N E W S
New Publications in Angewandte Chemie and Accounts of Chemical Research
Rhodium-Catalyzed Enantioselective Intermolecular Hydroalkoxylation of Allenes and Alkynes with Alcohols: Synthesis of Branched Allylic Ethers
Regio- and enantioselective additions of alcohols to either terminal allenes or internal alkynes provides access to allylic ethers by using a RhI/diphenyl phosphate catalytic system. This method provides an atom-economic way to obtain chiral aliphatic and aryl allylic ethers in moderate to good yield with good to excellent enantioselectivitieZ. Liu, B. Breit, Angew. Chem. 2016, 128, 8580–8583 ; (link) Angew. Chem. Int. Ed. 2015, 55, 8440-8443. (link)
Enantioselective Rhodium-Catalyzed Atom-Economical Macrolactonization
A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom-economical rhodium-catalyzed coupling of ω-allenyl-substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM-diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β-unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio- and diastereoselectivity.S. Ganss, B. Breit, Angew. Chem. 2016, 128, 9890-9894 ; (link) Angew. Chem. Int. Ed. 2015, 55, 9738-9742. (link)
Branching Out: Rhodium-Catalyzed Allylation with Alkynes and Allenes
We present a new and efficient strategy for the atom-economic transformation of both alkynes and allenes to allylic functionalized structures via a Rh-catalyzed isomerization/addition reaction which has been developed in our working group. Our methodology thus grants access to an important structural class valued in modern organic chemistry for both its versatility for further functionalization and the potential for asymmetric synthesis with the construction of a new stereogenic center. This new methodology, inspired by mechanistic investigations by Werner in the late 1980s and based on preliminary work by Yamamoto and Trost, offers an attractive alternative to other established methods for allylic functionalization such as allylic substitution or allylic oxidation. The main advantage of our methodology consists of the inherent atom economy in comparison to allylic oxidation or substitution, which both produce stoichiometric amounts of waste and, in case of the substitution reaction, require prefunctionalization of the starting material. Starting out with the discovery of a highly branched-selective coupling reaction of carboxylic acids with terminal alkynes using a Rh(I)/DPEphos complex as the catalyst system, over the past 5 years we were able to continuously expand upon this chemistry, introducing various (pro)nucleophiles for the selective C–O, C–S, C–N, and C–C functionalization of both alkynes and the double-bond isomeric allenes by choosing the appropriate rhodium/bidentate phosphine catalyst. Thus, valuable compounds such as branched allylic ethers, sulfones, amines, or γ,δ-unsaturated ketones were successfully synthesized in high yields and with a broad substrate scope. Beyond the branched selectivity inherent to rhodium, many of the presented methodologies display additional degrees of selectivity in regard to regio-, diastereo-, and enantioselective transformations, with one example even proceeding via a dynamic kinetic resolution. Many advances presented in this account were driven by detailed mechanistic investigations including DFT-calculations, ESI-MS and in situ IR experiments and enabled the application of our chemistry for target-oriented syntheses demonstrated by several examples shown herein. In general, this research topic has matured over the past years into a viable option when synthesizing chiral compounds, from small molecules such as quercus lactones to complex target structures such as Homolargazole or Clavosolide A. This demonstrates the importance and utility of these coupling reactions, especially considering the ease with which carbon–heteroatom bonds can be built stereoselectively, with many of the product classes displaying motifs common in modern APIs.P. Koschker, B. Breit, Acc. Chem. Res. 2016, 49, 1524-1536 ; (link)
New Publication in Angewandte Chemie
Stereodivergent and Protecting-Group-Free Synthesis of the Helicascolide Family: A Rhodium-Catalyzed Atom-Economical Lactonization Strategy
All in the family: The natural product family of the helicascolides A–C are one of countless groups of natural products containing six-membered lactones in their core structure. The rhodium-catalyzed regio- and diastereoselective addition of carboxylic acids with allenes permits the atom-economic and highly diastereoselective synthesis of the lactone core and allows for rapid access to this product family.
New Publications in Angewandte Chemie and Chemical Science
Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed Addition of Carboxylic Acids to Allenes: Protecting-Group-Free Synthesis of Clavosolide A and Late-Stage Modification
Better late than early: The natural product clavosolide A features a C2-symmetric core. A rhodium-catalyzed dimerization reaction involving the regio- and diastereoselective addition of carboxylic acids to allenes (see scheme) provided rapid access to this complex structure in only eight steps from penta-3,4-dienal and a readily accessible chiral crotyl-transfer reagent. The method is broadly applicable and suited to late-stage diversification.A. Haydl, B. Breit, Angew. Chem. 2015, 127, 15750–15754; (link) Angew. Chem. Int. Ed. 2015, 54, 15530–15534. (link)
Z-Selective Hydrothiolation of Racemic 1,3-Disubstituted Allenes: An Atom-Economic Rhodium-Catalyzed Dynamic Kinetic Resolution
Zelectivity: The title reaction permits the synthesis of valuable allylic thioethers and sulfones in excellent Z selectivity. By using unsymmetrically 1,3-disubstituted allenes, good to high regioselectivities were obtained. Asymmetric hydrothiolation of racemic allenes with (S,S)-Me-DuPhos meets the criteria of a dynamic kinetic resolution. Me-DuPhos=2′,5′,2′′,5′′-tetramethyl-1,2-bis(phospholanyl)benzene.A. B. Pritzius, B. Breit, Angew. Chem. 2015, 127, 16044–16048; (link) Angew. Chem. Int. Ed. 2015, 54, 15818–15822. (link)
Asymmetric synthesis of allylic amines via hydroamination of allenes with benzophenone imine
Rhodium-catalyzed highly regio- and enantioselective hydroamination of allenes is reported. Exclusive branched selectivities and excellent enantioselectivities were achieved applying a rhodium(I)/Josiphos catalyst. This method permits the practical synthesis of valuable α-chiral allylic amines using benzophenone imine as ammonia carrier.K. Xu, Y.-H. Wang, V. Khakyzadeh, Chem. Sci. 2016, articles ASAP; (link)
Khwarizmi International Award for Prof. Dr. Bernhard Breit
The Iranian Research Organization for Science and Technology (IROST), affiliated to the Iranian Ministry of Science, Research and Technology, is awarding the Khwarizmi International Award to Prof. Breit for his dedication, excellence and sustained hard work in the field of research. Since 1987, the KIA is presented to scientists for outstanding achievements and innovations that advance science and technology. It is the most important Iranian distinction of its kind and is presented by the President of Iran, Hassan Rouhani, and the Iranian Minister for Science, Research and Technology.
The award ceremony took place on 7 March 2016 in Iran’s capital Tehran in the presence of Prof. Breit. He is staying in Iran for several days and will present his research at renowned Iranian universities and institutions.
Sustainable catalysts: a German-Japanese cooperation combines the strong points of the University of Freiburg and expertise from Nagoya
The project “Multicomponent Supramolecular Catalysts for Sustainable Chemical Synthesis” conducted by Prof. Dr. Bernhard Breit (University of Freiburg), Prof. Dr. Takashi Ooi and Prof. Dr. Kenichiro Itami (Nagoya University) tackles the development of environmentally friendly and energy-efficient catalysts. Catalysts are substances that increase the rate of a chemical reaction by minimizing the required amount of activation energy, an energetic barrier between chemical reaction partners. During this process, the catalysts themselves are not consumed.
Around 80 percent of all chemical products are manufactured using catalytic processes. This means that increased environmental compatibility and energy efficiency of catalysts entails direct positive effects in the manufacture of chemical and pharmaceutical products. The project group draws inspiration from natural catalysts, such as enzymes, and aims to develop a new generation of supramolecular catalysts. Furthermore, the group’s groundbreaking research is to lay the basis for an international graduate school.
New Postdoctoral position in Organic Synthesis/Medicinal Chemistry
The research group of Prof. Breit at the Institute for Organic Chemistry is offering a
Postdoctoral position in Organic Synthesis/Medicinal Chemistry
At the Institute of Organic Chemistry at the Albert-Ludwigs University Freiburg in the research group of Professor Breit a postdoctoral position is available. The position is sponsored by the collaborative research center “Medical Epigenetics - SFB992“ and is part of a team consisting of structural biology and bioinformatics. The scientific goals are to synthesize small target molecules (primarily heterocyclic structures) and to evaluate within this team the biological properties, binding properties towards epigenetic target proteins in order to identify new molecular probes. Extensive experience in preparative organic chemistry including multistep synthesis is expected.
Please send a letter of motivation, a complete CV, a summary of research achievements and two letters of recommendation to Prof. Dr. Bernhard Breit.
New Publication in Nature Communications
Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines
The asymmetric synthesis of N-allylic indoles is important for natural product synthesis and pharmaceutical research. The regio- and enantioselective N-allylation of indoles is a true challenge due to the favourable C3-allylation. We develop here a new strategy to the asymmetric synthesis of N-allylic indoles via rhodium-catalysed N-selective coupling of aryl hydrazines with allenes followed by Fischer indolization. The exclusive N-selectivities and good to excellent enantioselectivities are achieved applying a rhodium(I)/DTBM-Segphos or rhodium(I)/DTBM-Binap catalyst. This method permits the practical synthesis of valuable chiral N-allylated indoles, and avoids the N- or C-selectivity issue.
K. Xu, T. Gilles, B. Breit, Nat. Commun., 2015, 6, 7616; (link)
New Publication in Journal of the American Chemical Society
Enantioselective Redox-Neutral Rh-Catalyzed Coupling of Terminal Alkynes with Carboxylic Acids Toward Branched Allylic Esters
We report on the first enantioselective variant of the atom-economic and redox-neutral coupling of carboxylic acids with terminal alkynes under rhodium catalysis utilizing the chiral, bidentate (R,R)-Cp-DIOP ligand. This represents the first example of this convenient asymmetric access to valuable branched allylic esters. The utility of this methodology is demonstrated by both a reaction performed on large scale and a short three-step synthesis of two naturally occurring γ-butyrolactones. A stereochemical model explaining the observed absolute configuration of the products based on DFT calculations is given.
P. Koschker, M. Kähny, B. Breit, J. Am. Chem. Soc., 2015, 137 (8), 3131–3137; (link)
35th Regiosymposium 2015
New Publication in Angewandte Chemie
Asymmetric Rhodium-Catalyzed Addition of Thiols to Allenes: Synthesis of Branched Allylic Thioethers and Sulfones
All about S: The rhodium-catalyzed enantioselective hydrothiolation of terminal monosubstituted allenes with aromatic and functionalized aliphatic thiols permits the atom-economic synthesis of valuable branched allylic thioethers and sulfones in high regio- and enantioselectivity. By varying the ligand and reaction conditions both aromatic and aliphatic thiols were tolerated.A. B. Pritzius, B. Breit, Angew. Chem. 2015, 127, 3164-3168; (link) Angew. Chem. Int. Ed. 2015, 54, 3121-3125. (link)
New Publication in Angewandte Chemie
Rhodium-Catalyzed Chemo-, Regio-, and Enantioselective Addition of 2-Pyridones to Terminal Allenes
A rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes to give branched N-allyl 2-pyridones is reported. Preliminary mechanistic studies support the hypothesis that the reaction is initiated from the more acidic 2-hydroxypyridine form, and the initial kinetic O-allylation product was finally converted into the thermodynamically more stable N-allyl 2-pyridone.C. Li, M. Kähny, B. Breit, Angew. Chem. 2014, 126, 14000-14004; (link) Angew. Chem. Int. Ed. 2014, 53, 13780-13784. (link )
New VIP-Publication in Angewandte Chemie
Unlocking the N2 Selectivity of Benzotriazoles: Regiodivergent and Highly Selective Coupling of Benzotriazoles with Allenes
Ligand control: Exceptionally high N2 and N1 selectivities have been achieved in the rhodium-catalyzed coupling of benzotriazoles with allenes by using DPEphos and JoSPOphos, respectively (see scheme). This method permits the atom-economic synthesis of valuable branched N2- and N1-allylated benzotriazole derivatives.K. Xu, N. Thieme, B. Breit, Angew. Chem. 2014, 126, 7396-7399; (link) Angew. Chem. Int. Ed. 2014, 53, 7268-7271. (link)
New Publication in Angewandte Chemie
Atom-Economic, Regiodivergent, and Stereoselective Coupling of Imidazole Derivatives with Terminal Allenes
Taking control:New Rh- and Pd-catalyzed regiodivergent and stereoselective intermolecular coupling reactions of imidazole derivatives with monosubstituted allenes are reported. Using a RhI/Josiphos system, perfect regioselectivities and high enantiomeric excess were obtained, while a PdII/dppf system gave the linear products with high regioselectivities and high E/Z selectivities. dppf=1,1′-bis(diphenylphosphino)ferrocene, Josiphos=(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldialkylphosphine.K. Xu, N. Thieme, B. Breit, Angew. Chem. 2014, 126, 2194-2197; (link) Angew. Chem. Int. Ed. 2014, 53, 2162-2165. (link)
New Publications in Journal of the American Chemical Society
(1) Rhodium-Catalyzed Chemo- and Regioselective Decarboxylative Addition of β-Ketoacids to Allenes: Efficient Construction of Tertiary and Quaternary Carbon Centers
A rhodium-catalyzed chemo- and regioselective intermolecular decarboxylative addition of β-ketoacids to terminal allenes is reported. Using a Rh(I)/DPPF system, tertiary and quaternary carbon centers were formed with exclusively branched selectivity under mild conditions. Preliminary mechanism studies support that the carbon–carbon bond formation precedes the decarboxylation and the reaction occurs in an outer-sphere mechanism.
C. Li, B. Breit, J. Am. Chem. Soc., 2014, 136 (3), 862–865; (link)
(2) Mechanistic Investigations of the Rhodium Catalyzed Propargylic CH Activation
Previously we reported the redox-neutral atom economic rhodium catalyzed coupling of terminal alkynes with carboxylic acids using the DPEphos ligand. We herein present a thorough mechanistic investigation applying various spectroscopic and spectrometric methods (NMR, in situ-IR, ESI-MS) in combination with DFT calculations. Our findings show that in contrast to the originally proposed mechanism, the catalytic cycle involves an intramolecular protonation and not an oxidative insertion of rhodium in the OH bond of the carboxylic acid. A σ-allyl complex was identified as the resting state of the catalytic transformation and characterized by X-ray crystallographic analysis. By means of ESI-MS investigations we were able to detect a reactive intermediate of the catalytic cycle.
U. Gellrich, A. Meißner, A. Steffani, M. Kähny, H.-J. Drexler, D. Heller, D. A. Plattner, B. Breit, J. Am. Chem. Soc., 2014, 136 (3), 1097–1104; (link)
New Publication in Chemistry - A European Journal
Realistic Energy Surfaces for Real-World Systems: An IMOMO CCSD(T):DFT Scheme for Rhodium-Catalyzed Hydroformylation with the 6-DPPon Ligand
A two-layer model (CCSD(T):DFT) in the framework of an integrated molecular orbital plus molecular orbital (IMOMO) scheme (see figure) was evaluated for rhodium-catalyzed hydroformylation with the self-assembling 6-diphenylphosphinopyridine-(2H)-1-one ligand (6-DPPon). By applying the energetic-span model, an excellent match between the calculated and experimentally observed turnover frequencies was achieved.
U. Gellrich, D. Himmel, M. Meuwly, B. Breit, Chem. Eur. J. 2013, 19, 16272-16281; (link)
New Publications in Angewandte Chemie
(1) Catalytic Asymmetric Synthesis of Allylic Alcohols and Derivatives and their Applications in Organic Synthesis
Allylic alcohols represent an important and highly versatile class of chiral building blocks for organic synthesis. This Review summarizes the plethora of methods developed for the catalytic asymmetric synthesis of enantioenriched allylic alcohols. These include: dynamic kinetic resolution (DKR/DKAT), nucleophilic 1,2-addition to carbonyl groups, allylic substitution, oxidation of C[BOND]H bonds, the addition of O nucleophiles to π systems, reduction of unsaturated carbonyl compounds, and an alternative route from enantioenriched propargylic alcohols. Furthermore, these catalytic asymmetric processes are exemplified by their applications in the syntheses of complex molecules such as natural products and potential therapeutic agents.
(2) Catalytic Hydrogenation of Amides to Amines under Mild Conditions
Under (not so much) pressure : A general method for the hydrogenation of tertiary and secondary amides to amines with excellent selectivity using a bimetallic Pd–Re catalyst has been developed. The reaction proceeds under low pressure and comparatively low temperature. This method provides organic chemists with a simple and reliable tool for the synthesis of amines.