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New Publication in Angewandte Chemie

 

Regio-, Diastereo-, and Enantioselective Decarboxylative Hydro-aminoalkylation of Dienol Ethers Enabled by Dual Palladium/Pho-toredox Catalysis

 angew2022Jun

 

Intermolecular photocatalytic hydroaminoalkylation (HAA) of alkenes have emerged as a powerful method for the construction of alkyl amines. Although there are some studies aiming at stereoselective photocatalytic HAA reactions, the alkenes are limited to electrophilic alkenes. Herein, we report a highly regio-, diastereo-, and enantioselective HAA of electron-rich dienol ethers and α-amino radicals derived from α-amino acids using a unified photoredox and palladium catalytic system. This decarboxylative 1,2-Markovnikov addition enables the construction of vicinal amino tertiary ethers with high levels of regio- (up to >19 : 1 rr), diastereo- (up to >19 : 1 dr), and enantioselectivity control (up to >99 % ee). Mechanistic studies support a reversible hydropalladation as a key step.

J. Zheng, N. Tang, X.Hui, B. Breit Angew. Chem. 2022, ASAP ; (link) Angew. Chem. Int. Ed. 2022, ASAP. (link)

 

 

Looking for a position? We are hiring!

 

 Join our team

Highly motivated and talented bachelor, master and PhD students welcome to join our group.

 

Please contact Prof. Dr. B. Breit directly either by e-mail or in person.

 

 

New Publication in Chemical Science

 

Rhodium-catalyzed asymmetric intramolecular hydroarylation of allenes: access to functionalized benzocycles

 Graphical abstract: Rhodium-catalyzed asymmetric intramolecular hydroarylation of allenes: access to functionalized benzocycles

A rhodium-catalyzed regio- and enantioselective cyclization of tethered allenylbenzenes is reported. Employing a RhI/Josiphos catalytic system a diverse set of 6-membered, α-chiral benzocycles were obtained, scaffolds found in many bioactive compounds. Moreover, a gram scale reaction as well as the application of suitable transformations are demonstrated.

D. Berthold, J. Klett, B. Breit, Chem. Sci. 2019, 10, 10048-10052. (link)

 

New Publication in Nature Communications

 

A domino reaction for generating β-aryl aldehydes from alkynes by substrate recognition catalysis

 

The development of universal catalyst systems that enable efficient, selective, and straightforward chemical transformations is of immense scientific importance. Here we develop a domino process comprising three consecutive reaction steps based on the strategy of supramolecular substrate recognition. This approach provides valuable β-aryl aldehydes from readily accessible α-alkynoic acids and arenes under mild reaction conditions, employing a supramolecular Rh catalyst containing an acylguanidine-bearing phosphine ligand. Furthermore, the synthesis of a key intermediate of Avitriptan using this protocol is accomplished. The first step of the reaction sequence is proved to be the regioselective hydroformylation of α-alkynoic acids. Remarkably, molecular recognition of the ligand and the substrate via hydrogen bonding plays a key role in this step. Control experiments indicate that the reaction further proceeds via 1,4-addition of an arene nucleophile to the unsaturated aldehyde intermediate and subsequent decarboxylation.

W. Fang, F. Bauer, Y. Dong, B. Breit, Nat. Commun. 2019, 10, 4868. (link)

 

New Publication in Angewandte Chemie

 

Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination of Allenes

 

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The rhodium‐catalyzed asymmetric intramolecular hydroamination of sulfonyl amides with terminal allenes is reported. It provides selective access to 5‐ and 6‐membered N‐heterocycles, scaffolds found in a large range of different bioactive compounds. Moreover, gram scale reactions, as well as the application of suitable product transformations to natural products and key intermediates thereof are demonstrated.

D. Berthold, A. G. A. Geissler, S. Giofré, B. Breit, Angew. Chem. 2019, 131, 10099-10102. (link) Angew. Chem. Int. Ed. 2019, 58, 9994-9997. (link)
 
 

 

 

 

New Publication in Angewandte Chemie

 

Rhodium-Catalyzed Parallel Kinetic Resolution of Racemic Internal Allenes Towards Enantiopure Allylic 1,3-Diketones

 

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A rare case of a parallel kinetic resolution of racemic 1,3‐disubstituted allenes by means of a rhodium‐catalyzed addition to 1,3‐diketones furnishing enantiopure allylic 1,3‐diketones is described. Mechanistic experiments demonstrate that the different allene enantiomers react in parallel to either the diastereomeric E‐ or Z‐allylic 1,3‐diketones with the same absolute configuration of the newly formed stereogenic center. A broad substrate scope demonstrates the synthetic utility of this new method.

L. Hilpert, B. Breit, Angew. Chem. 2019, 131, 10044-10048. (link) Angew. Chem. Int. Ed. 2019, 58, 9939-9943. (link)

 

 

 

New Publication in Chemical Science

 

A Rhodium-Catalyzed Cycloisomerization and Tandem Diels-Alder Reaction for Facile Access to Diverse Bicyclic and Tricyclic Heterocycles

 

 236

A regioselective distal cycloisomerization of 1,6-allenenes was successfully developed to afford six-membered ring exocyclic 1,3-dienes employing a rhodium/diphosphine catalyst system. Deuterium labelling experiments and DFT calculations were performed to provide insights into the reaction mechanism of this unprecedented transformation. In addition, one-pot tandem Diels–Alder reactions with various dienophiles could readily construct diverse bicyclic and tricyclic nitrogen heterocycles, which are ubiquitous core scaffolds for a variety of natural products and bioactives. High efficiency and exclusive chemo and regioselectivities for a broad substrate scope were achieved under mild conditions using a low catalyst loading of 0.5 mol%.

Y. Zhou, A. Nikbakht, F. Bauer, B. Breit, Chem. Sci. 2019, 10, 4805-4810. (link)

 

 

 

New Publication in Chemical Science

 

Transition Metal Catalyzed Synthesis of syn- and anti-delta-Vinyl-Lactames: Formal Total Synthesis of (-)-Cermizine C and (-)-Senepodine G

 

 233

A stereodivergent and diastereoselective transition-metal-catalyzed intramolecular hydroamidation of allenes and alkynes furnishing delta-vinyl-lactams is reported. Employing a rhodium catalyst allowed for the selective synthesis of the syn-delta-lactam. Conversely, a palladium catalyst led to the formation of the anti-delta-lactam in high selectivity. The new method shows high functional group compatibility and assorted synthetic transformations were demonstrated as well as its utility for the enantioselective formal total syntheses of (−)-cermizine C and (−)-senepodine G.

J. P. Schmidt, B. Breit, Chem. Sci. 2019, 10, 3074-3079. (link)

 

 

 

New Publication in Angewandte Chemie

 

Regiodivergent Hydroaminoalkylation of Alkynes and Allenes by a Combined Rhodium and Photoredox Catalytic System

 

 232

A direct cross‐coupling of alkynes and allenes with amines to access α‐allylated amines using a Rh/photoredox dual catalyst system was developed. Starting from easily available internal alkynes, tertiary amines, and secondary amines, various branched homoallylic amines were obtained with good to excellent yields and regioselectivity. In contrast, with a modified reaction conditions, the alkynes and terminal allenes could couple with various substituted N‐aryl‐tetrahydroisoquinolines smoothly affording (E/em)‐linear homoallylic amines in good to excellent yields and regioselectivity.

J. Zheng, B. Breit, Angew. Chem. 2019, 131, 3430-3435; (link) Angew. Chem. Int. Ed. 2019, 58, 3392-3397. (link)

 

 

 

New Publication in Angewandte Chemie

 

Palladium- and Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazole

 

 231

A complementing Pd‐ and Rh‐catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N‐allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry as drugs and drug candidates. The new methods feature high chemo‐, regio‐ and enantioselectivity displaying a broad substrate scope and functional group compatibility. A mechanistic rational explanation for allene racemization and trans‐alkene selectivity is discussed.

L. J. Hilpert, S. V. Sieger, A. M. Haydl, B. Breit, Angew. Chem. 2019, 131, 3416-3419; (link) Angew. Chem. Int. Ed. 2019, 58, 3378-3381. (link)

 

 

 

New Publication in Angewandte Chemie

 

Tandem Regioselective Hydroformylation‐Hydrogenation of Internal Alkynes Using a Supramolecular Catalys

 

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Good behaviour: A supramolecular catalyst enables a tandem Rh‐catalysed hydroformylation‐hydrogenation of unsymmetrical internal alkynes, functionalized with carboxylic acids in the β‐position, to give access to aliphatic aldehydes in high regio‐ and chemoselectivities. Control experiments confirm the enzyme‐like catalyst behaviour. DCE=1,2‐dichloroethane, CSA=camphorsulfonic acid.

W. Fang, B. Breit, Angew. Chem. 2018, 130, 15033-15037; (link) Angew. Chem. Int. Ed. 2018, 57,14817-14821. (link)

 

 

 

New Publication in Angewandte Chemie

 

Enantioselective Rhodium‐Catalyzed Dimerization of ω‐Allenyl Carboxylic Acids: Straightforward Synthesis of C2‐Symmetric Macrodiolides

 

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Two in one: A highly atom‐efficient one‐step rhodium‐catalyzed dimerization of ω‐allenyl carboxylic acids was developed that furnishes C2‐symmetrical homodiolides, a structural motif found in numerous natural products. The method features high enantioselectivity, generating two stereogenic centers concomitantly.

P. Steib, B. Breit, Angew. Chem. 2018, 130, , 6682-6686; (link) Angew. Chem. Int. Ed. 2018, 57,6572-6576. (link)

 

 

 

New Publication in Angewandte Chemie

 

Inducing Axial Chirality in a Supramolecular Catalyst

 

 221

Self‐organization of two chiral ligands coordinated to a metal center and connected by a twisted, hydrogen‐bonded backbone gives axially chiral supramolecular complexes. Formation of the tropos diastereomers was studied by a combination of computational and spectroscopic methods. The self‐assembled ligand systems were evaluated in rhodium‐catalyzed asymmetric hydrogenation and led to high product enantioselectivities.

K. M. Wenz, G. Leonhardt‐Lutterbeck, B. Breit, Angew. Chem. 2018, 130, 5194-5198 ; (link) Angew. Chem. Int. Ed. 2018, 57,5100-5104. (link)

 

 

 

Open House - AK Prof. Breit (Achtung, Raum- und Zeitänderung)

 

Bei der Vorstellung der Bachelorthemen des AK Breit gibt es eine Termin- und Raumänderung. Die Open House Veranstaltung findet nun am Freitag, 25.01.19 um 12:15 Uhr im SR 04002 statt.

Open_House_2019

 

New Publications in Angewandte Chemie

 

Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement: Facile Acess to 2-Allyl-3-oxazolin-5-ones and Trisubstituted Pyridines

 

 212

A triple domino process involving in situ azlactone formation, rhodium-catalyzed alkyne coupling, and aza-Cope rearrangement furnishes useful 2-allyl-3-oxazolin-5-ones in one step. Thermolysis of these products results in pyridines, thereby providing a facile approach to de novo pyridine synthesis.

J. Kuang, S. Parveen, B. Breit,  Angew. Chem. 2017, 129, 8542-8545 ; (link) Angew. Chem. Int. Ed. 2017, 56, 8422-8425. (link)

 

New Publications in Angewandte Chemie

 

Regio- and Enantioselective Rhodium-Catalyzed Addition of 1,3-Diketones to Allenes: Construction of Asymmetric Tertiary and Quaternary All Carbon Centers

 

 208

Rh-Catalysis: A regio- and enantioselective atom-economic catalytic addition of 1,3-diketones to allenes is reported furnishing tertiary and quaternary all-carbon stereocenters under mild reaction conditions. The reaction shows a broad functional-group tolerance and numerous variations on both reaction partners highlight its synthetic utility.

T. M. Beck, B. Breit, Angew. Chem. 2017, 129, 1929-1933 ; (link) Angew. Chem. Int. Ed. 2017, 56, 1903-1907. (link)

 

 

Enantioselective and Regiodivergent Addition of Purines to Terminal Allenes: Synthesis of Abacavir

 

 207a

An atom-economic and regiodivergent Rh- and Pd-catalyzed coupling of purine derivatives and terminal allenes has been developed. High regioselectivity and excellent enantiomeric excess and yields were achieved with various functionalized substrates. Additionally, the developed methodology was applied to a straightforward synthesis of carbocyclic nucleoside abacavir.

N. Thieme, B. Breit, Angew. Chem. 2017, 129, 1542-1546 ; (link) Angew. Chem. Int. Ed. 2017, 56, 1520-1524. (link)

 

New Publication in Angewandte Chemie

 

Rhodium-Catalyzed Diastereoselective Cyclization of Allenyl-Sulfonylcarbamates: A Stereodivergent Approach to 1,3-Aminoalcohol Derivatives

 

 204

A diastereoselective and stereodivergent rhodium-catalyzed intramolecular coupling of sulfonylcarbamates with terminal allenes is described and it provides selective access to 1,3-aminoalcohol derivatives, scaffolds found in bioactive compounds. The reaction is compatible with a large range of different functional groups, thus furnishing products with high diastereoselectivities and yields. Moreover, multigram scale reactions, as well as the application of suitable product transformations were demonstrated.

P. Spreider, A. Haydl, M. Heinrich, B. Breit Angew. Chem. 2016, 128, 15798-15802 ; (link) Angew. Chem. Int. Ed. 2015, 55, 15569-15573. (link)

 

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

 

 198

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 enantioselectivities

Z. Liu, B. Breit, Angew. Chem. 2016, 128, 8580–8583 ; (link) Angew. Chem. Int. Ed. 2016, 55, 8440-8443. (link)

 

Enantioselective Rhodium-Catalyzed Atom-Economical Macrolactonization

 

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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

 

 200

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

 

 197

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.

A. Haydl, D. Berthold, P. A. Spreider, B. Breit, Angew. Chem. 2016, 128, 5859–5863; (link) Angew. Chem. Int. Ed. 2016, 55, 5765–5769. (link)

 

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

 190

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

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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

 194

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, 7, 3313-3316; (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.

 link

Sustainable catalysts: a German-Japanese cooperation combines the strong points of the University of Freiburg and expertise from Nagoya

Nagoya_Freiburg

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.

 link

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.

 e-mail

New Publication in Nature Communications

 

Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines

 

                                187abstract

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)

 

 

 

 

 

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