Oxocarbenium Ions in Organic Synthesis

Graph 1Mechanistic Studies: Some time ago, we became interested in the mechanism of the addition of soft carbon nucleophiles to the chiral acetal reagents developed by W. S. Johnson. These reactions can proceed either by a dissociative mechanism wherein the Lewis acid first opens the acetal to an oxocarbenium ion, or by a direct displacement mechanism wherein C-C bond formation is concerted with acetal opening. We and others probed these two limiting mechanisms using models, however there was significant mechanistic divergence depending on the structure of the acetal and as such no conclusions could be drawn about the W. S. Johnson system. We then devised an experiment using a deuterated acetal wherein the deuterium labels the proximal oxygen, and allows us to determine which C-O bond was cleaved en-route to the product. If we observe product specificity in the C-O bond cleavage, such that one isomer of the product is derived from one bond cleavage and the isomer from the other C-O bond cleavage, then we can conclude that the reaction does not proceed by an equilibrating oxocarbenium ion mechanism. However, if we see scrambling of the C-O bond cleavage, then we can conclude that the reaction does not proceed via a direct displacement. Our results showed scrambling of the deuterium label under a variety of conditions, and are not consistent with a direct displacement mechanism. We also studied the mechanism additions to achiral acyclic acetals by a related method and were able to rule out an SN2 mechanism in those substrates as well.


Sammakia, T.; Smith, R. S. "Evidence for an Oxocarbenium Ion Intermediate in Lewis Acid Mediated Reactions of Acyclic Acetals" J. Am. Chem. Soc.1994116, 7915 –7916. 

Sammakia, T.; Smith, R. S. "Direct Evidence for an Oxocarbenium Ion Intermediate in the Asymmetric Cleavage of Chiral Acetals" J. Am. Chem. Soc.1992114, 10998 – 10998.

Sammakia, T.; Smith, R. S. "On the Mechanism of the Lewis Acid Mediated Cleavage of Chiral Acetals" J. Org. Chem. 199257, 2997 – 3000. 

Graph of method developmentMethods Development: The results described above suggest that chiral oxocarbenium ions can undergo addition reactions with very high levels of stereoselectivity, and prompted us to study the Diels-Alder reactions of chiral vinyl oxocarbenium ions. In two methods studies, we generated the chiral oxocarbenium ions by cleavage of a cyclic chiral acetal to an acyclic chiral acetal (in a similar fashion to the W.S. Johnson method) and by cleavage of an acyclic acetal to an oxocarbenium ion that then is attacked by a ketone to form a new cyclic oxocarbenium ion. Under the optimal conditions and substrates, both methods provide very high levels of asymmetric induction. We then studied the reduction of cyclic oxocarbenium ions to protected 1,3-diols, and again found that with the appropriate oxocarbenium ion precursor and reducing agent, very levels of anti- selectivity can be observed.


Cullen, A. J.; Sammakia, T. "Highly Selective Reduction of Acyclic β-Alkoxy Ketones to Protected syn-1,3-Diols”Org. Lett. 20046,3143 – 3145.

Sammakia, T.; Berliner, M. A. "Asymmetric Diels-Alder Reactions via Cyclic Vinyl-Oxocarbenium IonsJ. Org. Chem. 199560, 6652 – 6653. 

 Sammakia, T.; Berliner, M. A. "Asymmetric Diels-Alder Reactions with α,β-Unsaturated Acetals" J. Org. Chem.199459, 6890 – 6891.

Application to total synthesis graphApplication to Total Synthesis: The utility of a new method can be illustrated by its application to the total synthesis of a natural product or otherwise important molecule, and we have applied a variation of our Diels-Alder method to the synthesis of the anti cholesterolemic (+)-dihydrocompactin. This synthesis addresses the issue of remote stereocontrol in this molecule by proceeding via an oxocarbenium ion intermediate as shown below. This reactive intermediate not only activates the alkene for Diels-Alder reaction, but it also bring the remote regions of the molecule in close proximity, and allows the stereocenter in the oxepine to dictate the stereochemical outcome in the ring formation. Surprisingly, the reaction proceeds in a contra-steric fashion wherein the diene approached the dienophile from the same face as substituent. A recent paper by Ken Houk provides an explanation for this outcome relying on his concept of “torsional steering”. 


Sammakia, T.; Johns, D. M.; Kim, G.; Berliner, M. A. "Remote Asymmetric Induction in an Intramolecular Ionic Diels−Alder Reaction: Application to the Total Synthesis of (+)-Dihydrocompactin" J. Am. Chem. Soc.2005127, 6504 – 6505.

Methods and Strategies for the Total Synthesis of the Oxo Polyene Macrolide Antibiotics

Selective Catalysis

Complex Natural Product Synthesis