Absolute Asymmetric Synthesis Involving Chiral Symmetry Breaking in Diels–Alder Reaction

Naohiro Uemura,Seiya Toyoda,Waku Shimizu,Takashi Mino,Yasushi Yoshida,Masami Sakamoto

doi:10.3390/sym12060910

Abstract

Efficient generation and amplification of chirality from prochiral substrates in the Diels–Alder reaction (DA reaction) followed by dynamic crystallization were achieved without using an external chiral source. Since the DA reaction of 2-methylfuran and various maleimides proceeds reversibly, an exo-adduct was obtained as the main product as the reaction proceeded. From single crystal X-ray structure analysis, it was found that five of ten exo-adducts gave conglomerates. When 2-methylfuran and various maleimides with a catalytic amount of TFA were reacted in a sealed tube, the exo-DA adducts were precipitated from the solution, while the reaction mixtures were continuously ground and stirred using glass beads. Deracemization occurred and chiral amplification was observed for four of the substrates. Each final enantiomeric purity was influenced by the crystal structure, and when enantiomers were included in the disorder, they reached an enantiomeric purity reflecting the ratio of the disorder. The final ee value of the 3,5-dimethylphenyl derivative after chiral amplification was 98% ee.

Highlights

AbstRraecceti:vedE:ffi27cAiepnritl 2g0e20n;eArcacteipotned:a1n8dMaaym20p2l0ifi; Pcuabtliioshnedo: fdactehirality from prochiral substrates in the Diels–Alder reaction (DA reaction) followed by dynamic crystallization were achieved without using an exAtebrsntraalcct:hEirffailciseonut rgceen.eSrainticoentahnedDaAmpreliaficctaitoionnooff2c-hmireatlhitylfruormanparoncdhivralrisouubstmraatelseiimn itdhesDpierlosc–eeds reverAslidbelyr,raenacetixoon-a(dDdAurcetawctiaosno) bfotlalionweeddabsythdeynmamaiinc cprryosdtaullcizt aatsiotnhewreeraecatciohinevperdocweietdhoeudt. uFsrionmg asningle crysteaxlteXrn-raal ychsitrraul cstouurrecea. nSianlcyesitsh,eiDt Awaresafcotiuonndofth2‐amt efithvyelfuorfatnenanedxov-aardioduuscmtsalgeiamviedecsonpgrolocemedesrates
FmOeRtrPiEcEaRmREpVliIfEicWation by dynamic crystallization, attrition‐enhanced deracemiz3atoifo1n5 was quite effective in promoting Viedam ripening by continuous grinding of the crystals using glass beads, and the enantiomer crystals converged to high enantiomeric purity [42]
The bottleneck of deracemization by the dynamic crystallization method is whether or not the target substrate crystallizes as a stable conglomerate

Summary

Introduction

AbstRraecceti:vedE:ffi27cAiepnritl 2g0e20n;eArcacteipotned:a1n8dMaaym20p2l0ifi; Pcuabtliioshnedo: fdactehirality from prochiral substrates in the Diels–Alder reaction (DA reaction) followed by dynamic crystallization were achieved without using an exAtebrsntraalcct:hEirffailciseonut rgceen.eSrainticoentahnedDaAmpreliaficctaitoionnooff2c-hmireatlhitylfruormanparoncdhivralrisouubstmraatelseiimn itdhesDpierlosc–eeds reverAslidbelyr,raenacetixoon-a(dDdAurcetawctiaosno) bfotlalionweeddabsythdeynmamaiinc cprryosdtaullcizt aatsiotnhewreeraecatciohinevperdocweietdhoeudt. uFsrionmg asningle crysteaxlteXrn-raal ychsitrraul cstouurrecea. nSianlcyesitsh,eiDt Awaresafcotiuonndofth2‐amt efithvyelfuorfatnenanedxov-aardioduuscmtsalgeiamviedecsonpgrolocemedesrates. A key feature of this technique is that it can be applied to deracemization in a system with a relatively low racemization rate, as compared with the method of promoting crystallization using a solvent evaporation method or a temperature gradient [55−58]. The crystals of the exo-adducts were analyzed by single crystal X-ray structure analysis.

Results

Conclusion