A potential breakthrough in carbocation chemistry is being explored, using tertiary alcohols as substrates to produce tertiary-alkyl amines.  The proposed mechanism stems from experimental research by Ryan A. Shenvi et.al, and aims to alter the stereochemistry of chiral tertiary alcohols, simultaneously making them susceptible to amine conversion by nucleophilic attack (1).  The experiment reveals a potential shortcut in forming molecules containing tertiary alkyl and alklyamine functional groups, which could greatly simplify synthesis of natural products as well as the design of new pharmaceutical biomaterials and practices.


 The reactions were performed using a specific type of nucleophilic substitution called solvolysis, where the nucleophiles are abundant in the actual solvent (1). The solvent used was scandium (III) trifluoromethanesulfonate which converts the substrate alcohols into trifluoroacetate esters (1,6).  The configuration of the triply substituted alcohol is flipped as the alcohol group on the central carbon is converted into an isonitrile (Figure 1 (1)).  Isonitriles can then be readily converted into a variety of nitrogen containing functional groups.

The experiment attempts to mimic the mechanistic synthesis of marine terpenoids from terrestrial terpene units (1).  These terpenes are an abundant class or organic molecule made up of isoprene units, another one of the most common biological building blocks (3).  Isoprene units are activated by Acetyl-CoA as HMG-CoA is reduced to mevalonic acid in the HMG-CoA reductase pathway, forming Isopentenyl pyrophosphates (3).  These units are then synthesized into terpenes depending on the number of isoprene units and serve a variety of cell functions as well as pathway intermediates, depending on the organism.  These biochemical pathways are found in most eukaryotes and bacteria (3).

Similarly, this experiment transforms tertiary alcohols, which are an abundant and easy substrate to come by, into alkylisonitriles and alkylamines (the equivalent of Acetyl-CoA activation of Isoprenes) (1, 2).   The reaction is chemo-selective for tertiary-trifluoroacetyl esters versus primary and secondary alcohols which do not react in the solvolysis. (1)  The activated ester groups are replaced by amine groups using the well-known nucleophilic SN2 substitution.  Figure 2 shows the percentages of targeted enantiomer inversions versus other, some of which reach well above 90% (1).  Many of the numerous potential alkaloid end products could be utilized to have various pharmaceutical effects.  Shenvi et.al have been working with the proposed mechanism as an antimalarial compound. (1)  They plan on using tertiary alcohols to explore similar SN2 reactions for incorporating other atoms such as sulfur and oxygen (1).

Works Cited

1)     Shenvi, Ryan A., Christopher A. Reiher, and Sergey V. Pronin. "Stereoinversion of Tertiary Alcohols to Tertiary-alkyl Isonitriles and Amines." C&EN 91.37 (2013): n.1)    
2)  Smith, Janice G. Organic Chemistry. 3rd ed. New York: McGraw Hill, 2011. Print.
3)     McKee, Trudy, and James R. McKee. Biochemistry - The Molecular Basis of Life. Fifth ed. New York: Oxford, 2012. Print. 
4) Ugi, Ivar, ed. Isonitrile chemistry. Vol. 20. Elsevier, 2012.
5) Evans, T. W., and K. R. Edlund. "TERTIARY ALKYL ETHERS PREPARATION AND, PROPERTIES." Industrial & Engineering Chemistry 28.10 (1936): 1186-1188.

6) Kobayashi, S., Hachiya, I., Araki, M. & Ishitani, H. Scandium trifluoromethanesulfonate  (Sc(OTf)3). A novel reusable catalyst in the Diels–Alder reaction. Tetrahedr.
Written by Nico Clemencon