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The enantioselective N-alkylation of indole and its derivatives with aldimines is efficiently catalyzed by a zinc-ProPhenol dinuclear complex under mild conditions to afford N-alkylated indole derivatives in good yield (up to 86 %) and excellent enantiomeric ratio (up to 99.5:0.5 e.r.). This method tolerates a wide array of indoles, as well as pyrrole and carbazole, to afford the corresponding N-alkylation products. The reaction can be run on a gram scale with reduced catalyst loading without impacting the efficiency. The chiral aminals were further elaborated into various chiral polyheterocyclic derivatives. The surprising stability of the chiral N-alkylation products will open new windows for asymmetric catalysis and medicinal chemistry.

Herein, a ruthenium-catalyzed cycloisomerization that transforms 1,6-haloenynes into 5-membered carbo- and heterocycles that bear exocyclic, stereodefined, tetrasubstituted vinyl halides is reported. The reaction is insensitive to air and water, tolerates a variety of functional groups, and proceeds with good to excellent stereoselectivity and yield.

Herein, we report a Zn-ProPhenol catalyzed aza-Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α-chloro-β-aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one pot fashion. Of note, the reaction can be run on gram-scale with low catalyst loading without impacting its efficiency. Moreover, this methodology was extended to α-bromoketones which are scarcely used in enantioselective catalysis because of their sensitivity and lack of accessibility.

A general method for the synthesis of cyclic α-amido-ethers containing different amide functionalities including lactams, tetramic acids, amino acids and nucleoside bases., Efficient synthesis of versatile building blocks for enabling medicinal chemistry research has always challenged synthetic chemists to develop innovative methods. Of particular interest are the methods that are amenable to the synthesis of chemically distinct and diverse classes of pharmaceutically relevant motifs. Herein we report a general method for the one-pot synthesis of cyclic α-amido-ethers containing different amide functionalities including lactams, tetramic acids and amino acids. For the incorporation of the nucleotide bases, a chemo and regioselective palladium-catalyzed transformation has been developed, providing rapid access to nucleoside analogs.

Herein is reported the first example of palladium-catalyzed asymmetric allylic alkylation (AAA) reactions involving 2-aza-π-allyl palladium intermediates. The 2-aza-π-allyl complex was generated via a novel mode of activation of N-allyl imines. Pd-catalyzed C(sp3)-H activation of N-allyl imines and subsequent nucleophilic attack by glycinates delivered vicinal diamino derivatives as the sole regioisomers with high levels of diastereo- and enantio-control in the presence of the chiral, bidentate (S,S)-Cy-DIOP ligand. This procedure is highly atom economical and could also be performed by a simple one-pot operation starting from aldehydes, allyl amines and glycinates under mild conditions. The products of this transformation could be converted into various useful derivatives, where the allyl substitution serves as a unique tool for differentiating the two amino moieties in the products.

A unique intramolecular Pd-catalyzed alkyne-alkyne coupling is presented. This transformation generates a strained, 1,3-bridged, macrocyclic enyne. The process was readily executed on gram-scale, and the structure of the product was elucidated via X-ray crystallographic analysis. A mechanistic rationale for the observed chemoselectivity is provided.

The isoquinoline alkaloids isolated from the genus Corydalis possess potent and diverse biological activities. Herein, a concise, divergent, and enantioselective route to access these natural products is disclosed. Key transformations of our approach include a challenging Zn-ProPhenol-catalyzed asymmetric Mannich reaction to build a quaternary stereogenic center and a rapid cationic Au-catalyzed cycloisomerization to the common structural skeleton of these natural products. Subsequent late-stage oxidations and modifications allow efficient access to the targeted alkaloids. Overall, seven natural products have been successfully synthesized in 6 to 10 steps from readily available starting materials, including (+)-corynoline, (+)-anhydrocorynoline, (+)-12-hydroxycorynoline, (+)-12-hydroxycorynoloxine, (+)-corynoloxine, (+)-6-acetonylcorynoline, and (+)-bulleyanaline.

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.

Nature's synthetic plans to construct molecules have been developed over millions of years of evolution and frequently prove to be among the most sophisticated. Mimicking nature's route can be a direct and feasible way for synthetic organic chemists to construct complicated molecules. However, lacking nature's ability to manipulate enzymes often prevents us from reproducing the same route. Modifying nature's approaches can provide a simpler synthetic alternative to access complex structural target molecules. Here we report a strategy that simplifies the synthesis of terpenes by inverting the order of nature's two-phase biosynthesis route. We first unite simple molecules into a polyfunctionalized linear polyenyne, with all the desired carbons and oxygens in the targeted places. This compound then undergoes polyenyne cycloisomerization, in the presence of all the functional groups, to give polyoxidized terpenes. The key reaction is a palladium-catalysed polyenyne cycloisomerization that not only tolerates the presence of all of the oxygen functionalities, but also is facilitated by them.

Sulfones are flexible functional groups that can act as nucleophiles, electrophiles, or even radicals. Changing the reaction conditions can completely alter the reactivity of a sulfonyl group, and as a result, molecules bearing multiple sulfones are versatile building blocks. This Review highlights the unique ability of 1,1- and 1,2-bis(sulfones) to masquerade as a vast array of reactive synthons including methane polyanions, vinyl cations, and all-carbon dipoles that would be difficult or impossible to access directly.

Pyrimidine nucleosides are an important class of compounds with versatile applications across many fields, including biology and medicinal chemistry. Synthesis of nucleoside analogs in optically pure form via traditional glycosylation has always been a challenge, especially for unnatural carbohydrate motifs which do not have C2 substitution to dictate the stereochemical outcome of the newly formed glyosidic bond. Herein, we report an asymmetric Pd-catalyzed synthesis of nucleoside analogs enabled by the development of a series of chiral ligands. A variety of 5-substituted pyrimidine nucleobases, ranging from 5- to 12-membered ring nucleoside analogs, are generated in excellent yield (up to 96%) as well as diastereo- (>20:1) and enantioselectivity (up to 99.5% ee). These nucleoside analogs bearing an iodide functional group handle allow for rapid transformation to a variety of other interesting pyrimidine nucleoside structures.

We describe the development of a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) of acyclic α-hydroxyketones using boronic acids as traceless templates. Condensation of boronic acids with hydroxyketones generates 1,3-dioxaboroles, which can be used directly as pronucleophiles in Pd-AAA reactions. This strategy enables control of the enolate geometry, while removing the issue of O-alkylation. Allylic alcohols can be directly ionized in the presence of Pd(0) and chiral ligands to afford alkylation products with regio- and enantioselectivity. Additionally, a dynamic kinetic asymmetric transformation of allenyl electrophiles affords C-alkylation products in high regio-, diastereo-, and enantioselectivity. To the best of our knowledge, this method represents the first example in Pd-AAA for setting point chirality on a nucleophile simultaneous to stereoinduction on an axial chiral allene.

The C19-oxo-functionalized eburnane alkaloids display unique chemical structure and interesting biological activity. Herein, we report a divergent enantioselective strategy to access these alkaloids by use of a challenging palladium-catalyzed asymmetric allylic alkylation of an N-alkyl-α,β-unsaturated lactam. 19-( S)-OH-Δ

Densely substituted chiral pyrrolidones are synthesized via phosphine-catalyzed cycloisomerization of enantioenriched β-amino ynones, which are prepared in a single step using a highly enantioselective Zn-ProPhenol-catalyzed Mannich reaction. The exocyclic alkenes in the cyclization products provide versatile handles for further transformations and typically form with good E/ Z selectivity. This cycloisomerization method can be performed in streamlined fashion, without purification of the intermediate Mannich adduct, and extends to anthranilic acid based scaffolds in addition to ProPhenol-derived Mannich adducts.

Genetic screens in cultured human cells represent a powerful unbiased strategy to identify cellular pathways that determine drug efficacy, providing critical information for clinical development. We used insertional mutagenesis-based screens in haploid cells to identify genes required for the sensitivity to Lasonolide A (LasA), a macrolide derived from a marine sponge that kills certain types of cancer cells at low-nanomolar concentrations. Our screens converged on a single gene, LDAH, encoding a member of the metabolite serine hydrolase family that is localized on the surface of lipid droplets. Mechanistic studies revealed that LasA accumulates in lipid droplets, where it is cleaved into a toxic metabolite by LDAH. We suggest that selective partitioning of hydrophobic drugs into the oil phase of lipid droplets can influence their activation and eventual toxicity to cells.

We describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd-aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd-allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N-to-C rearrangement to five-membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

We report the first enantio- and diastereoselective 1,4-addition of butenolides to chromones. Both α,β- and β,γ-butenolide nucleophiles are compatible with the Zn-ProPhenol catalyst, and preactivation as the siloxyfurans is not required. The scope of electrophiles includes a variety of substituted chromones, as well as a thiochromone and a quinolone, and the resulting vinylogous addition products are generated in good yield (31 to 98%), diastereo- (3:1 to >30:1), and enantioselectivity (90:10 to 99:1 er). These Michael adducts allow rapid access to several natural product analogs, and can be easily transformed into a variety of other interesting scaffolds as well.

Nonreducing, pH-neutral conditions for the selective cleavage of the 2,2,2-trichloroethoxycarbonyl (Troc) protecting group are reported. Using trimethyltin hydroxide in 1,2-dichloroethane, Troc-protected alcohols, thiols, and amines can be selectively unmasked in the presence of various functionalities that are incompatible with the reducing conditions traditionally used to remove the Troc group. This mild deprotection protocol tolerates a variety of other hydrolytically sensitive and acid/base-sensitive moieties as well.

The synthesis of des-epoxy-amphidinolide N was achieved in 22 longest linear and 33 total steps. Three generations of synthetic endeavors are reported herein. During the first generation, our key stitching strategy that highlighted an intramolecular Ru-catalyzed alkene-alkyne (Ru AA) coupling and a late-stage epoxidation proved successful, but the installation of the α,α′-dihydroxyl ketone motif employing a dihydroxylation method was problematic. Our second generation of synthetic efforts addressed the scalability problem of the southern fragment synthesis and significantly improved the efficiency of the atom-economical Ru AA coupling, but suffered from several protecting group-based issues that proved insurmountable. Finally, relying on a judicious protecting group strategy together with concise fragment preparation, des-epoxy-amphidinolide N was achieved in a convergent fashion. Calculations disclose a hydrogen-bonding bridge within amphidinolide N. Comparisons of 13C NMR chemical shift differences usin...

A full account of our efforts toward an asymmetric redox bicycloisomerization reaction is presented in this article. Cyclopentadienylruthenium (CpRu) complexes containing tethered chiral sulfoxides were synthesized via an oxidative [3 + 2] cycloaddition reaction between an alkyne and an allylruthenium complex. Sulfoxide complex 1 containing a p-anisole moiety on its sulfoxide proved to be the most efficient and selective catalyst for the asymmetric redox bicycloisomerization of 1,6- and 1,7-enynes. This complex was used to synthesize a broad array of [3.1.0] and [4.1.0] bicycles. Sulfonamide- and phosphoramidate-containing products could be deprotected under reducing conditions. Catalysis performed with enantiomerically enriched propargyl alcohols revealed a matched/mismatched effect that was strongly dependent on the nature of the solvent.

The synthesis of densly functionized α-silyl-β-hydroxyl vinylsilanes via ruthenium-catalyzed multicomponent reaction (MCR) is reported herein. Exceptionally high regio- and diastereoselectivity was achieved by employing an unprecedented hydrosilylation of bifunctional silyl-propargyl boronates. The simple protocol, mild reaction conditions, and unique tolerability of this method make it a valuable tool for the synthesis of highly elaborated building blocks. The one-pot synthesis of stereodefined olefins, the generation of a valuable cyclohexene building block through a four-component MCR, and further functionalization in an abundance of diastereoselective reactions is disclosed herein.

Diorganocuprate(I) reagents derived from lithiated heterocycles and CuCN react with enantioenriched secondary propargyl bromides to give the corresponding propargylated heterocycles. While propargyl electrophiles typically undergo SN2′ displacement, this transformation represents the first example of the reaction of hard carbanions with propargyl electrophiles in an SN2 fashion and occurs with excellent levels of stereoinversion. The new method was applied to the formal synthesis of (+)-frondosin B.

We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction. The process exhibits a high functional group tolerance, and this enables the synthesis of a broad range of chiral products from simple, readily available alkyne precursors. The utility of the method is demonstrated through the elaboration of the chiral β-alkynyl products into a variety of different molecular scaffolds. Its value in complex molecule synthesis is further validated through a concise, enantioselective synthesis of AMG 837, a potent GPR40 receptor agonist.

The metal-catalyzed coupling of alkynes is a powerful method for the preparation of 1,3-enynes, compounds that are of broad interest in organic synthesis. Numerous strategies have been developed for the homo- and cross coupling of alkynes to enynes via transition metal catalysis. In such reactions, a major issue is the control of regio-, stereo-, and, where applicable, chemoselectivity. Herein, we highlight prominent methods for the selective synthesis of these valuable compounds. Further, we illustrate the utility of these processes through specific examples of their application in carbocycle, heterocycle, and natural product syntheses.

Herein, we report a Zn-ProPhenol catalyzed Mannich reaction using α-branched ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of quaternary carbon stereocenters. The reaction can be run on a gram-scale with a low catalyst loading without impacting its efficiency. Moreover, the Mannich adducts can be further elaborated with complete diastereocontrol to access molecules possessing complex stereotriads.

Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone enolates, became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This method produces α-substituted β-amino ynones with excellent chemo-, diastereo-, and enantioselectivity. The products can be readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particular, alkynyl alkyl ketones resolve the long-standing problem of the inability to use the enolates of unsymmetrical dialkyl ketones lacking α-branching for regio- and stereoselective reactions.

The synthesis of vinyl boronates and vinyl silanes was achieved by employing a Ru-catalyzed alkene-alkyne coupling reaction of allyl boronates or allyl silanes with various alkynes. The double bond geometry in the generated vinyl boronates can be remotely controlled by the juxtaposing boron- and silicon groups on the alkyne substrate. The synthetic utility of the coupling products has been demonstrated in a variety of synthetic transformations, including iterative cross-coupling reactions, and a Chan-Lam-type allyloxylation followed by a Claisen rearrangement. A sequential one-pot alkene-alkyne-coupling/allylation-sequence with an aldehyde to deliver a highly complex α-silyl-β-hydroxy olefin with a handle for further functionalization was also realized.

A concise and convergent total synthesis of piericidin A is disclosed. The synthesis hinges on the utilization of propene as a synthetic linchpin to merge the properly elaborated alkyne fragments, leading to the 1,3,6-triene motif of piericidin A. Utilization of propene as a unique alkene, capable of sequential coupling with two alkynes, is further illustrated in the context of various 1,3,6-triene products. The latter process proceeds with high atom economy and efficiently gives rise to complex frameworks from readily accessible alkyne substrates. This strategic C–C bond formation offers an orthogonal paradigm in the design of synthetic routes, leading to higher step economy and more efficient syntheses of polyunsaturated natural products.

Steps to smaller rings Certain ring-forming reactions in organic chemistry are efficient because the orbital symmetries match up in the reactants and products. Oxyallyl ions tend to react with dienes in this paradigm to form seven-membered rings. Under palladium catalysis, Trost et al. redirected this reaction toward more common five-membered tetrahydrofuran rings by appending an ester to the diene. Although that pathway is symmetry-forbidden, the electron-withdrawing ester appears to stabilize a key intermediate along a stepwise route to the smaller ring. Science , this issue p. 564

We report a Zn-ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods.

We report a Zn-ProPhenol catalyzed reaction between butenolides and imines to obtain tetrasubstituted vinylogous Mannich products in good yield and diastereoselectivity with excellent enantioselectivity (97 to >99.5% ee). Notably, both α,β- and β,γ-butenolides can be utilized as nucleophiles in this transformation. The imine partner bears the synthetically versatile N-Cbz group, avoiding the use of the specialized aryl directing groups previously required in related work. Additionally, the reaction can be performed on gram scale with reduced catalyst loading as low as 2 mol %. The functional group-rich products can be further elaborated using a variety of methods.

The aldol reaction represents an important class of atom-economic carbon-carbon bond-forming reactions vital to modern organic synthesis. Despite the attention this reaction has received, issues related to chemo- and regioselectivity as well as reactivity of readily enolizable electrophiles remain. To help overcome these limitations, a new direct approach toward aldol products that does not rely upon carbonyl substrates is described. This approach employs room-temperature contemporaneous lanthanum/vanadium dual catalysis, whereby a vanadium-catalyzed 1,3-transposition of allenols is coupled with a lanthanum-catalyzed Meinwald rearrangement of epoxides in situ to directly form aldol products.

I am highly honored to be the co-recipient of the Tetrahedron Prize for 2014 with Professor Jiro Tsuji for our work on metal catalyzed allylic alkylation, notably that using palladium. In the context of this award, this report deals only with the evolution of our work. Nevertheless, it is important to note that innumerable groups around the world have and are playing essential roles metal catalyzed allylic alkylations. The reader can find citations to such work in the references to our work that appears in this report. My involvement with this field derived from work in my laboratory dealing with the structure determination and synthesis of the insect juvenile hormone.1 The juvenile hormone is one of three hormones that control the stages of insect development from the pupae to the larvae and finally to the adult. Thus, these hormones, most notably the juvenile hormone that prevented molting was targeted as a potentially more environmentally benign insecticide. The structural relationship of the insect juvenile hormone and methyl farnesoate suggests a possible biosynthetic pathway may be involving the homologation of two of the olefinic methyl groups to ethyl groups. Such an approach, if feasible, would be very attractive, short, and potentially very practical. Unfortunately, such a synthetic protocol did not exist – a fact that intrigued me. While the reactions of the oxygen analog wherein alkylation at the carbon adjacent to the π-unsaturated carbonyl group is one of the most important synthetic reactions, the inability of the all carbon analog to undergo a similar transformation was very attractive.

The development and application of a new generation of non-C2-symmetric ProPhenol ligands is reported herein. Rational design of the ProPhenol ligand paved the way to the first catalytic and asymmetric vinylation of N-Boc imines via hydrozirconation giving rise to valuable allylic amines in excellent yields and enantioselectivities. The utility of this method was demonstrated by developing the shortest reported asymmetric synthesis of the selective serotonine reuptake inhibitor (SSRI) (-)-dapoxetine.

Stickstoff-, Sauerstoff- und Phosphorliganden mit chiralen Grundgerusten sind die historischen Arbeitspferde fur asymmetrische ubergangsmetallkatalysierte Reaktionen. Dagegen wurden am Schwefelatom chirale Sulfoxide uberwiegend als chirale Auxiliare fur diastereoselektive Reaktionen verwendet. Obwohl diese Verbindungen gegenuber den ublichen Ligandengerusten mehrere deutliche Vorteile bieten, z. B. die Nahe der chiralen Information zum Metallzentrum und die Fahigkeit, zwischen S- und O-Koordinierung zu wechseln, entwickelten sie sich erst in jungster Zeit zu einer vielseitigen Klasse chiraler Liganden. In diesem Aufsatz wird die Geschichte der Entwicklung chiraler Sulfoxidliganden fur die asymmetrische Katalyse eingehend besprochen. Daruber hinaus geben wir kurze Beschreibungen der Metall-Sulfoxid-Bindung und der Synthesestrategien fur enantiomerenreine Sulfoxide. Abschliesend werden Einblicke in die kunftige Entwicklung dieser nur wenig genutzten Ligandenklasse gegeben.

The phosphine-catalyzed synthesis of 1,2-dihydropyridines via an alkyne isomerization/electrocyclization sequence is described. Propargylidenecarbamate substrates were prepared following a one-pot procedure between a terminal alkyne, a benzonitrile, and a chloroformate in the presence of trimethylaluminum. This methodology gives access to a diverse set of 2,6-disubstituted 1,2-dihydropyridines in high yield. The products can be easily converted into substituted piperidines or pyridines, and this methodology was applied to the synthesis of indolizidines.

We report the discovery, synthesis, and application of a new class of non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity.

Conspectus The development of catalytic enantioselective transformations has been the focus of many research groups over the past half century and is of paramount importance to the pharmaceutical and agrochemical industries. Since the award of the Nobel Prize in 2001, the field of enantioselective transition metal catalysis has soared to new heights, with the development of more efficient catalysts and new catalytic transformations at increasing frequency. Furthermore, catalytic reactions that allow higher levels of redox- and step-economy are being developed. Thus, alternatives to asymmetric alkene dihydroxylation and the enantioselective reduction of α,β-unsaturated ketones can invoke more strategic C–C bond forming reactions, such as asymmetric aldol reactions of an aldehyde with α-hydroxyketone donors or enantioselective alkynylation of an aldehyde, respectively. To facilitate catalytic enantioselective addition reactions, including the aforementioned aldol and alkynylation reactions, our lab has developed the ProPhenol ligand. In this Account, we describe the development and application of the ProPhenol ligand for asymmetric additions of both carbon- and heteroatom-based nucleophiles to various electrophiles. The ProPhenol ligand spontaneously forms chiral dinuclear metal complexes when treated with an alkyl metal reagent, such as Et2Zn or Bu2Mg. The resulting complex contains both a Lewis acidic site to activate an electrophile and a Brønsted basic site to deprotonate a pronucleophile. Initially, our research focused on the use of Zn-ProPhenol complexes to facilitate the direct aldol reaction. Fine tuning of the reaction through ligand modification and the use of additives enabled the direct aldol reaction to proceed in high yields and stereoselectivities with a broad range of donor substrates, including acetophenones, methyl ynones, methyl vinyl ketone, acetone, α-hydroxy carbonyl compounds, and glycine Schiff bases. Additionally, an analogous magnesium ProPhenol complex was used to facilitate enantioselective diazoacetate aldol reactions with aryl, α,β-unsaturated, and aliphatic aldehydes. The utility of bimetallic ProPhenol catalysts was extended to asymmetric additions with a wide range of substrate combinations. Effective pronucleophiles include oxazolones, 2-furanone, nitroalkanes, pyrroles, 3-hydroxyoxindoles, alkynes, meso-1,3-diols, and dialkyl phosphine oxides. These substrates were found to be effective with a number of electrophiles, including aldehydes, imines, nitroalkenes, acyl silanes, vinyl benzoates, and α,β-unsaturated carbonyls. A truly diverse range of enantioenriched compounds have been prepared using the ProPhenol ligand, and the commercial availability of both ligand enantiomers makes it ideally suited for the synthesis of complex molecules. To date, enantioselective ProPhenol-catalyzed reactions have been used in the synthesis of more than 20 natural products.

3-(Propan-2-ylidene)benzofuran-2(3 H )-one, C 11 H 10 O 2 , crystallizes in the monoclinic space group P2 1 /c with unit cell parametersa =7.1869(3), b = 18.0636(10), c = 13.1656(7) b= 96.763(3), V =1697.28(15) , Z = 8 (Z? = 2 independent molecules, A and B, per asymmetric unit), D c = 1.363 g cm -3 and the linear absorption coefficient = 0.093 mm -1 . The crystal structure determination was carried out using MoKa X-ray data measured at 120(2) K. In the final refinement cycle the data/restraints/parameter ratios were 3827/0/239, the goodness-of-fit on F2 = 1.019. Final R indices for [I>2sigma(I)] were R1 = 0.0517, wR2 = 0.1115 and R indices (all data) R1 = 0.1007, wR2 = 0.1354. The largest electron density difference peak and hole were 0.254 and -0.244 electrons sup>-3, respectively. The two independent molecules A and B have essentially identical bond lengths and angles and are highly planar, with rms deviation for all 12 non-H atoms of 0.0292 for molecule A and 0.0592 for molecule B. The two molecules in the asymmetric unit are assembled parallel to each other within 1.58(4) with each of the six atoms of benzene ring A overlapping with one of the atoms in benzene ring B at a mean distance of 3.84(3) . The closest contacts between molecules A and B are C(12A)H---O(4B) = 3.521 and C(11B)H---O(4A) = 3.441 The crystal structure is formed by infinite sheets of these assemblies all lying parallel to the (1 0`1) plane. The presence of two independent molecules in the asymmetric unit provides an opportunity to examine the molecular geometry in detail by comparison. The benzene ring in both molecules A and B exhibits distortions as a result of the presence of the furan moiety. In particular, C(1)-C(6) = 1.369(2) in molecule A and 1.367(2) in molecule B are both significantly less than the average of the other 10 C-C bonds, 1.393(2), by about 12?. Other examples of crystal structures are discussed where this effect is observed.

A vanadium catalyzed 1,3-rearrarngement of allenols to form transient vanadium enolates that selectively couple with electrophilic nitrogen sources is reported even in the presence of competing simple protonation and Alder-ene pathways. The hydrazine products can be cyclized in a 6-endo-trig fashion which, upon reductive cleavage of the N-N bond, yield 1,4-diamines. Additionally, cleavage of the N-N bond before cyclization can be achieved to form β-hydroxy amines, a common structural motif of biologically active compounds.

Enamides represent bioactive pharmacophores in various natural products, and have become increasingly common reagents for asymmetric incorporation of nitrogen functionality. Yet the synthesis of the requisite geometrically defined enamides remains problematic, especially for highly substituted and Z-enamides. Herein we wish to report a general atom economic method for the isomerization of a broad range of N-allyl amides to form Z-di-, tri-, and tetrasubstituted enamides with exceptional geometric selectivity. This report represents the first examples of a catalytic isomerization of N-allyl amides to form nonpropenyl disubstituted, tri- and tetrasubstituted enamides with excellent geometric control. Applications of these geometrically defined enamides toward the synthesis of cis vicinal amino alcohols and tetrasubstituted α-borylamido complexes are discussed.

Diorganocuprate(I) reagents derived from lithiated heterocycles and CuCN react with enantioenriched secondary propagryl bromides to give the corresponding propargylated heterocycles. While propargyl electrophiles typically undergo SN2′ displacement, this transformation represents the first example of the reaction of hard carbanions with propargyl eletrophiles in an SN2 fashion and occurs with excellent levels of stereoinversion. The new method was applied to the formal synthesis of (+)-frondosin B.

A concise asymmetric synthesis of aminocyclitols such as diastereomeric 2-deoxystreptamine analogues and conduramine A is described. The Pd-catalyzed asymmetric desymmetrization of meso 1,4-dibenzolate enables the synthesis of highly oxidized cyclohaxane architectures. These scaffolds can potentially be used to access novel aminoglycoside antibiotics and enantiomerically pure α-glucosidase inhibitors.

Die Koordination von Ubergangsmetallen an organische Einheiten kann zu Komplexen mit faszinierenden und unerwarteten Bindungsmustern fuhren. Untersuchungen von Benzylmetall-Komplexen haben die Moglichkeit einer η3-Koordination ergeben, die zu einem desaromatisierten Ring fuhrt. Als Zwischenstufen in Katalysezyklen bieten diese Komplexe zudem Einblicke in Reaktionsmechanismen. In diesem Aufsatz werden die Synthese und Charakterisierung dieser Komplexe mit spaten Ubergangsmetallen sowie die nachfolgende Entwicklung katalytischer Methoden zur Funktionalisierung der Benzylposition einschlieslich asymmetrischer Varianten besprochen.

The coordination of transition metals to organic fragments can yield complexes with fascinating and unexpected binding patterns. The study of metal-benzyl complexes has demonstrated the feasibility of η(3)-coordination, which results in a dearomatized ring. These complexes also offer insight into reaction mechanisms as proposed intermediates in catalytic cycles. In this Review we discuss the synthesis and characterization of these complexes with late transition metals and the subsequent development of catalytic benzylic functionalization methods, including asymmetric variants.

The palladium-catalyzed oxidative desymmetrization of meso-dibenzoates yields γ-benzoyloxy cycloalkenones in good yields and with excellent levels of enantioselectivity. These compounds serve as precursors to a broad range of substituted cycloalkenones, including well-established synthetic building blocks and elaborated cycloalkanone derivatives. The ability to prepare both enantiomers of the oxidative desymmetrization products enables a unified strategy toward stereochemically diverse epoxyquinoid natural products.