Design And Synthesis Of Proline Derived Catalysts And Their Applications In The Construction Of Chiral Oxygen Heterocycles

Oxygen heterocycles are found in many natural products and synthetic molecules,exhibiting fascinating biological and pharmacological activities. The synthesis of this typeof compound is of great importance to the field of natural products chemistry andmedicinal chemistry. So, it is essential to establish some simple, atom economicmethodologies for the construction of oxa-heterocycles with high efficiency and highstereoselectivity. The topic of my thesis mainly focused on the deveploping of asymmetriccarbonyl involved C-C bond forming reactions and their applications in preparing oxygenheterocycles such as benzopyrans and benzofurans.Based on enamine activation mode, several novel prolylprolinol catalysts5a-d havebeen synthesized for the C-C bond forming reactions. By rational design, the formation ofunreactive species hemiaminal between catalyst and aldehyde was avoided. So, this typeof catalysts showed high catalytic efficiency on promoting the direct addition ofunmodified aliphatic aldehydes to nitroalkenes. Among the catalysts surveyed, the leastbulky5d exhibited the best performance on both efficiency and stereoselectivity,providing the products with up to97%ee and up to99:1dr value with1.5-5mol%catalyst loading. Additionally, computational studies of transition state have beenconducted to explain the high diastereo-and enantioselectivity of5d.Then this asymmetric Michael addition methodology had been used in the reactionbetween aliphatic aldehydes and (E)-2-(2-nitrovinyl)-phenols. By the followingspontaneous hemiactalization, this cascade was successfully applied in the synthesis ofbenzopyran frameworks. Interestingly, the diastereo-and enantioselectivities changedmarkedly when the reaction was mediated by different types of secondary-amine catalysts.The diphenylprolinol silyl ether2promoted the reaction with excellent enantioselectivities(up to99%ee) while suffered from poor reactivity and diastereoselectivities (2.8:1to10:1).(L,L)-prolylprolinol5d is also identified as an effective catalyst that showed highcatalytic activity, good enantioselectivities (up to89%ee) and excellentdiasereoselectivities (up to50:1dr). In addition, the chroman-2-ols11b yielded in the above reactions could be conveniently transformed to synthetically and biologicallysignificant chiral dihydrocoumarin, chroman and4H-chromene derivatives.The Proline derivatives are also applicable as chiral ligands along with metal saltsfor the Lewis acid promoted carbonyl addition reactions. By combining the copper(II)catalyzed asymmetric Henry reaction of o-alkynylbenzaldehydes with subsequent gold(I)catalyzed cycloisomerization, optically active1H-isochromenes and1,3-dihydroiso-benzofurans were successfully synthesized in good overall yields with good to excellentenantioselectivities (up to98%). The employment of gold catalyst is vital to thecycloisomerization step because the intermediate β-nitroalcohols18are fairly unstable andprone to racemize under basic, thermo or strong acidic conditions. Various substrates wereinvestigated and a correlation between the regioselectivity and electronic nature of thesubstrates was studied. By tuning the electronic property of the substituents, manysubstrates could be selectively transformed to either1H-isochromene or1,3-dihydroisobenzofuran.The hetero-Diels-Alder reaction between chiral dienes and highly reactive acylnitroso compouns is another method for construction of chiral oxygen containingheterocycles. The regioselectivity seems largely depended on the substituent on diene.Compared to OAc, the OTIPS group makes the dienen more electronicly asymmetric andleads to the excellent selectivity of the reaction between nitroso and OTIPS-diene25a.This reaction seccessifully introduced two hetero substituents on chiral ketene moleculessimultaneously in one step.