Ahmad Masarwa

Selectivity in Metal‐Catalyzed CarbonCarbon Bond Cleavage of Alkylidenecyclopropanes

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.

Selective carbon-carbon bond cleavage for the stereoselective synthesis of acyclic systems.

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-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.

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

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 manner. 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 bonds, instead of the conventional construction of new C–C bonds. Here we present an approach that exploits the multifold reactivity of easily accessible substrates 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 activations. 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.

Cyclopropenylcarbinol Derivatives as New Versatile Intermediates in Organic Synthesis: Application to the Formation of Enantiomerically Pure Alkylidenecyclopropane Derivatives

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.

Synthesis and Stereochemical Assignment of Crypto-Optically Active (2) H6 -Neopentane.

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 (2) H6 -1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to (2) H6 -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.

Quinazoline-based tricyclic compounds that regulate programmed cell death, induce neuronal differentiation, and are curative in animal models for excitotoxicity and hereditary brain disease

Expanding on a quinazoline scaffold, we developed tricyclic compounds with biological activity. These compounds bind to the 18 kDa translocator protein (TSPO) and protect U118MG (glioblastoma cell line of glial origin) cells from glutamate-induced cell death. Fascinating, they can induce neuronal differentiation of PC12 cells (cell line of pheochromocytoma origin with neuronal characteristics) known to display neuronal characteristics, including outgrowth of neurites, tubulin expression, and NeuN (antigen known as ‘neuronal nuclei’, also known as Rbfox3) expression. As part of the neurodifferentiation process, they can amplify cell death induced by glutamate. Interestingly, the compound 2-phenylquinazolin-4-yl dimethylcarbamate (MGV-1) can induce expansive neurite sprouting on its own and also in synergy with nerve growth factor and with glutamate. Glycine is not required, indicating that N-methyl-D-aspartate receptors are not involved in this activity. These diverse effects on cells of glial origin and on cells with neuronal characteristics induced in culture by this one compound, MGV-1, as reported in this article, mimic the diverse events that take place during embryonic development of the brain (maintenance of glial integrity, differentiation of progenitor cells to mature neurons, and weeding out of non-differentiating progenitor cells). Such mechanisms are also important for protective, curative, and restorative processes that occur during and after brain injury and brain disease. Indeed, we found in a rat model of systemic kainic acid injection that MGV-1 can prevent seizures, counteract the process of ongoing brain damage, including edema, and restore behavior defects to normal patterns. Furthermore, in the R6-2 (transgenic mouse model for Huntington disease; Strain name: B6CBA-Tg(HDexon1)62Gpb/3J) transgenic mouse model for Huntington disease, derivatives of MGV-1 can increase lifespan by >20% and reduce incidence of abnormal movements. Also in vitro, these derivatives were more effective than MGV-1.

Zirconocene-Mediated Selective C–C Bond Cleavage of Strained Carbocycles: Scope and Mechanism

Several approaches using organozirconocene species for the remote cleavage of strained three-membered ring carbocycles are described. ω-Ene polysubstituted cyclopropanes, alkylidenecyclopropanes, ω-ene spiro[2.2]pentanes, and ω-ene cyclopropyl methyl ethers were successfully transformed into stereodefined organometallic intermediates, allowing an easy access to highly stereoenriched acyclic scaffolds in good yields and, in most cases, excellent selectivities. DFT calculations and isotopic labeling experiments were performed to delineate the origin of the obtained chemo- and stereoselectivities, demonstrating the importance of microreversibility.