Most of the efforts of organic chemists have been directed to the development of creative strategies to build carbon–carbon and carbon–heteroatom bonds in a predictable and efficient manner. In this Review, we show an alternative approach where challenging molecular skeletons could be prepared through selective cleavage of carbon–carbon bonds. We demonstrate that it has the potential to be a general principle in organic synthesis for the regio-, diastereo-, and even enantioselective preparation of adducts despite the fact that CC single bonds are among the least reactive functional groups. The development of such strategies may have an impact on synthesis design and can ultimately lead to new selective and efficient processes for the utilization of simple hydrocarbons.

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of ²H₆-1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to ²H₆-1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

An approach to construct enantiopure complex natural product-like frameworks, including the first reported synthesis of a C17 oxygenated taxoid scaffold, is presented. A palladium-catalyzed C–C activation/cross-coupling is utilized to access these structures in a short sequence from (+)-carvone; the scope of this reaction is explored.

The continued development of transition-metal-mediated C−C bond activation/cleavage methods would provide even more opportunities to implement novel synthetic strategies. We have explored the Rh(I)-catalyzed C−C activation of cyclobutanols resident in hydroxylated derivatives of pinene, which proceed in a complementary manner to the C−C bond cleavage that we have observed with many traditional electrophilic reagents. Mechanistic and computational studies have provided insight into the role of C−H bond activation in the stereochemical outcome of the Rh-catalyzed C−C bond activation process. Using this new approach, functionalized cyclohexenones that form the cores of natural products, including the spiroindicumides and phomactin A, have been accessed.

Merging allylic carbon–hydrogen and selective carbon–carbon bond activation

• Ahmad Masarwa,
• Dorian Didier,
• Tamar Zabrodski,
• Marvin Schinkel,
• Lutz Ackermann
• & Ilan Marek

• Affiliations
• Contributions
• Corresponding author

Nature

505,

199–203

(09 January 2014)

doi:10.1038/nature12761

Received

22 August 2013

Accepted

08 October 2013

Published online

08 December 2013

When more complex system leads to simpler reactivity profile; the ring-opening of strained three-membered rings such as methylene- and alkylidenecyclopropanes generally lead to several products. If one starts with more functionalized carbon skeletons, selective reactions are now observed and rationalization as well as synthetic applications are described in this concept article. This methodology could be used to the preparation of challenging structural motifs possessing quaternary carbon stereocenters in acyclic systems.

The copper-catalyzed carbomagnesiation (or hydrometalation) reaction of chiral cyclopropenylcarbinol derivatives, obtained by means of a kinetic resolution of secondary allylic alcohols, leads to an easy and straightforward preparation of enantiomerically pure alkylidenecyclopropane derivatives. The reaction mechanism is composed of a syn-carbometalation followed by a syn-elimination reaction. To gain further insight into the reaction mechanism of the carbometalation, the diastereoselective formation of cyclopropylcarbinol was also achieved and was found to be very sensitive to the nature of the organometallic species used for the addition reaction. Cyclopropylcarbinol could also be prepared through a diastereoselective reduction of cyclopropenylcarbinol derivatives. Finally, functionalization of enantiomerically enriched cyclopropenylcarbinols into the corresponding acetate or phosphinite derivatives leads, under mild conditions, to various enantiomerically pure heterosubstituted alkylidenecyclopropanes.

Pd(II)- and Pt(II)-catalyzed ring-expansion of enantiomerically pure alkylidenecyclopropane derivatives leads to the formation of cyclobutene species with a complete preservation of the stereogenic center.

Enantiomerically enriched cyclopropene derivatives, the smallest possible unsaturated carbocycles, are of great synthetic interest since they serve as versatile reactive building blocks. Their reactivity results from the relief of the ring strain in the small molecule. They can be transformed into a wide variety of complex chiral structures and a special emphasis will be directed towards the preparation of enantiomerically enriched methylene- and alkylidenecyclopropane derivatives. The ready availability of a wide range of these chiral entities now provides an excellent opportunity to discover new and unique transformations that can further enrich mainstream synthetic methodology.

With just a nudge (in the form of silica gel, an acidic ion-exchange resin, or heating at about 40 °C), the acetate derivatives of enantiomerically enriched cyclopropenyl alcohols undergo sigmatropic rearrangement to give alkylidenecyclopropanes with high ee  values (see scheme). Similarly, the rearrangement of phosphinite derivatives at room temperature leads to phosphine oxide precursors of unusual chiral phosphine ligands. R¹, R²=alkyl, aryl.

The straightforward approach: The copper-catalyzed carbomagnesiation reaction of chiral cyclopropenylcarbinol derivatives, obtained through kinetic resolution of secondary allylic alcohols, leads to the preparation of enantiomerically pure alkylidenecyclopropane derivatives. The reaction mechanism is composed of a syn carbometalation followed by a syn elimination reaction.