Remote Functionalization of Hydrocarbons with Reversibility Enhanced Stereocontrol

Alexandre Vasseur, Technion, Haifa, Israel
Lionel Perrin, Technion, Haifa, Israel
Ilan Marek, Technion, Haifa, Israel

Manipulation of functionality at a specific position of a hydrocarbon that would generate a reaction at a different location represents a major challenge in synthetic organic chemistry. The difficulty of such remote functionalization is even more pronounced for acyclic systems where flexible alkyl chains are present between the initiating and the final reactive centers. In this context, reaction of a metal complex with a functionality that would generate an unidirectional “walking-process” over an alkyl chain of an hydrocarbon producing a chemical reaction at a defined terminus position is a promising approach to functionalize molecules.¹ We have reported the transformation of unsaturated fatty alcohols derivatives as a source of substituted allylmetal species² and the stereoselective preparation of conjugated dienyl metal complexes from non-conjugated enol ethers.³ Such reactions could be triggered by initiating allylic C-H bond activations from the terminal double bond followed by an elimination reaction to generate the terminus remote functionalization. To further extend our approach, we became interested to investigate the case of ω-ene cyclopropanes. Its remote functionalization could be achieved through successive zirconocene-mediated allylic C-H bond activations followed by a selective C-C bond cleavage⁴ (Scheme 1). Importantly, in this study, the reaction proceeds through a very high 1,4-stereocontrol and turns out to be an efficient way for the diasteroselective synthesis of acyclic fragments possessing an all-carbon quaternary stereogenic center. Determination of the reaction mechanism by density functional theory calculations shows that the high diastereoselectivty observed in this process results from a large number of energetically accessible equilibria feeding a preferred reactive channel that leads to the major product. A paradoxal consequence of this pattern is that stereoselectivity is enhanced upon heating.

1.  C. R. Larsen, G. Erdogan, D. B. Grotjahn, J. Am. Chem. Soc. 2014, 136, 1226; (b) T. O. Northcutt, D. D. Wick, A. J. Vetter, W. D. Jones, J. Am. Chem. Soc. 2001, 123, 7257; (c) R. A. Periana, R. G. Bergman, J. Am. Chem. Soc. 1986, 108, 7332
2. I. Marek, N. Chinkov, A. Levin, Synlett, 2006, 4, 501.
3. N. Chinkov, S. Majumdar, I. Marek, J. Am. Chem. Soc. 2003, 125, 13258.
4. A. Masarwa, D. Didier, T. Zabrodski, M. Schinkel, L. Ackermann, I. Marek, Nature, 2014, 505, 199.