Organophosphonium salts containing C(sp³)–⁺P bonds are among the most utilized reagents in organic synthesis for constructing C–C double bonds. However, their use as C-selective electrophilic groups is rare. Here, we explore an efficient and general transition-metal-free method for sequential chemo- and regioselective C–H and C(sp³)–⁺P bond functionalizations. In the present study, C–H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component, cross-coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp³)–⁺PPh₃ groups to achieve aminations, thiolations, and arylations. In this way, Anchorbenzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs which feature in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anti-cancer agents from simple materials in only two to three steps. Additionally, a protocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research.

Although gem-diborylalkenes are known to be among the most valuable reagents in modern organic synthesis, providing a rapid access to a wide array of transformations, including the construction of C−C and C‐heteroatom bonds, their use as dienophile-reactive groups has been rare. Herein we report the Diels-Alder (DA) reaction of (unsymmetrical) gem-diborylalkenes. These reactions provide a general and efficient method for the stereoselective conversion of gem-diborylalkenes to rapidly access 1,1-bisborylcyclohexenes. Using the same DA reaction manifold with borylated-dienes and gem-diborylalkenes, we also developed a concise, highly regioselective synthesis of 1,1,2-tris- and 1,1,3,4-tetrakis(boronates)cyclohexenes, a family of compounds that currently lack efficient synthetic access. Furthermore, DFT calculations provided insight into the underlying factors that control the chemo-, regio, and stereoselectivity of these DA reactions. This method also provides stereodivergent syntheses of gem-diboryl-norbornenes. The utility of the gem-diboryl-norbornene building blocks was demonstrated by ring-opening metathesis polymerization (ROMP), providing a highly modular approach to the first synthesis of the gem-diboron-based polymers. Additionally, these polymers have been successfully submitted to post-polymerization modification reactions. Given its simplicity and versatility, we believe that this novel DA and ROMP approach holds great promise for organoboron synthesis as well as organoboron-based polymers and that it will result in more novel transformations in both academic and industrial research.

Unsymmetrical 1,1-bis(boryl)alkanes and alkenes are organo-bismetallic equivalents, which are synthetically important because they allow for sequential selective transformations of C–B bonds. We reviewed the synthesis and chemical reactivity of 1,1-bis(boryl)alkanes and alkenes to provide information for the synthetic community. In the first part of this review, we disclose the synthesis and chemical reactivity of unsymmetrical 1,1-bisborylalkanes. In the second part, we describe the synthesis and chemical reactivity of unsymmetrical 1,1-bis(boryl)alkenes.

The use of gem-diborylalkenes as light-reactive groups is explored for the first time. These reactions provide an efficient and general method for the photochemical conversion of gem-diborylalkenes to rapidly access 1,1-bisborylalkanes. This method exploits a novel photoredox decarboxylative radical addition to gem-diborylalkenes to afford α-gemdiboryl carbon-centered radicals, which benefit from additional stability by virtue of an interaction with the empty p-orbitals on borons. The reaction offers a highly modular and regioselective approach to γ-amino gem-diborylalkanes. Furthermore, EPR spectroscopy and DFT calculations have provided insight into the radical mechanism underlying the photochemistry reaction.

Organoborons are extremely important for synthetic organic chemistry; they can serve as advanced intermediates for a variety of transformations. Such a well-known transformation involves the loss of the boron moiety, creating alkyl radicals. Although these originally developed protocols for alkyl radical generation remain in active use today, in recent years their α-boryl carbon-centred radicles have been joined by a new array of radical generation strategies that offer a unique reactivity to forge a wider diversity of organoborones that often operate under mild and benign conditions. Herein, we will highlight the stability and reactivity of α-borylalkyl radicals and their remarkably recent advances in order to further utilise them for C–C and C–heteroatom bond formation. Their use for this purpose has been reported over the last decade in an attempt to guide the synthetic community. Various transition-metal and metal-free methods for their generation are presented, and more advanced photoredox approaches are discussed, mainly for the period of time 2009-2019.

In the past four decades, the chemistry of 1,1‐ and 1,2‐bisboronate compounds has been extensively explored. Many interesting structural features and reaction patterns have emerged, and more importantly, these compounds now feature prominently in both metal‐catalyzed and metal‐free transformations for the formation of CC bonds and C–heteroatom and other processes. This chapter aims to highlight the recent development in this rising research field, focusing on the synthesis of 1,1‐ and 1,2‐bisboronate compounds and their reactivity and selectivity that originate from the use of these bisboronates.

An efficient and general method for the chemoselective synthesis of unsymmetrical gem-diborylalkanes is reported. This method is based on a novel late-stage desymmetrization via nucleophilic “trifluorination”, providing chiral gem-diborylalkanes bearing a trifluoroborate group. The reaction offers a highly modular and diastereoselective approach to synthesize gem-diborylcyclopropanes. The utility of the gem-diborylalkane building blocks was demonstrated by selective post-functionalization of the trifluoroborate group. These functionalizations include inter- and intra- Pd-catalyzed Suzuki−Miyaura coupling reactions.

Recently, gem-diborylalkanes have attracted much attention as versatile building blocks and fundamental intermediates in organic synthesis, because they enable multiple C–C bond construction and further transformation at C–B bonds. Importantly, gem-diborylalkanes can be utilised as bisnucleophilic partners in a variety of chemo-selective C–C bond-forming reactions. This review describes recent developments in synthesising gem-diborylalkanes in complex molecules along with their chemical transformation. In the first part of the review the different synthetic approaches used to synthesise gem-diborylalkanes are described. In the second part, an overview of the chemoselective transformation of gem-diborylalkanes into various functionalized materials is discussed along with one-carbon homologation of diborylmethane via a selective uni- and bidirectional method.

Several approaches using organozirconocene species for the remote cleavage of strained three-membered ring carbocycles are described. -Ene polysubstituted cyclopropanes, alkylidenecyclopropanes, -ene spiro[2.2]pentanes and -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.

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.

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