*This is the 5th post of the helicene series*
After asymmetric synthesis of carbon-sulfur helicene, we went back to the drawing board…. plugging away at the connection/annelation sequences…the next challenge was carbon-sulfur helicene. Here is the retrosynthesis.
It seemed pretty trivial….just connect two helicene by homocoupling reaction, followed by mono-annelation reaction to give the corresponding helicene. Right? We tried just that…homocoupling of dibromohelicene by palladium mediated C-C bond forming reactions. Well, surprise, surprise… no homocoupling product was detected! Instead, we isolated the product of intramolecular cyclization, in which the C-C bond was formed at the inner helical termini of the dibromohelicene.
The cyclic product, planar structure of annelated aromatic ring with cross-conjugated π-system, appears to resemble the “sulflower”, carbon-sulfur circulene (C2S)8, recently prepared by Nenajdenko and co-workers (Angew. Chem., Mendeleev Commun), we thought we could remove the protecting group and add the sulfur atom to form the circulene, but we failed.
We actually investigated further this intramolecular cyclization reaction in a series of helicenes and the results were published in JOC.
Ok, there was no easy way out! We tried the alternative route…as shown below.
We already had in hand the bis(β-trithiophene) and the first step, monoprotection of the most acidic positions, seemed trivial. We tried trimethylsilyl (TMS) as the protecting group, but poor solubility was a serious problem, especially in the subsequence connection steps. We then used the large tripropylsilyl (TPS) group to obtain the monoprotected bis(β-trithiophene) with enhanced solubility and steric shielding at one of the CBr moieties. The steric shielding provided selectivity in the connection step, Pd-catalyzed reductive CC-homocoupling of monoprotected bis(β-trithiophene) to form tetrakis(β-trithiophene), as carbon–carbon bond formation is preferred at the less sterically shielded CBr moiety.
Tri-annelation of the tetrakis(β-trithiophene) would give the corresponding helicene but that requires effective hexalithiation of the tetrakis(β-trithiophene) and formation of three thiophene rings. A bit too difficult…but we gave it a shot anyway. As expected, the hexalithiation step was too much to ask for.
So we tried the di-annelation route. Tetrakis(β-trithiophene) was tetralithiated with lithium diisopropylamide (LDA) in the presence of (-)-sparteine, and then treated with bis(phenylsulfonyl)sulfide ((PhSO2)2S) to form two new thiophene rings. The chiral bishelicene product was obtained in approximately 20% yield after isolation and had a modest enantiomeric excess (ee) value. The two helicene moieties in bishelicene were likely to possess identical configurations, MM or PP. An alternative meso-diastereomer with the helicene moieties of the opposite configuration (PM) was not detected.
Alright, one more step to go… mono-annelation… and we were very happy! It turned out that one step had us kept saying,…just one step…c’mon, just one step, to the longest carbon-sulfur helicene.
The mono-annelation step looked quite simple, dilithiation of the chiral bishelicene with LDA in the presence of (-)-sparteine, and then treated with ((PhSO2)2S) to form just one new thiophene ring. Supposedly, the bishelicene had the right configuration for ring closer. Dilithiation of bishelicene was not a problem, as indicated by deuterium quenching experiments. So what was the problem? We couldn’t really figure out this puzzle.
Perhaps it was a combination of luck and having a great crystallographer as collaborator, we were able to obtain x-ray structure of both the tetrakis(β-trithiophene) and bishelicene. Have a look at those beautiful structures.
Both x-ray structures gave us a clue to the puzzle. The tetrakis(β-trithiophene) folds into a helical conformer, and a chiral conformer is as well detected in solution. The helical folding was likely driven by steric repulsion and pairwise π-stacking of the annelated β-trithiophene moieties. This helical folding sets up the preference for di-annelation leading to a helically-folded bishelicene, i.e., with helicene moieties MM or PP. In bishelicene structure, the β,β-linkage (between helicene moieties) resembles a molecular hinge in which two rigid helicene moieties form an intramolecular π-stack assembled in a helical motif. The short intramolecular distances on both sides of the molecular hinge lead to a rigid conformation that prohibits their relative rotation to facilitate bond formation. So, the mono-annelation …that one step…could not be achieved.
Of course, we wanted to make helicenes but came up short with just one missing link! Disappointed, but it turned out to be not as bad as we thought.
We calculated electronic CD and UV-vis absorption spectra of simplified structures of bishelicene and helicene, in which the large TPS group was replaced with a TMS group, and found that their spectra are qualitatively similar. For bishelicene, excellent agreement between experiment and theory was found, the weak, long-wavelength band at approximately 330 nm is qualitatively reproduced in the calculated spectrum. We concluded that bishelicene adopts a helicene-like rigid conformation in the solid state and in solution, and it possesses an electronic structure similar to that for the corresponding helicene.
We predict that a strong preference for helical folding, driven by intramolecular π-stacking and steric repulsion, may be realized in oligomers of [n]helicene monomers with the same configuration and which are connected at the inner rim of the [n]helicenes. For moderate values of n, such oligomers could provide extended rigid–rod helical structures that are precisely defined at the molecular level and are expected to possess enhanced chiral properties.
Read more about Carbon-Sulfur Bis Helicene…
Makoto Miyasaka, Maren Pink, Suchada Rajca,Andrzej Rajca, “Noncovalent Interactions in the Asymmetric Synthesis of Rigid, Conjugated Helical Structures”, Angew. Chem. Int. Ed., 2009, 48, 5954-5957. DOI: 10.1002/anie.200901349