Rings and Retrosynthesis for this Natural Product - Organic Chemistry скачать в хорошем качестве

Rings and Retrosynthesis for this Natural Product - Organic Chemistry

A classical disconnection approach to the retrosynthesis of racemic mesembrine, showcasing an intramolecular Mannich reaction, enolate chemistry, Michael additions and decarboxylation strategies. #chemistry #organicchemistry #orgo #ochem #education #science #stem # This natural product has a 6,5-cis ring fused structure which contains a ketone, a tertiary amine and a quaternary all-carbon stereocentre. Analysis of the functional group relationships indicates a 1,3-diX difunctionalised setup, which can be disconnected using enolate chemistry – in this case as an intramolecular Mannich reaction. This leads back to a 1,5-diX system which are easily synthesised using conjugate addition (Michael addition) of an enamine on to an enone (alpha,beta-unsaturated ketone). This reactivity is matched as both the intended nucleophile and electrophile are soft. The Michael acceptor needed is methylvinylketone (MVK) which is cheap and readily available. The substituted enamine can be constructed by elimination of water from a tertiary alcohol. Tertiary alcohols are simply synthesised from the addition of Grignard reagents to ketones. This approach will work well for this molecule as E1 is favourable when the product is treated with acid, based on good carbocation stabilisation. The Grignard reagent here can be made from 1,2-dimethoxybenzene, doing some standard aromatic chemistry for bromination (Br2, FeBr3), and then final metalation by treatment of the aryl bromide with magnesium metal. The Grignard reagent will be added to the pyrrolidone, which can be made by functional group interconversion to the beta-keto ester, by installation of a temporary extra ester functional group – this can be removed by decarboxylation later. A number of other strategies are explored for synthesis of the pyrrolidone that won’t be easy in practice. These strategies involves cleavage of the carbon-heteroatom (C-N) bond and ring closure. These ring closures should be assessed by Baldwin’s Rules to check if they are favourable (5-exo-trig is favourable, 5-endo-trig is not favourable). The C-N disconnections also go back to small molecules with a few too many reactive functional groups that would make control in reactions tricky due to chemoselectivity problems. References for related total synthesis/work: J. Am. Chem. Soc. 1933, 55, 1233 https://doi.org/10.1021/ja01330a065 Tet. Lett. 1968, 9, 1441 https://doi.org/10.1016/S0040-4039(01...