four roles: 1) after reduction, O-li or o-al bond is converted into O-H bond; 2) excessive LiAlH (t-buo) 3 decomposition is promoted; 3) lactone 7 formation is promoted; 4) Si pH bond is converted into Si-F bond The ability of a single reagent to play various roles in multi-step reactions constitutes the feature of "one pot method" Finally, the author studies the universality of the key series reaction, namely the [3 + 2] cycloaddition of α, β - unsaturated aldehydes and ethyl 4-oxo-2-pentenoate (2) (Table 1) First of all, the reaction of cinnamaldehyde was investigated under the optimal reaction conditions, but the reaction efficiency was poor In the presence of p-nitrophenol, the yield (98%) and enantioselectivity (> 99% ee) of the substrate were optimized Next, the author studied the universality of the reaction: for the β - substituents of α, β - unsaturated aldehydes, not only phenyl and 2-naphthyl, but also other electron rich aromatic compounds such as p-tolyl and p-methoxyphenyl; for the electron deficient aromatic compounds such as p-fluoro, p-chloro, p-bromophenyl and m-bromo, o-bromophenyl and furan, they are also suitable substituents In all cases, the substrate has excellent enantioselectivity and enantioselectivity Conclusion: Yujiro Hayashi research group completed the asymmetric total synthesis of Corey lactone with excellent yield by using the commercially available raw materials in the same reaction vessel for 152 min The key point is that the trisubstituted cyclopentanone produced by Michael / Michael addition of α, β - enol and 4-oxo-2-pentenoic acid ethyl ester (2) mediated by diphenyl prolyl alcohol silica ether is a single isomer, and three consecutive chiral centers are constructed; then, the whole synthesis is rapidly completed by "one pot" method of returning the original internal esterification oxidation In view of the wide versatility of asymmetric [3 + 2] cycloaddition mediated by organic catalysts, cyclopentanone derivatives with high functionalization are useful chiral intermediates for the synthesis of various natural products and drugs.