René Slot Bitsch

An enantioselective eliminative inverse electron-demand Diels–Alder reaction of α-branched aldehydes, providing hydrindanone scaffolds in high yields and enantioselectivities, enabled by a cinchona alkaloid-based primary amine catalyst is reported.

Troponoids exhibit unique reactivity in Diels–Alder and higher-order cycloadditions, since they can partake as 2π-, 4π-, 6π-, and 8π-components, affording various peri- and regioisomers depending on both the reaction conditions and, importantly, their substitution pattern. Herein, we identify 2-cyanotropone as a promising lead substrate and demonstrate an aminocatalytic, dienamine-mediated, enantioselective [4 + 2] cycloaddition with α,β-unsaturated aldehydes providing the corresponding cycloadducts in good yields, high enantioselectivity, and moderate-to-high diastereocontrol as separable isomers. One of the cycloadducts undergoes an intramolecular aldol-type cyclization upon treatment with a reductant, generating an octahydro-2,6-methanonaphthalen-9-one scaffold. The mechanistic details of this substituent-controlled reaction were investigated by DFT studies to (i) identify a suitable troponoid substrate to unlock the anticipated reactivity; (ii) shed light on the observed regio-, diastereo-, and periselectivity; and (iii) understand the difference in enantiocontrol obtained using an aminocatalyst capable of hydrogen-bonding with the troponoid substrate to induce facial selectivity versus an aminocatalyst relying on steric bulk to achieve facial discrimination.

Access to the full array of stereoisomers of molecules bearing multiple stereocenters from the same substrates is an enduring challenge in asymmetric synthesis. In the ideal scenario, stereodivergence is achieved using a single-catalyst system, where a minimal modification of the catalyst enables access to both diastereoisomers, while exploiting identical activation modes. Here, we applied this strategy by a simple modification of a prolinol-derived catalyst in fully stereodivergent, enamine-mediated inverse electron-demand Diels-Alder reactions of aldehydes with electron-deficient dienes. Modulation of the bulkiness of the β'-substituent of the prolinol catalyst proved key to achieving diastereodivergence, allowing for the formation of both diastereoisomers with excellent enantioselectivity. First, it is shown by using enantiomers of the catalysts that all four stereoisomers of the cycloadduct can be obtained, followed by extending the reaction to optically active aldehydes, thereby allowing for the selective formation of all eight stereoisomers. The general scope of the inverse electron-demand Diels-Alder reaction proceeds in high to excellent yields and diastereoselectivity, and enantioselectivities up to >99% ee. Computational and experimental studies revealed that stereodivergence originates from a catalyst-dependent mechanistic dichotomy. Surprisingly, DFT calculations reveal that one catalytic system enforces diastereocontrol during the initial C-C bond-forming event, while the other, having increased steric bulk, perturbs the elimination kinetics, rendering downstream catalyst elimination stereodetermining under Curtin-Hammett control. The role of the catalyst for controlling the stereochemical outcome of the computationally proposed mechanisms for the inverse electron-demand Diels-Alder reaction was supported by a series of experiments and the isolation of a catalyst-bound adduct.

A new chapter starts now . Since its discovery in 2005, the diarylprolinol silyl ether catalytic concept has emerged as a general and reliable aminocatalytic tool for the synthesis of enantioenriched molecules. Recently its combination with emerging technologies, as well as its application in more complex molecular systems has opened new avenues for novel enantioenriched scaffolds. In this review, we will highlight these recent developments, unfolding five primary categories that define new horizons in the use of diarylprolinol silyl ethers: Photochemical‐, electrochemical‐, dual‐catalytic transformations, higher‐order cycloadditions and applications in total synthesis of complex natural products.

A new chapter starts now . Since its discovery in 2005, the diarylprolinol silyl ether catalytic concept has emerged as a general and reliable aminocatalytic tool for the synthesis of enantioenriched molecules. Recently its combination with emerging technologies, as well as its application in more complex molecular systems has opened new avenues for novel enantioenriched scaffolds. In this review, we will highlight these recent developments, unfolding five primary categories that define new horizons in the use of diarylprolinol silyl ethers: Photochemical‐, electrochemical‐, dual‐catalytic transformations, higher‐order cycloadditions and applications in total synthesis of complex natural products.

Bicyclo[1.1.0]butanes have opened a new area of chemical space for construction of bicyclo[2.1.1]hexanes – a scaffold showing promise as ortho- and meta-aryl bioisosteres. Herein, we present the first aminocatalytic concept that enables the enantioselective [2 + 2] cycloaddition of bicyclo[1.1.0]butanes with α,β-unsaturated aldehydes. The reaction is general for α,β-unsaturated aldehydes, substituted at the γ-position with aromatic functionalities, esters and ketones, by applying a secondary aminocatalyst and Yb(OTf)₃ as a Lewis acid to activate the bicyclo[1.1.0]butane. For cinnamaldehydes, bicyclo[2.1.1]hexane cycloadducts are obtained in moderate to good yields, and up to 96.5 : 3.5 e.r. Pleasingly, α,β-unsaturated aldehydes containing ester and ketone functionalities in the γ-position provided high yields and enantioselectivities up to 98.5 : 1.5 e.r. For all three classes of [2 + 2] cycloadditions, a range of α,β-unsaturated aldehydes and bicyclo[1.1.0]butanes were successfully tolerated. Several transformations adding further complexity to the bicyclo[2.1.1]hexane scaffolds are disclosed. Finally, a reaction mechanism is proposed.

A mechanistic investigation into the novel combination of the pseudo-halogen effect with enantioselective aminocatalysis unravels the mechanistic intricacies of [6 + 4] and [10 + 6] higher-order cycloadditions and the succeeding new Favorskii-like rearrangements. By introducing the OTf-group into the tropone framework, it can serve both as an activator for the cycloaddition and as a proficient leaving group within the corresponding cycloadduct, thus enabling unprecedented ring-contracting Favorskii-like rearrangements. Integrating the -OTf group creates an electron-deficient 6π-component leveraging the pseudo-halogen effect by enhancing the polarization and introducing new strategic interaction points. This modification complements electron-rich 4π- and 10π-components from amino-activated 2,4-dienals or indene-carbaldehydes. A comprehensive DFT investigation supported by experimental results demonstrates that the [6 + 4] system proceeds through a rate-limiting stepwise exo-cycloaddition leading to a cycloadduct initially in a boat-conformation, subsequently transitioning to the more stable chair-conformation. The change in conformation ensures an S_N1-like expulsion of the -OTf group, generating a stable carbocation bridgehead primed for a novel Favorskii-like seven-to-six ring-contracting rearrangement, resulting in the experimentally observed product. As proof-of-concept for the cycloaddition/Favorskii-like rearrangement, it is demonstrated that this approach can be extended to an unprecedented [10 + 6] cycloaddition. In contrast to the [6 + 4] system, the [10 + 6] system distinguishes itself with a concerted S_N1-like/Favorskii-like six-to-five ring-contracting rearrangement, representing the rate-limiting step. This novel concept results in the experimental isolation of structurally complex products in high peri-, diastereo-, and enantioselectivity with moderate yield. These findings demonstrate the pseudo-halogen effect's multifaceted role in promoting and enabling novel reactivity.

This study presents a novel photoredox-enabled enantioconvergent catalytic strategy used to construct chiral 2H-1,3-benzoxazines via an unprecedented oxa-6π electrocyclization utilizing racemic α-substituted glycinates as substrates. The approach leverages a cobalt-based chiral Lewis acid catalyst, which promotes the transformation under thermal or photoredox conditions. While the thermal reaction selectively converts only the (S)-configured glycinates into enantioenriched 2H-1,3-benzoxazines (up to 96:4 e.r.), the addition of 0.5 mol % of a commercially available iridium photocatalyst under visible light irradiation transforms the reaction into an enantioconvergent process. Detailed mechanistic and time course studies of optically pure α-deuterated substrates revealed the presence of an enantiospecific kinetic isotope effect, which helped to clarify the role of both the photo- and chiral Lewis acid catalyst in the reaction sequence. In this dual catalytic system, the photocatalyst promotes a dynamic interconversion between the substrate enantiomers─a process not accessible via ground-state chemistry─while the chiral Lewis acid selectively transforms only the (S)-configured substrates. Further mechanistic evidence for the proposed mechanism is provided by linear free energy relationship analysis, which suggests that the stereodetermining step involves a 6π electrocyclization under both thermal and photoredox conditions.

The combination of asymmetric organocatalysis with the (pseudo)-halogen effect enables the formation of chiral norcarane scaffolds in high yields and selectivities (up to 92% yield, >99% ee, and >95:5 d.r.). This was achieved by reacting (pseudo)-halogenated 3-vinyl chromones with in situ generated chiral dienamines in an inverse electron demand [4 + 2] cycloaddition followed by an intramolecular S_N2 reaction. These scaffolds could easily undergo photoinduced rearrangements or lactonization to form intricate chiral ring structures.