Reformatsky Reaction Research Articles

Synthesis of β‐Keto Lactone with Basic Skeleton of Przewalskin B

The synthesis of β‐keto lactone was completed using cyclohexanone as starting material. The α,β‐unsaturated lactone was obtained through Reformatsky reaction and iodolactonization. The aforementioned lactone was converted into target compound 1 (β‐keto lactone) by Nef oxidation and Claisen condensation in six steps with 17.9% overall yield.

Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity

Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co-transfected with full length human LXRβ expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3β,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the case of the difluoroalcohol, the fluorine atoms actively participated in the interaction with several residues in the ligand binding pocket leading to a stabilization of the active receptor conformation.

Variations on the Blaise Reaction: Synthesis of 3,5-Dioxopentanoates and 3-Amino-5-oxopent-3-enoates

We have achieved a facile and convenient synthesis of a variety of 3,5-dioxopentanoates (3,5-diketo esters) and 3-amino-5-oxopent-3-enoates by a zinc-mediated condensation of readily available 3-oxopropanenitriles (α-cyano ketones) with ethyl bromoacetate. The reaction is a variation on the classical Blaise reaction, tuned to the synthesis of trifunctional compounds having 3,5-diketo ester or 3-enamino 5-keto ester functional groups. Our studies revealed that the Blaise reaction on the nitrile occurs in preference to the Reformatsky reaction on the neighboring ketone when the two functional groups are in a <i>geminal</i> relationship, as found in α-cyano ketones, possibly due to zinc complexation leading to increased electrophilicity of the nitrile.

Multicomponent Strategy for the Synthesis of Prostaglandin E2 Methyl Ester under Anion Relay Chelation Control.

Starting with four components, the enantioselective synthesis of prostaglandin E2 methyl ester has been achieved through a highly stereoselective heteroatom-directed conjugate addition reaction and cyclopentanone ring cyclization as the key steps. This asymmetric strategy includes (i) an asymmetric Reformatsky reaction; (ii) conjugate addition of a chiral vinyllithium reagent; (iii) cyclization to form a sulfonylated cyclopentanone in one-pot; followed by (iv) allylation of the side chain. Four carbon-carbon bond-forming processes and three stereogenic centers were established, with the steps from (ii) to (iii) being achieved in a one-pot process.

Regioselective synthesis of functionalized dihydroisoquinolines from o-alkynylarylaldimines via the Reformatsky reaction.

A novel approach for the synthesis of functionalized 1,2-dihydroisoquinolines from o-alkynylarylaldimines via the Reformatsky reaction without the aid of an external Lewis acid has been described. The chemistry involves the dual role of the Reformatsky reagent which has been generated in situ in the reaction. We propose that one molecule of the Reformatsky reagent is being utilised for the activation of alkynes, whereas the second molecule acts as a nucleophile on the iminium carbon. This synthetic pathway has high functional group tolerance, and can be utilized on a gram scale. The proposed mechanistic pathway is well supported by the control experiments. The 1,2-dihydroisoquinoline derivatives showed up to 90% inhibition of the strand transfer activity of the HIV integrase enzyme.

Chemical methods for the conversion of Prednisolone to 11-β-hydroxy-1,4-androstadiene-3,17-dione

Several microbial transformations of steroids to 17-keto cortisones through side chain cleavage have been presented in the literature; however, yields and product selectivity in these methods were low. In the present study, some new methods have been identified for the side chain cleavage of prednisolone (1) to form 11- β-hydroxy-1,4-androstadiene-3,17-dione (11- β-hydroxy ADD). Prednisolone upon reaction with zinc chloride in dry THF results in the formation of cleavage product in good yield (76%). 11- β-hydroxy ADD (2) has been formed in moderate yield (60%) under the Reformatsky reaction conditions by reacting with zincate. While performing the Wittig reaction using stable ylides, again results in the formation of compound 2 in good yield (56%). Side chain cleavage of prednisolone was confirmed from the physical and analytical data and similar when compared with the literature reports. A few chemical methods were investigated for the side chain cleavage of prednisolone in order to obtain 11-β-hydroxy-1,4-androstadiene-3,17-dione. Among these methods, ZnCl2 mediated transformation gives the best results with 76% yield.

ChemInform Abstract: Metal‐Mediated Reformatsky Reaction of Bromodifluoromethyl Ketone and Imine.

AbstractThe Reformatsky reaction of bromodifluoromethyl ketones and imines took place readily in the presence of Zn/CuBr at room temperature to afford β‐amino α,α‐difluoro ketones in good yields.

Concise synthesis of the core structures of saundersiosides.

A divergent synthesis of three core pentacyclic lactones of nine rearranged cholestane sapogenins, saundersiosides A-H (1-8) and candicanoside A (9), is reported. Key features include a one-flask CBS reduction/Brown hydroboration-oxidation, a SmI2-mediated intramolecular Reformatskii reaction, and an intramolecular transesterification. This synthesis provides a general strategy and key precursors for the collective synthesis of natural and designed saundersiosides. An efficient formal synthesis of candicanoside A is also achieved.

Highly Stereoselective Carbon–Carbon Bond-forming Reactions on Cyclopropane Rings Using 1-(Methoxycarbonyl)cyclopropylzinc Bromides

Abstract Highly stereoselective Reformatsky reaction and Pd-catalyzed arylation using 1-(alkoxycarbonyl)cyclopropylzinc bromide proceeded to give the trans-adduct as the major product in good to high yields with good to excellent stereoselectivities.

Metal‐Mediated Reformatsky Reaction of Bromodifluoromethyl Ketone and Imine

AbstractThe Reformatsky reaction of bromodifluoromethyl ketones and imines took place readily in the presence of Zn/CuCl at room temperature to afford β‐amino α,α‐difluoro ketones in good yields. Using (S)‐tert‐butanesulfinyl as a chiral auxiliary, the asymmetric Reformatsky reaction was also achieved and found to proceed with excellent diastereoselectivities. A plausible model is proposed to account for the high stereoselectivity of the reaction.

ChemInform Abstract: Enantioselective Synthesis of α,α‐Difluoro‐β‐lactams Using Amino Alcohol Ligands.

A practical and highly enantioselective Reformatsky reaction of ethyl bromodifluoroacetate with imines using a cheap and commercially available amino alcohol ligand is described. A variety of α,α-difluoro-β-lactams were obtained in up to 74% yield with high enantioselectivity in excess of 99% ee. The use of ethyl bromodifluoroacetate provides for ease of operation because of the inherent chemical stability of this reagent.

ChemInform Abstract: Asymmetric Reformatsky Reaction of Aldehydes Catalyzed by Novel β‐Amino Alcohols and Zinc Complexes.

Abstract A series of β-amino alcohols derived from (1R, 2S)-2-amino-1,2-diphenylethanol and substituted salicylaldehydes as novel chiral tridentate ligands has been applied to an asymmetric Reformatsky reaction of aldehydes with ethyl iodoacetate in the presence of ZnMe2. This novel catalytic system produced the desired β-hydroxyl esters with moderate to good enantioselectivities (up to 81% ee) and yields for many aldehydes, including aromatic, heteroaromatic, conjugated, and aliphatic aldehydes.

The Synthesis of Medium-Chain-Length β-Hydroxy Esters via the Reformatsky Reaction

The synthesis of medium-chain-length β-hydroxy esters in good yield via the Reformatsky reaction is described. This work will be used as the basis for further investigation of hydroxyalkanoate polymers as potential feedstock for biofuel production.

A short stereoselective synthesis of prepiscibactin using a SmI2-mediated Reformatsky reaction and Zn2+-induced asymmetric thiazolidine formation.

Prepiscibactin (1) is a possible intermediate in the biosynthesis of piscibactin, the siderophore responsible for the iron uptake of the bacterium Photobacterium damselae subsp. piscicida, the aethiological agent of fish pasteurellosis. Compound 1 was synthesized by a convergent approach starting from L-/D-cysteine and 2-hydroxybenzonitrile. The key steps were a highly diastereoselective SmI2-mediated Reformatsky reaction and Zn(2+)-induced asymmetric thiazolidine formation followed by lactamization. The absolute configuration 9R,10S,12R,13S was established for 1, and this confirmed the previous relative stereochemistry proposed on the basis of NOE and computational methods.

Improved chemical synthesis, X-ray crystallographic analysis, and NMR characterization of (22R)-/(22S)-hydroxy epimers of bile acids.

We report an improved synthesis of the (22R)- and (22S)-epimers of 3α,7α,12α,22-tetrahydroxy-5β-cholan-24-oic acid and 3α,7α,22-trihydroxy-5β-cholan-24-oic acid from cholic acid (CA) and chenodeoxycholic acid (CDCA), respectively. The principal reactions involved were as follows: (1) oxidative decarboxylation of the bile acid peracetates with lead tetraacetate, and (2) subsequent Reformatsky reaction of the 23,24-dinor-22-aldehydes with ethyl bromoacetate in the presence of activated Zn as a catalyst with the reaction temperature maintained precisely at 75 °C. The absolute configuration of the chiral center at C-22 of each epimer was established by single-crystal X-ray diffraction data using its ethyl ester-peracetate derivative. The (1)H- and (13)C-NMR spectra that permit the (22R)- and (22S)-epimers to be distinguished are reported as well as the specific (1)H shift effects induced by C(5)D(5)N. Bile acids having hydroxyl groups at C-22 are present in a variety of animal biles, previously have been difficult to identify, and are known to have distinctive physicochemical and biological properties.

ChemInform Abstract: Stereoselectivity of the Honda—Reformatsky Reaction in Reactions with Ethyl Bromodifluoroacetate with α‐Oxygenated Sulfinylimines.

AbstractThe Honda—Reformatsky reaction involving bromodifluoroacetate (II) is investigated with both sulfinylimines derived from aliphatic aldehydes as well as those derived from aldehydes bearing a chiral α‐oxygenated substituent.

ChemInform Abstract: Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction.

A series of β-amino esters were synthesized by the reaction of N-tosyl aldimine or N-hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β-N-hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β-lactam also was synthesized by the reaction of N-p-methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.

A Concise Synthesis of Mupirocin H Using a Cross‐Metathesis‐Based Strategy

AbstractA highly efficient (10.1 % overall yield) and convergent (longest linear sequence of 16 steps) synthesis of mupirocin H has been achieved, starting from commercially available (+)‐(R)‐Roche ester. The route relies on an efficient Grubbs cross‐metathesis reaction to generate a key, late‐stage E‐olefin intermediate, and a cobalt‐catalysed diastereoselective Reformatsky reaction to produce a β‐hydroxy ester that serves as a late‐stage intermediate.

ChemInform Abstract: First Total Synthesis of Prunustatin A.

AbstractThe first total synthesis of prunustatin A (I) is achieved via a Reformatsky reaction and a Shiina macrolactonization in the presence of 2‐methyl‐6‐nitrobenzoic anhydride and DMAP.

Efficient synthesis of mibefradil analogues: an insight into in vitro stability.

This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation.