Enantioselective Synthesis of Quaternary alpha-Aminophosphonates via Conjugate Addition of alpha-Nitrophosphonates to Enones

Enantioselective Michael addition of alpha-nitrophosphonates to enones for the synthesis of alpha-aminophosphonates is reported for the first time. The reaction proceeds in good to high yields and moderate to high selectivity in the presence of a new quinine thiourea catalyst. The quaternary nitrophosphonates were conveniently transformed to cyclic quaternary alpha-aminophosphonates via in situ reduction intramolecular cyclization or Baeyer-Villiger oxidation followed by in situ reduction intramolecular cyclization

Stereoselective intramolecular 1,3-dipolar cycloadditions

An in depth account of intramolecular 1,3-dipolar cycloadditions involving dipoles such as nitrile oxides, silyl nitronates, H-nitrones, azides, and nitrilimines is presented with particular emphasis on the stereochemistry during the cyclo addition. Various methods employed for the generation of the dipoles and their applications to stereoselective synthesis are also discussed

Enantioselective synthesis of alpha-nitro-delta-ketosulfones via a quinine-squaramide catalyzed conjugate addition of alpha-nitrosulfones to enones

Conjugate addition of alpha-nitrosulfones to vinyl ketones in the presence of 0.2 mol% of a quinine-squaramide organocatalyst afforded alpha-nitro-delta-ketosulfones possessing a tetrasubstituted chiral center in excellent yield and enantioselectivity in most cases. This strategy also offers a facile and convenient entry into gamma-sulfonylhydroxamates that are one carbon homologs of potent enzyme inhibitors

Synthesis of Functionalized Pyrazoles via 1,3-Dipolar Cycloaddition of alpha-Diazo-beta-ketophosphonates, Sufones and Esters with Electron-Deficient Alkenes

1,3-Dipolar cycloaddition of diazo compounds with olefinic substrates is a promising atom-economic strategy for the construction of functionalized pyrazoles. Over the last few years, our group has been engaged in the synthesis of phosphonyl/sulfonylpyrazoles and pyrazole esters by employing Bestmann-Ohira Reagent (BOR) and its sulfur and ester analogs as 1,3-dipole precursors with various dipolarophiles. This account describes the novel synthetic methods developed in our laboratory, in the perspective of closely related work by others, for the synthesis of phosphonyl/sulfonylpyrazoles, pyrazole esters and the total synthesis of Withasomnine, a natural product, by using 1,3-dipolar cycloaddition as the key step

On The Temperature-Dependence of Regioselectivity in the Amination of Bromobenzotropones

The ipso/cine ratio in the amination of 5-bromo-2,3-benzo- or 2-bromo-4,5-benzotropone shows a dependence upon the temperature at which the reaction is conducted, changing in favour of the ipso-product when the temperature is maintained high, ruling out an aryne-type mechanism. A comparison of independent mechanisms envisaged for the formation of the two isomeric products suggests a two-part reason: (i) at a higher reaction temperature, C-protonation, a step necessary for the formation of the cine-product, could be retarded when a direct internal mode is interfered with by a less efficient external one, and (ii) reketonisation by elimination of bromide, needed to form the ipso-product, is likely to have a high temperature coefficient enabling the rate of its formation to overtake that of the cine-product

One-Pot Regioselective Synthesis of meta-Terphenyls via [3 + 3] Annulation of Nitroallylic Acetates with Alkylidenemalononitriles

A highly efficient one-pot method has been developed for the synthesis of meta-terphenyls via a regioselective [3 + 3] annulation-elimination sequence involving Morita-Baylis-Hillman (MBH) acetates of nitro-alkenes and alkylidenemalononitriles. The reaction takes place in a regioselective manner under mild conditions (Et3N, room temperature) to afford a wide variety of meta-terphenyls bearing aryl, heteroaryl and styrenyl groups. This novel [3 + 3] annulation takes advantage of the 1,3-bielectrophilic character of MBH acetates and 1,3-binucleophilic character of alkylidenemalononitriles and proceeds in a cascade fashion comprising an S(N)2' substitution, intramolecular 6-endo-trig Michael addition and double elimination. Representative synthetic transformations of the products, for instance, to meta-terphenyl derived isoindolinones have also been demonstrated

Regioselective Synthesis of Sulfonylpyrazoles via Base Mediated Reaction of Diazosulfones with Nitroalkenes and a Facile Entry into Withasomnine

A base mediated reaction of alpha-diazo-beta-ketosulfone with nitroalkenes affords sulfonylpyrazoles as single regioisomers in excellent yield in a one-pot room temperature reaction. Aryl, heteroaryl, styrenyl, alkyl, hydroxymethyl, and hydrazinyl groups could be introduced on the pyrazole ring by the appropriate choice of nitroalkenes. Synthesis of sulfonylpyrazole fused to other heterocycles and application of the methodology to an expedient synthesis of a pyrazole alkaloid, Withasomnine, are also reported

Quinine-Derived Thiourea and Squaramide Catalyzed Conjugate Addition of alpha-Nitrophosphonates to Enones: Asymmetric Synthesis of Quaternary alpha-Aminophosphonates

Conjugate addition of a-nitrophosphonates to enones was carried out in the presence of two sets of organocatalysts, viz. a quinine-thiourea and a quinine-squaramide. The quinine-thiourea provided the products possessing an a-quaternary chiral center in high enantioselectivities only in the case of electron rich enones. On the other hand, the quinine-squaramide was more efficient in that a wide variety of electron rich and electron poor enones underwent Michael addition of nitrophosphonates to afford the quaternary a-nitrophosphonates in excellent yields and enantioselectivities. The hydrogen bonding donor ability of the bifunctional catalyst, as shown in the proposed transition states, appears primarily responsible for the observed selectivity. However, a favorable p-stacking between the aryl groups of thiourea/squaramide and aryl vinyl ketone also appeared favorable. The reaction was amenable to scale up, and the enantioenriched quaternary a-nitrophosphonates could be easily transformed to synthetically and biologically useful quaternary a-aminophosphonates and other multifunctional molecules

Enantioselective synthesis of gamma-tetrasubstituted nitrosulfonyl carboxylates and amides via L-tert-leucine-derived-squaramide catalyzed conjugate addition of nitrosulfones to acrylates and acrylamides

Michael addition of alpha-nitrosulfones to aryl-and alkyl acrylates and acrylamides proceeds in the presence of 5-10 mol% of an amino acid derived new organocatalyst to provide gamma-tetrasubstituted gamma-nitro-gamma-sulfonyl carboxylates and amides in excellent yields and enantioselectivities. Scale-up of the reaction to multi-grams, convenient recovery of the catalyst and its recyclability without any drop in yield and selectivity are attractive features of this methodology