Nucleophile-nucleophile coupling is ac hallenging transformation in organic chemistry.Herein we present anovel umpolung strategy for a-functionalization of aldehydes with nucleophiles.T he strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions.T hese quinol-intermediates react with different classes of nucleophiles.T he focus is on an unprecedented organocatalytic oxidative a-thiolation of aldehydes.T he reaction scope is demonstrated for ab road range of thiols and extended to chemoselective bioconjugation, and applicable to alarge variety of aldehydes.This strategy can also encompass organocatalytic enantioselective coupling of a-branched aldehydes with thiols forming quaternary thioethers.S tudies indicate as tereoselective formation of the intermediate followed by as tereospecific nucleophilic substitution reaction at aquaternary stereocenter,w ith inversion of configuration.

The first stereoselective organocatalyzed [3+2] cycloaddition reaction of donor-acceptor cyclopropanes is presented. It is demonstrated that by applying an optically active bifunctional Brønsted base catalyst, racemic di-cyano cyclopropylketones can be activated to undergo a stereoselective 1,3-dipolar reaction with mono- and polysubstituted nitroolefins. The reaction affords functionalized cyclopentanes with three consecutive stereocenters in high yield and stereoselectivity. Based on the stereochemical outcome, a mechanism in which the organocatalyst activates both the donor-acceptor cyclopropane and nitroolefin is proposed. Finally, chemoselective transformations of the cycloaddition products are demonstrated.

An asymmetric catalytic aza-Diels-Alder/ring-closing cascade reaction between acylhydrazones and in situ formed trienamines is presented. The reaction proceeds through a formal aza-Diels-Alder cycloaddition, followed by a ring-closing reaction forming the hemiaminal ring leading to chiral bicyclic azaheterocycles in moderate to good yield (up to 71 %), good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). Furthermore, transformations are presented to show the potential application of the formed product.

An enantioselective methodology to construct trans-Diels-Alder scaffolds by organocatalysis with excellent selectivity,h igh yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and an ovel discovered pseudo-halogen effect to direct an endo-selective,s econdary-amine catalyzedD iels-Alder reaction allowing for the subsequent formation of trans-Diels-Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an a-brominated or a-pseudo-halogenated enone to form af leeting cis-Diels-Alder intermediate.T he endo-transition state-enhanced by the (pseudo-)halogen effectsets the stereochemistry that allows for as ubsequent S N 2-like reaction at at ertiary center to obtain the trans-Diels-Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

Chiral eight-membered carbocycles are important motifs in organic chemistry, natural product chemistry, chemical biology, and medicinal chemistry. The lack of synthetic methods toward their construction is a challenge preventing their rational design and stereoselective synthesis. The catalytic enantioselective [4 + 4] cycloaddition is one of the most straightforward and atom-economical methods to obtain chiral cyclooctadiene derivatives. We report the first organocatalytic asymmetric [4 + 4] cycloaddition of 9H-fluorene-1-carbaldehydes with electron-deficient dienes affording cyclooctadiene derivatives in good yields and with excellent control of peri-, diastereo-, and enantioselectivities. The reaction concept is based on the aminocatalytic formation of a polarized butadiene component incorporated into a cyclic extended π-system, with restricted conformational freedom, allowing for a stereocontrolled [4 + 4] cycloaddition. FMO analysis unveiled that the HOMO and LUMO of the two reacting partners resemble those of butadiene. The methodology allows for the construction of cyclooctadiene derivatives decorated with various functionalities. The cyclooctadienes were synthetically elaborated, allowing for structural diversity demonstrating their synthetic utility for the formation of, for example, chiral cyclobutene- or cyclooctane scaffolds. DFT computational studies shed light on the reaction mechanism identifying the preference for an initial but reversible [4 + 2] cycloaddition delivering an off-cycle catalyst resting state, from which catalyst elimination is not possible. The off-cycle catalyst-bound intermediate undergoes a retro-[4 + 2] cycloaddition, followed by a [4 + 4] cycloaddition generating a cycloadduct from which catalyst elimination is possible. The reaction pathway accounts for the observed peri-, diastereo-, and enantioselectivity of the organocatalytic [4 + 4] cycloaddition.