Radical Umpolung: Efficient Options for the Synthesis of 1,4-Dicarbonyl Compounds.

Radical developments: Photochemical/secondary amine dual catalysis has proven to be an efficient strategy for radical umpolung reactions. Two new processes provide an elegant solution to a long-standing chemoselectivity problem for the synthesis of 1,4-dicarbonyl compounds.

Enantioselective Total Syntheses of (+)-Hippolachnin A, (+)-Gracilioether A, (-)-Gracilioether E, and (-)-Gracilioether F.

The Plakortin polyketides represent a structurally and biologically fascinating class of marine natural products. Herein, we report a unified strategy that enables the divergent syntheses of various Plakortin polyketides with high step-economy and overall efficiency. As proof-of-concept cases, the enantioselective total syntheses of (+)-hippolachnin A, (+)-gracilioether A, (-)-gracilioether E, and (-)-gracilioether F have been accomplished based on a series of bio-inspired, rationally designed, or serendipitously discovered transformations, which include (1) an organocatalytic asymmetric 1,4-conjugate addition to assemble the common chiral γ-butenolide intermediate enroute to all of the aforementioned targets, (2) a challenging biomimetic [2+2] photocycloaddition to forge the oxacyclobutapentalene core of (+)-hippolachnin A, (3) a [2+2] photocycloaddition followed by one-pot oxidative cleavage of methyl ether/Baeyer-Villiger rearrangement to access (-)-gracilioether F, and (4) an unprecedented hydrogen-atom-transfer-triggered oxygenation of vinylcyclobutane to afford (+)-gracilioether A and (-)-gracilioether E in one pot.

Achieving Molecular Complexity via Stereoselective Multiple Domino Reactions Promoted by a Secondary Amine Organocatalyst.

In the last two decades, organocatalysis has emerged as an intensively investigated and rapidly growing area of research facilitating many known and many new transformations to provide efficient novel entries to complex molecules of high stereochemical purity. The organocatalysts have not only shown their efficiency for catalyzing the reactions in which one bond is formed, but they have also been effectively exploited in various versions of one-pot reactions. Domino reactions are one of the most important classes of one-pot reactions, where the target structure can be obtained in one pot without changing any reaction conditions while each reaction occurs as a consequence of the intermediates generated in previous steps. Owing to the synthetic importance and operational advantages associated with the use of organocatalysts and the development of domino reactions, various asymmetric transformations leading to a complex structure of choice have been explored. The early era of organocatalysis exhibits a limited growth in the development of asymmetric domino reactions with special emphasis on two reactions occurring one after the other. In 2006, our group made a step forward to develop more complex domino reactions catalyzed by a secondary amine organocatalyst, wherein three reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. This triggered our interest to develop new organocatalytic domino sequences, especially for multiple domino reactions. After our seminal contribution, domino reactions catalyzed by secondary amine organocatalysts not only became more popular, but they also could be catalyzed by other classes of organocatalysts, such as bifunctional hydrogen bonding catalysts, chiral Brønsted acids, and N-heterocyclic carbenes. The mode of activation in this triple domino reaction relied on the sequential generation of enamine and iminium intermediates using a proline-based chiral secondary amine organocatalyst. By employing this strategy, we have developed several triple domino reactions leading to the formation of carbo- and heterocyclic structures bearing multiple stereogenic centers with excellent levels of stereoselectivities. The applications of the secondary amine organocatalysts have been further extended to more complex quadruple domino sequences. Moreover, these multiple domino sequences have been combined successfully with other transformations in one pot to create densely functionalized polycyclic compounds. This Account gives an overview of our research in the area of organocatalytic asymmetric multiple domino reactions with special emphasis on the secondary amine catalyzed triple and quadruple domino reactions via a sequential generation of enamine and iminium intermediates. The multiple cascade reactions assisted by di- and tri-iminium and -enamine species as well as other types of organocatalysts have been excluded from the scope of this Account.

Highly Enantioselective Kinetic Resolution of Michael Adducts through N-Heterocyclic Carbene Catalysis: An Efficient Asymmetric Route to Cyclohexenes.

A highly efficient strategy for the kinetic resolution of Michael adducts was realized using a chiral N-heterocyclic carbene catalyst. The kinetic resolution provides a new convenient route to single diastereomers of cyclohexenes and Michael adducts in good yields with high enantiomeric excesses (up to 99 % ee with a selectivity factor of up to 458). This "two flies with one swat" concept allows the synthesis of these two synthetically valuable compound classes at the same time by a single transformation.

Asymmetric organocatalytic methods for the synthesis of tetrahydropyrans and their application in total synthesis.

Recent advancement in the area of asymmetric organocatalysis led to the development of new methodologies for the construction of valuable enantiopure molecules, including various heterocycles. As one of the latter class of compounds tetrahydropyrans (THPs) constitute a core structure of a wide array of bioactive natural products. A noticeable growth has been observed in the asymmetric synthesis of THPs using small organic molecules as catalysts. This Tutorial Review describes the organocatalytic methods available to furnish THPs as well as the application of these methodologies in the total synthesis of THP-based natural products.

N-Heterocyclic Carbene Catalyzed Quadruple Domino Reactions: Asymmetric Synthesis of Cyclopenta[c]chromenones.

An N-heterocyclic carbene catalyzed domino sequence via α,ß-unsaturated acyl azolium intermediates has been developed. This strategy provides a convenient enantioselective route to functionalized tricyclic coumarin derivatives and cyclopentanes. DFT studies and control experiments were performed to gain better insight into the reaction mechanism.

N-Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations.

N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC-catalyzed transformations involving Breslow intermediates, acyl azoliums, α,ß-unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC-catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates.

Asymmetric Synthesis of Spirocyclic ß-Lactams through Copper-Catalyzed Kinugasa/Michael Domino Reactions.

The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic ß-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter.

Control of N-Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole-γ-Amino Acid Derivatives.

A strategy to control the switch between a non-cycloaddition reaction and a cycloaddition reaction of enals, using N-heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to γ-amino-acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo-Mannich reactions of enals and isatin-derived ketimines. By simply changing the N-ketimine substituent to an ortho-hydroxy phenyl group, the corresponding spirocyclic oxindolo-γ-lactams are obtained.

N-Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals with Masked Cinnamates for the Asymmetric One-Pot Synthesis of Adipic Acid Derivatives.

A novel short entry to 3,4-disubstituted adipic acids has been developed by employing an asymmetric NHC-catalyzed [3+2] cycloaddition of enals with masked cinnammates in moderate to good yields and high stereoselectivities. The synthetic utility of the protocol was demonstrated by the basic conversion of the masked cyclopentanone intermediates to 3S,4S-disubstituted adipic acid precursors of pharmaceutically important gababutins.

Asymmetric Synthesis of Amino-Bis-Pyrazolone Derivatives via an Organocatalytic Mannich Reaction.

A new series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in asymmetric Mannich reactions with pyrazolones. The amino-bis-pyrazolone products are obtained in excellent yields and stereoselectivities by employing a very low loading of 1 mol % of a bifunctional squaramide organocatalyst. Depending on the substitution at position 4 of the pyrazolones, the new protocol allows for the generation of one or two tetrasubstituted stereocenters, including a one-pot version combing the Mannich reaction with a base-mediated halogenation.

Merging N-Heterocyclic Carbene Catalysis and Single Electron Transfer: A New Strategy for Asymmetric Transformations.

Radical chemistry meets NHCs: NHC catalysis and single electron oxidants have been merged in several transformations, allowing the synthesis of useful ß-hydroxy esters, cyclopentanones, and spirocyclic γ-lactones in a highly stereoselective manner. The key step is the oxidation of the NHC homoenolate equivalent to a radical species via a single-electron transfer process.

Squaramide-Catalyzed Asymmetric aza-Friedel-Crafts/N,O-Acetalization Domino Reactions Between 2-Naphthols and Pyrazolinone Ketimines.

N-Boc ketimines derived from pyrazolin-5-ones were explored to develop an unprecedented domino aza-Friedel-Crafts/N,O-acetalization reaction with 2-naphthols. The novel method requires a catalyst loading of only 0.5 mol % of a bifunctional squaramide catalyst, is scalable to gram amounts, and provides a new series of furanonaphthopyrazolidinone derivatives bearing two vicinal tetra-substituted stereogenic centers in excellent yields (95-98 %) and stereoselectivity (>99:1 d.r. and 97-98 % ee). A different reactivity was observed in the case of 1-naphthols and other electron-rich phenols, which led to the aza-Friedel-Crafts adducts in 70-98 % yield and 47-98 % ee.

Switchable Access to Different Spirocyclopentane Oxindoles by N-Heterocyclic Carbene Catalyzed Reactions of Isatin-Derived Enals and N-Sulfonyl Ketimines.

A novel NHC-catalyzed annulation protocol for the asymmetric synthesis of biologically important ß-lactam fused spirocyclopentane oxindoles with four contiguous stereocenters, including two quaternary carbon centers, was developed. Alternatively, spirocyclopentane oxindoles containing an enaminone moiety can be achieved using the same starting materials, isatin-derived enals, and N-sulfonyl ketimines, in the presence of a slightly different NHC catalytic system. This switchable annulation strategy enables the selective assembly of both heterocyclic scaffolds with good yields and excellent enantioselectivities for a broad range of substrates.

N-Heterocyclic Carbene Catalyzed [4+2] Annulation of Enals via a Double Vinylogous Michael Addition: Asymmetric Synthesis of 3,5-Diaryl Cyclohexenones.

A strategy for the N-heterocyclic carbene (NHC) catalyzed asymmetric synthesis of 3,5-diaryl substituted cyclohexenones has been developed via oxidative [4+2] annulation of enals and alkenylisoxazoles. It is the first example of using NHC organocatalysis in a double vinylogous Michael type reaction, a challenging but highly desirable topic. This unprecedented protocol affords good yields as well as high to excellent diastereo- and enantioselectivities.

Therapeutic nuclear shuttling of YB-1 reduces renal damage and fibrosis.

Virtually all chronic kidney diseases progress towards tubulointerstitial fibrosis. In vitro, Y-box protein-1 (YB-1) acts as a central regulator of gene transcription and translation of several fibrosis-related genes. However, it remains to be determined whether its pro- or antifibrotic propensities prevail in disease. Therefore, we investigated the outcome of mice with half-maximal YB-1 expression in a model of renal fibrosis induced by unilateral ureteral obstruction. Yb1+/- animals displayed markedly reduced tubular injury, immune cell infiltration and renal fibrosis following ureteral obstruction. The increase in renal YB-1 was limited to a YB-1 variant nonphosphorylated at serine 102 but phosphorylated at tyrosine 99. During ureteral obstruction, YB-1 localized to the cytoplasm, directly stabilizing Col1a1 mRNA, thus promoting fibrosis. Conversely, the therapeutic forced nuclear compartmentalization of phosphorylated YB-1 by the small molecule HSc025 mediated repression of the Col1a1 promoter and attenuated fibrosis following ureteral obstruction. Blunting of these effects in Yb1+/- mice confirmed involvement of YB-1. HSc025 even reduced tubulointerstitial damage when applied at later time points during maximum renal damage. Thus, phosphorylation and subcellular localization of YB-1 determines its effect on renal fibrosis in vivo. Hence, induced nuclear YB-1 shuttling may be a novel antifibrotic treatment strategy in renal diseases with the potential of damage reversal.

Asymmetric, Three-Component, One-Pot Synthesis of Spiropyrazolones and 2,5-Chromenediones from Aldol Condensation/NHC-Catalyzed Annulation Reactions.

A novel one-pot, three-component diastereo- and enantioselective synthesis of spiropyrazolones has been developed involving the aldol condensation of an enal to generate α,ß-unsaturated pyrazolones, which react with a second equivalent of enal through an N-heterocyclic carbene (NHC)-catalyzed [3+2] annulation. The desired spirocyclopentane pyrazolones are obtained in moderate to good yields and good to excellent stereoselectivities. Alternatively, starting from cyclic 1,3-diketones, 2,5-chromenediones are available through [2+4] annulation.

Catalytic Conia-ene and related reactions.

Since its initial inception, the Conia-ene reaction, known as the intramolecular addition of enols to alkynes or alkenes, has experienced a tremendous development and appealing catalytic protocols have emerged. This review fathoms the underlying mechanistic principles rationalizing how substrate design, substrate activation, and the nature of the catalyst work hand in hand for the efficient synthesis of carbocycles and heterocycles at mild reaction conditions. Nowadays, Conia-ene reactions can be found as part of tandem reactions, and the road for asymmetric versions has already been paved. Based on their broad applicability, Conia-ene reactions have turned into a highly appreciated synthetic tool with impressive examples in natural product synthesis reported in recent years.

Combining Organocatalysis and Lanthanide Catalysis: A Sequential One-Pot Quadruple Reaction Sequence/Hetero-Diels-Alder Asymmetric Synthesis of Functionalized Tricycles.

A stereoselective one-pot synthesis of functionalized complex tricyclic polyethers has been achieved using the combination of secondary amine and lanthanide catalysis. This one-pot quadruple reaction/Hetero-Diels-Alder sequence gave good yields (per step) as well as excellent diastereo- and enantioselectivities. Furthermore, the particular combination of lanthanide complexes with organocatalysis is one of the first examples described for sequential catalysis.

Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds.

An asymmetric organocatalytic domino oxa-Michael/1,6-addition reaction of ortho-hydroxyphenyl-substituted para-quinone methides and isatin-derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4-phenyl-substituted chromans bearing spiro-connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).