Asymmetric transition metal catalysis toward screw-shaped aromatic compounds

The helix is a widespread chiral geometrical form in nature, and its elegant three-dimensional shape can be associated with different natural items (e.g., the spiral shells of molluscs and snails, the vines entwined with trees, or the left-handed helical tusk of the narwhal). Nature has also selected the homochiral topology for its biological systems at microscopic level, such as the two right-handed helices of DNA and the right-handed helical substructures (i.e., the -helices) in many proteins. Thus, helicity is a fundamental element of molecular chirality, and supramolecular interactions between helices are of outmost importance in molecular biology.1 In the chemist’s synthetic world, one remarkable example of helicity is provided by the helicenes, whose name contains both the prefix "helic-", denoting the nonplanar shape, and the suffix "-enes" indicating the presence of unsaturated system. According to the IUPAC rules, helicenes are polycyclic aromatic or heteroaromatic compounds which contain at least five ortho-fused rings that adopt a nonplanar screw-shaped skeleton due to the steric repulsive interaction between the terminal rings. Because of their nonplanarity, these molecules are chiral and, based on the helicity rule proposed by Cahn, Ingold, and Prelog,2 a left-handed helix is designed "minus" and denoted as M while a right-handed one is designed "plus" and denoted P (Figure 1). Helicenes composed by solely carbocyclic aromatic rings in their structure are defined carbohelicenes, whereas heterohelicenes contain at least one heteroaromatic ring in the screw skeleton (Figure 2).3,4 The introduction of heteroatom(s) in the helical framework significantly affects the geometric parameters and the electronic structure of the helix, providing unique functions and chiroptical response.5,6 The inherent chirality in combination with the extended -conjugated system provide helicenes with outstanding chiroptical properties, and they have been proposed in a plethora of cutting-edge applications, including nonlinear optics, circularly polarized luminescence (CPL) materials, sensors and responsive switches, asymmetric catalysis, and chiral recognition of biomolecules, among other.3,4 Therefore, the search for highly efficient and versatile stereoselective syntheses of structurally diverse helicenes is highly sought after. Numerous synthetic methodologies for the preparation of carbo and heterohelicenes have been so far reported, and they have played a key role in the progress of the helicene chemistry. Among them, the photocyclo-dehydrogenation of cis/trans stilbene-like molecules is the most common route to helicenes,7,8 even if it often suffers from low regioselectivity in the presence of two different ortho positions in the stilbene substrate, and further oxidative cyclization processes of the formed helicene sometimes occur. Moreover, this approach usually provides racemic helicenes, whose resolution into the corresponding enantiomers is accomplished through expensive and time-consuming chiral HPLC separations. From this perspective, asymmetric transition metal catalysis represents one of the most straightforward and efficient strategy for the synthesis of enantioenriched molecules, and its application in the asymmetric synthesis of helicenes has attracted much attention in the last two decades.9,10,11 In particular, intra and intermolecular alkyne-based cyclization reactions promoted by transition metal-based catalysts have become a valuable alternative to photochemical processes for the synthesis of (hetero)helicenes, especially in enantioenriched form.11 On the other hand, cycloisomerizations of ortho-alkynylated biaryls and [2+2+2]-cycloadditions of triyne derivatives are versatile, atom economical and group tolerant methods for the synthesis of carbo- and heterocycles, including helicenes and their congeners. These processes involve the formation of several carbon-carbon bonds in a single step and allow enynes and related substrates to be converted into more structurally complex polycyclic products, such as (hetero)helicenes, with both high efficiency and regioselectivity. Noteworthy, the asymmetric version of these alkyne-based cyclizations have also been developed to obtain nonracemic helicenes with high stereoselectivity. In this contribution, the most representative and recent examples of transition metal catalyzed alkyne-based cyclizations applied to the synthesis of helicenes will be described, with a special focus on the enantioselective synthesis of heterohelicenes through the intramolecular Au-catalyzed alkyne hydroarylation and the transition metal catalyzed [2+2+2]-cycloaddition of triyne derivatives, which represent the most efficient and selective approaches for the asymmetric synthesis of (hetero)helicenes thus far. The challenges and limitations still present for these procedures will be also discussed, taking into account that efforts to develop novel and improved asymmetric synthetic approaches toward (hetero)helicenes will lead to more and more important and advanced applications of these fascinating class of polycyclic aromatic compounds.