Phosphinoyl-aziridines as a new class of chiral catalysts for enantioselective Michael addition

A series of new optically pure phosphine oxides containing chiral aziridine subunit were synthesized in good yields and applied as organocatalysts in asymmetric Michael reaction of various aliphatic aldehydes with β-nitrostyrene. The corresponding organocatalysts were synthesized starting from optically pure aziridines in a few simple efficient steps. The appropriate Michael adducts were obtained in most cases in very high chemical yield (up to 97%), excellent enantioselectivity (up to 98% of ee) and diastereoselectivity (up to 95:5 of dr).     

Highly enantioselective approach to geminal bisphosphonates by organocatalyzed Michael-type addition of beta-ketoesters

A valuable organocatalyzed protocol has been developed for the asymmetric synthesis of bisphosphonate derivatives, a class of pharmaceutically important molecules. Cheap and commercially available dihydroquinine effectively catalyzed conjugate additions of cyclic beta-ketoesters to ethylidenebisphosphonate esters, leading to optically active geminal bisphosphonates, bearing an all-carbon substituted quaternary stereocenter, in high yields and enantioselectivities of up to 99 % ee. Further elaborations of Michael adducts to the corresponding bisphosphonic acids or vinyl phosphonates have also been successfully performed, with conservation of optical purity.     

Highly enantioselective conjugate addition of fluoromalonates to nitroalkenes using bifunctional organocatalysts

The enantioselective conjugate addition of fluoromalonates to aromatic nitroalkenes catalyzed by chiral amine-thiourea bifunctional organocatalysts generated a stereocenter at the carbon bearing the aromatic group and an adjacent prochiral center from the fluoromalonate. Treatment of fluoromalonates with aromatic nitroalkenes under mild reaction conditions afforded the corresponding 2-fluoro-2-(2-nitro-1-arylethyl)malonates with high yields (72-93%) and excellent enantioselectivities (91-98% ee).     

Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intramolecular oxo-Michael addition

Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A was achieved by a quinine-catalyzed asymmetric intramolecular oxo-Michael addition as a key step.     

Mechanistic study of asymmetric Michael addition of malonates to enones catalyzed by a primary amino acid lithium salt

A mechanistic study was carried out for the asymmetric Michael addition reaction of malonates to enones catalyzed by a primary amino acid lithium salt to elucidate the origin of the asymmetric induction. A primary β-amino acid salt catalyst, O-TBDPS β-homoserine lithium salt, exhibited much higher enantioselectivity than that achieved with the corresponding catalysts derived from α- and γ-amino acids for this reaction. Detailed studies of the transition states with DFT calculations revealed that the lithium cation and carboxylate group of the β-amino acid salt catalyst have important roles in achieving high enantioselectivity in the Michael addition reaction of malonates to enones.     

Tandem SN2-Michael addition to vinylogous carbonates for the stereoselective construction of 2,3,3,5-tetrasubstituted tetrahydrofurans

A stereoselective method for the synthesis of substituted tetrahydrofuran derivatives employing a tandem alkylation-Michael addition sequence to vinylogous carbonates is developed. The method could be used to synthesize THFs bearing tertiary ethers. Further, the method is extended to the synthesis of adjacent bis-THFs.     

Double Michael addition of azoles to methyl propiolate: a straightforward entry to ligands with two heterocyclic rings

The synthesis of methyl bis(azol-1-yl)propionates is reported for the first time. These bridge-functionalized bis(azol-1-yl)methanes are prepared by a double Michael addition of azoles to methyl propiolate, representing a new methodology for the synthesis of polydentate ligands.     

Catalytic electronic activation as a tool for the addition of stabilised nucleophiles to allylic alcohols

This paper describes the activation of 2-cyclohexen-1-ol (1) and 2-cyclopenten-1-ol (11) through the use of aluminium-catalysed transfer hydrogenation. The electronically activated substrates are demonstrated to undergo facile conjugate addition and, when the alcohol functional group is subsequently restored in a one-pot procedure, this leads to an indirect addition of nucleophiles to allylic alcohols. This novel methodology has been termed catalytic electronic activation.The aluminium tert-butoxide catalysed conversion of 2-cyclohexen-1-ol (1) into 2-(3-hydroxycyclohexyl)-2-methylmalononitrile (18) and 2-cyclopenten-1-ol (11) into 2-(3-hydroxycyclopentyl)-2-methylmalononitrile (16) in 90 and 60% yield, respectively has been demonstrated through an efficient domino Oppenauer/Michael addition/Meerwein-Ponndorf-Verley process.     

Pyrrolidine-ureas as bifunctional organocatalysts for asymmetric Michael addition of ketone to nitroalkenes: unexpected hydrogen bonding effect

A series of pyrrolidine-urea bifunctional organocatalysts was efficiently synthesized and applied to the asymmetric Michael addition of ketone to nitroolefin. Theoretical study was performed to shed light on the origin of their different activities and revealed that the rigid structure formed between catalyst 1b with nitroolefin via double hydrogen bonding retarded the approach of nucleophilic enamine intermediate.     

Polystyrene-immobilized pyrrolidine as a highly stereoselective and recyclable organocatalyst for asymmetric Michael addition of cyclohexanone to nitroolefins

Polystyrene-immobilized pyrrolidine 4 has been developed as a highly efficient, reusable, and stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of trifluoroacetic acid, 4 catalyzed the reaction of cyclohexanone to a variety of nitroolefins with high yields (up to >99%) and excellent diastereoselectivities (up to >99:1 dr), and enantioselectivities (up to >99% ee). Furthermore, 4 could be recovered and recycled by a simple filtration of the reaction solution and used for more than 10 consecutive trials without significant loss of its catalytic activity.     

Superelectrophilicity of the nitroolefinic fragment of 4-nitrobenzodifuroxan in Michael-type reactions with indoles: a kinetic study in acetonitrile

The kinetics of the coupling of 4-nitrobenzodifuroxan (NBDF) with a series of indoles 8 a-e to give the expected Michael-type adducts 9 a-e have been investigated in acetonitrile solution. No significant influence of the nature of the isotopic substitution at C-3 of the indole ring has been found, indicating that the NBDF addition step is the rate limiting step of the SEAr substitution of the indole moiety. This implies that the measured second-order rate constants (k) for the reactions are identical to the second order rate constants (k1NBDF) associated to the C--C coupling step. By using the known N and s parameters characterizing the nucleophilicity of indoles, the k1NBDF rate constants are found to fit nicely to the three parameters equation logk1=s(N+E) introduced by Mayr to describe the feasibility of nucleophilic-electrophilic combinations. Based on this, the electrophilicity parameter E of NBDF could be determined as E=-6.15. This corresponds to a positioning of the reactivity of the nitroactivated double bond of NBDF in the domain of superelectrophilicity previously defined for nitrobenzofuroxans, in accord with the finding that the rates of coupling of 8 a-e with NBDF are only one order of magnitude lower than those for the coupling of these indoles with 4,6-dinitrobenzofuroxan (DNBF). The theoretical scale of electrophilicity introduced by Domingo et al. on the basis of the global electrophilicity index omega defined by Parr is also a very useful tool to discuss the relative reactivities of NBDF, DNBF, and a number of differently activated C==C double bonds.     

Solvent-free asymmetric conjugate addition of malonates to enones using a diaminomethylenemalononitrile organocatalyst

Diaminomethylenemalononitrile organocatalyst 1 efficiently promotes the asymmetric conjugate addition of malonates to α,β-unsaturated ketones to afford the corresponding addition products in high to excellent yields with up to 98% ee.     

Expanding Mg-Zn hybrid chemistry: inorganic salt effects in addition reactions of organozinc reagents to trifluoroacetophenone and the implications for a synergistic lithium-magnesium-zinc activation

Numerous organic transformations rely on organozinc compounds made through salt-metathesis (exchange) reactions from organolithium or Grignard reagents with a suitable zinc precursor. By combining X-ray crystallography, NMR spectroscopy and DFT calculations, this study sheds new light on the constitution of the organometallic species involved in this important synthetic tool. Investigations into the metathesis reactions of equimolar amounts of Grignard reagents (RMgX) and ZnCl(2) in THF led to the isolation of novel magnesium-zinc hybrids, [{(thf)(2)Mg(μ-Cl)(3)ZnR}(2)] (R=Et, tBu, nBu or o-OMe-C(6)H(4)), which exhibit an unprecedented structural motif in mixed magnesium-zinc chemistry. Furthermore, theoretical modelling of the reaction of EtMgCl with ZnCl(2) reveals that formation of the mixed-metal compound is thermodynamically preferred to that of the expected homometallic products, RZnCl and MgCl(2). This study also assesses the alkylating ability of hybrid 3 towards the sensitive ketone trifluoroacetophenone, revealing a dramatic increase in the chemoselectivity of the reaction when LiCl is introduced as an additive. This observation, combined with recent related breakthroughs in synthesis, points towards the existence of a trilateral Li/Mg/Zn synergistic effect.     

Chiral NHC ligands bearing a pyridine moiety in copper-catalyzed addition of diethylzinc to nitroalkenes

Chiral N-heterocyclic carbenes, derived from amino acids containing a pyridine ring, are effective ligands in the enantioselective copper-catalyzed addition of diethylzinc to β-nitroalkenes, which provides access to chiral nitroalkanes. The advantages of this process include high yields, broad and complementary substrate scope, and good to high enantioselectivities.     

A General Approach to Angucyclines: Synthesis of Hatomarubigin A, Rubiginone B2, Antibiotic X-1488E, 6-Hydroxytetrangulol, and Tetrangulol

Hatomarubigin A was prepared in 41% yield in a single procedure from acyl naphthoquinone 15 and 5-methylcyclohexane-1,3-dione (16). The net reaction consists of Michael addition to an acyl quinone followed by intramolecular aldol condensation. Hatomarubigin A then served as a common intermediate in syntheses of the angucyclinone antibiotics rubiginone B2, antibiotic X-1488E, 6-hydroxytetrangulol, and tetrangulol.     

Regioselective nucleophilic addition to carbonyl ylide intermediates: a novel diastereoselective synthesis of cycloalkyl fused furan-3-ones

[structures: see text] A range of cis-fused hexahydro-1-benzofuran-3(2H)-one or tetrahydro-2H-cyclopenta[b]furan-3(3aH)-one ring systems was synthesized by the rhodium(II) acetate catalyzed reaction of alpha-diazo carbonyl compounds in the presence of various oxygen, nitrogen, and sulfur nucleophiles. A double-nucleophilic addition was possible by using an excess of alpha-diazo ketone. These reactions proceeded with complete diastereoselectivity, and the stereochemistry was confirmed by the single-crystal X-ray analysis. This process discloses the first example of tandem cyclization-nucleophilic addition reaction.     

The MARDi cascade: a Michael-initiated domino-multicomponent approach for the stereoselective synthesis of seven-membered rings

The MARDi cascade is a recently invented three-component Michael-initiated condensation involving 1,3-dicarbonyl derivatives. It allows regio- and stereocontrolled access to a variety of functionalised and substituted seven-membered rings. The substitution array can be diastereoselectively modulated by appropriate choice of the reaction partners, and the reaction allows the control of up to five newly created stereocentres and a complete chiral induction in the case of an optically active ketone precursor. The high level of diastereoselectivity observed has been attributed to total thermodynamic control of the reaction. The attractiveness of the present domino three-component approach to seven-membered rings resides in the diversity of carbo- and heterocyclic structures that can be accessed with total regiocontrol and high stereocontrol by starting from simple substrates, under user and environmentally friendly conditions, as now required in modern organic chemistry.     

Microwave-induced clay-catalyzed ring opening of N-tosylaziridines: a green approach to achiral and chiral diamines

N-Tosylaziridines react efficiently with amines in the presence of Montmorillonite K-10 as catalyst under microwave irradiation in solvent-free conditions to yield the corresponding achiral and chiral diamines regio- and stereoselectively, in a few minutes and in high yields.     

o-Phenylenediamine as a New Catalyst in the Highly Regioselective Conversion of Epoxides to Halohydrins with Elemental Halogens – A Reinvestigation

Summary. In contrast to a previous report, o-phenylenediamine is not a catalyst in the ring opening reaction of epoxides by means of bromine or iodine. The o-phenylenediamine is just a reactant which reacts with iodine to give phenazine-2,3-diamine and hydrogen iodide, or with bromine to give a mixture of brominated and polymerized products as well as hydrogen bromide. The hydrogen halogenides are in fact the real epoxide ring opening reactants.     

Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes with 4,5-methano-l-proline as organocatalysts

The 4,5-methano-l-prolines were used as chiral organocatalysts in asymmetric Michael addition of aldehydes to nitroolefins. These proline-like catalysts are unique for their rigid bicyclic structure with a cyclopropane and two H atoms attached to the bridgehead C atoms lying on the same side of the ring. They therefore showed high efficiency in asymmetric Michael addition of aldehydes to nitroolefins. Under the optimal conditions, excellent diastereo- and enantioselectivities (up to 97/3 dr and 98% ee) were obtained in high yields for a series of aldehydes and nitroolefins using only 5 mol % catalyst loading. The methodology features easily available catalysts, high catalytic efficiency and environmentally friendly procedures.