New Magnesium-based Enantioselective Deprotonation Methods; Greener General Base Strategies and the Development of a Catalytic Protocol x ref 040625

Project: Research

Project Details

Key findings

The requirement to access molecules in single mirror-image forms (for use in medicines, agrochemicals, materials, and fine chemicals) has placed enantioselective synthesis at the forefront of international activity in organic chemistry. At the outset of this programme, preliminary studies at Strathclyde had led to the formation of new magnesium bisamide reagents that had delivered appreciable selectivities in selected asymmetric processes. In this funded study, more efficient Mg-based reagents were devised, prepared, and used in enantioselective synthesis. More specifically, a series of Mg-amide bases that incorporate metal chelating side-arms were accessed, and which showed further enhanced levels of enantioselectivity in the deprotonation of a series of substituted cyclohexanones (in up to 94:6 enantiomeric ratio (e.r.)). A range of new aryloxy- and alkoxymagnesium amide base systems were also accessed, which showed moderate to good selectivity in benchmark asymmetric processes. More notably, an array of C2- and psuedo-C2-symmetric Mg-amine based systems were also explored, with excellent selectivities being observed (up to 95:5 e.r.), and at levels which are significantly higher than alternative simple chiral (lithium) amide bases. These new Mg base systems can be also employed at more elevated temperatures (e.g. -20˚C to 0˚C) with only minimal drop-off in e.r.; the same is also the case with the new chelating chiral bases prepared as part of this programme. This latter observation, has significant positive implications for the more widespread and energy-efficient use of such emerging Mg-amide bases; such higher temperature processes are not feasible with the equivalent Li-based systems.



Alkylmagnesium amide bases have now also been shown to deliver efficiencies and enantioselectivities comparable with those of the Mg-bisamides but with only half the quantity of chiral amine. This further improves the cost-effectiveness of the new Mg-amide base systems. Formulation of sought after catalytic asymmetric deprotonation reaction processes were also targeted. In this regard, a recycling system has started to emerge, with sub-stoichiometric quantities of chiral amine (up to 43% yield and 83:17 e.r.).



During the catalytic asymmetric studies, when employing hindered dialkyl- or diaryl-Mg reagents, it has been shown that desired deprotonations can be performed by a non-nucleophilic carbon-centred base (i.e. without any amine). Moreover, these processes proceed effectively without any significant reaction cooling and using only 0.5 mol. of the organometallic reagent, to offer appreciable advantages to the preparative chemistry community. This exciting departure is now the subject of both on-going studies within our laboratory and future grant applications.



It should be noted that an additional series of publications has yet to emerge from this project overall, with an estimated further seven papers forthcoming. Overall, a spectrum of new and efficient methods for employment in organic synthesis has emerged from this funded programme. As such, this work will be of considerable value to beneficiaries in academia, the pharmaceutical, agrochemical, materials, and fine chemicals industries, and, in turn, the UK economy and quality of life.
StatusFinished
Effective start/end date1/09/0531/01/09

Funding

  • EPSRC (Engineering and Physical Sciences Research Council): £205,288.00

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  • Research Output

    New potentially chelating chiral magnesium amide bases for use in enantioselective deprotonation reactions

    Kerr, W., Middleditch, M. & Watson, A., 2011, In : Synlett. 2, p. 177-180 3 p.

    Research output: Contribution to journalArticle

  • 8 Citations (Scopus)

    Towards energetically viable asymmetric deprotonations: selectivity at more elevated temperatures with C2-symmetric magnesium bisamides

    Bennie, L. S., Kerr, W., Middleditch, M. & Watson, A., 2011, In : Chemical Communications (London). 47, 8, p. 2264-2266 3 p.

    Research output: Contribution to journalArticle

    Open Access
    File
  • 11 Citations (Scopus)
    131 Downloads (Pure)

    Di-tert-butylmagnesium as an atom-efficient, carbon-centred base reagent for the preparation of silyl enol ethers from ketones

    Kerr, W. J., Watson, A. J. B. & Hayes, D., 23 May 2008, In : Synlett. 2008, 9, p. 1386-1390 5 p.

    Research output: Contribution to journalArticle

  • 5 Citations (Scopus)