Synthetic efforts towards the synthesis of fluorinated C-glycosidic analogues of α-galactosylceramides

An overview of the work realized by the group regarding the synthesis of fluorinated C-glycosides is described. The various strategies that were investigated allowed the synthesis of CF₂-glycosides for many carbohydrate series (glucose, mannose and galactose) and for any pseudo-anomeric center configuration (α or β). This work culminated in an efficient preparation of a synthetically useful α-CF₂-galactoside intermediate and its conversion to α-CF₂-galactoconjugates. A synthesis of α-CF₂-galactosylceramide, based on this last methodology, is currently investigated.     

Toward the Total Synthesis of Scleritodermin A: Preparation of the C(1)-N(15) Fragment

The synthesis of the C₁-N₁₅ fragment of the marine natural product Scleritodermin A has been accomplished through a short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of the α-keto amide linkage by the use of a highly activated α,β-ketonitrile.     

Inositolphosphoglycan Mediators: An Effective Synthesis of the Conserved Linear GPI Anchor Structure*

An effective new preparative synthesis of the conserved linear pseudopentasaccharide structure of the GPI anchors and of the full GPI structure has been carried out that has permitted obtaining both molecules in sufficient quantities as to perform further structural and biologic studies. The synthesis involves a 3+2 block synthesis strategy in which a conveniently protected Man α(1→4) GlcN₃ α(1→6) myo‐Ins building block, previously used in the synthesis of inositolphosphoglycan (IPG) mediators, is glycosylated with a protected Man α(1→2) Man trichloroacetimidate.     

Lewis acid-promoted alpha-hydroxy beta-dicarbonyl to alpha-ketol ester rearrangement

The decarbomethoxylation reaction of a substituted α-hydroxy-α-carbomethoxy pentacyclic substituted ketone, used as an advanced intermediate in the synthesis of the alkaloid aspidophytine, can be effected by heating with MgI₂ in CH₃CN. The reaction was shown to proceed by a novel α-hydroxy β-dicarbonyl to α-ketol ester rearrangement. It was possible to isolate a carbonate intermediate in 75% yield, thereby providing support for the proposed pathway.     

Functional Polymers by Cationic Techniques

Extensive studies on the mechanism of carbocationic polymerization initiation and particularly termination yielded information useful for the synthesis of a variety of new mono- and difunctional (telechelic) polymers. Unraveling aspects of initiation has opened new avenues toward the synthesis of novel cationic graft copolymers. Understanding details of termination has led among other products to cyclopentadiene-ended polyisobutylene and cyclopentadienylated rubbers. The latters crosslink by Diels-Alder addition and produce thermally reversible networks. Combination of controlled initiation and termination yielded telechelic products e. g., α, ω-diene-polyisobutylene. The use of Cl₂/BCl₃ combinations led to the synthesis of α, ω-dichloropolyisobutylenes.     

Efficient one-pot synthesis of α-aminophosphonates from aldehydes and ketones catalyzed by ytterbium(III) triflate

An efficient three component one-pot synthesis of N-silylated α-aminophosphonates and α,α-disubstituted α-aminophosphonates was developed using Yb(OTf)₃ as a catalyst at room temperature under mild conditions.     

A mild and variable synthesis of α-ketoesters

The ZnCl₂ promoted addition of 1,2-diethoxy-1,2-disilyloxyethylene 1 with electrophiles such as aldehydes, ketones, α,β-unsaturated ketones or tertiary alkyl halides allows for a simple synthesis of α-ketoesters.     

N-Boc-Protected α-Amino Acids by 1,3-Migratory Nitrene C(sp3)−H Insertion

N-Boc-protected α-amino acids are synthesized in two steps from linear or branched carboxylic acid feedstocks. In the first step, the carboxylic acid is coupled with tert-butyl aminocarbonate (BocNHOH) to generate azanyl ester (acyloxycarbamate) RCO₂NHBoc. In the second step, this azanyl ester undergoes a stereocontrolled iron-catalyzed 1,3-nitrogen migration to generate the N-Boc-protected non-racemic α-amino acid. This straightforward protocol is applicable to the catalytic asymmetric synthesis of α-monosubstituted α-amino acids with aryl, alkenyl, and alkyl side chains. Furthermore, α,α-disubstituted α-amino acids are accessible in an enantioconvergent fashion from racemic carboxylic acids. The new method is also advantageous for the synthesis of α-deuterated α-amino acids. N-Boc-protected α-amino acids synthesized using this two-step protocol are ready-to-use building blocks.     

An efficient synthesis of (Z)-α-fluorochalcones via the palladium-catalyzed cross-coupling reaction of (Z)-α-fluorocinnamoyl chloride with boronic acids

An efficient synthesis of α-fluorochalcones (1,3-diphenyl-2-fluoroprop-2-en-1-one) based on the Suzuki–Miyaura palladium-catalyzed cross-coupling reaction of arylboronic acids with α-fluorocinnamoyl chlorides in the presence of Cs₂CO₃ in toluene is described. This approach allows the synthesis of fluorinated analogues of functionalized natural chalcones.     

Synthesis of optically active α-(allenyl)- and α-substituted-α-(allenyl)glycines

The synthesis of various types of optically active α-(allenylsilane-containing)glycines via a chirality-transferring ester-enolate Claisen rearrangement of α-acyloxy-α-alkynylsilanes is described. The conversion of the rearranged products into the optically active silicon-free α-(allenyl)- and α-substituted-α-(allenyl)glycines was achieved by the removal of the Me₂PhSi- or TMS group from the allene terminus.     

Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by chiral sulfinyl auxiliary

Aminophosphonic acids have become increasingly important in different fields of chemistry, medicine and agriculture. This account outlines the results obtained in the author’s laboratory on the asymmetric synthesis of acyclic and cyclic aminophosphonic acids mediated by chiral sulfinyl auxiliary. A key reaction in the synthesis of enantiopure α- and β-aminoalkanephosphonic acids involving a highly diastereoselective addition of phosphite anions or α-phosphonate carbanions to enantiopure sulfinimines is discussed. The asymmetric cyclopropanation of enantiopure α-phosphorylvinyl sulfoxides with sulfur ylides is presented as a platform for developing a new approach to optically active β-aminocyclopropanephosphonic acids. It is exemplified by the total synthesis of enantiopure β-amino-γ-phenylcyclopropanephosphonic acid - a constrained analogue of the GABA_B antagonist phaclofen.     

A chemoselective Reformatsky–Negishi approach to α-haloaryl esters

A practical synthesis of α-haloaryl esters has been achieved via a chemoselective Negishi coupling of poly-halogenated aromatics and Reformatsky reagents in the presence of catalytic Pd(dba)₂ and Xantphos. This chemistry tolerates a variety of aryl halides and was successfully applied to the synthesis of Ibuprofen. The α-haloaryl ester products, exemplified by ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a), can be further functionalized via palladium or copper catalysis to afford an array of α-aryl esters.     

Synthesis of homoallylic oxygenated α-methylene-γ-butyrolactones: a model for preparing biologically active natural lactones

In this Letter we describe a 12% overall yield synthesis of a model for homoallylic oxygenated α-methylene-γ-butyrolactones with relative stereochemistry defined by selective hydrogenation with Rh/Al₂O₃. The synthesis was realized in 9 steps involving simple reactions.     

Efficient three-step sequence for the deamination of α-aminoesters. Application to the synthesis of CysLT1 antagonists

A practical and efficient three-step sequence for the deamination of α-aminoesters is reported. This method is based on the NaBH₄-mediated selective reduction of α-diazoesters to α-hydrazonoesters and has been successfully applied to the deamination of several representative α-aminoesters including some l-cysteine ethyl ester derivatives, key intermediates in the synthesis of a series of CysLT1 antagonists.     

Vicinal difunctionalization of dehydropiperidines using α-chloro-β-sulfonyl eneformamides

The synthesis of α,β-difunctionalized dehydropiperidines has been accomplished using α-halo-β-sulfonyl eneformamides. This outcome is achieved through sequential regioselective C_β-alkylative desulfonation and C_α-palladium-catalyzed cross-coupling. In most cases, high yields of the vicinally functionalized eneformamides are obtained.     

Effect of chromium(III) oxide on corundum formation from products of shock-wave synthesis of aluminum oxide

Formation of α-Al₂O₃ in thermal treatment of ultradispersed aluminum oxide powders produced by shock-wave synthesis with addition of Cr₂O₃-(NH₄)₂Cr₂O₇ as a precursor was studied. The acceleration of the conversion of δ-and θ-Al₂O₃ to α-Al₂O₃ upon introduction of additives in the stage of synthesis of aluminum oxide was examined.     

Bi(NO3)3.5H2O catalyzed phosphonylation of aldehydes: An efficient route to α-hydroxyphosphonates

The Bi(NO₃)₃.5H₂O mediated synthesis of α-hydroxyphosphonates via phosphonylation of aldehydes is reported herein. Both conventional and microwave technology was efficiently applied to range of aromatic, heteroaromatic, α,β-unsaturated aldehydes under solvent-free conditions. The solvent free conditions, avoidance of toxic reagents and excellent yield are some of the remarkable features of this protocol to access the medicinally privileged structure, α-hydroxyphosphonates.     

Biomimetic synthesis of α-amino acids from α-keto acids

Protonated α-imino acids, RC(=NH₂⁺)COOH, were easily reduced to α-amino acids by an acid-stable NADH analogue, 1-benzyl-3-carbamoyl-1,4-dihydroquinoline. This is the first model reaction of NADH-mediated α-amino acid synthesis from α-keto acids.     

Facile aerobic photo-oxidative synthesis of α-diketones from alkynes

We report a useful method for facile aerobic photo-oxidative synthesis of α-diketones from alkynes with MgBr₂·OEt₂. This procedure provides a practical synthetic method of α-diketones using easily handled bromine sources, harmless visible light, and molecular oxygen as terminal oxidant.     

Synthesis of RGD analogues containing α-Tfm-arginine as potential fibrinogen receptor antagonists

The synthesis of two peptide mimetics of RGD, α-Tfm-Arg-Gly-Asp-Phe-NH₂ 9 and α-Tfm-Arg-Gly-Asp-NH-(CH₂)₂-C₆H₅ 13, is described. The precursor of α-Tfm-ornithine was obtained in two synthetic steps from 2-N-Cbz-2-Tfm-hexanediacid-1-alkyl ester and introduced into the peptide chain by α-carboxy-group activation via oxazolone. The introduction of the guanidine residue led to the final peptides as mixtures of the two diastereomers. Configurationally pure peptides were obtained in good yields by RP-HPLC.