Publications

2015
Selective Carbon-Carbon Bond Cleavage for the Stereoselective Synthesis of Acyclic Systems
Marek*, I. ; Masarwa, A. ; Delaye, P. - O. ; Leibeling, M. Selective Carbon-Carbon Bond Cleavage for the Stereoselective Synthesis of Acyclic Systems. Angew. Chem. Int. Ed. 2015, 54, 414-429. Publisher's VersionAbstract

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 C[BOND]C 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.

Synthesis and Stereochemical Assignment of Crypto-Optically Active 2H6-Neopentane
Masarwa, A. ; Gerbig, D. ; Oskar, L. ; Loewenstein, A. ; Reisenauer, H. P. ; Lesot*, P. ; Schreiner*, P. R. ; Marek*, I. Synthesis and Stereochemical Assignment of Crypto-Optically Active 2H6-Neopentane. Angew. Chem. Int. Ed. 2015, 54, 13106–13109. Publisher's VersionAbstract

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.

Construction of Enantiopure Taxoid and Natural Products-Like Scaffolds Using a C-C Bond Cleavage/Arylation Reaction
Weber, M. ; Owens, K. ; Masarwa*, A. ; Sarpong*, R. Construction of Enantiopure Taxoid and Natural Products-Like Scaffolds Using a C-C Bond Cleavage/Arylation Reaction. Org. Lett. 2015, 17, 5432–5435. Publisher's VersionAbstract

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.

Selective C-C and C-H bond Activation/Cleavage of Pinene Derivatives: Synthesis Of Enantiopure Cyclohexanone Scaffolds and Mechanistic insights
Masarwa, A. ; Weber, M. ; Sarpong*, R. Selective C-C and C-H bond Activation/Cleavage of Pinene Derivatives: Synthesis Of Enantiopure Cyclohexanone Scaffolds and Mechanistic insights. J. Am. Chem. Soc. 2015, 137, 6327-6334. Publisher's VersionAbstract

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.

2014
Merging Allylic Carbon-Hydrogen and Selective Carbon-Carbon bond Activation
Masarwa, A. ; Didier, D. ; Zabrodski, T. ; Schinkel, M. ; Ackermann, L. ; Marek*, I. Merging Allylic Carbon-Hydrogen and Selective Carbon-Carbon bond Activation. Nature 2014, 505, 199–203. Publisher's VersionAbstract

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

Nature
505,
199–203
(09 January 2014)
doi:10.1038/nature12761
Received
22 August 2013
Accepted
08 October 2013
Published online
08 December 2013

Since the nineteenth century, many synthetic organic chemists have focused on developing new strategies to regio-, diastereo- and enantioselectively build carbon–carbon and carbon–heteroatom bonds in a predictable and efficient manner1, 2, 3. Ideal syntheses should use the least number of synthetic steps, with few or no functional group transformations and by-products, and maximum atom efficiency. One potentially attractive method for the synthesis of molecular skeletons that are difficult to prepare would be through the selective activation of C–H and C–C bonds4, 5, 6, 7, 8, instead of the conventional construction of new C–C bonds. Here we present an approach that exploits the multifold reactivity of easily accessible substrates9 with a single organometallic species to furnish complex molecular scaffolds through the merging of otherwise difficult transformations: allylic C–H and selective C–C bond activations10, 11, 12. The resulting bifunctional nucleophilic species, all of which have an all-carbon quaternary stereogenic centre, can then be selectively derivatized by the addition of two different electrophiles to obtain more complex molecular architecture from these easily available starting materials.

2010
selective in Metal-Catalyzed Carbon-Carbon Bond Cleavage of Alkylidenecyclopropanes
Masarwa, A. ; Marek*, I. selective in Metal-Catalyzed Carbon-Carbon Bond Cleavage of Alkylidenecyclopropanes. Chem. Eur. J. 2010, 16, 9712–9721. Publisher's VersionAbstract

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.

2009
Cyclopropenylcarbinol Derivatives as New Versatile In Organic Synthesis: Application to the Formation of Enantiomerically Pure Alkylidenecyclopropane Derivatives
Simaan, S. ; Masarwa, A. ; Zohar, E. ; Stanger, A. ; Bertus, P. ; Marek*, I. Cyclopropenylcarbinol Derivatives as New Versatile In Organic Synthesis: Application to the Formation of Enantiomerically Pure Alkylidenecyclopropane Derivatives. Chem. Eur. J. 2009, 15, 8449–8464. Publisher's VersionAbstract

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.

Metal-Catalyzed Rearrangement of enantiomerically Pure Alkylidenecyclopropane Derivatives as a New access to Cyclobutenes Possessing Quaternary stereocenters
Masarwa, A. ; Fürstnerb, A. ; Marek*, I. Metal-Catalyzed Rearrangement of enantiomerically Pure Alkylidenecyclopropane Derivatives as a New access to Cyclobutenes Possessing Quaternary stereocenters. Chem. Commun. 2009, 5760-5762. Publisher's VersionAbstract

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.

2008
Enantiomerically Enriched Cyclopropene Derivatives: Versatile Building Blocks in Asymmetric Synthesis
Marek*, I. ; Simaan, S. ; Masarwa, A. Enantiomerically Enriched Cyclopropene Derivatives: Versatile Building Blocks in Asymmetric Synthesis. Angew. Chem. Int. Ed. 2008, 46, 7364–7376. Publisher's VersionAbstract

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.

2007
An Efficient , Facial, and General Stereoselective Synthesis of Heterosubstituted Alkylidenecyclopropanes
Masarwa, A. ; Stanger, A. ; Marek*, I. An Efficient , Facial, and General Stereoselective Synthesis of Heterosubstituted Alkylidenecyclopropanes. Angew. Chem., Int. Ed. 2007, 46, 8039-8042. Publisher's VersionAbstract

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.

2006
Enantiomercally Pure Cyclopropeneylecarbenols as a Source of Chiral Alkylidenecyclopropane Derivatives
Simaan, S. ; Masarwa, A. ; Bertus, P. ; Marek*, I. Enantiomercally Pure Cyclopropeneylecarbenols as a Source of Chiral Alkylidenecyclopropane Derivatives. Angew. Chem., Int. Ed. 2006, 45, 3963-3965. Publisher's VersionAbstract

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.

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