One-Pot Zinc-Promoted Asymmetric Alkynylation/Brook-Type Rearrangement/Ene–Allene Cyclization: Highly Selective Formation of Three New Bonds and Two Stereocenters in Acyclic Systems

by Polina Smirnov, Jomon Mathew, Anne Nijs, Einat Katan, Miriam Karni, Carsten Bolm, Yitzhak Apeloig, Ilan Marek*

It’s as easy as 1, 2, 3: In a one-pot sequence, two stereocenters and three new bonds were created with high selectivity through an asymmetric alkynylation of acyl silanes, a tandem Brook-type rearrangement and Zn–ene–allene cyclization, the addition of an electrophile, and finally oxidation (see scheme). The straightforward nature of the synthetic procedure contrasts strongly with the complexity of the densely functionalized products obtained.

Angewandte Chemie Internation Edition

Article first published online: 23 OCT 2013

DOI: 10.1002/anie.201306749

Organoytterbium Ate Complexes Extend the Value of Cyclobutenediones as Isoprene Equivalents

by Emma Packard, David D. Pascoe, Jacques Maddaluno, Théo P. Gonçalves, David C. Harrowven*

Changing course: While organolithium and Grignard reagents favor addition to C1 of A (R=Me), the corresponding organoytterbium reagents add to C2 (R=tBu). Computational studies provide insights into the nature of organoytterbium species and their reactivity, and a total synthesis of (−)-mansonone B illustrates the utility of the method in terpenoid synthesis. Tf=trifluoromethanesulfonyl.

Angewandte Chemie Internation Edition

Article first published online: 23 OCT 2013

DOI: 10.1002/anie.201307193

Palladium(II)-Catalyzed Intramolecular Hydroamination of 1,3-Dienes to Give Homoallylic Amines

by Justin M. Pierson, Erica L. Ingalls, Richard D. Vo, Forrest E. Michael*

A pincer for high selectivity: A mild palladium-catalyzed hydroamination of protected amino-1,3-dienes has been developed. This highly regioselective reaction employs a tridentate PNP pincer ligand and leads to cyclic and homoallylic protected amines in high yields. Substrates with a wide array of amine protecting groups and diene substitution patterns were cyclized to form five- and six-membered heterocycles. PG=protecting group.

Angewandte Chemie Internation Edition

Article first published online: 24 OCT 2013

DOI: 10.1002/anie.201305766

Total Synthesis and Structural Revision of the Alkaloid Incargranine B

by Patrick D. Brown, Anthony C. Willis, Michael S. Sherburn, Andrew L. Lawrence*

Seeing double: Consideration of the biosynthetic origins of incargranine B, which was originally assigned an unprecedented indolo[1.7]naphthyridine structure, led to the proposal of a dipyrroloquinoline framework as a more biosynthetically feasible structure (see scheme; Piv=pivaloyl). This hypothesis was validated by a short biomimetic synthesis of incargranine B.

Angewandte Chemie Internation Edition

Article first published online: 24 OCT 2013

DOI: 10.1002/anie.201307875

Atropisomeric Chiral Dienes in Asymmetric Catalysis: C2-Symmetric (Z,Z)-2,3-Bis[1-(diphenylphosphinyl)ethylidene]tetralin as a Highly Active Lewis Base Organocatalyst

by Masamichi Ogasawara*, Shunsuke Kotani, Hikaru Nakajima, Haruka Furusho, Mitsuru Miyasaka, Yasushi Shimoda, Wei-Yi Wu, Masaharu Sugiura, Tamotsu Takahashi*, Makoto Nakajima*

Diene catalysts with a twist: The title C₂-symmetric tetralin-fused 1,3-butadiene derivative is atropisomeric and can be resolved into the two helical enantiomers. The optically pure compound showed excellent enantioselectivity as well as unusually high catalytic activity as a chiral Lewis basic organocatalyst in the asymmetric allylation of various aldehydes with β-substituted allyltrichlorosilanes (see scheme).

Angewandte Chemie Internation Edition

Article first published online: 25 OCT 2013

DOI: 10.1002/anie.201308112

Diastereoselective Synthesis of Eight-Membered-Ring Allenes from Propargylic Epoxides and Aldehydes by Silylene Insertion into Carbon–Oxygen Bonds

by Christina Z. Rotsides, Chunhua Hu, K. A. Woerpel*

Bent out of shape: Silver-catalyzed insertions of silylenes into propargylic CO bonds of epoxides regioselectively form 1,2-silaoxetanes, which add to aldehydes to give the title allenes as single diastereomers (see scheme; Ts=4-toluenesulfonyl). An X-ray crystal structure confirmed the stereochemistry of the allene, which is bent significantly from linearity (164°).

Angewandte Chemie International Edition

Article first published online: 9 OCT 2013

DOI: 10.1002/anie.201306093

Palladium-Catalyzed Synthesis of Benzofurans and Coumarins from Phenols and Olefins

by Upendra Sharma, Togati Naveen, Arun Maji, Srimanta Manna, Debabrata Maiti*

Triple CH functionalization: Palladium-catalyzed synthesis of benzofurans and coumarins by reacting phenols and unactivated olefins is described. The reaction comprises sequential CH functionalization and shows diverse functional group compatibility. Preliminary mechanistic studies shed light into the possible mechanisms.

Angewandte Chemie International Edition

Article first published online: 11 OCT 2013

DOI: 10.1002/anie.201305326

Silver-Catalyzed Hydrogenation of Aldehydes in Water

by Zhenhua Jia, Feng Zhou, Mingxin Liu, Xingshu Li,  Albert S. C. Chan, Chao-Jun Li*

Silver bullet: The first silver-catalyzed hydrogenation in water was developed. A silver complex containing a bulky monodentate phosphine ligand was used to generate alcohols from a broad range of aldehydes, including aliphatic, aromatic, and heterocyclic aldehydes. This method provides a direct and efficient route to alcohols from aldehydes and opens a new avenue in silver catalysis.

Angewandte Chemie International Edition

Article first published online: 14 OCT 2013

DOI: 10.1002/anie.201306243

Copper-Mediated Synthesis of 1,2,3-Triazoles from N-Tosylhydrazones and Anilines

by Zhengkai Chen, Qiangqiang Yan, Zhanxiang Liu, Yiming Xu, Yuhong Zhang*

NNNifty targets: In a straightforward copper-mediated synthesis of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles, readily available aniline and N-tosylhydrazone substrates underwent cyclization through C-N and N-N bond formation (see scheme; Piv=pivaloyl, Ts=p-toluenesulfonyl). This method enables the preparation of 1,2,3-triazoles with high efficiency under mild conditions without the use of azides.

Angewandte Chemie International Edition

Article first published online: 15 OCT 2013

DOI: 10.1002/anie.201306416

Transfer of Chirality in the Rhodium-Catalyzed Intramolecular [5+2] Cycloaddition of 3-Acyloxy-1,4-enynes (ACEs) and Alkynes: Synthesis of Enantioenriched Bicyclo[5.3.0]decatrienes

by Xing-zhong Shu, Casi M. Schienebeck, Wangze Song, Ilia A. Guzei, Weiping Tang*

Chiral bicycles: Enantioenriched bicyclo[5.3.0]decatrienes were prepared from readily available chiral 3-acyloxy-1,4-enynes (ACEs) for the first time. In most cases, the chirality of the ACEs could be transferred to the bicyclic products with high efficiency. Inversion of the configuration was observed, thus confirming the predictions of previous computational studies.

Angewandte Chemie International Edition

Article first published online: 21 OCT 2013

DOI: 10.1002/anie.201306919

Asymmetric Palladium(II)-Catalyzed Cascade Reaction Giving Quaternary Amino Succinimides by 1,4-Addition and a Nef-Type Reaction

by Manuel Weber, Wolfgang Frey, René Peters*

Simple starting materials, high-value products: A dinuclear ferrocene-based Pd^II complex transforms mixtures of racemic N-benzoyl α-amino acids, nitroolefins, acetic anhydride, and manganese acetate into biologically interesting quaternary aminosuccinimides. The products are obtained as single diastereomers in enantioenriched form. Key steps of the cascade mechanism are a 1,4-addition of in situ generated azlactones to nitroolefins and a Nef-type reaction.

Angewandte Chemie International Edition

Article first published online: 21 OCT 2013

DOI: 10.1002/anie.201307334

Catalytic Enantioselective Synthesis of Functionalized Tropanes Reveals Novel Inhibitors of Hedgehog Signaling

by Rishikesh Narayan, Jonathan O. Bauer, Carsten Strohmann, Andrey P. Antonchick*, Herbert Waldmann*

Dipolar cycloaddition: A highly efficient copper(I)-catalyzed enantioselective [3+2] cycloaddition reaction of 1,3-fused cyclic azomethine ylides and nitroalkenes has been developed. This method provides access to functionalized tropane scaffolds with several quaternary and tertiary stereocenters in a single step under mild reaction conditions.

Angewandte Chemie International Edition

Article first published online: 21 OCT 2013

DOI: 10.1002/anie.201307392

A Streamlined Strategy for Aglycone Assembly and Glycosylation

by Katherine M. Partridge, Scott J. Bader, Zachary A. Buchan, Christopher E. Taylor, John Montgomery*

Multipurpose sugars: Carbohydrate-derived silane reagents are utilized as the reductant for nickel-catalyzed aldehyde–alkyne reductive coupling reactions and as the glycosyl donor for subsequent intramolecular glycosylation. The approach enables the assembly of the carbon–carbon framework and stereochemical features of an aglycone while simultaneously establishing the site of glycosylation.

Angewandte Chemie International Edition

Article first published online: 21 OCT 2013

DOI: 10.1002/anie.201307680

Profound Methyl Effects in Drug Discovery and a Call for New CH Methylation Reactions

by Heike Schönherr, Tim Cernak*

The methyl group is one of the most commonly occurring carbon fragments in small-molecule drugs. This simplest alkyl fragment appears in more than 67 % of the top-selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of C-H to C-Me improves the IC₅₀ value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp²)-H and C(sp³)-H bonds. It is our hope that the relevance of the meager methyl group to drug discovery as presented herein will inspire reports on new C-H methylation reactions.

It′s a kind of magic: The methyl group is one of the most prominent functional groups in bioactive small molecules and appears in more than 67 % of the top-selling drugs. This Review highlights examples of the magic methyl effect, whereby the installation of a single methyl group boosts potency by more than two orders of magnitude. New C-H activation reactions are required to facilitate the direct introduction of methyl groups.

Angewandte Chemie International Edition

Article first published online: 22 OCT 2013

DOI: 10.1002/anie.201303207

Synergistic Effect of Ketone and Hydroperoxide in Brønsted Acid Catalyzed Oxidative Coupling Reactions

by Bertrand Schweitzer-Chaput, Abhishek Sud, Áron Pintér, Stefanie Dehn, Philipp Schulze, Martin Klussmann*

Waste not wasted: A mechanistic study of the autoxidative coupling of xanthene with cyclopentanone uncovered an autoinductive effect of the waste product hydrogen peroxide. It generates radicals in the presence of acid and ketones, which accelerate the reaction by providing an additional pathway to the reactive hydroperoxide intermediate. This discovery could be applied to achieve other Brønsted acid-catalyzed oxidative coupling reactions.

Angewandte Chemie International Edition

Article first published online: 22 OCT 2013

DOI: 10.1002/anie.201306752

Thiophosphoramide-Based Cooperative Catalysts for Brønsted Acid Promoted Ionic Diels–Alder Reactions

by Alina Borovika, Pui-In Tang, Seth Klapman, Pavel Nagorny*

Three's a crowd: The combination of a Brønsted acid and a hydrogen-bond donor cocatalyst was found to promote various ionic [2+4] cycloadditions under mild reaction conditions (see scheme; Ts=4-toluenesulfonyl). Thiophosphoramides are the most effective cocatalysts because of the stronger counterion activation effect resulting from three, rather than two, hydrogen bonds involved in anion binding.

Angewandte Chemie International Edition

DOI:10.1002/anie.201307133