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Synthesis of hydroxyphthioceranic acid using a traceless lithiation–borylation–protodeboronation strategy

Nature Chemistry volume 6, pages 810–814 (2014)Cite this article

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Abstract

In planning organic syntheses, disconnections are most often made adjacent to functional groups, which assist in C–C bond formation. For molecules devoid of obvious functional groups this approach presents a problem, and so functionalities must be installed temporarily and then removed. Here we present a traceless strategy for organic synthesis that uses a boronic ester as such a group in a one-pot lithiation–borylation–protodeboronation sequence. To realize this strategy, we developed a methodology for the protodeboronation of alkyl pinacol boronic esters that involves the formation of a boronate complex with a nucleophile followed by oxidation with Mn(OAc)3 in the presence of the hydrogen-atom donor 4-tert-butylcatechol. Iterative lithiation–borylation–protodeboronation allows the coupling of smaller fragments to build-up long alkyl chains. We employed this strategy in the synthesis of hydroxyphthioceranic acid, a key component of the cell-wall lipid of the virulent Mycobacterium tuberculosis, in just 14 steps (longest linear sequence) with full stereocontrol.

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Figure 1: Complex molecules with limited functionality present in nature and the potential traceless strategy for their synthesis.
Figure 2: Brief survey of the scope and mechanism of the protodeboronation reaction.
Figure 3: Complex molecules of interest in this study associated with the cell-wall lipid of MTB.
Figure 4: Synthesis of building blocks 13 and 14 used in the synthesis of hydroxyphthioceranic acid 10.
Figure 5: Total synthesis of hydroxyphthioceranic acid 10.

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Acknowledgements

We thank the Engineering and Physical Science Research Council (EP/I038071/1) and the European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support. R.R. thanks the Marie Curie Fellowship program (EC FP7, No 329578). We thank A. Scott for technical assistance.

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  1. School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK

    Ramesh Rasappan & Varinder K. Aggarwal

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V.K.A. conceived the project and wrote the manuscript with R.R. R.R planned and carried out the experiments. R.R. and V.K.A. discussed the experiments and results.

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Correspondence to Varinder K. Aggarwal.

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Rasappan, R., Aggarwal, V. Synthesis of hydroxyphthioceranic acid using a traceless lithiation–borylation–protodeboronation strategy. Nature Chem 6, 810–814 (2014). https://doi.org/10.1038/nchem.2010

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