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Video Source: www.youtube.com/watch?v=0GNDVK4z5i8
Organic Chemistry: Retrosynthesis of this polyene hydrocarbon exploiting symmetry and transition metal catalysis for the stereoselective formation of C-C bonds. • This fully conjugated polyene has rotational symmetry about its centre. A powerful disconnection for dienes and more extended conjugated hydrocarbons is to use cross-coupling 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 semi-metal). 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 cross-coupling reaction, a Stille cross-coupling reaction, and a Suzuki cross-coupling reaction. After transmetallation, and possible precipitation of a salt (depending on the solvent used), both organic (carbon-based) fragments have been assembled on to a palladium(II) centre. Then a reductive elimination can occur to form a new C-C bond and joining the two sp2 carbon centres to form the central C-C 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 cross-coupling 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 game-changers 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 carbon-carbon triple bond. This is because you can exploit a carboalumination reaction to install both the required methyl groups, an E-geometry 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 zirconium-containing 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 cross-coupling 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 palladium-mediated cross-coupling reaction in a similar way. The one of the coupling partners needed for this cross-coupling 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 palladium-mediated cross-coupling. 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 beta-ionane, a very cheap terpene-type 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 beta-ionane by carbocation-mediated cyclisation of a linear precursor, in a biomimetic fashion. • #chemistry #organicchemistry #orgo #ochem #retrosynthesis #synthesis #catalysis #stem #education #science • 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
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