This Review summarizes the development of catalytic asymmetric dearomatization (CADA) reactions. The CADA reactions discussed herein include oxidative dearomatization reactions, dearomatization by ...Diels–Alder and related reactions, the alkylative dearomatization of electron‐rich arenes, transition‐metal‐catalyzed dearomatization reactions, cascade sequences involving asymmetric dearomatization as the key step, and nucleophilic dearomatization reactions of pyridinium derivatives. Asymmetric dearomatization reactions with chiral auxiliaries and catalytic asymmetric reactions of dearomatized substrates are also briefly introduced. This Review intends to provide a concept for catalytic asymmetric dearomatization.
Breaking up the party: Arenes can be transformed efficiently into enantiomerically enriched, versatile ring systems by catalytic asymmetric dearomatization reactions. Known reaction types include oxidative dearomatization, dearomatization by Diels—Alder reactions, alkylative dearomatization of electron‐rich arenes, transition‐metal‐catalyzed dearomatization reactions (see example), and cascade reaction sequences involving asymmetric dearomatization as the key step.
Conspectus Dearomatization reactions serve as powerful methods for the synthesis of highly functionalized, three-dimensional structures starting with simple planar aromatic compounds. Among processes ...of this type, catalytic asymmetric dearomatization (CADA) reactions are attractive owing to the large number of aromatic compounds that are readily available and the fact that they enable direct access to enantiopure polycycles and spirocycles, which frequently are key structural motifs in biologically active natural products and pharmaceuticals. However, as a consequence of their high stabilities, arenes only difficultly participate in dearomatization reactions that take place with high levels of enantioselectivity. Transition-metal-catalyzed asymmetric allylic substitution reactions have been demonstrated to be powerful methods for enantioselective formation of C–C and C–X (X = O, N, S, etc.) bonds. However, the scope of these processes has been explored mainly using soft carbon nucleophiles, some hard carbon nucleophiles such as enolates and preformed organometallic reagents, and heteroatom nucleophiles. Readily accessible aromatic compounds have been only rarely used directly as nucleophiles in these reactions. In this Account, we present the results of studies we have conducted aimed at the development of transition-metal-catalyzed asymmetric allylic dearomatization reactions. By utilizing this general process, we have devised methods for direct dearomatization of indoles, pyrroles, phenols, naphthols, pyridines, and pyrazines, which produce various highly functionalized structural motifs bearing all-carbon quaternary stereogenic centers in a straightforward manner. In mechanistic investigations of the dearomatization process, we found that the five-membered spiroindolenines serve as intermediates, which readily undergo stereospecific allylic migration to form corresponding tetrahydro-1H-carbazoles upon treatment with a catalytic amount of TsOH. It is worth noting that no notable loss of the enantiomeric excess of the spiroindolenine derivatives takes place during the rearrangement process as a consequence of the intervention of a “three-center–two-electron”-type transition state, a proposal that has gained support from the results of DFT calculations. Equally intriguing, upon tuning of the electronic nature of the tethers, pyrroles or indoles undergo unprecedented Ir or Ru catalyzed intramolecular allylic alkylation promoted dearomatization/migration reactions. The operation of this novel reaction pathway provides additional information leading to a greater mechanistic understanding of the transition-metal-catalyzed enantioselective intramolecular functionalizations of pyrroles and indoles. The combined results of this effort provide not only methods for the efficient synthesis of highly enantioenriched fused and spiro polycycles but also novel strategies in the field of asymmetric catalysis.
Baring all: The title reaction provides β‐naphthalenones bearing an all‐carbon quaternary center in good to excellent yields, as well as excellent chemo‐ and enantioselectivity (see scheme).
The marine natural product pateamine A (1) and its somewhat simplified designer analogue DMDA-Pat A (2) (DMDA = desmethyl-desamino) are potently cytotoxic compounds; most notably, 2 had previously ...been found to exhibit a promising differential in vivo activity in xenograft melanoma models, even though the ubiquitous eukaryotic initiation factor 4A (eIF4A) constitutes its primary biological target. In addition, 1 had also been identified as a possible lead in the quest for medication against cachexia, an often lethal muscle wasting syndrome affecting many immunocompromised or cancer patients. The short supply of these macrodiolides, however, rendered a more detailed biological assessment difficult. Therefore, a new synthetic approach to 1 and 2 has been devised, which centers on an unorthodox strategy for the formation of the highly isomerization-prone but essential Z,E-configured dienoate substructure embedded into the macrocyclic core. This motif was encoded in the form of a 2-pyrone ring and unveiled only immediately before macrocyclization by an unconventional iron-catalyzed ring opening/cross-coupling reaction, in which the enol ester entity of the pyrone gains the role of a leaving group. Since the required precursor was readily available by gold catalysis, this strategy rendered the overall sequence short, robust, and scalable. A surprisingly easy protecting group management together with a much improved end game for the formation of the trienyl side chain via a modern Stille coupling protocol also helped to make the chosen route practical. Change of a single building block allowed the synthesis to be redirected from the natural lead compound 1 toward its almost equipotent analogue 2. Isolation and reactivity profiling of pyrone tricarbonyliron complexes provide mechanistic information as well as insights into the likely origins of the observed chemoselectivity.
The marine macrolide pateamine A and its non‐natural sibling DMDA‐Pat A are potent translation inhibitors targeting the eukaryotic initiation factor 4A (eIF4A), an enzyme with RNA helicase activity. ...Although essential for every living cell, this protein target seems “drugable” since DMDA‐Pat A has previously been shown to exhibit remarkable in vivo activity against two different melanoma mouse models. The novel entry into this promising compound presented herein is shorter and significantly more productive than the literature route. Key to success was the masking of the signature Z,E‐configured dienoate subunit of DMDA‐Pat A in the form of a 2‐pyrone ring, which was best crafted by a gold‐catalyzed cyclization. While the robustness of the heterocycle facilitated the entire assembly stage, the highly isomerization‐prone seco‐Z,E‐dienoic acid could be unlocked in due time for macrolactonization by an unconventional iron‐catalyzed ring opening/cross coupling. Moreover, the crystal structure analysis of an advanced intermediate gave first insights into the conformation of the macrodilactone framework of the pateamine family, which is thought to be critical for eliciting the desired biological response.
Closed and open: A pyrone ring, formed by a gold‐catalyzed cycloisomerization, was used to encode the highly isomerization‐prone Z,E‐dienoate subunit of a pateamine‐type macrolide. The closed, robust pyrone was unlocked to reveal the sensitive open dienoate by an unorthodox iron‐catalyzed ring opening/cross coupling only immediately prior to macrocyclization.
The first highly diastereo‐ and enantioselective synthesis of five‐membered spiro‐2H‐pyrroles was achieved using an Ir‐catalyzed asymmetric allylic dearomatization reaction. The spiro‐2H‐pyrrole ...derivatives readily undergo a controllable and stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values. Additionally, the novel Ir‐complex K1, derived from Ir(cod)Cl2 (cod=1,5‐cyclooctadiene) and N‐benzhydryl‐N‐phenyldinaphthophosphoramidite (BHPphos), showed excellent control of both diastereo‐ and enantioselectivities.
It's all under control: The highly diastereo‐ and enantioselective synthesis of five‐membered spiro‐2H‐pyrroles was achieved using an Ir‐catalyzed asymmetric allylic dearomatization. The spiro‐2H‐pyrrole derivatives readily undergo a stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values.
Aromaticity lost: In the presence of {Ir(cod)Cl}2 and a binol‐derived phosphoramidite ligand, spirocyclohexadienone derivatives were obtained with up to 97 % ee through iridium‐catalyzed ...intramolecular asymmetric allylic dearomatization of phenols (see scheme; cod=cycloocta‐1,5‐diene).
A chiral iridium(I) N‐heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method ...provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74–91 %) and excellent enantioselectivities (92–99 % ee). Preliminary mechanistic investigations reveal that the C−H activation occurs at the position ortho to the N‐aryl group of the ligand.
A chiral iridium(I) N‐heterocyclic carbene complex catalyzes highly enantioselective intramolecular allylic amination reactions. This method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields. Mechanistic investigations reveal that the C−H activation occurs at the position ortho to the N‐aryl group of the ligand.
The transition‐metal‐catalyzed cyclopropanation of alkenes by the decomposition of diazo compounds is a powerful and straightforward strategy to produce cyclopropanes, but is tempered by the ...potentially explosive nature of diazo substrates. Herein we report the Mo‐catalyzed regiospecific deoxygenative cyclopropanation of readily available and bench‐stable 1,2‐dicarbonyl compounds, in which one of the two carbonyl groups acts as a carbene equivalent upon deoxygenation and engages in the subsequent cyclopropanation process. The use of a commercially available Mo catalyst afforded an array of valuable cyclopropanes with exclusive regioselectivity in up to 90 % yield. The synthetic utility of this method was further demonstrated by gram‐scale syntheses, late‐stage functionalization, and the cyclopropanation of a simple monocarbonyl compound. Preliminary mechanistic studies suggest that phosphine (or silane) acts as both a mild reductant and a good oxygen acceptor that efficiently regenerates the catalytically active Mo catalyst through reduction of the Mo‐oxo complexes.
Readily available and bench‐stable 1,2‐dicarbonyl compounds are shown to undergo Mo‐catalyzed regiospecific deoxygenative cyclopropanation. This method has led to an array of valuable cyclopropanes in yields of up to 90 % and with exclusive regioselectivity. This strategy was further applied to the cyclopropanation of a simple monocarbonyl compound.
A highly efficient catalytic asymmetric dearomatization of naphthols by means of an electrophilic amination reaction catalyzed by chiral phosphoric acid is presented. This protocol provides a facile ...access to functionalized β‐naphthalenone compounds with a chiral quaternary carbon center in excellent yields and enantioselectivity (up to 99 % yield, up to 96 % ee).
Useful skeletons: An electrophilic amination reaction catalyzed by chiral phosphoric acid is the basis for a highly efficient asymmetric dearomatization of naphthols. This protocol provides functionalized β‐naphthalenone compounds with a chiral quaternary carbon center in excellent yields and enantioselectivity. These motifs are found in various biologically active natural products and therapeutic reagents.
