Using a family of novel mononuclear and dinuclear palladium complexes of phanephos ligands, the simultaneous control of regioselectivity and enantioselectivity in the hydroxycarbonylation and alkoxycarbonylation of styrene derivatives has been realised for the first time.

Abstract:The reactivity of N-tosyl-3-pyrroline is significantly lower than that of mono-substituted alkenes in Pd catalysed methoxycarbonylation reactions. For example, most bulky diphosphine/ Pd catalysts, including the well-known Pd catalyst derived from 1,2-bis(Di-TertButylPhosphinoXylene (DTBPX), were found to give no product at all in the methoxycarbonylation of N-tosyl-3-pyrroline. The competing pathways in methoxycarbonylation of N-methane-sulfonyl-3-pyrroline using Pd/ DTBPX were studied using DFT calculations; these show that the coordination of the alkene is unfavourable, and once coordinated, isomerisation is a lower energy pathway that ultimately leads to an alternative product. Experimentally a side product resulting from alkene isomerisation and addition of methanol is formed slowly (if CO is present), and rapidly if CO is not. A less bulky derivative of DTBPX forms the required alkene complex with much lower barriers. A study has been made of the enantioselective carbonylation of N-tosyl-3-pyrroline using water, methanol or aniline as nucleophile. This revealed that there is a range of possible products with most of these initiated by a Pd-catalysed isomerisation of the alkene. Using less bulky members of the Pd/Phanephos family of catalysts, it is possible to produce the methoxycarbonylation product from this poorly reactive alkene with reasonably good chemoselectivity and around 80% e.e. at higher pressures of CO. IntroductionPalladium catalysed alkene carbonylation is a very important reaction in industrial synthesis, since it uses very cheap reagents in a very atom efficient manner. [1][2][3][4][5][6] Applications that have been practiced at commercial scale include: polymer synthesis by co-polymerisation, methyl propionate synthesis by ethylene methoxycarbonylation and formation of racemic fine chemicals by hydroxycarbonylation of vinyl arenes (sometimes generated in situ from alcohols).1,2 A stand-out catalyst is the Pd complex formed from 1,2-bis(Di-Tert-ButylPhosphinoXylene (DTBPX from this point forward), which gives very high rates in ethylene methoxycarbonylation, 1b, 1l, 1o and has also been used for some other applications. 5 The potential for enantioselective hydroxycarbonylation and alkoxycarbonylation to be a useful method for large scale asymmetric synthesis has been appreciated for a long time.2-4 However, this is a challenging reaction and despite many important contributions, high enantioselectivity is rare especially for the intermolecular reaction; further research is needed. Catalysts which do give good enantioselectivity, combined with high regioselectivity in the methoxycarbonylation of styrene are Pd catalysts derived from the bulkier members of the Phanephos ligand family (shown in Scheme 1), 3,4 providing impetus to seek to evaluate and increase substrate scope for alkene carbonylation. In the literature, there are very sparse examples, even using achiral catalysts. Most examples of methoxycarbonylation of internal alkenes have led to tandem isomerisation-linear select...

We thank the EC FP6 (Marie Curie EST Fellowship to PDD; Contract: MEST-CT-2005-020744), The University of Edinburgh and Eli Lilly for funding. Supporting information:Experimental procedures for the synthesis of compounds 3, 4c, 4h-m and 6d-g; spectroscopic data for Evans-Tishchenko minor diastereomers and RAAT products 5e-g. This material is available free of charge via the Internet at http://pubs.acs.org Graphical abstract: AbstractThe low temperature Evans-Tishchenko coupling of a range of functionalised heteroaryl aldehydes with -hydroxy ketones in the presence of a Sm(III) catalyst has been achieved with high yields (90-99%) and good to excellent diastereoselectivity (90:10->95:5 dr). However, at room temperature a retro-aldol aldol-Tishchenko reaction was found to compete with the desired Evans-Tishchenko reaction. Identification of these byproducts has allowed the corresponding aldol-Tishchenko reaction to be optimised for several heteroaryl aldehydes.

This chapter seeks to provide the nonspecialist chemist with information regarding the potential scope of the title reactions in asymmetric synthesis. Hydroformylation of alkenes is discussed in detail, and a description of the reactivity and regioselectivity patterns is provided and illustrated with examples that produce chiral intermediates used in the synthesis of drugs and natural products. A short review of the emerging area where Pd‐catalyzed hydroxy‐ or alkoxycarbonylation is used in target synthesis is also provided. Although a few examples of these latter reactions are being actively pursued as methodology in medicinal chemistry laboratories, recent developments in the catalysts available mean that this is anticipated in the near future. The chapter closes with some useful practical information for those wishing to conduct an asymmetric hydroformylation for the first time and three experimental procedures from the authors' laboratories.

Simultaneous Control of Regioselectivity and Enantioselectivity in the Hydroxycarbonylation and Methoxycarbonylation of Vinyl Arenes. -A family of novel mononuclear and dinuclear Pd-complexes of phanephos ligands, allows the highly regioselective formation of the corresponding branched isomers (III) and (VI) in the hydroxycarbonylation and methoxycarbonylation of styrene derivatives (I) and (IV). -(KONRAD, T. M.; DURRANI, J. T.; COBLEY, C. J.; CLARKE*, M. L.; Chem. Commun. (Cambridge) 49 (2013) 32, 3306-3308, http://dx.doi.org/10.1039/c3cc41291a ; Sch. Chem., Univ. St. Andrews, St. Andrews, Fife KY16 9ST, UK; Eng.) -S. Karsten 31-075