Tag Archives: Nature

Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

Sergey Pronin, Christopher Reiher, and Ryan Shenvi
DOI: 10.1038/nature12472


The bimolecular nucleophilic substitution (SN2) reaction is a well understood and widely used chemical transformation that allows a chemist to affect useful functional group interconversions or combine two molecules. A significant advantage of the SN2 reaction over the related (and often competitive) unimolecular nucleophilic substitution (SN1) reaction is that it provides predictable stereoinversion at the electrophilic carbon centre. SN2 processes do, however, suffer from a significant limitation: intolerance of tertiary electrophilic carbon atoms, where steric crowding inhibits the approach of the nucleophilic reacting partner. This drawback limits the stereochemical complexity of possible reaction substrates and the utility of nucleophilic substitution in the synthesis of challenging chiral molecules.

Now, a team of researchers from California led by Ryan Shenvi have developed a process that allows the stereochemical inversion of tertiary alcohols with nitrogen-based nucleophiles. The key reaction in their discover y involves Lewis-acid-catalyzed solvolysisof a tertiary alcohol derivative – trifluoroacetate or perfluoroalkanoate esters — in the presence of excess trimethylsilyl cyanide. Addition of the cyanide nucleophile to the carbocation of a postulated contact ion pair, generated by solvolysis, occurs with high enantioselectivity, giving tertiary isonitrile products in a remarkably simple transformation. The researchers compare this process to proposed biosynthetic pathways of nitrogen-based marine terpenoids, which are known to derive from the addition of inorganic cyanide to highly substituted carbon centres.


As well as extending the scope of traditional SN2 processes, Lewis-acid-catalyzed solvolysis also provides complementary reactivity. Because the reaction is conceptually related to the SN1 reaction in the generation of a reactive carbocation in the contact ion pair, activated primary and secondary alcohols do not undergo solvolysis even over extended reaction times. The utility of the process was further demonstrated by converting the isonitrile products into various useful nitrogen-based compounds, such as amines, formamides and isothiocyanates.

The influence of steric crowding on this SN2-like reaction has not, however, been eliminated; branched tertiary alcohols react with lower stereoselectivity than minimally substituted analogues. Despite this, the reported transformation fills a gap in modern synthetic methodology and may lead to further developments in the synthesis of other stereo-defined tertiary-substituted compounds.

The hexadehydro-Diels–Alder reaction

Thomas Hoye, Beeraiah Baire, Dawen Niu, Patrick Willoughby and Brian Woods
DOI: 10.1038/nature11518

This isn’t the first time a [4+2] alkyne-diyne cycloaddition has been reported, but the reaction is remarkable in that this approach to reactive arynes hasn’t been widely exploited before now. Hoye and coworkers have devised a simple intramolecular hexadehydro-Diels-Alder reaction, which proceeds at relatively low temperature or without a lewis acid. The aryne adducts are trapped with a variety of reactive tethers.

Clearly this chemistry can prepare complex polycyles very quickly form acyclic precursors. I wonder if it will find wide use in synthesis.

Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol

Eric M. Simmons and John F. Hartwig Nature

The selective incorporation of functional groups, particularly hydroxy and amino groups, into small molecules is a major challenge facing the synthetic organic chemist. Typically, methods for incorporating such groups require the interconversion of existing functionality which may require many steps rendering these transformations laborious, costly and time consuming.

Simmons and Hartwig have recently described the method for introducing β-hydroxy groups through a formal iridium catalysed C-H activation method directed by proximal silyl ethers. This strategy exploits the affinity of silicon for transition metals, in this case iridium, to direct the formation of a C-Si bond. The resulting oxasilolane was then transformed, by a Tamao-Fleming oxidation, to the corresponding 1,3-diol. For ease of isolation, the diols were finally acetylated to give the 1,3-diacetates.

The versatility of this methodology is demonstrated by converting both simple and complex alcohols into the 1,3-diol analogues.

DOI: 10.1038/nature10785