Ryan A. Altman

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Name: Altman, Ryan

Organization: The University of Kansas , USA

Department: Department of Medicinal Chemistry

Title: Assistant(PhD)

TOPICS

Organic Chemistry

Fluorination Trifluoromethylation allene

Chemicals
References

Exploiting the unusual effects of fluorine in methodology

Co-reporter:Douglas L. Orsi

Chemical Communications 2017 vol. 53(Issue 53) pp:7168-7181

Publication Date(Web):2017/06/29

DOI:10.1039/C7CC02341C

Fluorination of organic molecules significantly impacts the basic physicochemical properties of small and large biologically active molecules, agrichemicals, and materials. Thus, the development of synthetic reactions to access these substructures is important for many applied fields of chemistry. However, these fluorine-induced perturbations of chemical properties can inhibit standard chemical transformations, which provides unique challenges for synthetic organic chemists. In addition, the physicochemical properties imparted by fluorinated substituents can enable distinct reactivity patterns relative to non-fluorinated substrates, thus making synthetic organofluorine chemistry a fertile ground for developing new, exciting transformations. In this feature article, we detail our experiences in methodology, wherein fluorinated substrates have enabled unique reactivity patterns relative to non-fluorous substrates. Specifically, we highlight the non-standard chemo- and regio-selectivities imparted by fluorinated substrates on Pd-catalyzed coupling reactions, nucleophilic addition reactions of olefins, and Cu-catalyzed decarboxylative fluoroalkylation reactions.

Palladium Catalysis Enables Benzylation of ,-Difluoroketone Enolates

Co-reporter:Ming-Hsiu Yang;Jordan R. Hunt;Dr. Niusha Sharifi;Dr. Ryan A. Altman

Angewandte Chemie 2016 Volume 128( Issue 31) pp:9226-9229

Publication Date(Web):

DOI:10.1002/ange.201604149

Abstract

A palladium-catalyzed decarboxylative benzylation reaction of α,α-difluoroketone enolates is reported, in which the key C(α)−C(sp³) bond is generated by reductive elimination from a palladium intermediate. The transformation provides convergent access to α-benzyl-α,α-difluoroketone-based products, and should be useful for accessing biological probes.

Palladium Catalysis Enables Benzylation of ,-Difluoroketone Enolates

Co-reporter:Ming-Hsiu Yang;Jordan R. Hunt;Dr. Niusha Sharifi;Dr. Ryan A. Altman

Angewandte Chemie International Edition 2016 Volume 55( Issue 31) pp:9080-9083

Publication Date(Web):

DOI:10.1002/anie.201604149

Abstract

Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes

Co-reporter:Brett R. Ambler, Santosh Peddi, and Ryan A. Altman

Organic Letters 2015 Volume 17(Issue 10) pp:2506-2509

Publication Date(Web):April 24, 2015

DOI:10.1021/acs.orglett.5b01027

“Cu–CF3” species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu–CF3-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate (trifluoromethyl)allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)allenes, which can be further modified to generate complex fluorinated substructures.

Ligand-Controlled Regiodivergent Palladium-Catalyzed Decarboxylative Allylation Reaction to Access ,-Difluoroketones

Co-reporter:Ming-Hsiu Yang;Douglas L. Orsi ;Dr. Ryan A. Altman

Angewandte Chemie International Edition 2015 Volume 54( Issue 8) pp:2361-2365

Publication Date(Web):

DOI:10.1002/anie.201410039

Abstract

α,α-Difluoroketones possess unique physicochemical properties that are useful for developing therapeutics and probes for chemical biology. To access the α-allyl-α,α-difluoroketone substructure, complementary palladium-catalyzed decarboxylative allylation reactions were developed to provide linear and branched α-allyl-α,α-difluoroketones. For these orthogonal processes, the fluorination pattern of the substrate enabled the ligands to dictate the regioselectivity of the transformations.

Ligand-Controlled Regiodivergent Palladium-Catalyzed Decarboxylative Allylation Reaction to Access ,-Difluoroketones

Co-reporter:Ming-Hsiu Yang;Douglas L. Orsi ;Dr. Ryan A. Altman

Angewandte Chemie 2015 Volume 127( Issue 8) pp:2391-2395

Publication Date(Web):

DOI:10.1002/ange.201410039

Abstract

Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates

Co-reporter:Brett R. Ambler, Lingui Zhu, and Ryan A. Altman

The Journal of Organic Chemistry 2015 Volume 80(Issue 16) pp:8449-8457

Publication Date(Web):July 30, 2015

DOI:10.1021/acs.joc.5b01343

Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation.

Metal-Free Trifluoromethylation of Aromatic and Heteroaromatic Aldehydes and Ketones

Co-reporter:Yupu Qiao, Tuda Si, Ming-Hsiu Yang, and Ryan A. Altman

The Journal of Organic Chemistry 2014 Volume 79(Issue 15) pp:7122-7131

Publication Date(Web):July 8, 2014

DOI:10.1021/jo501289v

The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl β,β,β-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing β,β,β-trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.

Preparation of Fluoroalkenes via the Shapiro Reaction: Direct Access to Fluorinated Peptidomimetics

Co-reporter:Ming-Hsiu Yang, Siddharth S. Matikonda, and Ryan A. Altman

Organic Letters 2013 Volume 15(Issue 15) pp:3894-3897

Publication Date(Web):July 23, 2013

DOI:10.1021/ol401637n

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products were accessed in one- or two-step sequences from widely available ketones. This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would be challenging to prepare by alternate strategies.

Copper-Catalyzed Decarboxylative Trifluoromethylation of Allylic Bromodifluoroacetates

Co-reporter:Brett R. Ambler and Ryan A. Altman

Organic Letters 2013 Volume 15(Issue 21) pp:5578-5581

Publication Date(Web):October 11, 2013

DOI:10.1021/ol402780k

The development of new synthetic fluorination reactions has important implications in medicinal, agricultural, and materials chemistries. Given the prevalence and accessibility of alcohols, methods to convert alcohols to trifluoromethanes are desirable. However, this transformation typically requires four-step processes, specialty chemicals, and/or stoichiometric metals to access the trifluoromethyl-containing product. A two-step copper-catalyzed decarboxylative protocol for converting allylic alcohols to trifluoromethanes is reported. Preliminary mechanistic studies distinguish this reaction from previously reported Cu-mediated reactions.

Copper-Mediated Deoxygenative Trifluoromethylation of Benzylic Xanthates: Generation of a CCF3 Bond from an O-Based Electrophile

Co-reporter:Dr. Lingui Zhu;Dr. Shasha Liu;Dr. Justin T. Douglas;Dr. Ryan A. Altman

Chemistry - A European Journal 2013 Volume 19( Issue 38) pp:12800-12805

Publication Date(Web):

DOI:10.1002/chem.201302328

Abstract

The conversion of an alcohol-based functional group, into a trifluoromethyl analogue is a desirable transformation. However, few methods are capable of converting O-based electrophiles into trifluoromethanes. The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto’s reagent as the source of CF₃ to form CCF₃ bonds is described. The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the CCF₃ bond forms by reaction of the substrate with in situ generated CuCF₃ and CuOTf. Further evidence suggests that the reaction could proceed via a radical cation intermediate.

Exploiting the unusual effects of fluorine in methodology

Co-reporter:Douglas L. Orsi and Ryan A. Altman

Chemical Communications 2017 - vol. 53(Issue 53) pp:NaN7181-7181

Publication Date(Web):2017/05/08

DOI:10.1039/C7CC02341C