Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

Tertiary alcohols are displaced with a nitrogen nucleophile with stereoinversion and with high selectivity over less substituted alcohols, providing complementarity to the S.sub.N2 reaction and efficient access to nitrogenous marine terpenoids. Tertiary alcohols as targets for stereoinversion This paper describes a new method for the stereoselective displacement of tertiary alcohols with a nitrogen nucleophile. The procedure leads to inversion of stereochemistry and enables short, stereo- and chemoselective syntheses of naturally occurring terpenoid isonitriles and amines. Displacement does not occur with secondary and primary substrates, representing a reversal of substitution demand compared to the S.sub.N2 reaction (bimolecular nucleophilic substitution), a well-known chemical transformation commonly used to join two smaller molecules together into a larger molecule or to exchange one functional group for another. The authors suggest that this new approach could lead to the development of other stereoinversion reactions of tertiary alcohols and stimulate further progress in carbocation chemistry. The S.sub.N2 reaction (bimolecular nucleophilic substitution) is a well-known chemical transformation that can be used to join two smaller molecules together into a larger molecule or to exchange one functional group for another. The S.sub.N2 reaction proceeds in a very predictable manner: substitution occurs with inversion of stereochemistry, resulting from the 'backside attack' of the electrophilic carbon by the nucleophile. A significant limitation of the S.sub.N2 reaction is its intolerance for tertiary carbon atoms: whereas primary and secondary alcohols are viable precursor substrates, tertiary alcohols and their derivatives usually either fail to react or produce stereochemical mixtures of products.sup.1,2,3. Here we report the stereochemical inversion of chiral tertiary alcohols with a nitrogenous nucleophile facilitated by a Lewis-acid-catalysed solvolysis. The method is chemoselective against secondary and primary alcohols, thereby complementing the selectivity of the S.sub.N2 reaction. Furthermore, this method for carbon-nitrogen bond formation mimics a putative biosynthetic step in the synthesis of marine terpenoids.sup.4 and enables their preparation from the corresponding terrestrial terpenes. We expect that the general attributes of the methodology will allow chiral tertiary alcohols to be considered viable substrates for stereoinversion reactions.
Author(s): Sergey V. Pronin [sup.1] , Christopher A. Reiher [sup.1] , Ryan A. Shenvi [sup.1] Author Affiliations: (1) Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, [...]