Asymmetric Synthesis of (-)-Cannabidiol (CBD), (-)-Δ9-Tetrahydrocannabinol (Δ9-THC) and Their cis Analogs Using an Enantioselective Organocatalyzed Diels-Alder Reaction.

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (-)-trans-CBD and psychoactive (-)-trans-Δ9-THC, as well as their synthetic cis diastereomers. The key step is an enantioselective Diels-Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.

Synthesis of 2-substituted bicyclo[1.1.0]butanes via zincocyclopropanation using bromoform as the carbenoid precursor.

Through a revisited Simmons-Smith type zincocyclopropanation using bromoform as the carbenoid source, the synthesis of 2-, 2,2- and 2,4-substituted bicyclo[1.1.0]butanes is reported. Few antecedents of the derivatives have yet been described. Ultimately, the underexplored scaffolds exhibited a complete discrepency of reactivity.

Rhodium-Catalyzed Intramolecular Cyclopropanation of Trifluoromethyl- and Pentafluorosulfanyl-Substituted Allylic Cyanodiazoacetates.

The synthesis of trifluoromethyl (CF3)- and pentafluorosulfanyl (SF5)-substituted cyclopropane-fused γ-lactones was carried out through Rh2(esp)2-catalyzed intramolecular cyclopropanation in up to 99% yields. Twelve examples of this interesting scaffold are reported, as well as postfunctionalizations that provide access to highly functionalized CF3- and SF5-substituted cyclopropanes. These novel SF5-substituted analogues join the very short list of available pentafluorosulfanyl intermediates.

Organocatalyzed Visible Light-Mediated gem-Borosilylcyclopropanation.

The borosilylcyclopropanation of styrene derivatives using a (diiodo(trimethylsilyl)methyl)boronic ester carbene precursor is reported herein. The key reagent was synthesized in a 4-step sequence using inexpensive and commercially available starting materials. This method enabled the preparation of novel 1,1,2-tri- and 1,1,2,2-tetrasubstituted borosilylcyclopropanes up to excellent yields and diastereoselectivity. The reaction is organocatalyzed by eosin Y in the presence of visible light. A mechanism consistent with the experimental observations was postulated based on density functional theory calculations. The versatility of these entities was highlighted through post-functionalization reactions.

Access to hexahydroazepinone heterocycles via palladium-catalysed C(sp3)-H alkenylation/ring-opening of cyclopropanes.

In this communication, we describe the synthesis of novel hexahydroazepinone derivatives starting from two simple building blocks in presence of a readily available palladium catalyst. The reaction proceeds through a selective C(sp3)-H alkenylation/ring-opening process to obtain the seven-membered ring products in good to excellent yields on a wide variety of substrates under batch, microwave, and continuous flow conditions.

Catalytic Asymmetric Syntheses of Alkylidenecyclopropanes from Allenoates with Donor-Acceptor and Diacceptor Diazo Reagents.

The first diastereo- and enantioselective cyclopropanation reactions of electron-deficient allenes with donor-acceptor and diacceptor diazo reagents are described. The desired enantioenriched alkylidenecyclopropanes (ACPs) were obtained in high yields with high diastereo- and enantioselectivities in the presence of Rh2 ((S)-TCPTAD)4 or Rh2 ((R)-BTPCP)4 catalysts (up to 95 % yield, >95 : 5 d.r. and 99 : 1 e.r.). This methodology gave a direct access to ACPs bearing multiple electron-deficient substituents and allows to further expand the availability of ACPs chemistry. Interestingly, during the examination of the scope of this reaction, the asymmetric intramolecular C-H insertion reaction into tert-butyl group was observed as a side reaction with up to 94 : 6 e.r.

Fluorocyclopropane-Containing Proline Analogue: Synthesis and Conformation of an Item in the Peptide Chemist's Toolbox.

Over the years, numerous modifications to the structure of proline have been made in order to tune its effects on bioactive compounds. Notably, the introduction of a cyclopropane ring or a fluorine atom has produced interesting results. Herein, we describe the synthesis of a proline containing fluorocyclopropane. This modified amino acid was inserted into a tripeptide, whose conformation was studied by nuclear magnetic resonance and density functional theory calculations.

Asymmetric Synthesis of Fluoro, Fluoromethyl, Difluoromethyl, and Trifluoromethylcyclopropanes.

Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH3 bond with fluorine or a fluorinated group (such as CF3 or CF2H) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent. In the past decade, we have sought to develop new routes for the stereoselective synthesis of these building blocks using the most reliable cyclopropanation methods and convenient and readily available starting materials. The challenge that had to be undertaken was how we could use the unique properties of the fluorine atom to improve upon the efficiency of a given process rather than shutting it down. This could be overcome by defining new substrate/reagent reactivity guidelines and carefully selecting whether the fluorinated group was introduced on the electrophilic or nucleophilic partner for a given reaction. In this Account, we describe our contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits. Our initial investigation relied on the development of a Michael-initiated ring closure reaction using the Reformatsky enolate derived from readily available ethyl dibromofluoroacetate and α,ß-unsaturated electrophiles. The reaction proceeded extremely well but with modest to good diastereoselectivities with ester acrylates. Further extension to various fluorinated nucleophiles such as oxazolidinone based and DABCO ylides led to similar selectivities.In order to access enantioenriched fluorocyclopropanes, we then investigated the chiral dioxaborolane mediated zinc carbenoid based approaches using the fluoroiodomethylzinc carbenoid/allylic alcohol combination or the iodomethylzinc carbenoid/fluoroallylic alcohol combination. Quite surprisingly, both approaches were equally successful at providing the corresponding fluorocyclopropanes with excellent diastereo- and enantioselectivities.To broaden the scope of fluorinated cyclopropane building blocks that could be prepared with good enantiocontrol, we then investigated the rhodium-catalyzed cyclopropanation of fluoro-, difluoromethyl-, and trifluoromethyl-substituted alkenes with acceptor-acceptor and donor-acceptor diazo reagents. Depending on the substrate/reagent combination, Hashimoto's Rh2((S)-TCPTTL)4 or Davies' Rh2((S)-BTPCP)4 catalyst proved be the most efficient catalysts providing the cyclopropane derivatives with the highest enantioselectivities.More recently, a collaboration with Fasan's group led to the use of engineered myoglobins to catalyze the reaction of ethyl diazoacetate and difluoromethyl-substituted alkenes. This biocatalyzed process led to high turnover number and high enantioselectivities.Although our work has significantly increased the number of tools in the organic chemist's toolbox, continuous efforts in this area would be beneficial to the development of diastereo- and enantioselective approaches to allow the preparation of any elusive isomers of these valuable chiral building blocks.

Synthesis of Fluoro-, Monofluoromethyl-, Difluoromethyl-, and Trifluoromethyl-Substituted Three-Membered Rings.

This Minireview describes recent advances toward the synthesis of fluoro-, monofluoromethyl-, difluoromethyl-, and trifluoromethyl-substituted three-membered rings such as cyclopropanes, aziridines, epoxides, episulfides, cyclopropenes, and 2 H-azirines. The main synthetic methodologies since 2016 for cyclopropanes and since 2010 for the other three-membered rings are reported.

Catalytic Asymmetric Synthesis of α,α-Difluoromethylated and α-Fluoromethylated Tertiary Alcohols.

The catalytic asymmetric synthesis of α,α-difluoromethylated tertiary alcohols is described, using an asymmetric dihydroxylation reaction. This protocol using either the AD-mix-α or AD-mix-ß allowed an easy access to these valuable fluorinated chiral building blocks, which have been obtained with excellent yields and er. In addition, the reaction was extended to the α-fluoromethylated analogues.

Non-stabilized diazoalkane synthesis via the oxidation of free hydrazones by iodosylbenzene and application in in situ MIRC cyclopropanation.

Electron-rich alkyl diazo compounds are powerful reagents in organic synthesis, but the risks associated with their toxicity and instability often limit their uses. Herein we describe an efficient, easy-to-handle and safe batch protocol for the in situ generation and cyclopropanation of these highly reactive non-stabilized diazoalkanes through the oxidation of free hydrazones using iodosylbenzene. Numerous substituted cyclopropanes have been synthesized using this methodology, including various gem-dimethylcyclopropanes of particular interest in medicinal chemistry.

Utilization of BozPhos as an Effective Ligand in Enantioselective C-H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones.

The bisphosphine monoxide ( R, R)-BozPhos enables enantioselective C-H functionalization of cyclopropanes in a palladium-catalyzed cyclization. The synthesis of a broad spectrum of dihydroisoquinolones and dihydroquinolones in good yields and high enantiomeric excess was achieved through the use of this hemilabile ligand. Furthermore, the isolation of an intermediary palladium(II)-BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and angles through a crystal structure.

Rhodium catalysed enantioselective synthesis of mono-(halo)-methyl-cyclopropanes.

The catalytic asymmetric synthesis of mono-fluoro-, -chloro- and -bromomethyl-1,2-diaryl cyclopropane ester is described. The reaction, using Rh2((S)-BTPCP)4 as a catalyst, allowed the formation of the desired cyclopropanes in good to excellent yields (up to 99%) and excellent diastereoselectivities (up to >20 : 1) and with a high level of enantioselectivities (up to 98% ee). Finally, the synthetic utility of the chiral cyclopropanes was also demonstrated.

Iron-catalyzed synthesis of cyclopropanes by in situ generation and decomposition of electronically diversified diazo compounds.

The modular synthesis of a variety of trans 1,2-disubstituted cyclopropanes in a safe and user-friendly one-pot iron-catalyzed cyclopropanation reaction is described. Easily synthesized N-nosylhydrazones are used as diazo precursors, allowing the in situ generation of electron-rich diazo compounds under mild reaction conditions and their direct participation in the cyclopropanation reaction.

Borocyclopropanation of Styrenes Mediated by UV-light Under Continuous Flow Conditions.

Herein, we report a user-friendly and metal-free UV-A light mediated borocyclopropanation of styrenes using continuous flow technology. A broad range of styrene derivatives can be cyclopropanated in good yields within 1 h residence time to produce highly valuable cyclopropylboronate esters with modest to good diastereoselectivities. The reaction is also applicable to α-substituted styrenes. Mechanistic studies support a photoredox process during which xanthone, a well-known organic photosensitizer, can easily reach a photoexcited state that is available for both an oxidative and a reductive quenching.

General Catalytic Enantioselective Access to Monohalomethyl and Trifluoromethyl Cyclopropanes.

An efficient catalytic enantioselective access to chiral functionalized trifluoromethyl cyclopropanes from two classes of diazo compounds and α-trifluoromethyl styrenes using Rh2 ((S)-BTPCP)4 as a catalyst is described. This method provides an efficient and practical strategy for the synthesis of highly functionalized CF3 -cyclopropanes with excellent diastereoselectivities (up to 20:1) and enantioselectivities (up to 99 % ee). The depicted methodology represents, to date, the most efficient catalytic enantioselective method to access highly decorated chiral CF3 -cyclopropanes. Extension to chiral monohalomethyl cyclopropanes in high ee is also reported.

Safe and Facile Access to Nonstabilized Diazoalkanes Using Continuous Flow Technology.

Despite the high synthetic potential of nonstabilized diazo compounds, their utilization has always been hampered by stability, toxicity, and safety issues. The present method opens up access to the most reactive nonstabilized diazoalkanes. Among diazo compounds, nonstabilized alkyl diazo compounds are the least represented because of their propensity to degrade during preparation. The continuous flow oxidation process of hydrazones on a silver oxide column afforded an output stream of base- and metal-free pure diazo solution in dichloromethane. Starting from innocuous ketones and aldehydes, this methodology allows the production of a broad range of unprecedented diazoalkanes compounds in excellent yields, while highlighting their synthetic potential and the possibility of safe large-scale diazo production.

Engineered, highly reactive substrates of microbial transglutaminase enable protein labeling within various secondary structure elements.

Microbial transglutaminase (MTG) is a practical tool to enzymatically form isopeptide bonds between peptide or protein substrates. This natural approach to crosslinking the side-chains of reactive glutamine and lysine residues is solidly rooted in food and textile processing. More recently, MTG's tolerance for various primary amines in lieu of lysine have revealed its potential for site-specific protein labeling with aminated compounds, including fluorophores. Importantly, MTG can label glutamines at accessible positions in the body of a target protein, setting it apart from most labeling enzymes that react exclusively at protein termini. To expand its applicability as a labeling tool, we engineered the B1 domain of Protein G (GB1) to probe the selectivity and enhance the reactivity of MTG toward its glutamine substrate. We built a GB1 library where each variant contained a single glutamine at positions covering all secondary structure elements. The most reactive and selective variants displayed a >100-fold increase in incorporation of a recently developed aminated benzo[a]imidazo[2,1,5-cd]indolizine-type fluorophore, relative to native GB1. None of the variants were destabilized. Our results demonstrate that MTG can react readily with glutamines in α-helical, ß-sheet, and unstructured loop elements and does not favor one type of secondary structure. Introducing point mutations within MTG's active site further increased reactivity toward the most reactive substrate variant, I6Q-GB1, enhancing MTG's capacity to fluorescently label an engineered, highly reactive glutamine substrate. This work demonstrates that MTG-reactive glutamines can be readily introduced into a protein domain for fluorescent labeling.