Transition metal catalytic asymmetric dearomatization reactions

Catalyzed asymmetric dearomatization reactions (CADA reactions) are a category of asymmetric dearomatization reactions that catalytically transform aromatic compounds into enantioenriched polycycles and heterocyclic skeletons. The term was coined in 2012 by You et al.

History In 2001, the field of asymmetric catalysis was pioneered with Nobel Prize winners Knowles, Noyori, and Sharpless for work in catalytic asymmetric hydrogenation and oxidation. More recently, many groups have begun applying transition metal (TM) catalysis to such processes with great success in enantiopurity of important biological molecules. The first TM CADA reactions used palladium catalysis, but methods evolved to include catalytic iridium and ruthenium for different applications. The first report of selective C-3 allylation of indoles under Pd(PPh3)4 catalysis was from Tamaru et al. in 2005. Shortly after in 2006, Trost, Quancard, et al. investigated catalytic enantioselective version (of dearomative allylation of indoles) with Pd2(dba)3CH3Cl with success. In April 2008, You et al. investigated a Friedel-Crafts type allylic alkylation (allylic substitution, intermolecular) of indoles, with [Ir(cod)Cl]2 as a catalyst. This led to intramolecular allylic alkylation. Shortly after, in 2009 Buchwald et al. explored a similarly intramolecular enantioselective Pd-catalyzed dearomatization of naphthalene derivatives. This led to the Pd-catalyzed arylative dearomatization of phenols to yield spirocyclohexadienone products with excellent yield. In August 2010, the You group then did intramolecular asymmetric dearomatization of indoles using Ir-catalyzed allylic alkylation, leading to the development of intramolecular asymmetric allylic dearomatization of phenols. The allylic alkylation of pyrroles was more challenging than the same allylic alkylation of indoles in terms of enantioselectivity and regioselectivity. However, this allylic dearomatization of pyrroles nonetheless yielded bicyclic spiro-2H-pyrroles with good yield, enantioselectivity, and diastereoselectivity. The same year, Hamada et al. explored an intramolecular dearomatization of phenols with Pd-catalyzed allylic alkylation, which gave spirocyclohexadienones in good yield, relating to diastereoselectivity. This was later applied by the same group to enantioselective dearomatization of naphthol derivatives. Other advances include in 2011 when You et al. found that the Ir-catalyzed allylic dearomatization applied to pyrroles., and later in 2016 when Wang et al. investigated Mg-driven napthols, discovered new hydride transfer pathway.

Mechanism Dearomatization reactions are useful in pharmaceutical/industry applications; however, historically, creating a purely enantioselective process was rare. Most enantioselective chemical processes require harsh reaction conditions to break the stability given through aromaticity. The You group once performed a synthesis of aza-spiroindolenines using a ruthenium catalyst, starting at room temperature, over a 72-hour period, resulting in an undetermined percent yield and diastereomeric ratio from partial decomposition. They then improved this synthesis over time, tuning the solvents and base to get better enantiopurity and percent yields.

You et al., decided to compile a lengthy list of dearomatization reactions to pull the best features from each mechanism to create the CADA reactions. Below is one in which a phenol reacts with a Michael acceptor in order to initiate a 'cascading effect' of electron movement to create an adamantane-like core.Prior to coining CADA, there was an asymmetric acylation and alkylation reaction involving palladium. This cycle (shown below) allows for enantioselection at every step other than the removal of the final product(s). While indole and pyrrole are most commonly used in CADA reactions, acting nucleophiles for the intra- or intermolecular reactions include phenol, β-naphthol, pyridine, or pyrazine. The Wang group discovered a tandem cyclization reaction, showing that a hydride ion can lead to formation of a polycyclic product via intramolecular dearomatization. With all of these previously found mechanisms combined, CADA found a way to dearomatize and form rings with high enantiopurity through the use of transition metals like Pd, Ru, and Ir. This mechanism was a hot topic from 2013 - 2018 but slightly fizzled out while other reactions took the spotlight. Although they seem to be making a comeback, as the most recent example of a catalytic dearomatization reaction was performed by Zhang et al., where the group sought to use a chiral N-Heterocyclic Carbene (NHC) to form a new ring from a saturated ester. In May 2024, they were able to achieve high enantiopurity (greater than 99% ee and 91% de) without the use of harsh chemicals or a chemically harsh environment.

Ruthenium (vs. Iridium) catalysis Sources: Two families of allylic Ru (IV) complexes were investigated for application in the Friedel-Crafts type allylic alkylation (previously performed with [Ir(cod)Cl]2 ) much better results. The Ru complex had a much broader substrate scope and was a cheaper, easier-to-synthesize catalyst, under much milder conditions than the previous Ir reactions. This success is hypothesized due to the variety of ligands the Ru center accepts, the range of oxidation states, tolerance to many substrates and conditions, as well as general use in the allylation of nucleophiles.

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