Organic Chemistry: Retrosynthesis of this polyene hydrocarbon exploiting symmetry and transition metal catalysis for the stereoselective formation of CC bonds.

This fully conjugated polyene has rotational symmetry about its centre. A powerful disconnection for dienes and more extended conjugated hydrocarbons is to use crosscoupling methodology that uses palladium catalysis to form bonds between two sp2 carbon centres – one that is bound to a leaving group (often a halogen such as bromine or iodine), and one that is bound to another cheaper metal (or semimetal). These alkenyl bromides/iodides (vinyl bromides/iodides) react with palladium in the zero oxidation state by oxidative addition to form the alkenyl palladium(II) species – an organometallic. This palladium(II) species will perform a transmetallation with the stoichiometric alkenyl metal species, made using, for example, zinc, tin or boron. Reactions based on these metal species are, respectively, called a Negishi crosscoupling reaction, a Stille crosscoupling reaction, and a Suzuki crosscoupling reaction. After transmetallation, and possible precipitation of a salt (depending on the solvent used), both organic (carbonbased) fragments have been assembled on to a palladium(II) centre. Then a reductive elimination can occur to form a new CC bond and joining the two sp2 carbon centres to form the central CC bond of a diene. At the same time, the palladium is reduced back to the zero oxidation state – palladium(0) – which can cycle round and react with another alkenyl halide. Hence, the expensive palladium metal compounds used in this reaction can be used catalytically and it turns out with a low molar loading. This catalytic crosscoupling reaction is a very common technique in modern synthetic organic chemistry and has found great use in the pharmaceutical industry. Transition metal catalysis really is a cornerstone of synthesis and these reactions are an example of homogeneous catalysis in chemistry. The reactions are gamechangers in organic chemistry.

In this particular molecule’s retrosynthesis, both the alkenyl halide (vinyl halide) and alkenyl metal (vinyl metal) species can be disconnected back to a common precursor alkyne with a carboncarbon triple bond. This is because you can exploit a carboalumination reaction to install both the required methyl groups, an Egeometry alkene (C=C double bond), and a terminal functional group at once. This reaction uses trimethylaluminium (AlMe3) to add across the alkyne in a stereoselectively syn fashion, and the reaction is catalysed by the zirconiumcontaining compound zirconocene dichloride, Cp2ZrCl2. This carboalumination reaction forms an alane as a new organometallic intermediate. This alane can be converted to both a more reliable organometallic for crosscoupling reaction, such as the organozinc for a Negishi coupling, but also to the vinyl halide by reaction with an electrophilic halogen source, for example elemental bromine (Br2) or iodine (I2).

With the common intermediate in hand, it can be further disconnected by palladiummediated crosscoupling reaction in a similar way. The one of the coupling partners needed for this crosscoupling can, in fact, be synthesised again by carboalumination reaction. In this video, I choose it to be the organometallic component, as the smaller coupling partner is quickly made as the vinyl halide.

The other component of this intermediated can be made by another palladiummediated crosscoupling. This time a Sonogashira reaction is appropriate for joining an sp2 carbon to an sp carbon. In this reaction, you do not need to make the organometallic separately – the cuprate can be formed in situ by treating the alkyne with copper iodide and triethylamine.

The smaller alkyne needs to be synthesised now and this is simply and cheaply done by dehydration of betaionane, a very cheap terpenetype molecule found readily in nature. You should just buy this in and perform a dehydration, via the enolate, using an electrophilic phosphorus reagent or equivalent. This allows elimination reaction across an enolate’s C=C bond. Alternatively, you could make the betaionane by carbocationmediated cyclisation of a linear precursor, in a biomimetic fashion.

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Reference:
Discussion inspired by this synthesis of a similar polyene:
F. Zeng, E. Negishi Org. Lett. 2001, 3, 719
https://doi.org/10.1021/ol000384y