Facile stereoselective synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones

The highly stereoselective synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones by the [2+2] cycloaddition of ketenes with imines derived from chloral is described.     

The stereoselective total synthesis of xestodecalactone C and epi-sporostatin via the Prins cyclisation

Syntheses of xestodecalactone C and epi-sporostatin are described utilising Prins cyclisations, Mitsunobu reaction and intramolecular Friedel-Crafts acylation. The approach is convergent and highly stereoselective.     

A Convenient Method for the Synthesis of Aminomethylmonoalkylphosphinate

Starting from the readily available 4‐methylbenzoic acid, an efficient protocol for the preparation of ethyl 4‐(aminomethyl) benzyl (methyl) phosphinate ( 1 ), a novel aminomethylmonoalkylphosphinate was reported in this communication. The important step involves the selective monochlorination of phosphonic ester by POCl₃ and forming the phosphonochloridate, and followed by nucleophilic addition of CH₃MgBr to the acid chloride intermediate.     

Convenient and Efficient Synthesis of 2,4-Dideoxy-levoglucosan

A convenient and efficient synthesis of 1,6-anhydro-2,4-dideoxy-β-D-threo-hexopyranose (2,4-dideoxy-levoglucosan) from levoglucosan has been developed. The method uses cheap reagents and requires only crystallization and distillation for preparation of pure product on a multigram scale.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource: Full experimental and spectral details.]     

A highly stereoselective reductive amination of 3-ketosteroid with amines: an improved synthesis of 3α-aminosteroid

A highly stereoselective reductive amination method was developed based on in situ generated sodium acyloxyborohydride and was successfully applied to a steroidal skeleton with various amine sources. High yield (96%) and a de of up to 95% were achieved by modifying the reducing reagent. The effect of this reagent will be discussed.     

An efficient synthesis of (−)-3-deazaaristeromycin

The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine) and (3aS,4S,6R,6aR)-tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta-[d][1,3]dioxo-4-ol under Mitsunobu reaction conditions provides, after three subsequent straightforward reactions, ready access to the highly biologically active (−)-3-deazaaristeromycin. The versatility of this procedure opens access to a diverse pool of 3-deazapurine carbocyclic nucleosides.     

A practical, two-step synthesis of 1-alkyl-4-aminopyrazoles

A novel synthesis of N1 alkyl-substituted pyrazoles with a free amino group at the C4 position is described. Commercially available 4-nitropyrazole was found to readily undergo Mitsunobu reactions with primary and secondary alcohols. Subsequent reduction of the nitro group via hydrogenation affords 1-alkyl-4-aminopyrazoles, which are valuable intermediates in the synthesis of pharmaceutically active compounds.     

The stereoselective total synthesis of isocladosorpin

A highly stereoselective total synthesis of isocladosorpin is described. The key steps involved in this synthesis are oxa-Michael reaction, asymmetric propargylation, and Alder–Rickerts reaction.     

Convenient synthesis of functionalized terphenyls

A convenient synthetic methodology amenable for rapid synthesis of differentially functionalized terphenyls is described. Orthogonality requirements for the incorporation of phenoxy acetic acid and carboxamide function have been satisfied by utilization of hydroxyethoxy group as a precursor of the acid. Highly efficient and universal procedures have been developed for acid and amide formation.     

Efficient and selective solid-phase synthesis of trans 3-alkyl β-lactams from nonactivated acid chlorides

An efficient and stereoselective procedure for a rapid access to diverse trans 3-alkyl β-lactams by solid-phase methodology is described.     

Enantioselective synthesis of oseltamivir phosphate

The key steps in the enantioselective synthesis of Tamiflu include an asymmetric Diels-Alder reaction, Mitsunobu inversion using Fukuyama modified Weinreb reagent, carbamate directed epoxidation. Epoxide opening with trimethylsilyl azide furnished a 3:1 mixture of regioisomers that converged to afford the same aziridine. Attempted preparation of the unsaturated ester regioselectively using 2-iodoxybenzoic acid (IBX) following Nicolaou’s protocol failed. The unsaturated ester was prepared by phenylselenylation followed by selenoxide elimination.     

A general strategy for the synthesis of azapeptidomimetic lactams

A selection of azapeptidomimetics containing constraining lactam rings have been prepared by Mitsunobu cyclization of serine/homologated serine-azaalanine derivatives. These include sterically-congested β-lactams, as well as γ-butyrolactam and δ-valerolactam analogs. A novel azaamino acid acylation method was developed to prepare the sterically demanding α-benzyl-serine-azaalanine precursor. In all cases, the Mitsunobu conditions were highly efficient in forming the desired azapeptidomimetic lactams. The reported process represents a general strategy for the synthesis of peptidomimetic structures with a constraining lactam ring.     

A new scalable synthesis of entecavir

A new synthesis of entecavir from d-glucose in an average total yield of 3.5% was achieved via an intramolecular nitrile oxide cycloaddition (INOC) reaction and a Peterson olefination as key-steps. The present process was designed for industrial application, using widely available raw materials, simple and cheap reagents and avoiding low reaction temperatures, which are very common in the synthetic approaches towards similarly complex structures.     

A versatile solid-phase synthesis of 3-aryl-1,2,4-oxadiazolones and analogues

We report here the first method to load acidic heterocyclic compounds (1,2,4-oxadiazol-5-one, 1,2,4-oxadiazol-5-thione and 1,2,3,5-oxathiadazol-2-oxide) on a polymer. Using Mitsunobu conditions, these heterocycles were anchored on a 4-hydroxymethyl-3-methoxyphenoxybutyric acid benzhydrylamine (HMPB-BHA) resin. After diversification, compounds can be recovered by a simple treatment in diluted TFA. To illustrate the utility of this procedure, iodophenyl derivatives were anchored on the same resin. A HRMAS-NMR analysis shed light on the reactivity of these heterocycles in Mitsunobu conditions. A subsequent diversification using a Sonogashira coupling produced a small array of novel (arylethynyl)-phenyl-1,2,4-oxadiazol-5-ones.     

Chemoenzymatic synthesis of novel adenosine carbanucleoside analogues containing a locked 3′-methyl-2′,3′-β-oxirane-fused system

Starting from a readily available enantiopure building block, a straightforward enantioselective approach to 3′-methyl-2′,3′-β-oxirane-fused carbanucleosides bearing adenosine analogues is detailed. The key steps in the syntheses involved a lipase-catalyzed regioselective monoacylation of a diol to obtain the key intermediate and direct coupling of this key intermediate with diversely substituted purine nucleobases under Mitsunobu reaction conditions providing only the N⁹ target molecules.     

Solid-phase synthesis of benzothiazoles using an alkoxyamine linker

An alkoxyamine linker was applied for the solid-phase synthesis of benzothiazoles. The substrate was anchored by aldoxime linkage and products were cleaved from the solid-support by aldoxime-imine exchange coupled with air-oxidation under the weakly acidic conditions. The tether is highly robust under Mitsunobu reaction, nucleophilic substitution reaction, and Pd-catalyzed reaction conditions.     

Palladium-catalyzed stereoselective synthesis of 3-(aminomethylene)-oxindoles

An efficient palladium-catalyzed protocol for the stereoselective synthesis of 3-(aminoarylmethylene)-oxindoles has been developed. In this approach, Ugi-4-component reaction adducts were used as starting materials for carbopalladative cyclization-Buchwald reaction sequences.     

Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines using Weinreb amide

A method of convergent synthesis of novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines 7 is developed. The synthetic intermediate of 7, 4,6-unsubstituted 2-aminodihydropyrimidines 9 having a Weinreb amide at the 5-position, is prepared by the sequential Staudinger/aza-Wittig/cyclization reactions of (E)-tert-butyl{3-azido-2-[methoxy(methyl)carbamoyl]allyl}carbamate (E)-10. The transformation of the Weinreb amide of 9 to an acyl group proceeds smoothly by a substitution reaction using aryllithiums or alkyllithiums in the presence of a catalytic amount of BF₃ etherate, affording 7 in good to high yield. The N-protecting group of 7 can be easily removed to obtain N-unsubstituted 2-amino-5-acyldihydropyrimidines 8, and the derivatives are observed as a single isomer in ¹H NMR spectroscopy. All dihydropyrimidines in this study were hitherto unavailable and difficult to synthesize by conventional methods.