Addition Of Grignard Reagents Research Articles

Asymmetric Total Synthesis and Assignment of Absolute Configuration of Arbornamine.

The asymmetric total synthesis of arbornamine was accomplished in 13 steps, leading to the assignment of its absolute configuration. The key features of the strategy include construction of the C16 quaternary carbon center by a highly diastereoselective Grignard reagent addition to N-tert-butanesulfinylimine, sequential site-selective amidation and N-alkylation to form the C and E rings, and [Ni(COD)2]-mediated Michael addition to close the D ring.

A One‐Pot Dearomative Approach to C4‐Alkylated Tetrahydropyridines and Tetrahydroquinolines

AbstractA regioselective one‐pot approach to the synthesis of C4‐alkylated tetrahydropyridines (THPs) and tetrahydroquinolines (THQs) by dearomatization of pyridines and quinolines has been developed. The transformation is achieved by the BF3 ⋅ OEt2‐mediated, C4‐selective addition of Grignard reagents, followed by a cascade of enamine protonation and the subsequent Et3SiH reduction of the resulting iminium ions. This protocol not only provides a facile synthetic approach to C4‐substituted THPs and THQs, but also offers a new strategy for the dearomatization of heteroaromatics.

Highly stereoselective synthesis of non-racemic 3-substituted dihydro-benzo[de]isoquinolinones via an addition-cyclization-substitution method

Substituted dihydrobenzo[de]isoquinolinones were synthesized via diastereoselective addition of Grignard reagents to the N-tert-butylsulfinylimine derived from 1,8-naphthaldehydic methyl ester, followed by cyclization and substitution at the sulfur atom. The products were obtained in 25–98% yield and with enantiomeric excess of 46–99%.

Conjugate Addition of Grignard Reagents to Thiochromones Catalyzed by Copper Salts: A Unified Approach to Both 2-Alkylthiochroman-4-One and Thioflavanone.

Grignard reagents undergo conjugate addition to thiochromones catalyzed by copper salts to afford 2-substituted-thiochroman-4-ones, both 2-alkylthiochroman-4-ones and thioflavanones (2-arylthiochroman-4-ones), in good yields with trimethylsilyl chloride (TMSCl) as an additive. The best yields of 1,4-adducts can be attained with CuCN∙2LiCl as the copper source. Excellent yields of 2-alkyl-substituted thiochroman-4-ones and thioflavanones (2-aryl substituted) are attained with a broad range of Grignard reagents. This approach works well with both alkyl and aromatic Grignard reagents, thus providing a unified synthetic approach to privileged 2-substituted thiochroman-4-ones and a potential valuable precursor for further synthetic applications towards many pharmaceutically active molecules. The use of commercially available and/or readily prepared Grignard reagents will expedite the synthesis of a large library of both 2-alkyl substituted thiochroman-4-ones and thioflavanones for additional synthetic applications.

Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning.

The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9- and 1.8-fold, respectively. Rescues of 1.2-1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.

Investigation into an Unexpected Impurity: A Practical Approach to Process Development for the Addition of Grignard Reagents to Aldehydes Using Continuous Flow Synthesis

This work presents a case study of process development using continuous flow synthesis. In developing a process for manufacturing drug substances in batch reactors, we unexpectedly obtained a signi...

Synthesis of 2,2,6-Trisubstituted 5-Methylidene-tetrahydropyran-4-ones with Anticancer Activity.

In our continuous search for new, relatively simple 2-alkylidene-1-oxoheterocycles as promising anticancer drug candidates, herein we report an efficient synthesis of 2,2,6-trisubstituted 5-methylidenetetrahydropyran-4-ones. These compounds were obtained in a four step reaction sequence, in which starting diethyl 2-oxopropylphosphonate was transformed into 2,2-disubstituted 5-diethoxyphosphoryldihydropyran-4-ones, followed by Michael addition of various Grignard reagents and Horner-Wadsworth-Emmons reaction of the obtained adducts with formaldehyde. Stereochemistry of the intermediate Michael adducts is also discussed. Final 5-methylidenetetrahydropyran-4-ones were tested for their possible antiproliferative effect against three cancer cell lines and 6-isopropyl-2,2-dimethyl-5-methylidenetetrahydropyran-4-one (11c), which showed very high cytotoxic activity against HL-60 human leukemia cells and was three times more active than known anticancer drug carboplatin, was selected for further biological evaluation, in order to disclose its mechanism of action. The obtained results indicated that 11c induced apoptosis in HL-60 cells and caused the arrest of the cell cycle in the G2/M phase, which may suggest its cytotoxic and cytostatic activity.

Transition metal-free domino acyl substitution/Michael addition of alkenyl Grignard reagents to lactam esters: synthesis of lactam-bearing homoallylic ketones.

A solvent-controlled protocol for the direct and transition metal-free addition of alkenyl Grignard reagents to vicinally functionalized sp3-rich morpholinones has been developed, leading to the chemo and regioselective synthesis of lactam-bearing homoallylic ketones. The addition of lithium chloride proved to be essential. In cases where a new stereocenter is generated, the doubly branched homoallylic ketones are obtained in unexpectedly high diastereoselectivities. Efforts to extend the methodology to other heterosubstituted lactams revealed some important reactivity and selectivity differences.

CuSCN Catalyzed Conjugate Addition of Grignard Reagents to Substituted Coumarins with Dilithium Tetrachloromanganate

The regioselective 1,4-addition of CuSCN catalyzed Grignard reagents to the substituted coumarins are reported. The Li2MnCl4 reagent is used to transmetallate magnesium by manganese. It adds regioselectively to coumarins and forms 1,4-addition products with higher yield under the atmosphere of nitrogen gas and at a lower temperature

Stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines: highly efficient synthesis of functionalized benzazepine scaffolds

An efficient and highly diastereoselective synthesis of 2-substituted benzo[b]azepin-5-ol via stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines has been developed. The reaction proceeds efficiently starting from versatile skeletons with mild reaction conditions as well as simple operation. Furthermore, 2-substituted benzazepinones could been obtained by simple Dess–Martin oxidation in excellent yields.

Substrate-controlled Diastereoselective Michael Addition of Alkylidene Malonates by Grignard Reagents

AbstractHerein is described a diastereoselective Michael addition of Grignard reagents to α, β- unsaturated diethyl malonates incorporated with a 2-oxazolidone chiral auxiliary. The catalyst-free Michael addition proceeds with good chemical efficiency and excellent stereoselectivity; and it provides new thoughts to the asymmetric synthesis of β-substituted β3 amino acid derivatives.

I-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions.

The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions. This strategy enables the modular synthesis of ketones from CO2 and the preparation of isotopically labeled pharmaceutical building blocks in a single operation.

Stereoselective addition of Grignard reagents to sulfinimines derived from tartrate diol (threitol): Generation of chiral building blocks for the collective total synthesis of lentiginosine, conhydrine and methyldihydropalustramate

A systematic investigation of the addition of Grignard reagents to sulfinimines derived from tartaric acid diol was undertaken. It was observed that the chirality of the inherent tartrate moiety influences the diastereoselectivity of the resultant sulfinamides formed in the reaction. The formed products serve as excellent building blocks for the synthesis of natural products. This has been demonstrated in the collective total synthesis of lentiginosine, (+)-α-conhydrine and methyldihydropalustramate.

Highly Enantioselective Catalytic Addition of Grignard Reagents to N‐Heterocyclic Acceptors

AbstractGeneral methods to prepare chiral N‐heterocyclic molecular scaffolds are greatly sought after because of their significance in medicinal chemistry. Described here is the first general catalytic methodology to access a wide variety of chiral 2‐ and 4‐substituted tetrahydro‐quinolones, dihydro‐4‐pyridones, and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.

Highly Enantioselective Catalytic Addition of Grignard Reagents to N-Heterocyclic Acceptors.

General methods to prepare chiral N‐heterocyclic molecular scaffolds are greatly sought after because of their significance in medicinal chemistry. Described here is the first general catalytic methodology to access a wide variety of chiral 2‐ and 4‐substituted tetrahydro‐quinolones, dihydro‐4‐pyridones, and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.

Catalytic enantioselective conjugate addition en route to paxilline indoloterpenoids

Development of enantioselective synthesis of precursor en route to paxilline indoloterpenoids is described. Evaluation of 25 diphosphine-based ligands has led to identification of JosiPhos derivative that allows for asymmetric conjugate addition of homoprenyl Grignard reagent to 2-methylcyclopent-2-en-1-one in excellent yield and with appreciable levels of enantioinduction. Application to the conjugate addition of other Grignard reagents is demonstrated.

Synthesis and Biological Evaluation of 3-cyano-4H-chromene Derivatives Bearing Carbamate Functionality.

2-Aminochromene derivatives display important pharmacological properties, including mainly antibiotic and anticancer activities. The study aims to synthesize new chromene derivatives via a new approach using Grignard reagents, for the evaluation of their antibiotic and antifungal properties. A series of novel 3-cyano-4-aminochromene derivatives bearing alkyl substituents at the 4-position was prepared for biological evaluation. These compounds were obtained by the addition of various Grignard reagents into Nethoxycarbonyl- 3-cyanoiminocoumarines in moderate to good yields (72-96%). The reaction is completely regioselective. The new chromene derivatives were screened for their in vitro antimicrobial activities against a panel of six bacterial and three fungal strains using agar dilution method. The antibacterial activity of the chromene derivatives was more pronounced on Gram-positive bacteria than on Gram-negative bacteria with a significant activity observed against Staphylococcus aureus. An interesting antifungal activity against Fusarium sp. and Fusarium oxysporum was also noticed.

Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

An efficient, versatile, enantioselective synthesis of 1,3-disubstituted and 1,3,6-trisubstituted 5-methylidenedihydrouracils applying Horner-Wadsworth Emmons methodology was developed. Starting 1,3-disubstituted 5-diethoxyphosphoryluracils were subjected to reduction of the double bond or addition of various Grignard reagents and obtained Horner-Wadsworth Emmons reagents were used for the olefination of formaldehyde. Enantioselective synthesis of 1,3,6-trisubstituted 5-methylidenedihydrouracils was accomplished by introducing (R,R)- or (S,S)-di(1-phenylethylamino)phosphoryl groups as chiral auxiliary. Additions of Grignard reagents in the presence of these groups were highly and complimentary diastereoselective (de ∼ 80%). Further separation of the diastereomeric mixtures by column chromatography enabled synthesis of (R)- and (S)-1,3,6-trisubstituted-5-methylidenedihydrouracils with ee ≥ 98%. Furthermore, absolute configuration of the adducts and final products was established using single crystal X-ray analysis. Stereochemical course of the addition reactions is also discussed.

Regioselectivity Issues in the Addition of Grignard Reagents to Trifluoromethylated α‐Bromoenones

The regioselectivity of addition of organomagnesium reagents to trifluoromethylated α‐bromoenones is reported. Alkyl and aryl Grignard reagents undergo 1,4‐ and/or 1,2‐addition but, in contrast to non‐fluorinated α‐bromoenones, the former direction is dominant for these fluorinated analogs. The high 1,4‐regioselectivity observed in most cases reflects the influence of the trifluoromethyl group on the direction of nucleophilic attack.

Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease.

Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. We report herein a straightforward synthetic strategy to afford C-2 substituted trihydroxypiperidines with different alkyl chains starting from low cost d-mannose. Stereoselective Grignard reagent addition onto a key nitrone intermediate in the presence or absence of a suitable Lewis acid afforded both epimers of the target compounds, after a final reductive amination-ring closure step. We show that the shift of the alkyl chain from the endocyclic nitrogen to the C-2 position leads to a considerable increase in chaperoning efficacy, affording a new compound (4a) able to induce a remarkable 1.9-fold maximal increase in GCase activity.